Beruflich Dokumente
Kultur Dokumente
Vicepresidency of Research
Finlay Institute, La Habana, Cuba
ISBN: 959-7076-12-8
Finlay Ediciones
Ave. 212 No. 3112 e/ 31 y 37,
La Coronela, La Lisa,
Ciudad de La Habana, Cuba
THE UN SECRETARY-GENERAL KOFI A. ANNAN
Message on World TB Day, 24 March 2005.
Ko A. Annan
1
INTRODUCTION
2
after e-mail (93%) and researching a product or service before buying (83%). (Inter-
net Health and Resources, Pew Internet & American Life Project, Susannah Fox and
Deborah Fallows, 16 July, 2003).
There are so many ways to access health information on the web and such a
broad selection of content that the search process can seem overwhelming. How-
ever, searching for health information is easy if you know where to start. The follow-
ing selected tuberculosis Web sites and links list (comprehensive but not exhaustive)
offer some suggestions. We hope that you may nd it useful when looking speci-
cally for tuberculosis information on Internet.
THE AUTHORS
La Habana, Cuba, May 2005.
3
TUBERCULOSIS SELECTED WEB SITES AND LINKS
(in alphabetical order)
2. About Tuberculosis Public information on the biology of tuberculosis from the Cana-
dian Lung Association http://www.lung.ca/tb
3. Action TB
8. American Lung Association The American Lung Association (ALA) was founded
in 1904 to combat tuberculosis. Today this organization ghts all forms of lung with special
emphasis on asthma, tobacco control and environmental health. The ALA has worked to
increase federal funding for tuberculosis research and control http://www.lungusa.org/dis-
eases/lungtb.html
10. American Thoracic Society The American Thoracic Society [ATS] is an independently
incorporated, international, educational and scientic society which focuses on respiratory
and critical care medicine. ATS was once called the American Sanatorium Association. It main-
tains a focus on medical aspects of tuberculosis, whereas the parent organization, American
Lung Association, concentrates on public health issues. Information links on tuberculosis at
this site can identied after using the search button http://www.thoracic.org/
11. Ask NOAH About: Tuberculosis Preguntale a NOAH Sobre la Tuberculosis Informa-
tion in English and in Spanish presented by the New York Online Access to Health (NOAH)
project.
4
12. Atlanta Tuberculosis Prevention Coalition Our Mission Collaborating Agencies Proj-
ects Screening Education Computerized TB registry Personnel Publications Training Funding
Other TB related Sites TB & Medicaid General TB information Georgia TB reference guide...
13. ATS Journals Online... Ofcial Journals of the American Thoracic Society, Stanford
University
Libraries HighWire Press assists in the publication of ATS Journals Online ... www.ats-
journals.org/
14. Bill & Melinda Gates Foundation Grant-making foundation supports initiatives in
education, world health and
population, and community giving in the Pacic Northwest www.gatesfoundation.org/
17. BUBL LINK: Tuberculosis BUBL LINK Catalogue of Internet Resources. Tuberculosis.
Titles. Descriptions. American Lung Association: Diseases A to Z ... cancer, tuberculosis, em-
physema ... Internet resources relevant to the respiratory system. Author: OMNI, Nottingham
University. Subjects: asthma, lung cancer, lungs, pneumonia, tuberculosis ... bubl.ac.uk/link/t/
tuberculosis.htm
20. Case Western Reserve University Tuberculosis Research Unit and HIVNET Projects
21. CBC News - Tuberculosis: Anatomy of A Killer Includes facts, videos, reports, and
links on Tuberculosis. Ever heard of White Plague? What about Potts disease? Lupus Vulgaris?
Kings evil? No? Okay then, surely youve heard of Consumption. All of these diseases are
actually the same disease, better known today as Tuberculosis or TB for short http://cbc.
ca/news/indepth/background/tb.html... CBC News - Includes facts, videos, reports, and links
on Tuberculosis
22. CDC Division of Tuberculosis Elimination News, reports, guidelines, and educational
materials for health professionals http://www.cdc.gov/nchstp/tb
24. Center for Pulmonary and Infectious Disease Control University of Texas Health Cen-
ter at Tyler
25. Charles P. Felton National Tuberculosis The goal is to meet the challenge of TB in Har-
lem by providing innovative prevention, treatment, and training programs to members com-
munity and healthcare providers serving the community http://www.harlemtbcenter.org
5
26. Clinicians Handbook of Preventive Services (TB Section)
27. Community Awareness Program for Tuberculosis Education from the Wetmore TB
Foundation
28. Community Health and Anti -Tuberculosis Charity organisation supporting preven-
tion, treatment and research into respiratory disease both internationally and in Australia
http://www.chata.org.au
29. Core Curriculum on Tuberculosis: What the Clinician Should Know This is the 4th edi-
tion (2000) of this textbook from the U.S. Centers for Disease Controls Division of Tuberculosis
Elimination. A note on the site states that The Internet (HTML) version of the Core Curriculum
on Tuberculosis is updated periodically. Therefore, the Internet version may differ from the
print version.
31. Danida Assisted Revised National Tuberculosis Control Programme Provides informa-
tion about the organization, initiatives, publications, a resource directory as well as the details
about the disease itself. Our goal is o bring down the incidence of TB in India to levels where
it will no longer be a public health problem http://www.dantb.org/
32. DANTB - Danida Assisted Revised National Tuberculosis Control ... Information about
the organization, initiatives, publications, a resource directory as well as the details about the
disease itself. www.dantb.org/
33. DEVELOPMENT OF VACCINES FOR BOVINE TUBERCULOSIS: REPORT OF THE ISG ... File
Format: PDF/Adobe Acrobat ... a large number of local sites to have a signicant impact on TB
in ... opportunities to identify tuberculosis vaccines that are more effective than ... www.defra.
gov.uk/animalh/tb/pdf/vsssc.pdf
34. Division of Tuberculosis Elimination - Institute of Medicine (IOM ... regimens would
have the greatest impact on the TB problem in the near term. ... for Tuberculosis Vaccine De-
velopment.39 The strategy should specify ... www.cdc.gov/nchstp/tb/pubs/iom/iomresponse/
goal3.htm
37. Duke Funding Alert: October 10, 2003 ... e-mail address or telephone number); and
3) one common Web site for all Federal ... applications for Tuberculosis Vaccine Testing Re-
search Materials. ... www.ors.duke.edu/nd/announce/alert/archive/03/03oct10.htmlhttp://
fedbizopps.cos.com/cgi-bin/getRec?id=20031006a8... ttp://fedbizopps.cos.com/cgi-bin/
getRec?id=20031006a8
38. EQUI-TB Knowledge Programme Details the international research program into
pro-poor strategies in tackling Tuberculosis http://www.equi-tb.org.uk
39. eMedicine Health - Tuberculosis Consumer health resource center providing informa-
tion on the causes, symptoms, and treatment of TB. http://www.emedicinehealth.com/arti-
cles/17621-1.asp
6
40. Emerging Infectious Diseases... ftp.cdc.gov/pub/EID/
42. Eugene Bell Foundation Since 1997, Eugene Bell has concentrated on delivering
tuberculosis assistance in the form of medication, equipment, and supplies to all of North
Koreas thirteen TB hospitals and sixty-three TB care centers http://www.eugenebell.co.kr/
english/index.htm
44. External Tuberculosis Resources External Tuberculosis Resources. This is a list of other
web sites that have information about tuberculosis. The resources have been categorized by
the ... http://www.cpmc.columbia.edu/resources/tbcpp/extre...
45. FAQ about BCG Frequently asked questions about the BCG immunisation - a review
article.
www.priory.com/cmol/bcg.htm
47. Florida Department of Health (select Tuberculosis in the Subject Choices box)
50. GFATM (PAHO/AMRO) resource page for Latin America and the Caribbean
52. Global Alliance for TB Drug Development Seeks to develop and ensure equitable ac-
cess to new tuberculosis drugs. Features organization information, disease information, new
drug development, and news http://www.tballiance.org
54. Hardin MD : Tuberculosis From the University of Iowa, the *best* lists of Internet
sources in tuberculosis. www.lib.uiowa.edu/hardin\md/tuberculosis.html
56. healthnder - your free guide to reliable health information AIDS alt med cancer
diabetes food safety Medicare tobacco more . . . the latest government health news health
media online special events calendars prevention and self-care choosing quality care online
health information fraud and...
57. Health Communication Partnership Tuberculosis Related Internet Sites. CDC Divi-
sion of Tuberculosis Elimination Education and Training Resources Web Site. Tuberculosis ...
7
International Union Against Tuberculosis and Lung Disease ... www.hcpartnership.org/Top-
ics/tuberculosis.php
58. How to obtain Surveillance of Drug Resistance in Tuberculosis Software from the Inter-
net How to obtain Surveillance of Drug Resistance in. Tuberculosis (SDRTB3) Software from
the Internet. Download and install the software. Before downloading the software, please
read all three steps in the instructions. www.who.int/emc/SDRTB_software/instructions.html
59. Huff & Puff Victoria - Lung Disease Links Australian respiratory support group with
international links to lung disease, medical sites, hospitals and respiratory support groups.
http://www.vicnet.net.au/~huffpuff
61. Infectious Disease Society of America IDSA is a medical society representing more
than 5,500 physicians and scientists devoted to patient care, education, research, and com-
munity health planning in the area of infectious diseases. IDSA members care for many of the
patients with tuberculosis (TB) in the United States. This site summarizes ISDA activities related
to tuberculosis http://www.idsociety.org/mo/adv/actions%5Ftuberculosis.htm
62. Initiative for Vaccine Research File Format: PDF/Adobe Acrobat ... Advisory Committee
on new tuberculosis vaccines (TBVAC) ... information and knowledge management for vaccine
R&D: websites, ...
www.who.int/vaccines-documents/DocsPDF05/16317.pdf
63. Institute for Tuberculosis Research - Dedicated to the discovery and development of
new effective, low-cost, therapeutics for the treatment of tuberculosis. Includes description
of research projects, facilities, and methods, and welcomes donations to sponsor drug dis-
covery.
66. Japan Anti-TB Association Services include information about the disease itself,
referrals to doctors and hospitals, plus its treatment and medical expenses.
67. Johns Hopkins Center For Tuberculosis Research Features research, epidemiology,
treatment, drug information, forum, news, articles, and resources http://www.hopkins-
tb.org/news/
68. Journal of Occupational and Environmental Medicine - Fulltext ... ... Journal of Oc-
cupational & Environmental Medicine... www.joem.org/pt/re/joem
69. Journal of Thoracic Imaging - Fulltext: Volume 18(1) January 2003 ... Www.thoracici-
maging.com/pt/re/ jti/
71. Korean National Tuberculosis Association (KNTA) Works with the government in
treatment, health worker training and public education on TB, and conducts various technical
and educational projects. www.knta.or.kr/
8
72. LARG Health Tuberculosis Patient Resources
74. Links Links to Tuberculosis Sites. Line. Click here to link to the Division of Tuberculosis
Elimination Web Site, TB-Related Links . ... http://www.phppo.cdc.gov/PHTN/tbmodules/
links.htm
76. Links Mycos Research provides PPDs and links to other Mycobacterium Tuberculosis
sites http://www.mycosresearch.com/links.htm
79. Links ... Tuberculosis Sites. Action TB; Ask NOAH About: Tuberculosis from the New
York Online Access to Health (NOAH); Atlanta TB Prevention Coalition ... http://www.umdnj.
edu/~ntbcweb/links.htm
81. L.R.S. Institute of Tuberculosis & Respiratory Diseasesases About the institute, its
objectives, functions, and activities http://lrsitbrd.nic.in/
82. MedHist: The gateway to Internet resources for the History of Medicine ... The gateway
to Internet resources for the History of Medicine. Top>Diseases>Tuberculosis. Tuberculosis ...
Association for the Study and Prevention of Tuberculosis. It was set up to ... 128.243.217.106/
browse/mesh/detail/D014376.html
84. Minority Lung Disease Data - Tuberculosis (TB) A fact sheet from the American Lung
Associations Lung Disease in Minorities 1999 booklet. The site covers recent U.S. historical
trends. However, the most recent statistics listed are from 1996. A source of U.S. T.B. statistics
from 1999 is the Division of Tuberculosis Eliminations 1999 Surveillance Report.
9
87. Multidrug-Resistant Tuberculosis Fact Sheet From the American Lung Association
88. Mycobacterial Genome Workshop, Division of Microbiology and ... ... tuberculosis
research at or near the present level for about another ve years.... The development of an
improved tuberculosis vaccine is of extreme ... www.niaid.nih.gov/dmid/tuberculosis/execsum.
htm
92. MYCOS Research - A Colorado limited liability company providing custom mycobacte-
rial research materials. Features products, services, company information, and research.
93. National Center for Infectious Diseases, Division of AIDS, STD, and TB Laboratory Re-
search
94. National Institute of Allergy and Infectious Diseases Home Page (NIAID), National Insti-
tutes of Health NIAID Home | About NIAID | News & Information | Activities | Opportunities
NIAID welcomes your comments and suggestions. Please click here to send us an email mes-
sage, or write to us at: NIAID Ofce of Communications and Public Liaison Buildin...
10
102. National Tuberculosis Nurse Consultant Coalition - http://www.ntca-tb.org/ The
home page of the National Tuberculosis Controllers Association (NTCA) and its associated
organization, the National Tuberculosis Nurse Consultant Coalition (NTNCC). See above.
103. Nature Medicine: Tuberculosis WebFocus Includes an historical overview, full-text re-
search articles from Nature Medicine, reviews, news items, commentaries, and links to other
sites
106. NJMS National Tuberculosis Center - An institution performing research on the pre-
vention and treatment of tuberculosis, particularly in inner-city environments in the United
States... NJMS National TB Center - Links Page Tuberculosis Sites. Action TB. Atlanta TB
Prevention Coalition. Brown Universitys TB/HIV Lab. CDCs Division of TB Elimination... http://
www.umdnj.edu/ntbcweb/links_frm.html and http://www.umdnj.edu/ntbcweb/tbsplash.
html
107. North West TB Nurses Forum - The Northwest TB Nurses Association consists of nurses
who specialise in the prevention and treatment of Tubercolis in the North West of England.
109. Occupational Safety and Health Administration (OSHA) OSHA: Tuberculosis Links
to regulation, compliance, and other issues about occupational exposure to tuberculosis from
the U.S. Occupational Safety & Health Administration
110. OI: Turberculosis -- GIS A comprehensive resource on tuberculosis and HIV infec-
tion, from AEGIS. www.aegis.com/topics/oi/oi-tb.html
113. Philippine Tuberculosis Society Inc.... Dedicated to the prevention, treatment and
control of TB in the country. Includes information about the disease and the organization
http://www.ptsi.org.ph
115. Preguntale a NOAH Sobre la Tuberculosis Information in English and in Spanish pre-
sented by the New York Online Access to Health (NOAH) project.
118. Public Health Research Institute Tuberculosis Center The Public Health Research
Institute (PHRI) Tuberculosis Center was created to address the re-emergence of tuberculosis
11
and the spread of multidrug resistant (MDRTB) strains in New York City. Today it focuses on
understanding and treating tuberculosis with activities in basic research, molecular epidemiol-
ogy, and treatment of tuberculosis http://www.phri.org/tb.htm
120. PulmonologyChannel In 1993, WHO (the World Health Organization) declared tu-
berculosis a global emergency. Tuberculosis (TB) is responsible for the deaths of more youths
and adults than any other infectious disease http://www.pulmonologychannel.com/tuber-
culosis...
123. Rapid Blood Tests: Infectious Diseases, Tuberculosis, HIV, AIDS, STD Prsentation
dune ligne de tests rapides RAPID 1-2-3 HEMA, sur le sang total proposs par HDS. VIH,
hpatites, dengue, maladie de Chagas, paludisme, ... www.rapid123.com/
124. Registre de Tuberculosi Guia per al compliment del full de declaraci de cas de
tuberculosi. Programa de prevenci i control de la tuberculosi a Andorra. www.col-legidemet-
ges.ad/docs/fulltb.html
125. Research Institute of Tuberculosis Conducts research and treatment of TB. Located
in Kiyose City, Tokyo http://www.jata.or.jp/eindex.htm
129. Smart Computing Directory Of Web Sites: Diseases ... You will also nd links to
tuberculosis sites, the latest information on conferences, a preventive therapy database, and
numerous reports. ... http://www.smartcomputing.com/input/websites/viewl...
131. Stanford Center for Tuberculosis Research Guestbook ... Websites with good pictures
related with TB will help very much. ... Near infrared spectroscopy for the analysis of tubercu-
losis antimicrobials. ... www.stanford.edu/group/molepi/guestbook.html
133. Stop TB Initiative The Stop TB Initiative is a partnership for global action. The mis-
sion of Stop TB is to ensure that every person with TB has all the necessary information and
access to treatment and cure; to protect vulnerable populations from TB and http://www.
stoptb.org
12
136. Translated Education Materials TB educational material in many languages from the
Minnesota Department of Health
137. TB Alert Details about this charity which supports health projects worldwide and
promotes awareness of tuberculosis. Includes publications, a newsletter and links http://
www.tbalert.org
138. TB Alliance
139. TbandU A laymans guide to Tuberculosis, including all other health and medica-
tion issues.
140. TB Control India An information site providing vital information about the status
of the RNTCP, Revised National Tuberculosis Programme being implemented in India. http://
www.tbcindia.org
141. TB Education Center Resources for Patient Care/Management - Texas Center for In-
fectious Disease
142. TB Education & Training Resources resources from the U.S. CDC
146. TB Patient Incentive Program (American Lung Association of Wisconsin web site)
149. TB Resources on the Internet Text-Only Site. State Directory. Agencies A-Z. About
Oregon.gov. Advanced. Help. Tuberculosis Control. About Us. Contact Us. Tuberculosis Con-
trol. Fact Sheets. Guidelines egov.oregon.gov/DHS/ph/tb/links.shtml
151. TBXrays.com - A graphics only site of x-rays and images of patients with tuberculosis
and other lung disease.
152. The Associate of North West TB Nurses The Northwest TB Nurses Association con-
sists of nurses who specialize in the prevention and treatment of Tuberculosis in the North
West of England http://www.tbinfoline.co.uk/
153. The Hong Kong Tuberculosis, Chest and Heart Diseases Association Provides an
introduction to the associations services and patient-oriented information on tuberculosis,
heart diseases and hypertension http://www.ha.org.hk/org/antitb/
154. The Indian Journal of Chest Diseases and Allied Sciences ... www.indegene.com/ijcd/
13
156. The International Journal of Tuberculosis and Lung Disease a ... ... The International
Journal of Tuberculosis and Lung Diseases... www.ingentaconnect.com/content/ iuatld/ijtld/
157. The International Union Against Tuberculosis and Lung Disease The International
Union Against Tuberculosis and Lung Disease [IUATLD] is a non-prot, non-governmental or-
ganization with members throughout the world. It is dedicated to the prevention and control
of tuberculosis and lung disease http://www.iuatld.org/
158. The Lupin Group Tuberculosis Lupin is a national leader in anti-TB drugs. This site
features anti-T.B. drugs produced by the company, frequently asked question, news, directory
of tuberculosis links, and discussion group http://www.lupinworld.com/antitb.htm
159. The Meaning of a Positive Tuberculosis Test / AAFP Patient Inform... http://home.aafp.
org/patientinfo/tbtest.html
161. The Sequella Foundation The Sequella foundation promotes basic and clinical re-
search to facilitate the development new tools for TB control by providing support to the
research community and interested companies http://www.sequellafoundation.org/
162. The TB Investigation Project A 2002 study investigating tuberculosis in Russia, the
USA, and the UK. Analysis of both the human and the scientic stories behind the ght against
TB. Includes TB links http://tbproject.tripod.com
164. The Vaccine Fund - Press Releases ... malaria and tuberculosis vaccines that are so
desperately needed.... www.vaccinefund.org/
165. Tinplate Hospital (BCG Vaccine) BCG Vaccine, Prevention of Tuberculosis, Vaccine,
BCG background, General guideline of BCG, Benets of BCG http://www.tinplatehospital.
com/bcg.asp
168. Tuberculosis Tuberculosis and Public Health for Health Care Professionals. Reviews
on issues in tuberculosis, applied epidemiology, and courses. An afliation of the International
Union Against Tuberculosis and Lung Disease http://www.tbrieder.org
170. Tuberculosis & Airborne Disease Weekly - A weekly publication with searchable ar-
chives
14
171. Tuberculosis and HIV, HIVemir (HIV: An Electronic Media Information Review)
174. Tuberculosis and Related Infectious Disease - Watson W. Wise ... ... Tuberculosis Sites
(Univ. of Medicine and Dentistry, New Jersey); Tuberculosis & HIV (The Body: An AIDS and HIV
Information Resource) ... http://library.uthct.edu/tb.htm
176. Tuberculosis Association of Ohio County Provides programs and services to Ohio
County, WV http://www.tboc.org/
177. Tuberculosis Clinical Resources Health: Diseases and Conditions: Tuberculosis. Ad-
ditional Tuberculosis Sites (These sites have not been reviewed.) ... http://capstoneclinic-dl.slis.
ua.edu/clinical/pulm...
178. Tuberculosis Clinical Resources Additional Tuberculosis Sites (These sites have not
been reviewed.) YAHOO - Health:Medicine:Respiratory Diseases ... http://ruralnurseorganiza-
tion-dl.slis.ua.edu/clini...
180. Tuberculosis Control India This site provides information about tuberculosis and
its control in India http://www.tbcindia.org/
183. Tuberculosis Facts Factsheet with cause, symptoms, risk factors, diagnosis, compli-
cations, treatment, and prevention. http://www.astdhpphe.org/infect/tb.html...
185. Tuberculosis Facts Factsheet with cause, symptoms, risk factors, diagnosis, complica-
tions, treatment,
and prevention. www.astdhpphe.org/infect/tb.html
188. Tuberculosis in Children - Keep Kids Healthy Tuberculosis information and answers
to common questions about TB in children, including the difference between tuberculosis
infection and disease, ...
www.keepkidshealthy.com/welcome/ infectionsguide/tuberculosis.html
15
189. Tuberculosis - Index- Pulmonology In 1993, WHO (the World Health Organization)
declared tuberculosis a global emergency. Tuberculosis (TB) is responsible for the deaths of
more youths and adults ... www.pulmonologychannel.com/tuberculosis/
190. Tuberculosis Information ... and Site Hosting - Web Hosting - Internet Store and
Ecommerce Solution Provider - High Speed Internet. Popular Searches: Tuberculosis Informa-
tion ... ccfdca.www1.50megs.com/TB.htm
204. Tuberculosis Resources Columbia University`s website with information about tu-
berculosis, TB testing and treatment. Spanish and English http://www.cpmc.columbia.edu/
resources/tbcpp
16
206. Tuberculosis Resources on the Internet Source:HealthNet. Title. URL. Publisher(s)
Comments. PubMed. http://www.ncbi.nlm.nih.gov/ entrez/ query.fcgi. National Center for
Biotechnology Information at the National Library of Medicine ,NIH ... and presented by Johns
Hopkins Cener for Tuberculosis Research ... part 2 of Table II. Global Tuberculosis Control Re-
port ... www.psgaidsinfo.org/tuberculosis_resurces_on_the_internet.htm
209. Tuberculosis Tuberculosis and Public Health for Health Care Professionals. Reviews
on issues in tuberculosis, applied epidemiology, and courses. An afliation of the International
Union Against Tuberculosis and Lung Disease http://www.tbrieder.org
212. Tuberculosis - Tuberculosis and Public Health for Health Care Professionals. Reviews
on issues in tuberculosis, applied epidemiology, and courses. An afliation of the International
Union Against Tuberculosis and Lung Disease.
215. Tuberculosis Vaccine Action Plan, Blueprint for Tuberculosis Vaccine Development,
National Institute of Allergy ... http://www.niaid.nih.gov/publications/blueprint/pa...
217. Tuberculosis Web Sites ... Consumer Health Sites. Enfermedades - Tuberculosis. This
Spanish language page from the Centers for Disease Control contains links to pamphlets in-
cluding Tuberculosis - !Enterese! ... Core Curriculum on Tuberculosis is updated periodically.
Therefore, the Internet version may differ ... www.lib.siu.edu/hp/divisions/sci/health/tb.html
219. Tuberculosis workplace standards related to TB from the U.S. Occupational Safety
and Health
220. www.tuberculosis.ru/
221. Understand and Fight Tuberculosis - Information for health care professionals From
the Tuberculosis Division of the International Union Against Tuberculosis and Lung Disease
(IUATLD) http://www.tbrieder.org/
17
222. Unidad de investigacin en Tuberculosis de Barcelona... Informacion sobre tuberculo-
sis, tratamientos, prevencion, vacunas, lineas y proyectos de investigacion, documentos, casos
clinicos, novedades, congresos, eventos y cursos http://www.imsb.bcn.es/uitb/
223. Unit de Gntique Molculaire Bactrienne ... projects is also available via the web
sites at Integrated Genomics, live tuberculosis vaccines Mycobacterium bovisBCG and My-
cobacterium microti. ... www.pasteur.fr/recherche/unites/Lgmb/mycogenomics.html
224. USDA Funded Projects ... Develop candidate tuberculosis vaccines for cattle and deer;
3. ... www.nal.usda.gov/awic/pubs/TB/USDAFunded.htm
226. Veiled Face of Tuberculosis - Find the authors attitude towards diagnostics of renal
tuberculosis, the way the investigations were performed, studied samples, and a note on the
author. Site is in English and Croatian
228. Welcome on the TB Vaccine Cluster Site Click on to enter. Updated : Tue, Jun 13,
2000. Site realised by Marie Guibert. http://www.pasteur.fr/recherche/EC_TBvaccine/
229. WHO Tuberculosis - Prevention and Control Web Site This World Health Organization
site includes several publications and fact sheets with an international focus, including the
2002 Global Tuberculosis Control Report, Treatment of Tuberculosis: Guidelines for National
Programmes (available in English, French, and Spanish), TB/HIV: A Clinical Manual, Tuberculosis
in Prisons (available in English and Russian), and information about drug-resistant TB.
233. World TB Day, March 24, 2005 information from the U.S. CDC
18
List of Noted Tuberculosis Victims
From Wikipedia, the free encyclopedia. (Redirected from List of famous tuberculosis vic-
tims). This is a list of famous people and celebrities who had, or are believed to have had,
tuberculosis.
Artists:
Frdric Bartholdi, Marie Bashkirtseff, Aubrey Beardsley, Harry Clarke, Paul
Gauguin, Amedeo Modigliani, Elizabeth Siddal ?, Pamela Anderson.
Composers:
Frdric Chopin, Stephen Foster, Wolfgang Amadeus Mozart, Niccolo Paganini,
Giovanni Battista Pergolesi, Henry Purcell, Johann Schein, Cat Stevens?.
Religious gures:
John Calvin, Cardinal Richelieu, St Thrse de Lisieux, St Bernadette Soubirous.
Leaders:
Simn Bolvar, Edward VI of England, Ulysses S. Grant, Andrew Jackson, Mu-
hammed Ali Jinnah, Sir Wilfrid Laurier, Louis XIII of France, Louis XVII of France, Nel-
son Mandela, Napoleon II of France, Manuel L. Quezon, Eleanor Roosevelt, Dmitri
Pavlovitch Romanov, Alexander Stephens, Tutankhamun, John Young.
19
Others:
Niels Abel, mathematician Rene Adore, Beulah Annan, Frdric Bastiat, Al-
exander Graham Bell, Sarah Bernhardt, Louis Braille, James Burke, Anders Celsius,
Cheng Man-ching, Tai Chi Chuan master, Charlie Christian, Arline Feynman, W. C.
Fields, Augustin-Jean Fresnel, Brenda Fricker, Abel Gance, Jay Gould, Emmett Hardy,
Richard Harris (actor)?, Doc Holliday, Immanuel Kant, Freddie Keppard, Ren Lan-
nec French physician; inventor of the stethoscope, Vivien Leigh, Christy Mathewson,
Dmitri Mendeleev?, James Bubber Miley jazz trumpeter, Barry Morse?, Anne Nev-
ille (queen consort of Richard III) (probably), Florence Nightingale, Mabel Normand,
Etti Plesch?, Joseph Mary Plunkett, Virginia Eliza Clemm Poe (wife of Edgar Allan
Poe), Herman Potonik, Gavrilo Princip, Jimmie Rodgers, Bernhard, Riemann, math-
ematician Erwin Schrdinger, Takasugi Shinsaku (1839-1867), samurai Okita Soji
(1844-1869), Japanese swordsman and troop captain in the Shinsengumi, Baruch
Spinoza, Adrianus Turnebus, Georges Vezina, Lev Vygotsky, Rube Waddell, William
Winchester (son of Oliver Winchester, husband of Sarah Winchester), Link Wray,
Eugene Wigner?.
Fictional characters:
Ukyo Tachibana from the Samurai Shodown video game series Sayo from the
Rurouni Kenshin anime, Hyatt from the Excel Saga anime, Helen Burns from Jane
Eyre by Charlotte Bront, Little Nell from The Old Curiosity Shop (Charles Dickens),
Mimi from La Bohme (Giacomo Puccini et. al.), Violette from Verdis La Traviata,
Buddy Willard from The Bell Jar by Sylvia Plath, Lin Dai-yu from The Story of Stone
by Cao, Satine from Moulin Rouge.
Reference:
Rothman, Sheila M. (1994). Living in the Shadow of Death: Tuberculosis and the Social Experience of Illness
in American History. ISBN 0801851866 .
20
SOME CUBAN MASTER PAINTERS VICTIMS OF TB...
... AND HIS WORKS
21
Carlos Enrquez (1900 - 1957)
El Rapto de las Mulatas
/ Brown girls abduction
22
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CANADA's ROLE in
FIGHTING TUBERCULOSIS
Glossary
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Two billion people - one third of the world's population - have been infected
with TB.
Someone is newly infected with TB every second.
Nearly 2 million people die of TB every year.
Distinguished scientist
M.M. Sharma of Mumbai,
India, has been named to
the Aeras Board of
Directors. Read more...
2004 Aeras Global TB Vaccine Foundation, 7500 Old Georgetown Road, Suite 800, Bethesda, MD
20814, USA
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All WHO
Publications Tuberculosis
Research tools
Advocacy report
WHO sites
TB home WHO/CDS/TB/2003.321
ISBN 92 4 259070 3 (NLM classification: WF 310)
Data and country
profiles
The publication, prepared for the World THE FILM
DOTS TB control Health Organization by editors and Tuberculosis
strategy photographers from Colors magazine, An informational film based on the
TB/HIV puts a human face on the TB epidemic report Tuberculosis.
and the deadly interaction between TB :: View the film
TB publications and HIV. Outlining the efficacy of the
DOTS programme, the report makes clear
About us THE REPORT
that continued commitment and
Tuberculosis
expanded resources are vital to combat
Events :: Photo gallery
TB.
:: Press release
Links
:: Report - text only [html]
Despite eight million new cases of TB being reported annually and
two million deaths a year the report reveals the many :: English/French [pdf 1.1mb]
misconceptions people have about the disease and how this :: English/Spanish [pdf 1.1mb]
ignorance is reflected in the misery of those infected with TB across
the world.
"The images are disturbing," said Colors editor-in-chief Renzo di Renzo, "but in fact they give just a mere
glimpse of the enormous challenges faced every day by TB health care workers."
All WHO
Data and country London/Geneva - 24 March, 2005 - In most areas :: News release
profiles of the world, the battle against tuberculosis is :: Access the full report online
being successfully fought, but in Africa the disease :: Report summary (English) [pdf
DOTS TB control has reached alarming proportions with a growing
strategy 81kb]
number of TB cases and deaths linked to HIV, the
World Health Organization said in a new report :: Report summary (French) [pdf
TB/HIV
released today. 95kb]
TB publications :: Report summary (Spanish) [pdf
The Global Tuberculosis Control report for 2005 89kb]
About us
finds that global TB prevalence has declined by
Events more than 20% since 1990 and that incidence
rates are now falling or stable in five of the six regions of the world. The glaring exception is Africa,
Links where TB incidence rates have tripled since 1990 in countries with high HIV prevalence and are still
rising across the continent at a rate of 3-4% annually.
Even Uganda, an African HIV reduction success story, is today curing fewer TB patients than it did four
years ago. More than half of all people with TB in Uganda remain without access to life-saving DOTS*
services due to strained general health facilities.
"Evidence in this report provides real optimism that TB is beatable, but it is also a clear warning," said
WHO Director-General Dr LEE Jong-wook. "As Nelson Mandela has said, we can't fight AIDS unless we do
much more to fight TB, and it is time to match his words with urgent action in Africa on the two
epidemics together."
There has been major progress in China and India, which account for one third of the global TB burden.
Both are leading the accelerated response to TB control by rapidly scaling up DOTS. As a result, the
number of cases treated under DOTS worldwide rose 8% in 2003 compared to the previous year. Other
countries such as Indonesia and the Philippines are showing similar progress.
Assuming strong commitment and resources are sustained, four regions - the Americas, Eastern
Mediterranean, South East Asia and Western Pacific - are on track to reach the United Nations Millennium
Development Goal of reducing TB incidence by 2015. The two exceptions are Africa due to the TB/HIV co-
epidemic, and Europe where there are high levels of multidrug-resistant TB and slow advances in DOTS
in countries of the former Soviet Union.
"Dedicated frontline health workers are making a difference, reaching out to the most vulnerable," said
Dr Mario Raviglione, Director of WHO's Stop TB Department. "But we need to push even further, to work
with new partners in both public and private health sectors, and in all regions, to reach more than half of
all patients that are still without access to DOTS treatments."
Since 1995, over 17 million people with TB have benefited from effective treatment under DOTS. But
more could be achieved within countries, and in research into new diagnostics, drugs and vaccines, if the
annual US$ 1 billion funding gap for TB control was filled.
The urgency of addressing TB has been highlighted in the UK-led Commission for Africa, which linked
improved TB control to strengthened health systems, as well as calling for full funding of WHO's 'Two
Diseases, One Patient' strategy for improved TB and HIV intervention.
"It is a remarkable achievement that we are on target to reach the goal of halving TB cases by 2015 in
most places," said the UK's International Development Secretary, Hilary Benn. "The Department for
International Development is a strong supporter of TB programmes in some of the countries which have
been making the fastest progress. However, as both the Global TB Control report and the Commission for
Africa report stress, the destructive link between TB and AIDS in Africa is causing an increase in cases. I
call on the international community to step up efforts to tackle both of these diseases together."
*DOTS is the internationally recommended strategy for controlling TB, consisting of five elements:
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January 2005
1. KUBO N , Furusyo N, Nakashima H, Kashiwagi K, et al
Strenuous physical labor is important as a cause of elevated alanine aminotransferase levels in Japanese
patients with chronic hepatitis C viremia.
Eur J Epidemiol 2005;20:251-61.
PubMed Related articles Abstract available
January 2004
2. CATALANI C , Biggeri A, Gottard A, Benvenuti M, et al
Prevalence of HCV infection among health care workers in a hospital in central Italy.
Eur J Epidemiol 2004;19:73-7.
PubMed Related articles Abstract available
prevalence of infection.
Eur J Epidemiol 2004;19:61-7.
PubMed Related articles Abstract available
January 2003
14. BACKMUND M, Meyer K, Wachtler M, Eichenlaub D
Hepatitis C virus infection in injection drug users in Bavaria: risk factors for seropositivity.
Eur J Epidemiol 2003; 18: 563-8.
PubMed Related articles Abstract available
17. JAIN A, Rana SS, Chakravarty P, Gupta RK, Murthy NS, Nath MC et al
The prevalence of hepatitis C virus antibodies among the voluntary blood donors of New Delhi, India.
Eur J Epidemiol 2003; 18: 695-7.
PubMed Related articles Abstract available
19. REDA AA, Arafa MA, Youssry AA, Wandan EH, Ab de Ati M, Daebees H
Epidemiologic evaluation of the immunity against hepatitis B in Alexandria, Egypt.
Eur J Epidemiol 2003; 18: 1007-11.
PubMed Related articles Abstract available
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Investigator: Tell, L. A.
Performing Institution:
Medicine & Epidemology
University of California (Vet-Med)
Davis, California 95616
OBJECTIVES: This project tests the hypothesis that polymerase chain reation (PCR) testing using
extracted mycobacterial deoxyribonucleic acid (DNA) from avian feces can provide a more rapid and
realiable screening method for the detection of Mycobacteria avium complex bacteria than conventional
culture methods.
APPROACH: Potential diagnostic procedures using extracted DNA for PCR from clinical samples have
been plagued by the presence of various inhibitors of the PCR reaction. This study is specifically
designed to assess three different DNA extraction protocols of avian feces for the presence or absence of
these potential PCR inhibitors and the overall efficiency and the suitability of the resulting DNA for PCR
reactions. Once an optimal method is identified, it will be used to evaluate the extraction and detection of
DNA from feces spiked with living Mycobacterium avium complex cells.
absence of potential PCR inhibitors, thus defining an optimal method for DNA extraction from bird fecal
samples. The first experiment compared three DNA extraction methods and heat treatment of the
extracted fecal DNA samples for their ability to overcome fecal PCR inhibition. Methods for extracting
DNA from feces of healthy Japanese quail (Coturnix coturnix japonica) included (a) bead beating + EL
(BB+EL), (b) bead beating + silicone dioxide (BB+SiO2), and (c) bead beating + phenol/chloroform. To
evaluate each extraction methods' ability to overcome PCR inhibition, extracted fecal DNA samples were
spiked with control M. avium subsp. avium DNA and quantitative real-time TaqMan PCR analysis was
performed. The BB+EL and BB+SiO2 methods returned positive PCR results. BB+EL resulted in the
highest purity and number of mycobacteria. Heating samples before PCR analysis decreased the mean
number of mycobacteria for all fecal DNA extraction methods. In the second experiment, living M.
avium subsp. avium cells were mixed with feces from healthy Japanese quail at concentrations of 1 x 106
CFU/g, 10 x 106 CFU/g, or 60x 106 CFU/g. Samples underwent DNA extraction using BB+EL,
followed by quantitative TaqMan PCR. Heated and unheated samples were analyzed. The mean number
of mycobacteria detected in feces with a spiking concentration of M. avium subsp. avium of 1 x 106
CFU/g was only 1 (range, 0 to 2.3) for both heated and unheated samples. Thus, the lower limit of
detection for quantitative PCR using the methods described is approximately 1x106 CFU/g or less. In
summary, this study demonstrated that DNA extraction methods used in sample preparation can have a
substantial impact on the DNA yield, purity, and amplification during subsequent PCR analysis on avian
fecal samples. The best preparation method tested incorporated bead beating and enzymatic lysis using a
commercial kit designed for use on stool samples. The lower limit of detection on avian fecal samples
spiked with M. avium subsp. avium was 1 million CFU/gram, so this test may be of most use in
identifying highly infective birds.
PROJECT CONTACT:
Name: Tell, L. A.
Phone: 530-752-1363
Fax: 530-752-0414
Email: latell@ucdavis.edu
Investigators: Nett, T. M.; Blair, C. D.; Bowen, R. A.; Orme, I. M.; Pearson, L. D.; Salman, M. D.
Performing Institution:
Microbiology, Immunology and Pathology
Colorado State University
Fort Collins, Colorado 80523
APPROACH: Molecular, immunological, and biochemical approaches will be used to elucidate the
pathogenetic mechanisms of infectious diseases of livestock and to develop new vaccines, therapies, and
diagnostics for important veterinary pathogens. This information will be exploited to develop new
control strategies for these important diseases. New technologies, such as polymerase chain reaction
amplification, randomly amplified polymorphic and mitochondrial DNA, phylogenetic analyses,
molecular epidemiologic approaches will be used to identify risks and propose management approaches
to maximize animal productivity.
marcescens, and Escherichia coli. The S. Newport class 1 integron was found to encode resistance to
trimethoprim, spectinomycin/streptomycin, and sulfonamides; and contained a defective version of the
quaternary ammonium compound resistance gene. The resident plasmid in these isolates also contained
genes for tetracycline and b-lactam and cephalosporin resistance, although these genes were not
contained within the class 1 integron. The results of these studies indicate that, unlike multidrug resistant
S. typhimurium DT104 (whose antibiotic resistance is encoded within an integron located on the
chromosome), multidrug resistance of S. Newport isolates is due to genes encoded on a resident plasmid.
The significance of this finding is that these resistance markers could presumably be transferred to other
Salmonella serotypes by conjugation and emphasizes the need to understand transfer of drug resistance in
Salmonella. Range and feedlot cattle with a high intake of sulfur can develop polio-encephalomalacia
(PEM), a neurological condition of ruminants characterized by necrosis of the cerebral cortex. An
important factor in the development of PEM is the sulfur reducing capacity of the ruminal microflora.
Little is known about the microbial population(s) involved in the production of neurotoxic concentrations
of H2S. In this study, the natural ruminal ecosystem was studied by comparative 16S ribosomal RNA
analysis followed by specific analysis of sulfate-reducing bacteria using DNA extracted from rumen fluid
collected from test cattle before, during, and after transition to high sulfur water. 16S rDNA was cloned
and 50 clones were analyzed from each rumen sample with restriction enzymes. Extreme diversity was
observed both within a time point among different animals and between time points. Sulfate-reducing
bacteria (SRB) belonging to the genera Desulfovibrio and Desulfomicrobium were detected in all of the
animals. In addition, Desulfobulbus species were detected in animals during the second time point when
ruminal H2S became maximal. Reverse Southern Analysis to determine the abundance of bacterial
species in the rumen failed to reveal any particular dominant species in cattle consuming high sulfur
concentrations.
3. M.J. Magill1, D.H. Gould1, J.J. Wagner2, N.M DuTeau1; Characterization of Ruminal Microflora
Associated With Pathologic Hydrogen Sulfide Production in Cattle Exposed to High Levels of Dietary
Sulfur. American Society for Microbiology 102nd General Meeting, May 19-23, 2002, Salt Lake City,
UT 1Colorado State University, Fort Collins, CO, 2Continental Beef Research, Lamar, CO
4. Thesis; Colorado State University: Magill, Molly Jean. Characterization of ruminal microflora
associated with pathologic hydrogen sulfide production in cattle exposed to high levels of dietary sulfur /
submitted by Molly Jean Magill. 2002.
PROJECT CONTACT:
Name: Nett, T. M.
Phone: 970-491-7051
Fax: 970-491-2250
Email: tnett@cvmbs.colostate.edu
Performing Institution:
Animal & Veterinary Science
University of Idaho
Moscow, Idaho 83843
APPROACH: 1. Intracerebrally inoculate mule deer fawns and domestic lambs with scrapie-infected
brain tissue. Montior for illness. Screen palpebral lymph nodes for prions at 18 and 24 months, and full
necropsy at 36 months post inoculation. 2. Inoculate elk and mule deer with Mycobacterium avium
organisms. Compare hypersensitive reactions to tuberculin intradermal inoculation made in the upper
eyelids, to those standard test sites in the cervical region. 3. Elk will be fed Brucella RB51 vaccine as a
top dressing in four, five-day series. Blood samples will be taken and evaluations conducted to determine
if, and when an immune response is achieved.
PROJECT CONTACT:
Name: Zaugg, J. L.
Phone: 208-454-8657
Fax: 208-454-8659
Email: jzaugg@uidaho.edu
Performing Institution:
National Animal Disease Ctr
Ames, Iowa 50010
OBJECTIVES: Characterize interactions between various host species, such as cattle and white-tailed
deer, and Mycobacterium bovis; develop and evaluate improved tests for diagnosis of M. bovis infection
in animals; and develop improved methods for differentiation of M. bovis isolates. NEW FUND OBJ:
Identify candidate antigens that would be efficacious in a mucosal vaccine for prevention of tuberculosis
in cattle, cervids (deer), and other wildlife.
APPROACH: Animals will be experimentally challenged w/M. bovis and blood and tissue samples will
be collected at different times to determine response of host to the organisms. Bacteriologic,
histopathologic, and immunologic methods will be used to characterize host responses. Tissue samples
w/b collected from naturally infected animals to determine distribution/characteristics of lesions. A
gamma interferon assay for diagnosis of TB in deer and elk is being developed; w/b evaluated to
determine test sensitivity/specificity. Blood samples from infected and noninfected animals w/b used for
test evaluation. A method using the polumerase chain reaction w/b developed for rapid detection of M.
bovis in tissue samples. Methods for DNA finger- printing M. bovis isolates will be improved by using
different DNA probes and enzymes. A method using PCR for direct detection and typing of M. bovis in
fresh tissue samples w/b modified for use w/formalin-fixed tissues. NADC,AmesIA:Bldg2A12,BL1-3
IBC-0193 Apprvd to 6/29/00;-0224 Apprvd to 6/3/00; -0239 Apprvd to 12/26/00
partners of the United States. Trade restrictions between the United States and Canada and between
Mexico and the United States have occurred because of bovine tuberculosis in animals. 3. How does it
relate to the National Program(s) and National Component(s)? The Bovine Tuberculosis research
project is assigned to the Animal Health National Program (103) and relates to the vision of this program
to ensure animal health through improved disease detection and control. The objectives of the project are
to 1) develop and evaluate improved tests for diagnosis of tuberculosis in cattle, deer and other
species,which relates to the National Program Component on Pathogen Detection; 2) develop improved
methods for differentiation of M. bovis isolates, which relates to the National Program Component on
Epidemiology of Disease; 3) define the interactions between various host species and M. bovis, which
relates to the National Program Component on Host/Pathogen Interactions and 4) develop and evaluate
vaccines for control and prevention of tuberculosis in animals, which relates to the National Program
Component on Disease Control Strategies. 4. What were the most significant accomplishments this
past year? A. Single Most Significant Accomplishment during FY 2000 year: Improved tests for
diagnosis of tuberculosis are needed so that animals infected with M. bovis can be identified and
eliminated as a source of infection to other animals and human beings. ARS scientists at NADC
conducted experiments to examine the immune responses of animals infected with M. bovis to identify
characteristics that could be used for diagnosis of infection. We developed a rapid diagnostic test that can
be used for detection of M. bovis infection in multiple species of animals. After further validation and
approval, the test may be used for the national program to eradicate tuberculosis from animals in the
United States. B. Other Significant Accomplishment(s), if any: In order to conduct controlled studies on
tuberculosis in animals, a system to experimentally infect animals with M. bovis is needed so that they
develop signs of disease that are similar to those observed in naturally infected animals. ARS scientists at
NADC developed a method to experimentally infect white-tailed deer, cattle, and other animals with
aerosolized M. bovis. We determined that animals experimentally infected with aerosolized develop
lesions and other signs of disease that mimic those seen in naturally infected animals. M. bovis The new
method for experimentally infecting animals with M. bovis is being used for controlled studies on
tuberculosis in animals. C. Significant Accomplishments/Activities that Support Special Target
Populations: None to report. 5. Describe the major accomplishments over the life of the project
including their predicted or actual impact. Since 1998, bovine tuberculosis has been detected in 16
herds of cattle in northeast Michigan where tuberculosis is endemic in the wild white-tailed deer
population. ARS scientists at the NADC experimentally infected white-tailed deer and allowed cattle to
have access to feed that had been offered to the deer and to pens that had been soiled by the deer. We
determined that cattle can become infected with M. bovis through indirect contact with experimentally
infected white-tailed deer. These results provide evidence that cattle do not need to have direct contact
with infected white-tailed deer in order for them to develop bovine tuberculosis and helps explain how
cattle in Michigan became infected with M. bovis. ARS scientists at the NADC experimentally infected a
group of deer and monitored routes of shedding and transmission to other deer. We determined that deer
infected with M. bovis shed organisms in saliva, nasal secretions, urine and feces and that infection is
readily transmitted from experimentally challenged deer to other deer sharing the same pen. These results
explain how tuberculosis is transmitted within a population of deer and will be used to develop strategies
for control of the disease. Current surveys to determine the prevalence of tuberculosis in wild white-
tailed deer are based on examination of tissues in the head to detect lesions. In a study that involved
detailed examination of the entire deer carcass, we determined that about 50% of the infected deer did
not have lesions in the head. These results indicate current methods to detect tuberculosis in wild white-
tailed deer underestimate the prevalence of disease by 50% and that improved methods for detection are
needed. Supplemental feeding and baiting of white-tailed deer in the winter in Michigan has been
practiced for many years and is thought to contribute to the spread of M. bovis among deer. ARS
scientists at the NADC experimentally inoculated samples of six feeds typically used for baiting deer and
stored them for various lengths of time at different temperatures. We determined that M. bovis survives
on all feeds when frozen for at least 4 months. These results have been used by regulatory officials to
make recommendations regarding feeding and baiting of deer in Michigan. A new test for detection and
identification of M. bovis in tissue samples that are collected for microscopic examination was
developed. When animals are slaughtered, meat inspectors collect tissue samples from animals that are
suspected of having tuberculosis. Tissue samples are examined for microscopic evidence of tuberculosis
and for the presence of organisms. Stains used to detect M. bovis in a tissue sample also stain other
organisms so that it is not possible to identify the organism in the sample. The new test detects a specific
piece of DNA that is present only in organisms that cause tuberculosis. The new test permits more
accurate and rapid identification of animals with tuberculosis than was previously possible. The test is
used extensively at the request of state and federal regulatory officials to confirm suspected cases of
tuberculosis in animals. We adapted and standardized methods for differentiation of strains of M. bovis.
Differences among various strains of M. bovis can be identified by using specific genetic markers. Using
these markers, it is possible to determine if different animals are infected with a common strain or
different strains of M. bovis. This information is used by epidemiologists to determine possible sources
of infection in outbreaks of tuberculosis in animals. 6. What do you expect to accomplish, year by
year, over the next 3 years? FY 2002: 1) Further characterize the disease produced when cattle and deer
are experimentally challenged with aerosolized M. bovis. 2) Determine if M. bovis can be transmitted
from experimentally infected raccoons to uninfected penmates. 3) Determine routes of transmission of
M. bovis from does to fawns. 4) Begin to characterize immune response of white-tailed deer to M. bovis.
5) Determine the sensitivity and specificity of a new diagnostic test 6) Continue research to develop
improved methods for differentiation of M. bovis isolates. FY 2003: 1) Further characterize the
progression of disease and immune responses of white-tailed deer infected with M. bovis. 2) Continue
research to determine the sensitivity and specificity of a new diagnostic test. 3) Identify potential
vaccines that can be used for prevention and control of tuberculosis in wildlife and domestic animals. 4)
Continue research to develop improved methods for differentiation of M. bovis isolates FY 2004: 1)
Determine the safety and effectiveness of candidate vaccines. 2) Continue research to develop and
evaluate improved diagnostic tests. 7. What science and/or technologies have been transferred and to
whom? When is the science and/or technology likely to become available to the end user (industry,
farmer, other scientists)? What are the constraints if known, to the adoption & durability of the
technology product? ARS scientists assigned to the Bovine Tuberculosis Research Project routinely
presented research findings to scientists, state and federal action agencies, and industry groups. In some
cases, results of research conducted by ARS scientists are used as the basis for regulatory action. ARS
scientists received invitations to present results of research to specfic groups, such as the Michigan
Department of Natural Resources, because of the direct impact that the research findings have on
recommendations of the group. ARS scientists are members of several organizations, committees, and
working groups and provide scientific expertise on a broad range of issues relating to bovine
tuberculosis. A patent has been approved for a new test that was developed by ARS scientists for
diagnosis of tuberculosis. (Invention Report No. 0152.01 "Diagnosis of Tuberculosis Infection Through
Analysis of Nitrite Production of Leukocytes Stimulated with Mycobacterial Antigens") 8. List your
most important publications in the popular press (no abstracts) and presentations to non-scientific
organizations and articles written about your work Presented results of research on CMU Public
Television program "Bovine Tuberculosis in Michigan: The Controversy," Spring, 2001. Presented talks
entitled "Use of the gamma-interferon assay for diagnosis of tuberculosis in cattle," "Naturally occurring
tuberculosis in white-tailed deer" and "Raccoons and Mycobacterium bovis: Maintenance or Spill-Over
Host" to participants of Bovine Tuberculosis in Michigan, conference 2001, March 5- 6, 2001, Lansing,
Michigan. Registered participants of the conference included state and federal animal health officials,
departments of natural resource and community health, livestock industry groups, private land owners,
hunt clubs, state legislators, congressional representatives, and members of the press. Presented talk
entitled "Emergence of tuberculosis in wildlife: Impact on animal agriculture and public health" at
Beltsville Symposium "Healthy Animals 2000", September, 2000.
Performing Institution:
National Animal Disease Ctr
Ames, Iowa 50010
APPROACH: Deer will be experimentally challenged with M. bovis and offered excess feed in a
portable bunk. After deer have eaten, the bunk with feed will be moved to a pen with cattle. This will be
repeated daily for up to 4 weeks. Cattle will be monitored for infection using standard diagnostic tests.
Pregnant white-tailed deer will be challenged with M. bovis. About 1 week before due date, fawns will be
delivered by cesarean and samples will be collected for isolation of M. bovis. Bottle-raised fawns will be
fed goat milk replacer that contains different doses of M. bovis on 5 consecutive days. Fawns will be
monitored for immune responses and shedding of organisms for 6 months. Animals will be necropsied
and samples will be collected to evaluate distribution of lesions and organisms. The gamma interferon
assay will be evaluated by comparing of the assay with those of skin testing, culture and histopathology.
Performing Institution:
National Animal Disease Ctr
Ames, Iowa 50010
OBJECTIVES: Develop and evaluate improved tests for diagnosis of Mycobacterium bovis infection in
different animal species; Develop improved methods for differentiation of M. bovis isolates; Characterize
M. bovis infection in domestic livestock and wildlife.
APPROACH: Sensitivity and specificity of tests for detection of M. bovis infection in live animals will
be determined. We will determine if new antigens can be used to improve skin tests and in-vitro
diagnostic tests. Improved PCR assays for direct detection of M. bovis in various specimens will be
developed by modification of existing tests. Improved methods for isolation of M. bovis from various
samples will be developed by changing processing methods and decontaminants. Improved methods for
DNA fingerprinting of M. bovis isolates will be developed by adapting published methods. Animals will
be exposed to M. bovis by different routes and clinical signs, immune system parameters, and lesion
distribution will be monitored. Routes of transmission of M. bovis from infected animals to uninfected
animals will be assessed by periodic sampling of oral and nasal secretions, urine, and feces. BSL-1-3-N;
Certified through April 10, 2002.
Performing Institution:
Agricultural Research Service
Ames, Iowa 50010
APPROACH: A group of reindeer will be sensitized with M. bovis BCG and matched with a group of
non-sensitized control animals. Blood samples will be collected and skin tests will be conducted
periodically throughout the study period. Various immune function assays will be conducted to monitor
immune responses. In the second study, reindeer will be challenged with virulent M. bovis. Blood
samples will be collected and skin tests will be conducted similar to the first study. In addition, tissue
samples will be collected at various times to characterize the progression of disease in reindeer. White-
tailed deer will be experimentally challenged with M. bovis using two routes of inoculation and three
dosages. Immune responses will be monitored by evaluating blood collected at various times and
conducting skin tests. Lesions will be characterized at the conclusion of the study. BSL-1-3-N; Certified
through April 10, 2002.
Investigator: Groves, M. G.
Performing Institution:
Pathobiological Sciences
Louisiana State University
Baton Rouge, Louisiana 70893
OBJECTIVES: Numerous novel synthetic compounds and natural products made available from the
repositories of the NCI will be evaluated for anti-tuberculosis activity.
APPROACH: Compounds are screened against M. tuberculosis H37Rv and single drug-resistant strains
Investigator: Klei, T. R.
Performing Institution:
Pathobiological Sciences
Louisiana State University
Baton Rouge, Louisiana 70893
OBJECTIVES: The nine-banded armadillo is a permissive host for leprosy and is essential for
providing enormous numbers of Mycobacterium leprae as a research resource. The production of M.
leprae allows for the purification and production of skin test antigens for detecting new cases of clinical
disease. The objective of this project is to identify, condition and screen armadillos to determine their
suitability for in vivo propogation of M. leprae.
APPROACH: Armadillos will be captured in the wild from areas non-enzootic for armadillo leprosy.
Animals' suitability for inclusion in the colony will be determined by normal hematology, serology and
fecal exams, freedom from Mycobacterium sp infections, and negative for M. leprae based on antibody
titer and PCR. An assisted breeding program will be developed for captive armadillos.
PROJECT CONTACT:
Name: Klei, T. R.
Phone: 225-578-9903
Fax: 225-578-9916
Email: klei@vetmed.lsu.edu
Investigators: Bolin, S. R.; Maes, R.; Grooms, D.; Mullaney, T.; Bolin, C.; Kiupel, M.; Kaneene, J.
Performing Institution:
Pathobiology & Diagnostic Investigation
Michigan State University
East Lansing, Michigan 48824
OBJECTIVES: Objective 1: Develop methods for diagnosis of emerging and reemerging diseases of
livestock and poultry. The infectious agents targeted for research include bovine enteric calicivirus
(BECV), Michigan rabbit calicivirus (MRCV), and porcine circovirus (PCV). Objective 2.: Determine
pathogenesis, modes of transmission, and distribution of emerging diseases of livestock and poultry. The
diseases targeted for research are postweaning multisystemic wasting syndrome of swine, neonatal
diarrhea of cattle, and Michigan rabbit hepatitis/hemorrhagic disease. Objective 3: Determine effects of
sample handling on laboratory test s for diagnosis of bovine tuberculosis.
APPROACH: A) Derivation of cell lines. Primary cell lines will be derived from embryonic tissues of
several species and tested for use in virus isolation. The embryos will be obtained from pregnant animals
that are brought to the Animal Health Diagnostic Laboratory for necropsy examination. Either filtered
fecal samples known to contain BECV, or liver homogenates know to contain MRCV, will be used to
inoculate the cells. Convalescent antiserum and polymerase chain reaction (PCR) tests will be used to
detect viral replication in cells. B) Expression of viral proteins. Viral proteins produced in eukaryotic
and/or prokaryotic expression systems will be used for detection of antibody against viruses that do not
grow in cell culture. The baculovirus expression system has proven very useful for expression of foreign
proteins and will be used extensively for production of recombinant protein. C) Nucleic acid based
diagnostic tests including PCR tests and in situ hybridization will be developed for newly emerged
diseases. D) Standard procedures for determining pathogenetic mechanisms, modes of disease
transmission, and disease distribution will be applied to newly emeerged diseases such as postweaning
multisystemic wasting syndrome and Michigan rabbit viral heaptitis. E) Determine the effects of sample
handling on laboratory tests for bovine tuberculosis. The gamma interferon whole blood test for bovine
TB requires viable and functional white blood cells. Blood will be subjected to conditions that affect
viability white blood cells or function of white blood cells. Pokeweed mitogen will be used as a positive
control to assess effects of harsh conditions on white blood cell function.
PROJECT CONTACT:
Name: Bolin, S. R.
Phone: 517-432-9926
Fax: 517-353-4426
Email: bolins@ahdl.msu.edu
Performing Institution:
Population Medicine Center
Michigan State University
East Lansing, Michigan 48824
OBJECTIVES: The research will consist of three integrated projects. Project 1: Epidemiological study
of Mycobacterium bovis in wild and domestic animals - Hypothesis: The spatial distribution of TB
occurrence in wild white-tailed deer is associated with the spatial distribution of supplemental feeding,
physical landscape factors, and location-specific human activity. Specific Aims: A. Determine the spatial
90 days post-inoculation, from fecal culture and various organ tissues. Organ tissues will be evaluated
microscopically at 30, 60, and 90 days post-inoculation. Project 3: Risk analysis of bovine TB for
surveillance and control programs Risk assessment: A prospective stochastic simulation model will be
developed to estimate the risk of a dairy or beef cattle herd developing TB infection, utilizing cattle herd-
related factors, deer-related factors, and other geographic factors. Results from the risk assessment model
will be forwarded to federal and state agencies, which can use this information to improve TB
eradication programs, and extension which can disseminate this information to the public. The results
will also be used in a proposed farm-level risk management model which will interface with the risk
simulation model.
PROJECT CONTACT:
Name: Kaneene, J. B.
Phone: 517-353-5941
Fax: 517-432-0976
Email: kaneene@cvm.msu.edu
Investigator: Estes, D. M.
Performing Institution:
Veterinary Medicine
University of Missouri
Columbia, Missouri 65211
APPROACH: Our studies are designed to delineate in vivo in the SCID-bo mouse, the contribution of
helper and cytotoxic T cells and the cytokines they produce to elimination or control of replication of the
model organism, Mycobacterium bovis. Our working hypothesis to be tested in this proposal is that
resistance to or control of infection will correlate with the development of a TH1-like response (IFN- and
IL-12 produced and not IL-4 or IL-10) in vivo which will augment both macrophage
activation/microbicidal activities and intracellular killing of M. bovis by cytotoxic (either CD4 or CD8+)
cells. We propose that in the later stages of disease, IFN- is key to maintenance and enhancement of
cytotoxic T cell activity (CTL) which is required to eliminate the organism from persistently infected
cells. Second, we will focus on the transcriptional control and kinetics of expression of cytokines known
to function in this capacity in vivo in the manipulated (cell subset-depleted) or unmanipulated SCID-bo
mouse during the innate (acute disease; first 20-30 days) and acquired response (chronic disease, >30
days). We will examine organ and local cytokine mRNA expression in vivo over time for those
modulators known to serve as "early" differentiation factors for TH0 lymphocytes to potentially either
TH1 or TH2-type, specifically IL-4, IL-10, IL12-p40 and IFN- .--All studies involving cytokine
expression will be correlated with bacterial.
effector capabilities following DNA immunization under the various protocols. Thus, the first sets of
experiments we performed in the chimeric mouse model were proof of concept experiments related to the
practical limitations of obtaining sufficient numbers of cells of the appropriate specificity to generate T
cell lines or clones. We have successfully generated antigen-specific T cell lines from immunized
animals.
Investigator: Quinn, M. T.
Performing Institution:
Veterinary Molecular Biology
Montana State University
Bozeman, Montana 59717
OBJECTIVES: We hypothesize that bison neutrophils contain mobilizable proteins, which have direct
antimicrobial properties with therapeutic potential against persistent bison diseases such as tuberculosis.
To address this hypothesis, we propose the following aims: 1) Characterize biochemically and
functionally the types of antibacterial proteins present in bison neutrophils and 2) Probe for and clone
selected bison neutrophil antimicrobial proteins.
APPROACH: Objective 1 will require the collection of blood from captive bison and further isolation
and purification of neutrophils. We will then use one or more procedures to extract a subset of proteins,
which is likely to contain neutrophil antimicrobial proteins (AMPs), as determined by bacterial killing
assays. Finally, we will systematically screen the proteins we have extracted, for killing activity against
E. coli, S. aureus, and M. bovis BCG. Following completion of objective 1, we hope to have identified
one or more proteins that have interesting antimicrobial activity; we then propose to find and clone the
gene(s) for these proteins, so that they can be produced as recombinant proteins for further detailed
mechanistic and microbiological testing. One possibility is that the protein of interest is one of the bison
bactenecins, which we have already begun to characterize, and we will continue cloning these genes as
described below. If the protein does not appear to be one of the bactenecins, we will use N-terminal
sequencing to obtain sufficient code to design primers for further sequencing/cloning.
PROJECT CONTACT:
Name: Quinn, M. T.
Phone: 406-994-5721
Fax: 406-994-4303
Email: mquinn@montana.edu
Investigator: Russell, D. G.
Performing Institution:
Veterinarian Microbiology & Immunology
Cornell University
Ithaca, New York 14853
NON-TECHNICAL SUMMARY: Mycobacterial species are important pathogens in both animals and
humans. Study into the lifestyles of mycobacteria species pathogenic to animals and humans such as M.
tuberculosis, M. leprae, M. bovis and M. avium reveals extensive parallels in their mechanisms of
intracellular survival and persistence. The laboratory is devoted to the study of microbial pathogens that
exploit the macrophage as their host cell.
OBJECTIVES: The laboratory is dedicated to the study of pathogen mycobacteria. The primary area of
interests are as follows: 1. Analysis of the biology of the interaction between the macrophage and the
bacillus with respect to the intracellular environment and the regulation of host cell function. 2. The
elucidation of the metabolism of the intracellular bacillus and its exploitation as possible targets of drug
action. 3. The appreciation of the modulation of the infection foci and the role of the granuloma in the
persistence of infection.
APPROACH: Cell Biology of Intracellular Infections by Mycobacterium avium: This delicate interplay
between the bacterium, and its potentially microbicidal host cell is little understood. Previous work in the
laboratory has fostered the belief that, with respect to the interaction with macrophages and the immune
responses at site of infection, there are many parallels between pathogenic mycobacteria species,
including Mycobacterium bovis. For this reason emphasis is also placed on exploitation of genetic
approaches available for other mycobacterial species, notably M. tuberculosis and M. bovis, for the
resolution of mechanisms common to all pathogenic mycobacteria. 2. Elucidation of Intermediate
Metabolism and Carbon Source Acquisition by M. bovis and M. tuberculosis: We have extensive
experience in modelling intracellular infections by both prokaryote and eukaryote pathogens and propose
to apply this expertise to determining the contribution of the glyoxylate shunt pathway to infection. 3.
Formation and Maintenance of the Granuloma and it role in Infection by Mycobacterium spp: We have
carried out a systematic analysis of bacterial lipidoglycans released and trafficked through infected
macrophages. These comprise 7 major species of lipids some, or all, capable of inducting granulomas in
mice. The ability of these lipids to expand the influence of the bacteria beyond the infected macrophages
and induce granuloma formation suggest that they play roles key to the evolution of this response. Our
recent development of an in vivo model exploiting these lipids will enable the functional determination
of the roles of these molecules in granuloma induction.
bacterium mobilizes the glyoxylate cycle, usually associated with a dependence on fatty acids as primary
carbon source. The promoter for the gene encoding the glyoxylate cycle enzyme isocitrate lyase appears
regulated tightly by factors such as oxygen tension and carbon source. We have adopted a genetic
approach that exploits this regulation to identify environmental factors and the bacterial sensors and
effectors responsible for this shift. Finally, the tissue surrounding the infected macrophages develops into
a granuloma. This structure, the tubercle, fulfills functions for both pathogen and host. For the host the
granuloma walls off the infection and restricts spread, but for the bacterium the granuloma actually
ensures persistence of the infection. The bacterium is able to persist because the granuloma structure
ensures that the lymphocytes capable of activating the macrophages are maintained as a mantle or cuff
around the periphery of the granuloma, away from the infected macrophages in the center. Bacterial cell
wall lipids are released by intracellular bacteria and appear to play an active role in the formation and
maintenance of this structure. The biological activities of these lipids are being explored in an in vivo
granuloma model.
PROJECT CONTACT:
Name: Wood, J. R.
Phone: 607-253-3759
Fax: 607-253-3756
Email: jrw7@cornell.edu
Investigator: Russell, D. G.
Performing Institution:
Microbiology and Immunology
Cornell University
Ithaca, New York 14853
OBJECTIVES: The laboratory is dedicated to the study of pathogen mycobacteria. The primary area of
interests are as follows: 1. Analysis of the biology of the interaction between the macrophage and the
bacillus with respect to the intracellular environment and the regulation of host cell function. 2. The
elucidation of the metabolism of the intracellular bacillus and its exploitation as possible targets of drug
action. 3. The appreciation of the modulation of the infection foci and the role of the granuloma in the
persistence of infection.
APPROACH: Cell Biology of Intracellular Infections by Mycobacterium avium: This delicate interplay
between the bacterium, and its potentially microbicidal host cell is little understood. Previous work in the
laboratory has fostered the belief that, with respect to the interaction with macrophages and the immune
responses at site of infection, there are many parallels between pathogenic mycobacteria species,
including Mycobacterium bovis. For this reason emphasis is also placed on exploitation of genetic
approaches available for other mycobacterial species, notably M. tuberculosis and M. bovis, for the
resolution of mechanisms common to all pathogenic mycobacteria. 2. Elucidation of Intermediate
Metabolism and Carbon Source Acquisition by M. bovis and M. tuberculosis: We have extensive
experience in modelling intracellular infections by both prokaryote and eukaryote pathogens and propose
to apply this expertise to determining the contribution of the glyoxylate shunt pathway to infection. 3.
Formation and Maintenance of the Granuloma and it role in Infection by Mycobacterium spp: we carried
out a systematic analysis of bacterial lipidoglycans released and trafficked through infected
macrophages. These comprise 7 major species of lipids some, or all, capable of inducting granulomas in
mice. The ability of these lipids to expand the influence of the bacteria beyond the infected macrophages
and induce granuloma formation suggest that they play roles key to the evolution of this response. Our
recent development of an in vivo model exploiting these lipids will enable the functional determination
PROJECT CONTACT:
Name: Wood, J. R.
Phone: 607-253-3759
Fax: 607-253-3756
Email: jrw7@cornell.edu
Investigator: Kent, M. L.
Performing Institution:
Microbiology
Oregon State University
Corvallis, Oregon 97331
NON-TECHNICAL SUMMARY: Diseases impact both wild and captive fishes. One of these is a
bacterial disease called 'fish mycobacteriosis' or 'fish tuberculosis.' Many strains or species of
Mycobacterium occur in fish, and we will use both traditional methods and molecular biology to resolve
their identity. The project examines the taxonomy of Mycobacterium pathogenic bacteria in fishes in
Oregon This study has demonstrated that several more Mycobacterium spp. infect fishes than previously
thought. Some of these strains may be related to pathogens of humans.
OBJECTIVES: Our overall objectives are 1) to continue to resolve the taxonomy of Mycobacterium
species infecting various commercially important fishes in Oregon, focusing on a more variable region of
the rDNA gene (ITS), 2) to evaluate the virulence of selected strains using macrophage assays, and 3) to
develop PCR-based diagnostic tests using these isolates. Such tests would ultimately be employed by fish
health researchers and diagnostic laboratories in the Department of Microbiology, the College of
Veterinary Medicine, and Oregon Department of Fisheries & Wildlife. Moreover, with we will evaluate
the potential virulence of the strains in culture to mammals and fish using in vitro macrophage models.
Using human, mouse and fish cell lines we will evaluate whether strains from fish are pathogens to both
mammals and humans, fish pathogens only, or merely opportunists
APPROACH: rDNA sequences.. We will obtain rDNA sequences using both direct PCR from tissues
and PCR from isolated colonies In addition, we will continue to use our new primers for amplification of
problematic samples, especially fish tissue samples, as they amplify smaller products and thus appear to
be more sensitive for certain samples These primer sets provide SSU sequence, and to more precisely
characterize and differentiate our isolates (e.g., the closely related salmonid isolates), we will examine a
more variable region of the gene (the ITS) using published primers After the various isolates are
sequenced, we will compare sequences using BLAST Search to compare with existing strains in
GenBank. Furthermore, we will conduct phylogenetic comparisons using standard molecular systematics
programs available through PAUP, etc. Virulence. We will characterize the virulence of representative
strains obtained from our epidemiological and taxonomy studies using in vitro macrophage assays. To
evaluate the ability of the bacterium to infect and survive in macrophages, we propose to employ the
systems currently in use in Dr. Bermudez's laboratory. We plan to determine: (1) efficiency of invasion
and (2) the ability of survive and replicate inside macrophages. For those experiments we propose to use
carp macrophage cell line, the zebrafish macrophage cell line we have recently established from
zebrafish spleens, and mouse macrophage cell line RAW 246.7. We also plan to use as controls for the
experiments a human isolate of Mycobacterium avium, a fish derived Mycobacterium marinum (also a
human isolate) and a non-virulent Mycobacterium smegmatis. The strain to be tested and the controls will
be cultured and then used to infect macrophages in a ratio of 0.1 to 1, 1 to 1 and 10 to 1
(bacteria:macrophage). Invasion will be determined after 1 hour. The inoculum will be plated onto 7H11
agar plates to determine the number of bacteria. Infected macrophage monolayers will be washed several
times with buffer in order to remove extracellular bacteria and then the monolayers will be lysed by
incubating them with water for 10 min as described (Bermudez and Young 1988; Bermudez et al. 1994).
Then 0.025% SDS will be added to the suspension for 10 additional minutes to prevent clumping. The
suspension will be plate onto 7H11 plates to determine the number of viable intracellular bacteria. The
efficiency of invasion will be calculated as a percentage of the initial inoculum used to infect the
monolayers. To determine the ability of the bacteria to grow intracellularly, monolayers will be
established and infected in a similar manner as described above. The intracellular bacteria will be
allowed to grow and 4 and 7 days after infection the monolayers will be lysed and the number of
intracellular bacteria quantified as reported (Wagner et al. 2002). The bacterial growth or decrease of the
number of intracellular bacteria will be calculated as the variation of the number of bacteria inside
macrophages 1 h after infection.
the fish with the M. haemophilum-like infection showed an unusual pathological condition with
numerous mycobacteria colonies within the central nervous system not associated with inflammatory
changes. (Facility 2.) A second research facility suffered a massive outbreak of mycobacteriosis in which
the entire colony was ultimately destroyed. Using our new 16s rDNA primers and those of Talaat et al.
(1997), we also obtained 16s rDNA sequence from two zebrafish from this epizootic. This isolate cluster
within a clade was comprised of M. septicum and M. peregrinum. These species are related to M.
fortuitum, forming a clade of fast growing bacteria known to be pathogens of humans. (Facilty 3.) We
maintain a sentinel fish monitoring program at the two zebrafish facilites at the University of Oregon
Zfish Facility - i.e., exposing zebrafish to effluent water from the entire system. Although no outbreaks
have been observed, we recently detected mycobacteiosis in a few sentinel fish based on histology. We
have obtained an isolate from these fish in culture, and it will be added to our phylogenetic analyses.
(Salmon Isolates.) We obtained five isolates from salmonids from the OSU fish pathogen culture culture
at the Hatfield Marine Science Ctr . All salmonid isolates, including one from Australia were very
closely related, showing only a maximum sequence difference of 4 bp over about 850 bp of the 16S
rDNA. These isolates cluster together as a group, near M. chelonae, a recognized pathogen of fishes.
(Marine Fish Isolates.) We obtained a culture from a moribund sable fish maintained at the Hatfield
Marine Science Ctr. which was clustered with the salmonid isolates near M. chelonae. We have several
kidneys (frozen) from rockfishes with Mycobacterium infections. To date we have not been able to
culture Mycobacterium spp. from these tissues. However, direct PCR using new primers that we
designed allowed us to obtain about 850 of reliable sequence. This specimen was identical to M.
monteflorense, a recently described Mycobacterium species from moray eels from Florida. This is the
first report of the infection in another fish species and from the Pacific Ocean.
PROJECT CONTACT:
Name: Kent, M. L.
Phone: 541-737-5088
Fax: 541-737-2166
Email: Michael.Kent@orst.edu
Investigator: Kent, M. L.
Performing Institution:
Microbiology
Oregon State University
Corvallis, Oregon 97331
APPROACH: 1.Diseases of importance in these fishes will be determined by complete necropsy and
subsequent laboratory analyses, including pathology, bacteriology, and virology. Conducting in vivo
transmission studies will elucidate the pathogenesis of various pathogens. 2.Molecular systematic
approaches will lead studies on identifications and phylogenetic relationships of the pathogens in study.
In addition, traditional morphology and culture characteristics will be included. 3.For bacteria and
parasites, will focus on using ribosomal DNA sequences for the development of sensitive and specific
PCR based tests.
PROJECT CONTACT:
Name: Kent, M. L.
Phone: 541-737-8652
Fax: 541-737-2166
Email: michael.kent@oregonstate.edu
Performing Institution:
Veterinary Pathobiology
Texas A&M University
College Station, Texas 77843
NON-TECHNICAL SUMMARY: Tuberculosis in cattle and wildlife causes economic and public
health concerns. The purpose of this project is to: 1.) Develop new diagnostic tests; 2.) Develop
candidate tuberculosis vaccines for cattle and deer; 3.) Develop fundamental understanding of cattle and
deer tuberculosis disease processes; and 4.) Produce cattle and deer genetically resistant to tuberculosis.
OBJECTIVES: 1. Develop new diagnostic tests. 2. Develop candidate tuberculosis vaccines for cattle
and deer. 3. Develop fundamental understanding of cattle and deer tuberculosis disease processes. 4.
Produce cattle and deer genetically resistant to tuberculosis. 5. Assess impacts of optimally implement
new technologies for control of tuberculosis.
APPROACH: 1. Develop rapid and sensitive tests that permit multiple testing of the same animal and
do not require repeated handling, including: PCR based tests for M. bovis specific DNA; cytokine
profiles; and restriction fragment length polymorphism (RFLP) analysis of M. bovis DNA. 2. Develop a
marker deletion vaccine with companion diagnostic for a specific antigen which is normally produced by
the wild-type disease agent but is deleted from the vaccine strain, thus the diagnostic test recognizes only
animals infected with wild-type field strains of M. bovis but not marker-deletion TB vaccinated animals.
3. Define the host-pathogen relationships that are critical to infection and development of disease
following exposure of livestock to M. bovis. 4. Define major new host genes encoding factors important
in the disease pathogenesis of tuberculosis infection vs. disease in these farmed species. 5. Predict the
epidemiologic and economic impact and application of existing and potential strategies for eradication of
TB from animals.
differential expression of eight clones was confirmed by reverse Northen blot and ribonuclease
protection assays. Most of the genes identified were associated with an overexpression pattern after
infection. Differential gene expression was observed at all the time points studied (0, 12, 24h), however
the majority of the changes in gene expression occurred at the early stages post-infection. A GenBank
sequence database search identified the differentially expressed genes as the putative bovine homologues
of serum amyloid A protein (SAAP), legumain, signaling lymphocytic activation molecule (SLAM),
alveolar macrophage-derived chemotactic factor II, ferritin heavy-chain and osteopontin. Results from
this study reveal that M. bovis modulates the gene expression of bovine macrophages shortly after
infection.
PROJECT CONTACT:
Name: Adams, L. G.
Phone: 979-845-9816
Fax: 979-862-1088
Email: gadams@cvm.tamu.edu
Performing Institution:
OBJECTIVES: This study has 5 specific objectives: 1) Determine progressive hematologic changes
associated with MAS infection by analyzing blood collected at set intervals post infection. 2) Determine
any change (either activation or suppression) in macrophage function because of bacterial infection
(macrophages play a crucial role in defense from bacterial pathogens). 3) Determine the pathophysiology
(uptake, dissemination and tissue damage) of Aeromonas hydrophila in the tissues by histopathological
evaluation. 4) Correlate the pathophysiology with changes in blood analytes, 5) Establish which blood
changes, if any, are characteristic of MAS infection allowing diagnosis of diseased individuals and
populations. Developing a tool for the early detection of bacterial diseases would decrease the incidence
and economic loss from disease in production hybrid striped bass and would result in greater numbers of
fish reaching marketable size. Additionally the results of this study will assist in the diagnosis of
infectious disorders in other species of fish.
APPROACH: Hybrid striped bass will be housed in 1000 gal recirculating system in a separate building
from the bacteria exposed fish to prevent accidental infection of stock fish. Isolates of A. hydrophila will
be obtained from the National Fish Health Research Laboratory and cultured with non-selective media.
Three experimental groups of fish will be used based on route of exposure: water borne, intramuscular
(IM) and saline injected controls. For the water borne challenge, bacterial suspensions will be added to
the water, fish will be exposed for 30 min to the bacteria and then bacteria flushed out of the system. For
the IM injections, fish will be sedated with MS-222 (150 mg/L) and injected IM with bacteria. The saline
injected group will be handled similar to IM infected fish. A total of 72 fish will be used in each
treatment group with18 fish placed in four replicate tanks. Fish will be acclimated to the experimental
tanks for 3 weeks prior to initiating the experiment. Blood and tissue samples will be collected at 7
equally spaced time intervals following bacterial exposure and analyzed for hematological and blood
biochemical parameters, macrophage activity and tissue histopathology. Fish will be rapidly netted and
placed in aerated, buffered MS-222 anesthetic. When anesthetized, fish will be bled from the caudal
vessels. Sampled fish will not be returned to the tanks to prevent repeat sampling of fish. For
hematologic analysis, blood will be placed into individual EDTA blood tubes held on ice and analyzed
for: packed cell volume, plasma protein, total red and white cell counts, differential white cell counts,
hemoglobin and red cell indices (mean cell volume, mean cell hemoglobin, and mean cell hemoglobin
concentration). For biochemical analysis, blood will be placed into individual heparinized tubes held on
ice. The tubes will be centrifuged immediately and the plasma removed to analyze the following with an
automated chemistry analyzer: total protein, albumin, globulin, creatinine, total bilirubin, alkaline
phosphatase, aspartate aminotransferase, glucose, cholesterol, sodium, chloride, potassium, calcium,
magnesium, and phosphorus. Hematologic reference intervals will be determined for the stock group of
fish and will be used as the standard of comparison for any changes in blood values due to the bacterial
infections. Macrophages will be isolated from the spleen and pronephros of control and exposed fish at
the 7 sampling times. Flow cytometry will be used to determine macrophage function and activation by
monitoring chemiluminescence and phagocytic activity. Additionally, tissue samples will be collected
and fixed in 10% neutral buffered formalin, paraffin embedded, sectioned, and stained with hematoxylin
and eosin and Gram stain. Tissue sections will be analyzed for the presence of bacteria and pathological
changes associated with the bacterial infection. The general linear model function of SAS System will be
used to perform analysis of variance to test for treatment effects, time effects and treatment time
interactions. Correlation will be used to associate tissue pathology with hematologic changes.
PROJECT CONTACT:
Name: Schurig, G. G.
Phone: 540-231-4992
Fax: 540-231-5815
Performing Institution:
College of Veterinary Medicine
Virginia Polytechnic Institute
Blacksburg, Virginia 24061
OBJECTIVES: The goal of this project is to create a safe, effective vaccine for piscine mycobacteriosis,
an important chronic, progressive bacterial disease of fish causing systemic granulomas in virtually any
tissue and often leading to death of the fish. Using an established vaccine vector and protocol proven
successful for a commercial brucellosis vaccine (RB51), a mycobacterial vaccine will be constructed for
an aquatic strain of Mycobacterium marinum. Striped bass, an economically-important cultured food fish
species shown to be highly susceptible to mycobacteriosis, will be immunized with the vaccine and both
humoral and cell-mediated immunity will be monitored post-exposure. After determining the optimum
concentration and route of administration necessary to generate an immune response in the fish, the
effectiveness of the mycobacterial vaccine will be tested with a live bacterial challenge of immunized
and non-immunized fish. Ultimately, a safe, effective mycobacterial vaccine would decrease the
aquaculture industry's dependence on antibiotics, improve the overall immunocompetence and health of
the fish, and decrease financial losses due to this fish disease.
APPROACH: A vaccine for fish mycobacteriosis will be constructed using the M. marinum 85A
protective antigen and strain RB51 of B. abortus overexpressing the Cu/Zn superoxide dismutase (SOD)
antigen. The recombinant strain will be obtained by transforming strain RB51 with a pBBR1MCS-based
plasmid containing the genes for SOD (sodC) and the 85A antigen (fbpA). The basis for the selection of
the 85A antigen is threefold: 1) the 85A antigen is one of the major secreted fibronectin binding proteins
of all mycobacterial species including M. bovis and M. marinum, 2) the 85A antigen induces an effective
protection against infection in other mycobacterial species, and 3) the 85A antigen shows high homology
with various mycobacterial species suggesting that the antigen may be cross-protective against other
mycobacterial species. Expression of sodC will be driven by its own promoter while that of fbpA will be
driven by the groE heat shock promoter of Brucella. The fbpA from M. marinum will be obtained by
amplification via PCR from the genomic DNA. Overexpression of SOD and expression of the 85A
antigen in the recombinant RB51 strain will be confirmed by Western blot analysis. The recombinant
strain will be subjected to heat-shock by incubating the cultures for 30 minutes at 42 degrees C to up-
regulate the production of the mycobacterial protein. After treatment, the bacteria will be washed in PBS,
resuspended to obtain approximately 1011 colony forming units (CFU) per ml, and frozen at -80 degrees
C. When the fish are ready for immunization, the bacteria will be subjected to 300 krad of radiation
which renders the bacteria completely inactivated without any effect on its adjuvant and antigenic
properties. Thus, the mycobacterial recombinant vaccine will be rendered completely non-infectious
without changing its immunomodulatory effects. Two routes of immunization, intraperitoneal injection
(IP) and water immersion (WI) will be tested. Juvenile striped bass will be divided into 5 groups/route of
140 fish each and individually identified. One group for each route will be sham-immunized with sterile
saline, while the other four groups will receive concentrations of x10E8, x10E9, x10E10, and x10E11.
On Days 0, 14, 28, and 42, fish will be bled and the serum analyzed by indirect ELISA for humoral
antibodies to the RB51 strain of B. abortus and the M. marinum 85A antigen. The cell-mediated response
will be evaluated by a lymphoproliferative assay where splenocytes will be harvested on Days 28, 42, 90,
and 120 and cultured in 96-well plates in the presence of M. marinum 85A antigen, B. abortus RB51
crude extract, concanavalin A (positive control), or no additives (negative control). The cells will be
cultured for 3-5 days and then pulsed with 1 micron Ci of [3H] thymidine/well for 18 hours, harvested,
and placed in a liquid scintillation counter to evaluate [3H] thymidine incorporation. On Days 42, 90, and
120, fish from each group will also be challenged with M. marinum. Tissue samples of fish from this
study will be routinely processed, stained with hematoxylin and eosin (H & E) and Zeihl-Neelson stain,
and examined by microscopy for granulomas or other pathology.
control), or no additives (negative control). The cells were cultured for 3-5 days and then pulsed with
1uCi of [3H] thymidine/well for 18 hours, harvested, and placed in a liquid scintillation counter to
evaluate [3H] thymidine incorporation. On Days 42, 90, and 120, fish from each group were challenged
with M. marinum. Tissue samples of fish from this study will be routinely processed, stained with
hematoxylin and eosin (H & E) and Zeihl-Neelson stain, and examined by microscopy for the presence
of granulomas or other pathology. To date, hybrid striped bass have been immunized with the DNA
vaccine and their humoral and cell-mediated immune responses have been documented. These responses
appear to be dose-dependant, with higher vaccine doses eliciting stronger immune responses. Preliminary
histopathology results suggest that the vaccine may have some protective effects against live bacterial
challenge.
PROJECT CONTACT:
Name: Schurig, G. G.
Phone: 540-231-4992
Fax: 540-231-5815
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JULY 2003
CONTENTS.
PAGE
Contents 2
Chairmans 3
Introduction
Recommendations 6
Badger Vaccines 8
Cattle Vaccines 13
References 16
Appendix 1 Epidemiological investigations into bovine TB the 17
potential for the use of vaccines in cattle and wildlife.
Appendix 2 Badger vaccination: ecological and epidemiological 23
considerations
Appendix 3 BCG vaccination of wildlife 29
Appendix 4 BCG in wild-life and domestic livestock; virulence and 39
efficacy
Appendix 5 Protocols for the development and evaluation of BCG 45
vaccination against M.bovis infection in badgers
Appendix 6 Vaccines for the control of bovine tuberculosis: 48
commercial product development and regulatory
approval
Appendix 7 Issues relating to the procurement of badgers for 53
vaccine research
Appendix 8 Feasibility & costs for providing accommodation for 58
badgers
Appendix 9 Immunological assays to support the development and 62
evaluation of a vaccine against badger tuberculosis
Appendix 10 Requirements of a field trial to test BCG in badgers 69
Appendix 11 Vaccination of badgers against bovine TB ecological 72
considerations
Appendix 12 Vaccination of cattle with BCG to protect against 82
M.bovis
Appendix 13 Chairmans discussion paper on format of final report 101
Appendix 14 Vaccination of cattle against TB 106
Appendix 15 Terms of Reference & Committee Members 108
2
1. CHAIRMANS INTRODUCTION.
1.4 From an operational perspective the field use of a cattle vaccine should
present few problems since there is direct access to the target species and
the vaccine could be given directly to each individual animal by injection.
However there are difficult scientific questions that need to be considered as
well as policy issues before use of a vaccine in the field could be
contemplated; it is worthy of note that all other countries with an intransigent
cattle TB problem have rejected the option of using currently available cattle
vaccines (in effect, only BCG is available) on the grounds of its relatively poor
efficacy and that its use would limit the ability to export breeding cattle.
1.5 We recognise that the demands of an ideal cattle vaccine are particularly
severe since the vaccine would need to prevent the establishment of
3
persistent infection and eliminate transmission. Such ideal demands will be
difficult to meet and it may be that the best that can realistically be achieved is
a reduction in pathology and transmission. Under current testing regimes, a
vaccine should also not give a positive reading in the tuberculin skin test since
this would confuse the regular herd testing procedures and create serious
regulatory problems. Although it may be possible to develop a diagnostic test
that distinguishes between vaccinated and infected animals, the more
important issue is whether vaccinated animals, even if fully protected, may
respond positively in a diagnostic test following challenge with M. bovis. This
is particularly relevant, given the likelihood that a wildlife reservoir of TB
infection will persist in the environment. The development of a diagnostic test
that meets these requirements may prove difficult.
1.6 Currently we do not feel that a suitable candidate vaccine is available for
use in cattle. Nevertheless, we believe that the option to use a cattle vaccine
in the future should be retained, and ongoing research to develop candidate
vaccines should continue to be supported. We recognise that adoption of
vaccination would require not only more effective vaccines but also the
development of improved diagnostic tests.
1.7 We have considered the potential future use of new improved vaccines in
cattle either in conjunction with a new diagnostic test or on their own in the
absence of herd testing. We accept that such vaccine strategies, applied
either nationally or zonally, would require a significant change to TB disease
control policy. Dispensing with herd testing would place greater demands on
other measures for protection of public health and could require tightening of
regulations concerning the sale of non-pasteurised milk products and carcass
inspection in slaughterhouses. The anticipated increasingly stringent EU rules
on visible lesioned carcasses would place even greater demands on a
vaccine in order to avoid wasteful carcass condemnation.
1.8 The primary goal of a badger vaccine would be to reduce the rate of
transmission of TB to cattle rather than to protect each individual badger.
Because of this, vaccination of wildlife would require a less demanding
vaccine than vaccination of cattle. Nevertheless, there are significant
scientific hurdles that have to be considered and overcome, even to get to the
point of conducting a field trial. Such a vaccine of course would only be
effective if most cattle TB infection derived from badgers, a point that is
currently being investigated in the Randomised Badger Culling Trial (RBCT).
4
in terms of developing an oral vaccine which stimulates an effective immune
response and its effective delivery.
1.10 One of the problems in developing a vaccine strategy for badgers is the
limited knowledge of the epidemiology and dynamics of TB in badgers. Some
new epidemiological data will be forthcoming from the ongoing RBCT and
other related research, which will indicate how vaccines in the field may best
be utilised. There are still important issues to resolve and at the moment any
attempt to model the disease, so as to provide better information on the
design of potential vaccine strategies and to predict their likely outcome, has
serious limitations.
1.11 The report and its appendices consider these issues, highlight the
questions that the Sub-Committee has needed to address and illustrate the
complexity of adopting vaccination-based TB control policies for either cattle
or wildlife. The option of the use of vaccines should in our view be retained.
Most of the necessary research has been commissioned, is in place and very
effectively linked to an International TB vaccine development programme
involving both veterinary and medical research workers. However, we have
identified areas of research that we believe are necessary to ensure that
progress towards taking a vaccine into the field is optimised. It is,
nonetheless, clear that there is no quick fix or short cut that can be taken to
speedily put in place a vaccine control policy option. In the short, or even
longer term, alternative control options will need to be adopted in order to
achieve better control of the disease in cattle.
1.12 I wish to thank members of the Sub-Committee and its Secretariat, for
their hard work and diligence in carrying out their task. I am particularly
grateful to the authors of papers that appear in the report. I hope that the
report is clear and comprehensive and that it has realistically considered and
presented the vaccine option.
1.13 Finally it is with great sadness that we learned of the premature and
sudden death of Dr Jo Colston. Jo was a close friend to many of us. Not only
was he a valued and extremely active member of the Sub-Committee but he
also played a significant and important part in supporting the work of the ISG
in other areas of its activity and had provided sound scientific advice to Defra,
particularly on its vaccine research programme.
John Bourne
July 2003
5
2. RECOMMENDATIONS.
2.1 Badgers.
2.1.1 BCG may be of value to protect badgers but before a field trial of BCG
can be put in place it is essential to await the outcome of vaccine protection
studies that are currently being carried out on a population of housed wild
badgers in the Republic of Ireland (RoI). We advise that even if a degree of
protection is shown in these studies that success in the field cannot be
guaranteed and that a field trial would inevitably have to be put in place and
designed on a large scale and continue for an extended time period, in order
to demonstrate its effect on the incidence of TB in cattle.
2.1.2 It will also be necessary to await the outcome of the RBCT in order to
obtain essential epidemiological data on TB in the badger and the impact of
badger culling on cattle TB before deciding on whether or not to proceed with
a field trial.
2.1.3 A field vaccine for badgers will need to be delivered as an oral bait.
Priority needs to be given to development of oral/respiratory delivery systems
that are effective in stimulating protective immune responses without capture
of badgers.
2.2 Cattle.
2.2.1 BCG is the only currently available vaccine candidate that could be
considered for practical use. Experimental challenge of vaccinated cattle has
demonstrated very variable protection of up to 70%, as judged by reduction in
pathology, but lower levels of protection against establishment of infection.
Field trials have generally provided poor protection. It is our view that BCG in
its present form would not provide an effective cattle vaccine and that cattle
vaccination could only be considered when an improved vaccine is available.
2.2.3 We also recommend studies on the oral sensitisation of cattle with BCG
and on the effect of vaccinating already infected animals particularly with
respect to lesion development.
6
2.2.4 We recommend that greater priority be given to developing improved
diagnostic tests for both cattle and badgers.
2.3 Other.
7
3. BADGER VACCINES.
3.1 Introduction.
3.2.1.2 The extent of the badger population to be covered and the optimal
area of coverage required to have a measurable impact on the disease in
cattle.
3.2.1.3 The route of delivery of the vaccine would need to be easy and
inexpensive, and while providing the maximum possible take-up rate in
badgers, it should avoid immunisation of non-target species and particularly
cattle.
8
3.2.1.4 How would a badger vaccine be used in the field? What are the
frequency and duration of vaccine application that would be required. What
proportion of badgers would eat the bait? What is the duration of immunity?
3.2.4 Considering the current situation regarding vaccine candidates, the only
vaccine which is currently available and which is likely to be available within
the medium term is the human vaccine, BCG (Bacille Calmette-Guerin). BCG
was developed during the early part of the 20th Century. It was derived from a
strain of virulent Mycobacterium bovis which became attenuated following
prolonged passage in laboratory culture medium. BCG was introduced as a
human vaccine on a large scale during the second half of the 20th Century and
is currently one of the most extensively used vaccines available (Appendices
3 and 4).
3.2.5 Unfortunately, it has now become evident that the efficacy of BCG
against the major form of TB in humans is extremely variable, ranging from
0% to approximately 80% in different trials. The basis for this variability is not
fully understood. BCG has been tested in experimental conditions in a wide
variety of animal species, both for efficacy against TB and for possible
virulence (Appendices 3 and 4). This extensive testing of BCG in a wide
variety of mammalian species has failed to reveal any substantive evidence
9
that the organism can cause disease (Appendix 3). At the same time, most
species which have been used in experimental efficacy studies have been
found to exhibit some level of protection against challenge with virulent M.
tuberculosis or M. bovis.
3.2.6 The most relevant information on the potential of BCG to protect wildlife
against M. bovis infection, and interrupt transmission to cattle comes from
work carried out (Appendix 5) in New Zealand (NZ). In NZ the Brushtail
possum is a major wildlife reservoir for M. bovis infection. In preliminary
experimental studies, BCG administered to Brushtail possums by a variety of
routes, including orally, gave low level protection against experimental
infection with M. bovis. Subsequently a field study was carried out in which
vaccinated and unvaccinated control possums were released into a study
area and the amount of TB in the possum population was monitored for 2
years. The results, which because of inadequate experimental design are
difficult to interpret, confirmed that BCG gave some protection to possums
against M. bovis infection in this field situation although the effects on cattle
TB could not be measured. Thus, these limited studies are the only grounds
for considering trialing BCG for protection against TB in badgers. However,
even with evidence of significant protection in badgers, it would be difficult to
predict how this translates to protection of cattle. Therefore, it would be
critical to design a trial to measure the impact of badger vaccination on TB in
cattle.
3.3.1 Given that there is some available evidence to suggest that BCG might
have a rle in the vaccination of badgers, the Sub-Committee felt it would be
useful to document the steps required in developing a field trial protocol. In
many ways this represents a best case scenario. Given the widespread use
of BCG in the human population and the considerable background information
on its safety in many species and optimal modes of administration, gaining
approval to implement a field trial is likely to be considerably more
straightforward than would be the case for a completely novel vaccine.
3.3.2.1 The fact that BCG has been so widely used in man, and has been
extensively studied for efficacy and toxicity in a large number of wildlife and
domestic species, means that many of the steps involved in authorising its
use in field trials will be considerably less demanding than would be the case
for a completely novel vaccine formulation. The probable steps required for
authorisation have been set out (Appendix 6).
3.3.2.2 As part of the regulatory requirements for the use of BCG as a wildlife
vaccine, it would be necessary to demonstrate safety and efficacy against the
target species under laboratory conditions (see below); this would mean
obtaining uninfected badgers from the wild for experimental purposes. The
legal aspects of the Badger Act on the procurement of badgers for research
purposes (see below) have been described (Appendix 7). It would also be
10
necessary to demonstrate safety in a number of non-target species that might
be exposed to the vaccine. Evidence of safety could include information from
previously published studies. In addition to the requirements under the Home
Offices Animals (Scientific Procedures) Act of 1986, there may also be issues
related to the procurement of protected species for these purposes.
3.3.3.3 Considering the delivery of BCG to badgers, the only practical means
of delivering a vaccine to badgers on a wide scale, is by the oral route.
Methods that combine oral and aerosol delivery are in development. In
general much larger doses are required for immunisation by the oral route as
opposed to delivery by injection. Although initial experimental work on the
effects of immunisation with BCG is likely to involve delivery by injection to
provide proof of principle, considerable research will be required to determine
the optimal procedures for oral immunisation. A limitation of both oral and
parenteral vaccine strategies is the difficulty of vaccinating pre-emerging cubs
below ground and preventing early transmission of infection from adults in the
same sett (pseudo-vertical transmission).
11
distribution of TB in badgers and also to develop a range of vaccination
strategies. For example it has been suggested that a potential vaccination
strategy for TB in badgers would be to target vaccination around infected
badger social groups, communities or local populations, coupled to the
coincidental culling of infected animals. Such a strategy would require a
highly sensitive, cage-side diagnostic test which could be performed on living
badgers; if applied along with vaccination on more than one occasion, the test
would also need to distinguish between vaccinated and infected animals.
However, even if this strategy was practical, it would need to be applied over
a large number of local sites to have a significant impact on TB in cattle and
thus would be extremely costly. Nevertheless, an improved diagnostic test
that distinguished infected from vaccinated animals would also be of value for
larger-scale vaccination programmes using baited vaccines, by allowing the
effect of vaccination to be monitored in samples of vaccinated animals
(Appendix 9).
3.5.1 In addition to the work described above, the ability to carry out an
effective vaccine trial in badgers will depend on a number of additional areas
of research support. These include:
12
BCG to wildlife in the form of an oral bait. It would be necessary, prior to a
trial, to carry out experimental studies of immune responses induced following
oral vaccination, in order to identify responses that can be used as markers to
evaluate vaccine take (i.e., that the vaccine has successfully induced an
immune response similar to that seen under experimental conditions) in
samples of vaccinated badgers (Appendix 9).
3.6.1 The cost and staff resource required to carry out the scientific studies
prior to the field trial, the field trial itself, and the necessary support work is
likely to be high. An estimate of costs of surveying for badger setts and bait
application can be made from costs of the RBCT. An estimate of the cost of
vaccination and the potential financial benefits that could result from
vaccination should be possible when the method and frequency of vaccine
administration are better defined. However, an accurate cost/benefit analysis
could only be carried out after a field trial was completed.
4. CATTLE VACCINES.
4.1 Introduction.
13
transmission from infected to uninfected animals but also prevent the
establishment of persistent infection. None of the vaccines that have been
tested so far for effectiveness against bovine TB, are efficient at preventing
persistent infection. Of greater concern for the use of cattle vaccination is the
likelihood that a wildlife reservoir of TB infection will persist in the environment
and vaccinated cattle, even if fully protected, might respond immunologically
when exposed to natural infection from this wildlife source. These animals
might react positively to the skin test, or any other immunological test that
might be used for diagnosis, and so with current control policy trigger a herd
breakdown.
4.2.1 As discussed above, the only vaccine that is likely to be available for
use in the field over the next few years is BCG. Although vaccination of cattle
with BCG has been shown to reduce the severity of pathology following
challenge with virulent M. bovis, a significant proportion of the vaccinated
animals continue to harbour viable bacteria and have visible pathological
lesions (Appendix 12). Moreover, animals vaccinated with BCG give a
positive reaction in the tuberculin skin test, and hence cannot be distinguished
from infected animals. Thus, current research activities aimed at generating
novel candidate vaccines should be continued, but in the short term
vaccination of cattle does not present a viable option.
14
Defra, is currently being devoted to the development of TB-specific interferon-
gamma (IFN-) assays incorporating defined M. bovis antigens. As with the
skin test, the IFN- assay measures the immunological response to M. bovis;
however using state-of-the-art genomic analysis it has been possible to
identify antigens which are present in M. bovis but absent in environmental
mycobacteria and also absent in BCG. Thus, such an assay is likely to be
more specific in defining TB infection than the existing skin test. In the short
term, it is envisaged that such assays could be used in conjunction with the
skin test to improve the efficiency of herd testing. It is likely that an IFN-
assay with similar or superior sensitivity to that of the skin test will be
developed over the next few years. If sensitivity can be achieved along with a
high level of specificity, serious consideration should be given to replacing the
skin test with the IFN- assay as the primary diagnostic assay for herd testing.
Such a laboratory-based assay would allow improved standardisation of TB
testing and require only one farm visit per test (as compared to two at
present).
15
efficacy under experimental conditions. The logistics of undertaking a field trial
are also more straightforward than for badgers, in that large numbers of
animals can be vaccinated rapidly and the impact of vaccination on the
incidence of disease can be measured directly. However, in the case of a
vaccine applied along with a new diagnostic test, information on the
performance of the diagnostic test under field conditions would be required
before proceeding with a vaccine trial. Trials of vaccines intended for use in
the absence of herd testing would need to incorporate close monitoring of
animals destined for slaughter.
5. REFERENCES.
16
APPENDIX 1.
John Bourne
1. INTRODUCTION.
1.1 The ISG in co-operation with Defra has put in place a range of studies to
gain more information on the epidemiology of TB in both cattle and wildlife
since it is our view that only through this knowledge can sustainable control
policies be developed.
1.2 Full details of the scientific approach taken and the research now in
place, which includes vaccine research, can be found in the Groups reports to
Ministers (2000, 2001).
1.3 The use of vaccines in either cattle or badgers remains a potential policy
option, although we regard this option as offering prospects only in a long
term context and also caution that success cannot be guaranteed. The
demands of an acceptable cattle vaccine are particularly severe since it would
need both to prevent the establishment of persistent infection and to eliminate
transmission. Additionally, it should not give a positive reading in the
tuberculin skin test since this would confuse the regular herd testing
procedure and create serious regulatory problems. However, an additional
concern about the use of cattle vaccination in Great Britain relates to the
strong likelihood that a wildlife reservoir of TB infection will persist in the
countryside environment, and exposure of cattle protected by a successful
vaccine to this source of infection would result in immunological responses
which may compromise the skin test.
1.4 Any diagnostic test based upon detecting an immune response would
need therefore to distinguish immune responses generated following infection
from those elicited following challenge of a protected vaccinated animal. This
would be difficult to achieve. In addition, to being highly sensitive such a test
would have to have a high level of specificity for it to be acceptable, since
false positive reactions would trigger a herd breakdown control response.
17
1.6 By contrast with the cattle situation, vaccination of wildlife would require a
less demanding vaccine since, although widespread coverage would be the
target, protection of each individual animal would not be essential. The
primary rle of a wildlife vaccine would be to reduce the severity of disease in
the target species and the consequent rate of transmission to cattle.
However, a wildlife vaccine would only be effective in controlling TB in cattle if
most cattle TB infections derived from wildlife, a point that at present is in
doubt.
1.9 While there is strong pressure from some groups for successful
vaccination of cattle or badgers to be considered as the preferred strategy
there are many difficult issues to be addressed if this policy is to be pursued.
1.10 The purpose of the present exercise is to consider these issues and to
assist the ISG in further advising Ministers on the requirements for pursuing
the vaccination strategy.
1.11 There are two issues to consider, namely a badger vaccine and a cattle
vaccine.
2. BADGER VACCINE.
2.1 We must consider the factors that could influence the impact of
vaccination and these are listed below.
18
2.1.3 The pattern of disease in badger populations, including prevalence,
clustering, the rle of super-excretors, the proportion of badger populations
that can be vaccinated or need to be vaccinated and cycles of infection.
19
2.3.3.3 Previous exposure to M. bovis or environmental mycobacteria should
be considered.
2.5 Field trial validation must be investigated. How are protective effects of
vaccination on disease in badgers and cattle measured?
2.5.1 Current live tests to diagnose TB in the badger or other wildlife have low
sensitivity; if sensitive tests were available, a large scale trial would be
required to evaluate the impact on badger TB (is there dependence on
prevalence?).
3. CATTLE VACCINE.
20
3.3.2 Experimental challenge models should be established.
4.1 Safety.
21
4.2.4 VMD and industry input must be considered.
4.4.7 Do we need to wait for culling Trial data / results before advising on the
commitment of significant expenditure?
4.4.8 The public perception of food products from vaccinated cattle must be
considered.
22
APPENDIX 2.
23
below one, and the pathogen will die out. The higher R0, the greater the
proportion of hosts that must be vaccinated to achieve eradication. Estimation
of R0 is therefore vital to determine the proportion of hosts that must be kept
immune through vaccination in order to achieve eradication.
2.3.1 The only vaccine currently available BCG has not been shown to
confer immunity to experimental challenge with M. bovis. Twelve badgers
vaccinated with BCG in captivity showed immune responses to vaccination
(Stuart et al., 1988). However, when seven of these were subsequently
challenged by intradermal injection of M. bovis they did become infected
(though they lived longer, and shed fewer bacteria), than did three
unvaccinated controls (Stuart et al., 1988), although it is not clear to what
extent experimental intradermal infection mimics natural exposure. It is
possible that reduced bacterial excretion by infected but vaccinated badgers
could reduce transmission and help to control the disease; however, in the
absence of any data on TB transmission routes among badgers, and on how
bacterial excretion influences infectiousness, it is impossible to make
quantitative predictions.
24
it would be virtually impossible to vaccinate prior to exposure. Hughes et al.
(1996) suggest that cubs might be vaccinated through regurgitation of baits by
their mothers, but, since regurgitation has been recorded only very rarely, this
possibility remains speculative. Pre-exposure vaccination might become
possible several years into a vaccination campaign, if transmission rates could
be reduced such that animals were first exposed at a later age; however it is
not possible to predict whether or when this might be possible.
2.3.4 While driving the average number of new hosts infected per case below
one will eradicate infection eventually (in the absence of reinfection from
outside sources), the process may be slow in a disease with a long infectious
period. Given the longevity of badgers, the time course of eradication might be
guesstimated to take more than a decade, and possibly longer.
2.3.5 Badgers are not the only species that becomes infected with TB. If
badgers are the only major reservoir host for TB, then eradication of TB from
badger populations could be expected to lead to disappearance of the
infection from other wildlife species (as well as from cattle), just as rinderpest
disappeared from African ungulate populations when it was eradicated from
cattle (Plowright, 1982). Vaccination cover might be suspended at that point.
However, badgers rle in maintaining TB infection in multi-host systems is
currently unknown; thus it would probably be necessary to maintain
vaccination coverage in the long term to avoid re-infection from other wildlife
hosts, or from cattle.
3.1.2 Data are not currently available to determine how TB risk to cattle
reflects bacterial shedding by badgers (or even TB prevalence in badgers).
Hence it is currently impossible to know what level of shedding might be
deemed sufficient to reduce cattle exposure.
4.1 The points raised above suggest that, at present, there can be little short-
term expectation of successfully controlling cattle TB by vaccinating badgers,
irrespective of the aim of the vaccination programme. Several other concerns
about these approaches also deserve attention.
25
4.1.1 What proportion of cattle TB cases originate in badgers? At present,
the proportion of cattle TB cases originating in badgers is unknown. Hence, it
is impossible to predict what proportion of cases might be prevented by
vaccination. General models suggest that vaccination is likely to control
infection more slowly and less effectively than culling (Barlow, 1996) although
this would depend upon the completeness and effectiveness of vaccination
compared with that of culling. Hence, as a first approximation, one might
expect vaccination to be less effective than culling, unless the social
disruption caused by culling greatly increases transmission rates (Swinton et
al., 1997). Results of the RBCT and associated research on social disruption,
should therefore help to provide a more informed picture of the possible
impacts of badger vaccination on cattle TB, and thus permit a closer
approximation of the potential cost-effectiveness of this approach.
4.1.2 How can the effects of vaccination be measured? Given the paucity of
data on TB transmission between badgers and to cattle, and the consequent
difficulties of building predictive models, at present not even the vaguest
estimate of the effectiveness of badger vaccination could be achieved without
a field trial. However, since general models suggest that vaccination is likely
to control infection more slowly and less effectively than culling (Barlow,
1996), a vaccination trial would need to be of comparable scale, and probably
greater duration, than the ongoing RBCT. Such a trial would require a very
substantial investment of time and funding, with (in contrast to culling) not
even anecdotal evidence to suggest a likely effect. Such an investment might
be better delayed until ongoing studies provide better guesstimates of the
possible effectiveness of badger vaccination in influencing cattle TB.
4.1.3 Safety concerns. Several delivery methods have been considered for
badger vaccines (Appendix 11). However, remote delivery using oral baits
or a combination of intranasal aerosol and conjunctival installation as used in
possums (Appendix 3) is favoured, given the costs, difficulties, and variable
effectiveness of capturing badgers (Hughes et al., 1996). Such remote
delivery methods have the potential to expose other wildlife and of perhaps
greater concern cattle to TB vaccine. Cattle vaccinated by accident in this
way could be expected to react to the tuberculin test; hence badger
vaccination has the potential to generate spurious and bogus breakdowns
that could be extremely costly. The risks of such events need to be assessed
carefully, since poorly designed or poorly implemented delivery systems could
have the potential to make the situation worse rather than better.
5.1 The points discussed above indicate great uncertainty about the potential
benefits of vaccinating badgers against TB. Using available data, it is
currently impossible to predict, even in the vaguest way, whether vaccination
might be expected to prove beneficial, ineffective, or damaging. While
vaccination could reduce cattle exposure to M. bovis, poorly designed or laxly
implemented delivery methods have the potential through accidental
vaccination of cattle to cause as many TB incidents in cattle as they prevent.
26
One firm conclusion can be drawn: vaccinating badgers is not a quick fix that
could be implemented outside the RBCT with any expectation of effectiveness
in the short or medium term.
5.2 These discussions highlight the fact that many of the concerns about the
potential effectiveness of badger vaccination stem from lack of data on the
transmission of TB among badgers, and between badgers and cattle. Some
of the necessary data will be provided by the ongoing RBCT and associated
research. Hence, the outcome of the trial might inform expectations of the
potential success of any vaccination programme and the extent to which
vaccinating badgers might potentially influence cattle TB. In addition, the trial
will provide much-needed data on TB epidemiology in badger populations that
would help in the design of vaccination programmes. However even with trial
data we will still lack some important information on transmission.
6. ACKNOWLEDGEMENTS.
6.1 I would like to thank Sir David Cox for epidemiological advice during the
preparation of this Appendix.
7. REFERENCES.
Barlow, N.D. (1996). The ecology of wildlife disease control: simple models
revisited. Journal of Applied Ecology, 33, 303-314.
Hughes, M.S., Neill, S.D., Rogers, M.S. (1996). Vaccination of the badger
(Meles meles) against Mycobacterium bovis. Veterinary Microbiology, 51,
363-379.
27
Stuart, F.A., Mahmood, K.H., Stanford, J.L., Pritchard, D.G. (1988).
Development of diagnostic tests for, and vaccination against, tuberculosis in
badgers. Mammal Review, 18, 74-5.
28
APPENDIX 3.
Glyn Hewinson
1. INTRODUCTION.
1.1 This appendix reviews current knowledge on the use and efficacy of BCG
in wildlife species. It concentrates on the use of BCG in possums, ferrets and
badgers although subcutaneous vaccination with between 104 to 107 cfu BCG
has also been shown to confer significant protection against infection and
disease in domesticated deer (Griffin et al, 1999).
2.1.1 Two models have been developed for the evaluation of vaccines in
possums. The first consists of an intratrachael inoculation of 100 - 1000 cfu of
M. bovis (Aldwell et al, 1995 a & b). In this model lesions are confined to the
lungs and lymph nodes of the thorax, except in the advanced stage of disease
(Cooke et al, 1999). However, disease progression is more rapid than
observed for natural infection and possums develop severe pneumonia six to
eight weeks after challenge. More recently a low dose aerosol challenge
model has been developed using an aerosol-generating chamber in which a
dose of 104 cfu in the nebuliser produces eight to fifteen primary lesions
resulting in a more natural time scale for disease progression (Skinner et al,
2001). In an attempt to develop a natural challenge model, vaccinated and
non-vaccinated possums were housed with possums that had been
experimentally infected with M. bovis using the intratrachael challenge model.
In these experiments transmission of disease was highly variable with
infection rates for in-contact possums ranging from 10% to 60%. This level of
variation prevented interpretation of the protection results (Skinner et al, 2001;
Corner, 2001).
29
lung lesions in vaccinated animals are mostly granulomas with minimal
necrosis and few acid fast bacilli (Aldwell et al, 1995a). Vaccination with BCG
might be expected to be more efficacious against natural infection where the
challenge is less stringent, the possums less stressed and where the course
of infection is longer. A recent field trial of BCG vaccination in possums
suggests that this may be the case (see below).
2.2.2 In the first BCG vaccination study, groups of possums were vaccinated
with 106 cfu BCG by the subcutaneous, intratrachael and intragastric routes of
vaccination (Aldwell et al, 1995a). Subcutaneous and intratrachael
vaccination resulted in a marked reduction in the severity of tuberculosis
compared with that observed in the non-vaccinated controls and animals
vaccinated intragastrically. Intragastric vaccination gave no protection against
experimental intratrachael challenge with M. bovis.
2.3.1 One of the key requirements for vaccination of wildlife is that protection
should be long lasting. In a recent study in captive possums, animal were
vaccinated with a single dose of approximately 1 x 105 cfu of BCG by
intranasal aerosol and challenged by intratrachael instillation of M. bovis 2, 6
or 12 months after vaccination (Corner et al, 2001). Vaccination induced
moderate protection from challenge as determined by a decrease in
pulmonary lesions and dissemination to body lymph nodes with intervals of 2
or 6 months between vaccination and challenge but a lower level of protection
was observed when the interval was increased to twelve months.
30
intervals while no benefit or detriment resulted from revaccination after longer
intervals (1-2 months).
2.5.1 To date one field trial using BCG has been completed in New Zealand
(Corner et al, 2002b). A population of possums in which M. bovis infection
was endemic within a 56 hectare site was vaccinated with 3 x 106 cfu BCG by
a combination of intranasal aerosol and conjunctival instillation. Possums
were revaccinated on average every 5 months and the population was
monitored bimonthly over 2 years by capture and release. Over the 2 years
300 possums were recruited to the study, with 149 being allocated to the
vaccination group. There were significantly fewer cases of tuberculosis in the
vaccinated (4 cases) than in the unvaccinated group (13 cases; p=0.023).
The vaccine efficacy was 69%.
2.5.2 Although the results are encouraging it is important to note that there
were a number of limitations in the design and conditions that occurred during
the study. The number of incident and prevalent cases at each trapping
session declined progressively during the study. No new cases of TB were
detected in the last 8 months of the study. This may have been caused by a
steady decline in the population of the site over time due to a culling operation
in the area surrounding the site. This encouraged dispersal of juvenile
possums away from the site and prevented recruitment of juveniles from the
surrounding area. At the conclusion of the study the susceptible population
on the site was 25% of the long term mean population. At this density the
transmission of infection appeared to be reduced. In an attempt to increase
the statistical power of the study and elevate the incidence of disease in the
population, possums experimentally infected with M. bovis of a unique
molecular profile were released onto the site. However, this did not result in
any additional cases of TB.
2.6.1 A number of encouraging studies using novel oral bait formulations for
BCG have been performed in New Zealand (Aldwell et al., 2003b Bryce
Buddle, personal communication). Although, BCG cultures delivered orally or
intragastrically were relatively ineffective, BCG delivered intraduodenally or
intragastrically with an ant-acid medication induced protection against an
experimental challenge (Buddle et al. 2002). These encouraging results
demonstrate that BCG could be effective if it was protected from degradation
in the stomach. BCG encapsulated in a lipid matrix (Aldwell et al., 2003a) has
been fed to possums and resulted in significant protection against an
experimental aerosol challenge with M. bovis (Aldwell et al., 2003b).
Currently a dose response trial is in progress to determine how much BCG is
required in oral bait to induce optimal protection (Bryce Buddle, personal
communication).
31
2.7.1 The very high susceptibility of possums to M. bovis infection and limited
protection of possums against experimentally-induced infection provides
opportunities to identify tuberculosis vaccines that are more effective than
BCG. In one study, killed Mycobacterium vaccae mixed with live BCG and
administered intranasally induced significantly greater protection than BCG
alone (Skinner et al., 2002). In another study, vaccination with two newly
derived attenuated M. bovis strains induced a higher degree of protection than
that seen with BCG (Buddle et al., 2002).
3.2.1 In a recent study ferrets were orally vaccinated with two doses of 5 x
108 cfu live BCG incorporated into dietary meat administered 4 weeks apart
(Qureshi et al, 1999). Although oral vaccination did not prevent infection,
significant manifestations of protection were observed most notably a
reduction in the bacterial burden, incidence and severity of TB in the head
lymph nodes. Interestingly, blood from only 2/9 vaccines gave tuberculin
specific lymphocyte responses suggesting that systemic immune responses
may have been less important than local immunity in mediating protection in
this study. Subcutaneous vaccination of ferrets with 5 x 106 cfu BCG between
the shoulder blades also induced protection against oral challenge but again
did not prevent infection (Cross et al, 2000). In this case protection was
characterised by a significant reduction in bacterial burden, the prevention of
gross lesions in the mesenteric lymph nodes and reduced bacterial spread to
thoracic lymph nodes. In contrast, to the favourable results in possums,
vaccination by intraduodenal inoculation of 5 x 107 cfu BCG was not effective
in reducing disease (Cross et al, 2000). Both subcutaneous and intra-
intestinal vaccination with BCG induced tuberculin-specific lymphocyte
reactivity.
4.1 Introduction.
32
4.1.1 The early observation that badgers may survive for a number of years
after natural or experimental infection (Mahmood et al., 1987; Newell et al,
1997) suggests that they are not especially susceptible to M. bovis infection.
Preliminary studies of the badger immune response to experimental infection
led to the conclusion that badgers exhibit an immune spectrum during
tuberculosis akin to other mammalian species (Thorns and Morris, 1983).
More recent studies on the pathology and immunology of tuberculous badgers
suggest that they are capable of mounting a vigorous cell-mediated immune
response even when heavily infected and that they can contain infection,
possibly for several years (Newell et al, 1997; Gavier-Widen et al, 2001).
4.2.1 Protocols for the experimental infection of badgers with M. bovis have
been developed at VLA in previous studies (Pritchard et al, 1988; Mahmood et
al, 1987). Two groups of four badgers were challenged with either 103 or 104
M. bovis either intradermally or intratracheally. Two animals thus received
each dose/route combination. The intratracheal challenge route failed to lead
to tuberculosis in all cases and their immunological responses were the same
as the control, uninfected animals. The four intradermally challenged animals
all developed miliary tuberculosis accompanied by positive skin test and
increases in lymphocyte transformation and anti-mycobacterial antibodies.
These studies highlighted the need to develop an improved challenge model
for badgers.
4.4.1 In a previous study performed at VLA, Stuart et al. (1988) reported the
protective effect of BCG against M. bovis in badgers. An intradermal
inoculation of 106 cfu of BCG was found to be non-pathogenic, was not
excreted by the badgers and was not transmitted to in-contact animals. There
was an increase in LTT response but no skin-test reaction or antibody
increase in all vaccinated badgers. When seven of these badgers were
subsequently challenged intradermally with 104 M. bovis, between 5 and 25
33
months after vaccination, the LTT response tended to fall and the antibody
response rose. Skin-test responses became positive. The vaccinated
badgers were shown to live longer, shed fewer tubercle bacilli and their
inoculation sites healed more rapidly after challenge than a group of three
control badgers. Thus, although only small numbers of badgers were
involved, cell-mediated immunity did seem to be enhanced by BCG
vaccination, leading to prolonged survival of the badgers and delayed
excretion of tubercle bacilli.
5. POST-EXPOSURE VACCINATION.
5.1 Vaccination of badgers in the field will inevitably result in the vaccination
of many badgers that have already been infected with M. bovis and have
clinical or subclinical disease. It is possible that the ensuing immune
response to vaccination may result in exacerbation of the disease (the Koch
phenomenon). This might have two effects. First, if post-exposure
vaccination exacerbates disease it might result in increased spread of
infection. Second, vaccination might reveal occult disease which could
confound interpretation of a field trial since the number of TB cases in the
vaccinated population would be selectively increased compared to that in the
untreated population.
34
or harm associated with BCG vaccination of tuberculin skin test positive
individuals with latent TB." (Egsmore, 1968).
6. CONCLUSIONS.
6.1 Although BCG does not induce sterilising immunity in possums, ferrets or
badgers, it has been shown to induce a marked reduction in pathology,
disease, bacterial burden and haematogenous dissemination of M. bovis. The
only recorded field trial of BCG in possums has indicated that an efficacy of
69% can be achieved with repeated doses of BCG.
6.2 To date the published data suggest that subcutaneous and aerosol
vaccination might be more effective than oral vaccination for BCG and that
further work is required to produce formulations which protect BCG from the
stomach acids. However, recent data have shown that some oral bait
formulations under development in New Zealand may be as effective as
subcutaneous vaccination, at least in possums. In humans, oral BCG
vaccination required much larger doses (ca. 3,000 times the dose) and was
hence more expensive. It also proved difficult to control the effective dose
with oral administration as some viable bacteria were inactivated in the
stomach and many passed right through the intestinal tract. If this were the
case in badgers oral vaccination would increase the risk of exposure of
sentinel animals including domestic livestock and other wildlife.
7.4 Proof of principle experiments to show that BCG can give demonstrable
protection against M. bovis challenge in badgers and reduce bacterial
excretion.
7.5 Safety data for BCG in badgers using a single dose, 10 x overdose, and
a repeated dose.
35
7.9 In addition to the above there may be a requirement to demonstrate that
BCG does not exacerbate disease in pre-infected badgers.
8. ACKNOWLEDGEMENTS.
8.1 Bryce Buddle, Leigh Corner, Frank Aldwell and Eamonn Gormley
provided unpublished data and information.
9. REFERENCES.
Aldwell F.E., Keen D.L., Stent V.C., Thomson A., Yates G.F., de Lisle G.W.,
Buddle B.M. (1995a). Route of BCG administration in possums affects
protection against bovine tuberculosis. NZ vet J, 43, 356-359.
Aldwell F.E., Pfeffer A., DeLisle G.W., Jowett G., Heslop J., Keen D.,
Thomson A., Buddle B.M. (1995b). Effectiveness of BCG vaccination in
protecting possums against bovine tuberculosis. Res Vet Sci., 58, 90-5.
Aldwell F.E., Tucker I.G., de Lisle G.W., Buddle B.M. (2003a). Oral delivery of
Mycobacterium bovis BCG in a lipid formulation induces resistance to
pulmonary tuberculosis in mice. Infect Immun., 71, 101-8.
Aldwell F.E., Keen D.L., Parlane N.A., Skinner, M.A., de Lisle G.W., Buddle
B.M. (2003b). Oral vaccination with Mycobacterium bovis BCG in a lipid
formulation induces resistance to pulmonary tuberculosis in brushtail
possums. Submitted for publication.
Buddle B.M., Aldwell F.E., Pfeffer A., de Lisle G.W. (1994). Experimental
Mycobacterium bovis infection in the brushtail possum (Trichosurus
vulpecula): pathology, haematology and lymphocyte stimulation responses.
Vet Microbiol., 38, 241-54.
Buddle B.M., Aldwell F.E., Keen D.L., Parlane N.A., Yates G., de Lisle G.W.
(1997). Intraduodenal vaccination of brushtail possums with bacille Calmette-
Guerin enhances immune responses and protection against Mycobacterium
bovis infection. Int J Tuberc Lung Dis., 1, 377-83.
Cooke M.M., Buddle B.M., Aldwell F.E., McMurray D.N., Alley M.R. (1999).
The pathogenesis of experimental endo-bronchial Mycobacterium bovis
infection in brushtail possums (Trichosurus vulpecula). NZ vet J., 47 187-192.
Corner L.A., Buddle B.M., Pfeiffer D.U., Morris R.S. (2001). Aerosol
vaccination of the brushtail possum (Trichosurus vulpecula) with bacille
Calmette-Guerin: the duration of protection. Vet Microbiol., 81,181-91.
36
Corner L.A.L. 2001. Natural transmission of bovine tuberculosis in captive
brushtail possums (Trichosurus vulpecula). In Bovine tuberculosis in brushtail
possums (Trichosurus vulpecula): Studies on vaccination, experimental
infection and disease transmission. PhD Thesis, Massey University, New
Zealand.
Corner L.A., Buddle B.M., Pfeiffer D.U., Morris R.S. (2002a). Vaccination of
the brushtail possum (Trichosurus vulpecula) against Mycobacterium bovis
infection with bacille Calmette-Guerin: the response to multiple doses. Vet
Microbiol., 84, 327-36.
Corner L.A., Norton S., Buddle B.M., Morris R.S. (2002b). The efficacy of
bacille Calmette-Guerin vaccine in wild brushtail possums (Trichosurus
vulpecula). Res Vet Sci., 73, 145-52.
Cross M.L., Labes R.E., Mackintosh C.G. (2000). Oral infection of ferrets with
virulent Mycobacterium bovis or Mycobacterium avium: susceptibility,
pathogenesis and immune response. J Comp Pathol., 123,15-21
Cross M.L., Labes R.E., Griffin J.F., Mackintosh C.G. (2000). Systemic but
not intra-intestinal vaccination with BCG reduces the severity of tuberculosis
infection in ferrets (Mustela furo). Int J Tuberc Lung Dis., 4, 473-80
Gavier-Widen D., Chambers M.A., Palmer N., Newell D.G., Hewinson R.G.
(2001). Pathology of natural Mycobacterium bovis infection in European
badgers (Meles meles) and its relationship with bacterial excretion. Vet Rec.,
148, 299-304.
Griffin J.F., Mackintosh C.G., Slobbe L., Thomson A.J., Buchan G.S. (1999).
Vaccine protocols to optimise the protective efficacy of BCG. Tuber Lung
Dis., 79, 135-43.
Mahmood K.H., Rook G.A.W., Stanford J.L., Stuart F. A., Pritchard D.G.
(1987). The immunological consequences of challenge with bovine tubercle
bacilli in badgers (Meles meles). Epidemiology and Infection, 98, 155-163.
Moreira A.L., Tsenova L., Aman M.H., Bekker L.G., Freeman S., Mangaliso
B., Schroder U., Jagirdar J., Rom W.N., Tovey M.G., Freedman V.H., Kaplan
G. (2002). Mycobacterial antigens exacerbate disease manifestations in
Mycobacterium tuberculosis-infected mice. Infect Immun. 70, 2100-7.
37
Pritchard D.G., Stuart F.A., Brewer J.I., Mahmood, K.H. (1987). Experimental
infection of badgers (Meles meles) with Mycobacterium bovis. Epidemiology
and Infection, 98, 145-154.
Qureshi T., Labes R.E., Cross M.L., Griffin J.F., Mackintosh C.G. (1999).
Partial protection against oral challenge with Mycobacterium bovis in ferrets
(Mustela furo) following oral vaccination with BCG. Int J Tuberc Lung Dis., 3,
1025-33.
Skinner, M. A., Keen D. L., Parlane N. A., Yates G. F., and Buddle B. M..
2002. Increased protection against bovine tuberculosis in the brushtail
possum (Trichosurus vulpecula) when BCG is administered with killed
Mycobacterium vaccae. Tuberculosis 82,15-22.
Southey A., Sleeman D.P., Lloyd K., Dalley D., Chambers M.A., Hewinson
R.G., Gormley E. (2001). Immunological responses of Eurasian badgers
(Meles meles) vaccinated with Mycobacterium bovis BCG (bacillus calmette
guerin). Vet Immunol Immunopathol., 79,197-207.
Turner J., Rhoades E.R., Keen M., Belisle J.T., Frank A.A., Orme I.M. (2000).
Effective preexposure tuberculosis vaccines fail to protect when they are
given in an immunotherapeutic mode. Infect Immun. 68, 1706-9.
38
APPENDIX 4.
Jo Colston (deceased)
National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7
1AA
1. INTRODUCTION.
1.1 Extensive testing of virulence was carried out by Calmette and his
colleagues during their development of BCG in the early part of the 20th
century. In addition to this there has been extensive work carried out in wild-
life or domestic livestock to investigate protective efficacy or immunogenicity
of BCG, rather than virulence; these studies allow us to draw some
conclusions about the virulence of BCG in these species. Calmette and
colleagues also carried out experiments in which large doses of BCG were
administered to animals which were already infected with M. tuberculosis;
because of the potential importance of these studies, these have been
included in the discussion (see section 3).
2.1 Cattle.
2.3 Rabbits.
2.3.1 1-5mg BCG injected sub-cutaneously had no effect on the health of the
rabbits. Intravenous injection of 100mg also had no effect.
2.4 Dogs.
2.4.1 A single 4Kg dog was given 0.5mg BCG intravenously, followed five
days later with 1mg by the same route, and three months later 10mg
39
intraperitoneally. The dog remained healthy in spite of a slightly elevated
temperature after the second and third injection. A post mortem examination
carried out six months after the last injection revealed no gross lesions, but
intact mycobacteria were detectable.
2.5 Monkeys.
2.6 Horses.
2.6.1 One horse was given 10mg BCG intravenously; the horse developed a
slight fever 12 days later lasting for 6 days. A second horse received 100mg
intravenously; this animal developed temperature oscillations between 39.5oC
and 40oC for two weeks. The animal lost appetite, developed rapid breathing
and a high pulse rate. There was evidence of pulmonary congestion between
seven and eight days, but by six weeks the animal had fully recovered.
Another horse was given 200mg intravenously and sacrificed two weeks later.
Mycobacteria could be found in lymphoid tissue, but there was no evidence of
tuberculosis-like lesions.
3.1 With the exception of the work by Calmette et al, most of the work which
has involved exposing wild-life or domestic livestock to BCG, has been carried
out to investigate protective efficacy or immunogenicity, rather than virulence.
Nevertheless, these studies do allow us to draw some conclusions about the
virulence of BCG in these species. The information set out below summarises
research on vaccination of different species of animals with BCG.
3.2 Cattle.
3.2.1 The original work of Calmette (see Section 2) would have involved
doses of more than 1010 BCG. More recently doses have ranged from 104 to
108 viable BCG, usually given subcutaneously. One study (Buddle et al,
1995) involved intratracheal vaccination. Virtually all of these studies reported
some level of protection in animals which were subsequently challenged with
virulent M.bovis, although this appeared to wane after approximately 5 years
(Bergeen, 1977). With the exception of the report by Calmette and Guerin
(see 2.1.1), there have been no reports of adverse affects following the
administration of BCG.
3.3 Deer.
40
al, 1999; Hook et al, 1996). As with cattle vaccination, all of these studies
reported some level of protection and there were no reports of adverse affects
from the vaccination.
3.4 Possums.
3.5 Ferrets.
3.5.1 BCG has been given orally to ferrets, followed by oral challenge with
virulent M.bovis. There was significant reduction in gross lesions, and in
culture and acid fast positive lymph nodes in the vaccinated groups. No
adverse side effects of vaccination were reported (Qureshi et al, 1999).
3.5.2 In another series of experiments, ferrets were vaccinated with live BCG
via subcutaneous injection or intra-duodenal inoculation. Only the
subcutaneous route was effective in reducing disease (Cross et al, 2000).
3.6 Badgers.
3.7 Rabbits.
3.8.1 Guinea pigs have been widely used for experimental tuberculosis
studies, and there are many reports of vaccination with BCG (e.g. Chambers
et al, 2000). There are no reports demonstrating that BCG can cause
progressive infections or have adverse side effects.
3.9 Mice.
41
3.9.1 Mice are the most commonly used experimental animals for testing
vaccination against tuberculosis. BCG does not cause progressive infections
in these animals.
4.1 Calmette and colleagues carried out a number of studies in which large
doses of BCG were administered to animals already infected with M. bovis.
Their general conclusion was that this did not produced aggravation of the
tuberculosis (Lintroduction de bacilles bilies, meme a fortes doses plusieurs
fois repetees, dans lorganisme des animaux deja tuberculises ne produit
aucune aggravation de la maladie).
4.2 A PPD-positive cow was given 10mg of BCG intravenously, followed nine
days later with 50mg, again intravenously. The animal was sacrificed and
subjected to post mortem examination two and a half months later. Two
small, caseous lung lesions were found, along with a number of calcified
lesions in mediastinal lymph nodes; however these were considered to be old
lesions, and there was no evidence of recent tuberculosis. Similar
experiments carried out with guinea pigs and rabbits failed to reveal evidence
of aggravation of the disease.
5. CONCLUSIONS.
6. REFERENCES.
Aldwell F.E., Keen D., Stent V.L.C. et al. (1995). Route of BCG administration
in possums effects protection against bovine tuberculosis. New Zealand Vet.
Rec., 43, 356-359.
Buddle B.M., Keen D., Thomson G. et al. (1995). Protection of cattle from
bovine tuberculosis by vaccination with BCG by the respiratory or
subcutaneous route, but not by vaccination with killed Mycobacterium vaccae.
Res. Vet. Sci., 59, 10-16.
42
Buddle B.M., Aldwell F.E., Keen D., et al. (1997). Intraduodenal vaccination
of brushtail possums with bacille Calmette-Guerin enhances immune
responses and protection against Mycobacterium bovis infection. Int. J.
Tuberc. & Lung Dis., 1, 377-383.
Cross M.L., Labes R.E., Griffin J.F.T., Mackintosh C.G. (2000). Systemic but
not intra-intestinal vaccination with BCG reduces the severity of tuberculosis
infection in ferrets (Mustelo furo). Int. J. Tuberc. & Lung Dis., 4, 473-480.
Lurie M.B., Zappasodi P., Cardona-Lynch E., Dannenberg A.M. (1952). The
response to the intracutaneous inoculation of BCG as an index of native
resistance to tuberculosis. J. Immunol., 68, 369-387.
Miller L.A., Johns B.E., Elias D.J., Killian G.J. (1999). Oral vaccination of
white-tailed deer using a recombinant Bacillus Calmette-Guerin vaccine
expressing the Borrelia burgdorferi outer surface protein A: prospects for
immunocontraception. Am. J. Rep. Imm., 41, 279-285.
Qureshi T., Labes R.E., Cross M.L., et al. (1999). Partial protection against
oral challenge with Mycobacterium bovis in ferrets (Mustelo furo) following
oral vaccination with BCG. Int. J. Tuberc. & Lung Dis., 3, 1025-1033.
Slobbe L., Lockhart E., ODonell M.A., et al. (1999). An in vivo comparison of
bacillus Calmette-Guerin (BCG) and cytokine-secreting BCG vaccines.
Immunology, 96, 517-523.
43
Southey A., Sleeman D.P.S., Lloyd K., et al. (2001). Immunological
responses of Eurasian badgers (Meles meles) vaccinated with Mycobacterium
bovis BCG (bacillus Calmette-Guerin). Vet. Immunol. Immunopath., 79, 197-
207.
44
APPENDIX 5.
1. INTRODUCTION.
1.2 In Appendix 3 was outlined a number of steps that would be required for
the development of BCG vaccination regimes for badgers. The main purpose
of the study would be to provide proof of principle that BCG can protect
against a stringent challenge with M. bovis and to determine the level of
protection conferred by BCG in this model. Previous studies in other wildlife
species have shown that, to date, the optimum level of protection for BCG has
been achieved by subcutaneous vaccination (Appendix 3). Therefore it would
be prudent to provide proof of principle that BCG can protect against M. bovis
infection in badgers using this route of vaccination before embarking on the
development of formulations and delivery systems for oral vaccination. The
aim of this Appendix is to discuss the development of protocols to achieve this
goal.
2.1 The first objective would be to develop an M. bovis challenge model for
badgers. The optimum dose for intratrachael challenge is being determined in
the Republic of Ireland (RoI) by titrating doses of M. bovis (10, 100, 1000 cfu).
The kinetics of the immune response and shedding during infection are being
measured and pathology will be defined by post mortem examination.
2.2 The second objective would be to define the variation in the parameters
that would be used for measuring protection against M. bovis challenge in this
model. This would ensure that a minimum number of animals were used for
subsequent vaccination and challenge studies.
2.3 Ideally, the experimental design would include a badger group size of
between twelve and twenty animals. At least two pre-bleeds should be taken
for each badger. The dose of M. bovis given would be determined from the
experiments performed in RoI outlined above (2.1). All badgers would be kept
12-18 weeks after challenge or until they showed severe clinical signs of
disease. A full post mortem would be carried out on each animal and
45
pathology, histopathology and cfu in lung, lymph nodes and other tissues
would be determined. Pathology scores would be determined for lungs and
lymph nodes using scoring systems developed for the bovine model of M.
bovis infection.
2.5.1 Serum IgG response (using the Brock Test, MAPIA/Lateral flow assays
and Dachs ELISA; Appendix 9).
2.5.4 IFN ELISA and ELISPOT using PPDM, PPDA, ESAT-6, CFP10 and
other antigens that might be useful in determining disease progression
(Appendix 9).
3.1 Group size for a BCG vaccination and challenge experiment would be
determined from the data obtained from the experiment outlined in 2. It should
be noted that groups of six cows were sufficient to demonstrate 80 %
protection (i.e. reduction in lesions) in BCG vaccinated animals compared to
controls. This is the minimum group size that could demonstrate a statistically
significant protective effect in cattle.
46
3.4 Immune responses of vaccinated badgers would be monitored as
described in section 2.5 above.
3.3 It is suggested that there would be a rest between BCG vaccination and
M. bovis challenge of ca. 8 weeks in the first instance.
47
APPENDIX 6.
Steve Houghton
Hoechst Roussel Vet Ltd., Walton Manor, Walton, Milton Keynes, MK7 7AJ
1. INTRODUCTION.
2.1 In deciding what projects to progress, the following are taken into
consideration:
2.1.1 The market. How many countries are involved and how widespread is
the disease? What is the likely uptake of the vaccine (prohibition or
prescription for use by control policies?), what are the manufacturing costs
and anticipated selling price?
2.1.3 Product profile. This sets the objectives for the project which primarily
involves defining the following:
48
2.1.4.1 The more complicated the production process, the higher the costs. It
is easier to predict the costs of a simple process, similar to established
methodology.
2.1.4.2 The vaccine strain(s), notably the history (particularly with respect to
culture conditions and TSE), and any IP issues are essential to address early
on.
2.1.5 Consumer concerns. The release of live strains with potential zoonotic
implications and perhaps the release of Genetically Modified Organisms
(GMOs) as live vaccine strains in particular will undoubtedly present problems
with consumer and regulatory acceptance.
3.1.3 The seeds have to be tested for identity and purity. The maximum and
minimum titre (for live vaccines) of the final product is set. If a range of titres
is specified for the product, all efficacy studies are carried out using minimum
titre and all safety studies at maximum titre.
3.1.4 Safety studies are carried out under GLP conditions and conducted in
the most susceptible category of animal (e.g. neonates, pregnant) and
include:
49
3.1.4.5 Persistence and shedding (live).
3.1.4.6 Numbers of the order of 5/6 per group are usually sufficient.
3.1.5 Efficacy studies are carried out under experimental conditions and
include studies which will enable the product claims to be substantiated
involving:
4.1 An animal health company partner. Studies are not relevant for
registration unless they involve the product manufactured in a manner
representative of full-scale manufacture.
4.4.2 Centralised registration applies to not just live GMOs but also any
material produced by a recombinant process - therefore even if the vaccine is
inactivated or a sub-unit protein the same rules apply.
4.5 Field Trials. These can only be carried out in the UK under an Animal
Test Certificate (ATC) according to GCP although trials could be done
elsewhere. An ATC application requires data on quality and safety in the form
of a dossier, but not efficacy. However as the definitive evidence of efficacy is
by experimental challenge, field studies would be expected to provide
supporting data at best for efficacy, and to confirm safety under field
conditions.
50
5. BCG.
5.1 From all the studies conducted so far BCG is the only realistic vaccine
candidate currently available.
5.2 BCG is a licensed product for humans in the UK, therefore there are no
significant zoonotic implications.
5.3 Adopting this vaccine for use in badgers or cattle is likely to save years in
development time. Collaboration and consent of the manufacturer would be
necessary.
5.4 For badgers the oral route in bait is likely to be the method of application
of choice. Efficacy and stability work would be necessary to develop this.
5.5 Ecology and the Environment. For any product a key part of the dossier
is the assessment (called the ecotoxicity section) of impact on the
environment and spread to other species. This assessment method is clearly
described in regulatory guidelines and involves key studies of the vaccine and
its stability. There is a wealth of published data on the safety and efficacy of
BCG in numerous species, including man, cattle and laboratory animals and
some in badgers.
6. REGULATORY STEPS.
51
6.1.3.1 Marketing Authorisation (MA) for BCG in Badgers. The sequence is
laid out in Table 1 for badgers but as essentially the Quality section of the
dossier would be provided by the licensed manufacturer(s) this would save
considerable time in development. Published data and new studies would
provide data for the safety and efficacy sections of the dossier. This would
lead to a national marketing authorisation in the UK which could then be
mutually recognised in Ireland or other interested Member States.
6.1.3.3 The development of a novel TB vaccine (i.e. not BCG) would require
a considerable amount of additional work. The early development and
screening of candidate vaccine components and formulations, and
establishing production and quality test methodologies in particular, would
probably add at least another 2 to 3 years to the programme.
7. CONCLUSIONS.
The provision of any vaccine to aid the control of Bovine TB, whether for use
in cattle or badgers, would be most likely achieved by a close collaboration
between a vaccine manufacturer and research institutes (perhaps several)
from the beginning. Co-ordination of research activities to provide the science
necessary to underpin the development programme, particularly with respect
to novel vaccines, is essential. From manufacturing, vaccine development
and probably regulatory/consumer acceptance perspectives, the use of BCG
in badgers is the option that would be quickest to market.
52
APPENDIX 7.
1. INTRODUCTION.
1.1 Captive badgers will be required for experimental research related to the
development of a TB vaccine for badgers. Consequently badgers will need to
be procured from the wild by live trapping.
2. GENERAL.
2.1 Badgers are social animals and therefore cannot be housed individually in
captivity on a long-term basis. However, although housing singly is not
desirable for welfare reasons, housing in pairs or groups will have implications
for cross-infection between individuals in the course of the vaccination
studies. Advice will be required from the relevant immunologists and
statisticians on the desired characteristics of badgers to be procured for
vaccine research, as this will influence the strategy for their capture. Are
badgers to be kept in pairs? If so what age and sex distribution is required?
Alternatively, will it be possible to house whole social groups? Will the
badgers be required to come from locations of varying history of exposure to
M. bovis?
3.2 The intention only to partially deplete social groups to avoid disruption
carries with it the need to assess group size, age and sex composition. For
example, it would not be desirable to remove two badgers from a group of
less than say five individuals. A possible alternative to this, if there were
53
appropriate facilities to house them, would be to capture whole social groups.
In this scenario, trapping could be condensed, as the required number of
badgers would be more quickly reached after fewer trap-events. As they are
social animals, it may be less stressful (see Sections 8.1.3 and 9) for badgers
if kept together as a group (see Section 8).
3.3 Advice received from people with experience of keeping captive badgers
suggests that it may not matter how pairs are mixed according to sex or even
social group origin. However, it is important to introduce them together,
monitor the situation and be prepared to separate them again if conflict
occurs. In order to overcome the potential problems of keeping pairs of adults
together, it may be better to remove animals from the wild as cubs, as they
settle into captivity much better than adults. The experience of badger
rehabilitation centres is that cubs of both sexes mix well, but they do exhibit a
behavioural change in the autumn where they spend much of their time trying
to escape. This period coincides with the time of year that cubs in the wild
become independent and disperse.
5.1 Although it is not possible to guarantee that procured badgers come from
areas where infection is definitely absent, there are areas of the country
where there is no history of infection in either badgers (although insufficient
sample sizes may be a factor) or cattle. Targeting these areas would provide
the best chance of obtaining disease free badgers. These areas would
however be outside TB hotspots if this is an important consideration (see
Genetic considerations). Confirmation of the disease-free status of these
badgers could be achieved by repeat ELISA testing, plus clinical sampling.
54
6. PROCURING KNOWN POSITIVE BADGERS.
6.2 One possible scenario is that target setts are trapped repeatedly until
sufficient animals of the desired disease status are caught. Badgers could be
blood tested in the field at capture. The high specificity of the ELISA test
means that any animal testing positive is highly likely to be infected. Positive
individuals could be taken into captivity, where further testing could be carried
out to confirm disease status. Culture of clinical samples from these badgers
would also help confirm disease status. At the time of the initial capture, all
badgers could be clinically sampled and given permanent identification marks.
Culture of clinical samples from all badgers would provide a further
opportunity to identify infection in animals not identified by the initial ELISA
test. Any additional positive individuals could be selected in subsequent
trapping operations.
7.1 Procurement of known negative badgers from the same genetic stock as
the known positive badgers may be required, which would involve capturing
them in TB hot spots. The limitations of current TB diagnostic techniques will
mean that it would be difficult to obtain disease-free badgers from these areas
with a high level of confidence.
8.1.1 Less trapping would have to be carried out to reach the numbers of
badgers required.
8.1.2 The badgers would be captive therefore it would be easier to carry out
repeated culture tests, and if necessary repeat ELISA tests.
8.1.3 The whole social group would be kept together, which might reduce
stress to the target individuals.
55
should also be noted that removal of badger from the wild by cage trapping is
not 100% effective.
10.1 Preliminary work suggests that the levels of genetic variability are very
similar between trial areas. No such information is available for non TB hot-
spot areas. Also, it is as yet unknown what implications differences in genetic
variability between areas would have for the immune response, or TB
pathogenicity in badgers. Therefore genetic composition is an issue which
cannot currently be resolved, and it is assumed that it will not be a
consideration for badger procurement.
11.1 Under the Protection of Badgers Act 1992, the killing or taking of
badgers and/or interference with their setts is prohibited. Section 10 of the
Act, however, makes provision for the issue of licences for specific purposes
to carry out otherwise unlawful activities against badgers and their setts.
Section 10(1) of the Act provides for the licensing of certain activities,
including the killing or taking of badgers, and interference with setts, for
scientific or educational purposes, or for the conservation of badgers. English
Nature is the licensing authority for licences issued under this Section.
11.2 In addition, the Act provides an exemption to the above offences for the
purpose of doing anything which is authorised under the Animals (Scientific
Procedures) Act 1986 e.g. experimental procedures approved under licence
to advance biological or behavioural knowledge.
56
11.3 One part of the Crown is, strictly speaking, unable to apply to another
part of the Crown for a licence and it may be a Crown laboratory that would
wish to carry out the research. In circumstances such as these it is usual for
Crown staff to operate within the spirit of the law, and should a "licence" prove
necessary, to submit an "application" and to comply with the conditions
attached to any "licence" subsequently issued.
12.1 Removal of animals from the wild for experimental purposes will attract
the attention of animal rights activists, both in the field and at the captive
facility. Consideration should be given to the possibility of procuring badgers
from a secure, perhaps Ministry of Defence, site.
13. REFERENCE.
14. BIBLIOGRAPHY.
Pope and Burke, preliminary report 6th March 2002. Report to Defra.
57
APPENDIX 8.
1. INTRODUCTION.
1.1 Work with badgers infected with bovine tuberculosis would require
containment at Level 3. Appropriate containment is also required to protect
local farming interests. As the work would require animals to be maintained in
captivity for an extended period particular attention needs to be paid to their
welfare and the conditions under which they would be held.
1.2 Given the containment and animal welfare considerations of this work a
new facility would be required. Existing secure facilities are available which
include sufficient open ground to accommodate a new unit while providing
access to trained animal technicians and scientists.
2. STANDARDS.
2.1 To comply with Level 3 containment and Home Office Procedures the
facilities must meet the following standards.
2.1.3 Liquid waste should be discharged via a sealed and leak-proof drainage
system into an impermeable holding or treatment enclosed tank within the
designated area.
2.1.5 An autoclave must be available within the facilities and all bedding,
animal waste and bodies must be autoclaved before disposal.
3. SERVICES.
3.1 Under The Animal (Scientific Procedures) Act 1986 all services should be
installed in such away that they are either buried within the fabric of the
building or clear of wall surfaces. Maintenance required to any services might
disturb the animals. Therefore the design for services such as lighting must
58
be accessible from outside the holding area. All holding areas should have
temperature and relative humidity control, which are carefully maintained.
The temperature should be within the range appropriate for the species and
the relative humidity would be maintained at 55%. Ventilation should provide
sufficient air of an appropriate quality and reduce the levels and spread of
odours, dust and infection; in order to comply with this recommendation 15-20
air changes per hour distributed throughout the holding area should be
adequate. No procedures or euthanasia must be performed in the normal
holding areas where animals are housed, i.e. there must be an adequate area
provided to carry out these.
4. HOLDING AREA.
4.1 These requirements mean that infected badgers will need to be kept in an
enclosed facility with no access to outdoor or grass runs. There is currently
no available information on the welfare requirements of badgers to be kept
under such containment conditions for an extended period of time. However,
working on the assumption of two animals to be kept in each enclosure, and
from experience with other species, it is suggested a holding area of 4.5m x
10m be an appropriate minimum. This area should be concrete floored with
steel walls. Within this area the animals would be kept on a deep litter system
and be provided with nest boxes.
5. COSTS.
59
5.2 In addition to the capital costs of construction there would also be staff,
veterinary consultancy and running costs associated with the facilities.
Approximate annual costs are outlined below.
5.3 Holding animals in existing facilities while checking disease status would
not change the above costs; these are largely determined by the number of
simultaneous challenges that are required, not by how long the animals are
held. If animals were to be held for a brief period to check disease status and
then for up to a year in category 3 for the challenge work, there would be a
slight saving in time, but not a significant one. Using holding pens would also
raise issues of soil contamination, risking infection of subsequent animals and
the surrounding environment.
6. FURTHER ENQUIRY.
60
6.1.7 Benefits of environmental enrichment.
6.1.9 It is anticipated that such a study would cost around 100,000 and
could be completed in 15 months.
61
APPENDIX 9.
1. INTRODUCTION.
1.1 One of the stumbling blocks to vaccine development for badgers is the
paucity of available immunological reagents that might be used to assess
vaccine take and to monitor M. bovis infection and vaccine efficacy in the
field. Over the past few years a number of immunological assays have been
developed for badgers. The purpose of this appendix is to review the assays
that are already available, to describe those that are in development and to
outline how each assay might be used in a vaccine development and
evaluation programme.
Test Rationale
ELISA for serological response to M. The existing Brock Test ELISA detects
bovis-specific antigen(s). IgG antibody against a single antigen,
MPB83, with a sensitivity of ca. 45%.
Adding further M. bovis specific
antigens has improved sensitivity to ca.
55% without a loss in specificity
(Kampfer et al., 2003; Greenwald et al.,
2003).
62
2.2 Assessment of vaccine take.
Test Rationale
As for 2.1 plus IFN ELISPOT assay. Use of an IFN ELISPOT assay would
allow assessment of the magnitude of
the memory response generated by
vaccination (e.g. Vordermeier et al.,
2002).
IgA ELISA
Detection of IgA against M. bovis
antigens would be especially useful for
detecting mucosal immune responses.
Test Rationale
LTA or IFN ELISA using antigen(s) Recent results in cattle have
present in M. bovis but not in vaccine demonstrated that, following BCG
(e.g. ESAT-6 and CFP10, in the case vaccination, protected animals could be
of vaccination with BCG). differentiated from those that were
developing disease (Vordermeier et al.,
2002) using this approach.
Test Rationale
Lateral flow-format serological assay. Seropositive badgers are at greatest
risk of shedding M. bovis (Chambers et
al., 2002, Clifton-Hadley et al., 1995).
This assay would allow detection of
super excretors within 15 minutes of
capture.
63
3. PROGRESS MADE ON TEST DEVELOPMENT: AVAILABLE ASSAYS.
3.2 Brock Test (indirect ELISA for detecting IgG antibodies against MPB83).
3.2.1 The only validated immunological test for the detection of tuberculosis
in the badger is the Brock Test. This is an indirect ELISA for a serological
response to MPB83, a 26 KDa protein antigen expressed by M. bovis
(Goodger et al., 1994; Hewinson et al. 1997). Evaluation of the Brock Test for
the detection of M. bovis infection in badgers gave the predictive value of a
positive test result of 67.5% and the predictive value of a negative test of
84.6%. The sensitivity of the test was significantly higher in animals with
gross tuberculous, which suggested the Brock Test may be useful for the
detection of badgers most likely to be excreting M. bovis (Clifton-Hadley et al.,
1995). The sensitivity of the test at the population level was 72.9%, compared
with 40.7% at the level of the individual animal, suggesting the test could also
be used to determine the burden of disease, at least for a population of
badgers.
64
3.3. Indirect ELISA for detecting IgA antibodies against MPB83.
3.3.1 Monoclonal antibodies against badger IgA have been raised and used
to develop an indirect ELISA for detecting IgA antibodies against MPB83 in
badgers. Preliminary data suggest that IgA responses can be detected in
tracheal aspirates and sera of M. bovis infected animals.
3.4.1 The existing serological ELISA test (Brock Test) looks for an antibody
response to a single mycobacterial antigen, MPB83, and has low sensitivity
for surveillance purposes (Clifton-Hadley et al., 1995). Recent work using a
technique known as Multi-Antigen Print ImmunoAssay (MAPIA) (Lyashchenko
et al, 2000), identified a proportion (16%) of M. bovis culture-positive badgers
that were negative by Brock Test but seropositive for their recognition of other
M. bovis-specific antigens. This study suggests that modifying the Brock Test
by incorporating a suitable cocktail of mycobacterial antigens results in
enhanced test sensitivity (Greenwald et al., 2003).
3.5.2 Preliminary results from 178 badgers (Greenwald et al., 2003) showed
that a lateral flow-format gave enhanced sensitivity and specificity over the
Brock Test and MAPIA-based assay (sensitivity 53% vs 47% vs 49%;
specificity 95% vs 89% vs 88%, respectively).
3.5.3 Although a lateral flow test is unlikely to have a sensitivity much beyond
55%, it is the only test that could be performed badger-side and should
preferentially detect those animals at greatest risk of shedding M. bovis
(Chambers et al., 2002). Such a test would enable a cull or vaccinate test
strategy to be adopted in the field, should this be an option.
3.6. Multi-antigen BrockTest (the Dachs ELISA; Kampfer et al., 2003). The
protocol used for the Dachs TB-ELISA is essentially the same as used in the
Brock Test. The antigens used for the Dachs TB-ELISA are MPB83,
MPB70, CFP10 and 16 kD antigen. In a preliminary evaluation of the test
(Kampfer et al., 2003), the Dachs TB-ELISA gave higher sensitivity (a 33%
improvement) than the Brock Test at the same specificity. These preliminary
results suggest that serodiagnosis of badger TB can be enhanced with the
new test. However, analysis of more sera with the Dachs TB-ELISA is
required to reduce the confidence intervals to confirm its improved
65
performance over the Brock Test; which was originally evaluated on nearly
two thousand sera (Clifton-Hadley et al., 1995).
4.1.3 A prototype sandwich ELISA has been produced that detects the
presence of badger IFN. However, the test requires further optimisation as
the sensitivity is currently too low to be of practical use. Blood from badgers
experimentally infected with M. bovis in the Republic of Ireland (RoI) will be
used for this purpose.
4.1.4 The IFN assay is not anticipated to be available and validated until
March 2005.
66
ESAT-6 and CFP-10, were still able to distinguish BCG vaccinated/diseased
animals from BCG vaccinated animals without signs of disease (differential
diagnosis). These results suggest that the determination of ESAT-6 specific
IFN-, whilst not a direct correlate of protection, constitutes a useful prognostic
immunological marker predicting both vaccine efficacy and disease severity
(Vordermeier et al., 2002). Preliminary data generated using the LTA assay
suggest that T cells from infected badgers also recognise these antigens.
Blood from badgers experimentally infected with M. bovis in the RoI will be
used for further evaluation of M. bovis specific antigens in T cell assays.
6. REFERENCES.
Dalley D., Chambers M.A., Cockle P., Pressling W., Gavier-Widen D.,
Hewinson R.G. (1999). A lymphocyte transformation assay for the detection
of Mycobacterium bovis infection in the Eurasian badger (Meles meles). Vet.
Immunol. Immunopathol., 70, 85-94.
Goodger, J., Nolan, A., Russell, W.P., Dalley, D.J., Thorns, C.J., Stuart, F.A.,
Croston, P., Newell, D.G. (1994). Serodiagnosis of Mycobacterium bovis
infection in badgers: development of an indirect ELISA using a 25 kDa
antigen. Vet. Rec., 135, 82-85.
Greenwald R., Esfandiari J., Lesellier S. Houghton R., Pollock J.., Aagaarde
C., Andersen P., Hewinson R.G., Chambers M.A., Lyashchenko K. (2003).
Development of a Lateral-Flow Immunoassay for Rapid Detection of
Mycobacterium bovis Infection in Badgers (Meles meles). Diagnostic
Microbiology and Infectious Disease. In press.
Hewinson R.G., Michell S.L., Russell W.P., McAdam R.A., Jacobs W.R. Jr.
(1996). Molecular characterization of MPT83: a seroreactive antigen of
Mycobacterium tuberculosis with homology to MPT70. Scand J Immunol. 43,
490-9.
Kampfer S., Dallet D., Hewinson R.G., Chambers M.A., Singh, M. (2003).
Multi-Antigen ELISA Test for Enhanced Diagnosis of Badger TB. Vet Record.
In press.
67
Lyashchenko K.P., Singh M., Colangeli R., Gennaro M.L. (2000). A multi-
antigen print immunoassay for the development of serological diagnosis of
infectious diseases. J. Immmunol. Methods, 242, 91-100.
Southey A., Sleeman D.P., Lloyd K., Dalley D., Chambers M.A., Hewinson
R.G., Gormley E. (2001). Immunological responses of Eurasian badgers
(Meles meles) vaccinated with Mycobacterium bovis BCG (bacillus calmette
guerin). Vet. Immunol. Immunopathol., 79, 197-207.
Vordermeier H.M., Chambers M.A., Cockle P.J., Whelan A.O., Simmons J.,
Hewinson R.G. (2002). Correlation of ESAT-6-specific gamma interferon
production with pathology in cattle following Mycobacterium bovis BCG
vaccination against experimental bovine tuberculosis. Infect. Immun. 70,
3026-32.
68
APPENDIX 10.
Ivan Morrison
1.1 The following information would be highly desirable not only to justify a
field trial with BCG but also to facilitate design of the trial and interpretation of
the results. Some of this information might be available from the literature, but
much of it would need to be generated from experimental studies.
1.1.4 Risk of uptake by, or transmission to, other species and potential
pathogenic effects.
2.1.1 Badger population density and structure. This can only be estimated on
the basis of survey data. It would be needed at outset to determine where
vaccine baits should be laid and also needed during the course of a trial to
ensure that the badger population does not change radically.
2.1.2 The rate of vaccine uptake. Methods would need to be tested and
validated prior to a trial; this need only be done on a sample of badgers.
69
needs to be done prior to starting a trial; it could perhaps be done as a risk
assessment based on information from experimental studies or it might
require field experiments prior to a trial.
3.2 For similar reasons, a small-scale trial is also unlikely to yield reliable
information on the effect of vaccination on prevalence of TB in the badger,
(even assuming there were reliable assays to diagnose TB in the live animal).
The prevalence of TB in most populations of badgers is probably less than
10%, it can vary considerably between local social groups and can also show
cyclical variation over a period of several years. As discussed above, two or
three years of vaccination might be required to have an impact on TB in the
badger. Therefore, large numbers of badgers would need to be vaccinated
and monitored by trapping and blood sampling over a prolonged period of
time to obtain meaningful data. In any event, current assays for detection of
infection by one-off sampling of live badgers have limited sensitivity and
specificity and the likelihood and time-scale for developing such assays is
uncertain.
70
3.3 For these reasons, it would be preferable to proceed directly to a large-
scale trial aimed primarily at examining the impact of vaccination on TB in
cattle, assuming that the experimental studies provided evidence of efficacy.
The precise design of the trial would depend on the area that would need to
be covered to include the numbers of herd breakdowns required. This might
be either a single large site or multiple sites, as in the current culling trial, with
appropriately matched control sites. Indeed, the control areas, and possibly
also the reactive areas (depending on the results), in the current culling trial
might be suitable for such a trial.
3.4 However, there may be a need for limited scale, short-term experiments
in the field to examine the feasibility of particular aspects of the trial, e.g.
assessment of environmental risks, measurement of vaccine uptake or
assessment of vaccine take.
71
APPENDIX 11.
1. INTRODUCTION.
2.2 Badger density varies widely throughout the UK, from less than a single
animal / km2 in marginal habitats to more than 25 / km2 in optimal habitats
(Wilson et al., 1997). The density of badgers in the TB cattle hotspot areas of
South West England is probably medium to high, perhaps typically varying
between 6-15 adults / km2 based on the presence of 1-2 social groups of
moderate size / km2. However, it is likely that in many of these areas current
population density is below carrying capacity as a result of previous culling
operations. It will be necessary to assess the size of target populations for
vaccination, and the methodology employed will depend on the proposed
scale of operations. Current Defra funded projects are investigating the
development of methods to estimate badger abundance.
72
collectively maintain territories. Although badgers may use several setts
within the group territory, much activity is concentrated at the main sett. This
stable pattern of social organisation allows the delineation of a target area for
vaccination that is ecologically meaningful.
2.6 Female badgers do not usually reproduce until they are two years old.
However, although the majority of females mate and produce blastocysts, in
many populations only a relatively small proportion produce litters. In badgers
examined from South West England only 44% of females implanted
(Cresswell et al., 1992). In high density populations (e.g. Woodchester Park)
more females per social group produce litters than in lower density
populations where suppression by dominant females is thought to be
resource-related (Woodroffe & Macdonald, 1995). However, within high
density areas the number of successful pregnancies (i.e. cubs weaned) might
decrease as the number of adult females per group increases (Woodroffe &
Macdonald, 1995). Generally, only one litter (typically of 2-3 cubs) is
produced per social group each year. This gives an annual productivity of 0.5
to 0.8 cubs per badger in the UK (Smith, 2002). Cub mortality rates are high
and variable (Cresswell et al., 1992; Rogers et al., 1997). Mortality rates of
uninfected adults are more constant: 0.30 and 0.24 per year for males and
females respectively (Wilkinson et al., 2000). This gives a per capita mortality
rate of about 0.5 (Smith, 2002).
73
2.7 Rates of immigration into stable badger populations and those that are
recovering from culling operations will influence the time scale for vaccine
deployment on all but the largest of areas (e.g. at a regional level). In high
density populations rates of movement of badgers between social groups are
relatively low (Cheeseman et al., 1988a; Rogers et al., 1998). However, rates
of movement within populations that are recovering from culling might be
higher (Cheeseman et al., 1993; Tuyttens et al., 2000b).
3.3 Evidence from the Woodchester Park study suggests that the greatest
risks of infection to cattle may be posed by a relatively small proportion of the
population, consisting of persistently infectious animals (Cheeseman &
Mallinson, 1981; Delahay et al., 2000a). Infected individuals can live for
several years and breed successfully whilst excreting bacilli (Clifton-Hadley et
al., 1993; R. Delahay, unpublished data). As the distribution of infected
individuals can also be highly aggregated within populations, this argues for a
spatially broad-based strategy for vaccination, since small foci of infection
cannot be adequately identified. It is possible that a proactive campaign
involving broad scale application of a vaccine could reach a high proportion of
the target population. However, if small foci of infectious animals were missed
(perhaps reflected in the persistence of local cattle breakdowns), then smaller-
scale, reactive applications of vaccine could be used to target these problem
areas. Delivery of a vaccine over an extensive area might be best achieved
by deployment of baits, whereas trapping and injection could be useful in
intensive localised operations.
74
3.4 It is not yet known whether badgers can naturally mount an effective
immune response to M. bovis capable of protecting against the development
of disease and excretion of bacilli. There is some evidence from the
Woodchester Park study, of a transient sero-positivity to M. bovis in badger
cubs. However, it is unclear whether this is the result of maternally derived
antibodies or prior exposure (Newell et al., 1997; Chambers et al., in press).
Nevertheless, in the majority of badgers that exhibited transient sero-positivity
as cubs, M. bovis could not be isolated from clinical samples during later life
(R. Delahay & G. Wilson, unpublished data). Both Newell et al. (1997) and
Chambers et al. (2002) reported that Western blotting may identify serum
antibodies that are correlated with prolonged culture negativity in later life.
However, at present there is insufficient information on the true immune status
(cellular immunity in particular) of these animals to predict the likely effects of
a vaccine.
3.5 It would also be important to consider what the effect of potential vaccines
would be on individuals that were already infected. If cubs are infected at an
early age by females (e.g. pre-weaning and/or pre-emergence from the sett)
then this would probably make it impossible to deliver a vaccine to them prior
to infection. However, in order for a badger vaccine to reduce the incidence of
TB in cattle it might only need to reduce the severity of disease rather than
protect against infection. It might be possible to reduce the rate of
transmission from badgers to cattle by either stopping or decreasing the
excretion of bacteria in infectious badgers. However, if the vaccine had no
effect on infected individuals, then this would suggest the necessity of
frequent follow up vaccination campaigns to prevent these animals from
causing new cases.
4. VACCINE DELIVERY.
4.1 The most likely options for successful delivery of a vaccine to wildlife are
by injection, by an aerosol spray, by ingestible bait or by an orally
administered bait with the capacity to deliver an aerosol to the respiratory
tract. The likelihood of successful immunisation resulting from each potential
delivery route will depend on the characteristics of the vaccine. For example
some vaccines might not survive passage through the gastro-intestinal tract.
The survival of the vaccine in the environment and its likely effects on non-
target species would also influence the choice of delivery vehicle. The pattern
of vaccine deployment would influence the proportion of the population that
could be reached, and this in combination with the immunisation rate would
determine the overall efficacy of the vaccine.
75
environment. Capture of animals would also allow a specific dose to be
delivered to each individual by a chosen route, and provide accurate data on
numbers vaccinated. In addition, if a suitable badger-side diagnostic test
was available then vaccination could be combined with selective culling of
infected individuals. Modelling studies suggest that as culling is more
effective in eradicating disease from the badger population than vaccination, a
combined strategy (of culling and ring vaccination for example) would be likely
to be more efficacious than vaccination alone (Smith et al., 2001).
Alternatively, vaccination by injection could be employed as a fall-back
strategy in specific problem areas, as an adjunct to bait delivery.
4.3 Badger setts are relatively conspicuous structures that could be used to
target delivery of a vaccine. Delivery of bait into the setts themselves would
limit opportunities for exposure to non-target species. Identification of setts for
bait delivery would require labour intensive surveys much like those already
carried out in treatment areas for the Randomised Culling Trial. Main setts
can often be identified (although not always with certainty), but at any given
time some badgers are also likely to be occupying other setts. Also, rates of
movement between setts might be higher in areas that have been the subject
of some disturbance in the past (Tuyttens et al., 2000b) and might change
seasonally. It is likely therefore, that in order to maximise uptake, bait would
have to be delivered to all active setts within the target area over a period of
several days, and that re-surveying for active setts would be required before
each subsequent application.
4.4 Bait uptake rates in carnivores have been monitored throughout Europe
and North America as part of strategies to control wildlife rabies by
vaccination. Bait uptake rates can be influenced by a variety of environmental
factors, including prevailing weather conditions, the availability of natural
foods and season. It might also take sometime for populations of bait nave
animals to become accustomed to a novel food source, so uptake might
improve with repeated applications.
4.5 The strategy of bait delivery to badgers would need to minimise the
opportunity for a few animals to monopolise the vaccine. This is also the aim
when carrying out studies of badger social organisation with marked bait. In
this case bait containing plastic markers is placed in badger setts and also
distributed in the immediate proximity of the holes at bait points under stones
and logs. This maximises the opportunity for all occupants of the sett to take
bait, protects it from the elements and reduces opportunities for exposure to
non-target species (Delahay et al., 2000b). Such a strategy could also be
employed to deliver a bait containing a vaccine.
76
deployment and the local availability of natural foods might have been
influential.
4.9 It is important that the vaccine had no detrimental effects if taken several
times by the same badger, as this would be extremely difficult to avoid. If
delivery of a specific dose was required, then this would seriously constrain
the options for use of an oral bait and could arguably rule it out. However, it
might be possible to use the principles of conditioned taste aversion (CTA) to
limit bait uptake by individuals. This would involve incorporating a CTA agent
in each bait, to induce nausea in any animal that consumed it. Work on foxes
and ferrets carried out by CSL suggests that this could induce a short-term
aversion to consuming further similar baits (G. Massei, unpublished data).
Trapping and injection would allow each captured animal to receive a known
dose and if these animals were marked in some way then re-dosing could be
avoided.
4.11 In New Zealand, vaccine delivery trials have been undertaken using a
mechanical device that sprays an aerosol at possums visiting a bait station .
Using this approach in badgers would require the development of suitable
technology, the vaccine would need to remain viable during storage in the bait
station and suitably prepared for reliable aerosolisation. However, automated
vaccine delivery systems could be prone to mechanical failure and it might be
difficult to monitor numbers receiving the vaccine. It is likely that a large
number of such devices would be required and it is not clear how delivery of a
specific dose and avoidance of multiple dosing could be assured, but it might
be possible to substantially reduce exposure of non-target species by such a
method.
4.12 Once a vaccine candidate and delivery route were identified then first-
order estimates of its effectiveness in the badger population could be obtained
77
from modelling studies. Following experimental dose-response and challenge
studies on captive badgers, field trials would be required to monitor the
immune responses in vaccinated and control animals in the wild, and the
effects of vaccination on patterns of disease prevalence. A field trial would
also provide the only measure of the efficacy of a badger vaccine in reducing
TB breakdown rates in cattle.
5. CONCLUSIONS.
5.5 At present, an orally delivered bait appears to be the most practical option
for vaccination (see Annex). However, the limited studies undertaken to date
suggest that rates of bait uptake could vary widely (e.g. G. Smith, unpublished
data; Southey et al., 2001), so further work would be required to identify
optimal strategies.
5.7 Field studies on the effects of a vaccine in wild badgers would require one
or more populations for which the prevalence of infection, social organisation
and demographic characteristics were already known.
6. REFERENCES.
78
badgers that shed Mycobacterium bovis. Veterinary Microbiology 86, 183-
189.
Cheeseman C.L., Jones G.W., Gallagher J. & Mallinson P.J. (1981). The
population structure, density and prevalence of tuberculosis (Mycobacterium
bovis) in badgers (Meles meles) from four areas in south-west England.
Journal of Applied Ecology, 18, 795-804.
Cheeseman C.L., Little T.W.A., Mallinson P.J., Page R.J.C., Wilesmith J.W. &
Pritchard D.G. (1985). Population ecology and the prevalence of tuberculosis
in badgers in an area of Staffordshire. Mammal Review, 15, 125-135.
Cheeseman C.L., Wilesmith J.W., Stuart F.A. & Mallinson P.J. (1988b).
Dynamics of tuberculosis in a naturally infected badger population. Mammal
Review, 18, 61-72.
Cresswell W.J., Harris S., Cheeseman C.L. & Mallinson P.J. (1992). To breed
or not to breed: an analysis of the social and density-dependent constraints on
the fecundity of female badgers (Meles meles). Philosophical Transactions of
the Royal Society of London Series B, 338, 393-407.
Delahay R.J., Langton S., Smith G.C., Clifton-Hadley R.S. & Cheeseman C.L.
(2000a). The spatio-temporal distribution of Mycobacterium bovis (Bovine
Tuberculosis) infection in a high density badger (Meles meles) population.
Journal of Animal Ecology, 69, 428-441.
Delahay R.J., Brown J.A., Mallinson P.J., Spyvee P.D., Handoll, D., Rogers,
L.M. & Cheeseman C.L. (2000b). The use of marked bait in studies of the
territorial organisation of the European badger (Meles meles). Mammal
Review, 30, 73-87.
79
McCarthy J. (1993). The badger vaccination trial in West Cork: Progress
report. In Hayden, T. J. (ed.). The Badger, 181-188. Royal Irish Academy,
Dublin.
Newell D.G., Clifton-Hadley R.S. & Cheeseman C.L. (1997). The kinetics of
serum antibody responses to natural infections with Mycobacterium bovis in
one badger social group. Epidemiology and Infection, 118, 173-180.
Rogers L.M., Delahay R.J., Cheeseman C.L., Langton S., Smith G.C. &
Clifton-Hadley R.S. (1998). Movement of badgers (Meles meles) in a high
density population: individual, population and disease effects. Proceedings of
the Royal Society Lond. B., 265, 1-8.
Rogers L.M., Delahay R.J., Cheeseman C.L., Smith G.C. & Clifton-Hadley
R.S. (1999). The increase in badger (Meles meles) density at Woodchester
Park, south-west England: a review of the implications for disease
(Mycobacterium bovis) prevalence. Mammalia, 63, 183-192.
Smith G.C., Richards M.S., Clifton-Hadley R.S. & Cheeseman C.L. (1995).
Modelling bovine tuberculosis in badgers in England: preliminary results.
Mammalia, 59, 639-650.
Smith G.C. (2002). The role of the badger (Meles meles) in rabies
epizootiology and the implications for Great Britain. Mammal Review, 32, 13-
26.
Southey A.K., Sleeman D.P., Prendergast J., OSullivan R.F.O. & Mulcahy
M.F. (2001). Use of biomarkers to assess the feasibility of delivering a
vaccine to badgers (Meles meles). Journal of Zoology, 253, 133-139.
Tuyttens F.A.M., Macdonald D.W., Delahay R. J., Rogers L.M., Mallinson P.J.,
Donnelly C. A. & Newman C. (1996). Differences in trappability of European
badgers Meles meles in three populations in England. Journal of Applied
Ecology, 36, 1051-1062.
Tuyttens F.A.M., Delahay R.J., Macdonald D.W., Cheeseman C.L., Long, B. &
Donnelly C.A. (2000a). Spatial perturbation caused by a badger (Meles
meles) culling operation: implications for the function of territoriality and the
80
control of bovine tuberculosis (Mycobacterium bovis). Journal of Animal
Ecology, 69, 815-828.
Tuyttens F.A.M., Macdonald D.W., Rogers L.M., Cheeseman C.L. & Roddam
A.W. (2000b). Comparative study on the consequences of culling badgers
(Meles meles) on biometrics, population dynamics and movement. Journal of
Animal Ecology, 69, 567-580.
Wilkinson D., Smith G.C., Delahay R.J., Rogers L.M., Cheeseman C.L. &
Clifton-Hadley R S. (2000). The effects of bovine tuberculosis
(Mycobacterium bovis) on mortality in a badger (Meles meles) population in
England. Journal of Zoology, 250, 389-395.
Wilson G., Harris S. & McLaren G. (1997). Changes in the British badger
population, 1988 to 1997. Peoples Trust for Endangered Species.
1. This example assumes that the strategy will involve two applications of bait
each year in the proximity of all the active badger setts in the target area.
2. Initially the area would need to be surveyed for all badger setts, in the
same manner as was carried out for each treatment area in the randomised
badger culling Trial. Between applications, follow-up surveys (directly
comparable to the re-surveys carried out in proactive treatment areas of the
Trial) would be required to identify any changes in sett use that may have
taken place. The resource requirements for survey work in Trial areas are
already known.
81
APPENDIX 12.
John Pollock
1. INTRODUCTION.
1.1 This appendix seeks to trace the sequence of the main events in almost a
century of attempts to develop cattle vaccines for bovine tuberculosis. Within
that broad aim, the main areas of focus have been selected to be of relevance
to the present need to assess potential strategies to address the ongoing
problem with this disease.
1.2.1 The problems the investigators were attempting to solve and the
background.
1.2.2 Any flaws now apparent which may limit the strength of the conclusions.
1.3 In a number of the studies which have been reviewed, particularly the
more historical ones, some of these details are difficult to ascertain. However,
with the benefit of previous reviews in this area (Francis, 1958; Zuckerman,
1980; OReilly and Daborn, 1995; Skinner et al., 2001; Buddle, 2001), it is
usually possible to fit each study into a perspective of how opinions and ideas
have changed with time.
82
different from present requirements. Around 100 years ago, knowledge of the
pathogenesis of the disease was in its infancy. At that time, up to a third of all
cattle were infected with tuberculosis, and there had been little attempt to deal
with the situation. Currently in the U.K., however, statutory programmes for
eradication have been in place for decades and have greatly decreased
disease prevalence. Additionally, it is become accepted that wildlife
reservoirs may play a significant rle in the maintenance of bovine
tuberculosis in particular areas (as reviewed by Krebs, 1997).
2.2 Within recent years, several authors have considered the features
required of a vaccine to effectively address bovine tuberculosis in developed
countries, like U.K. and New Zealand, where there are potential wildlife
reservoirs of infection (badgers and possums, respectively). In such a
situation, the vaccine could be targeted towards either cattle or wildlife, and
the profile of the vaccine will be different in each situation.
3. BCG.
3.1.1 The initial Bacillus Calmette Gurin was developed from a strain of M.
bovis, which had been isolated by Nocard from a case of tuberculous mastitis
by 230 passages through glycerinated bile potato medium between 1908 and
1919 (Oettinger et al., 1999). The initial strain was dispersed to many
countries in the 1920s and continuing maintenance in differing conditions
83
resulted in the production of a considerable number of substrains (such as
Moreau, Tokyo, Gothenburg, Danish, Tice, Montreal, Connaught, Glaxo,
Merieux and Pasteur). Importantly, it has been shown that the substrains of
BCG do not have identical properties and differ, for example, in their antigenic
repertoire (Behr et al., 1999). Indeed, several important T-cell antigens of M.
bovis, such as MPB64, MPB70 and MPB83, are differentially expressed by
substrains of BCG (Li et al., 1993; Matsuo et al., 1995; Wiker et al., 1996).
These differences have the implication that the substrain of BCG that is
selected for vaccination will determine the antigenic profile of the resulting
immunological priming. To that end, it has been shown that different
substrains of BCG induce differing immune responses in mice (Lagranderie et
al., 1996). Therefore, it has been considered likely that the substrain
selected, and other factors such as dose and route of vaccination, may
influence the efficacy of BCG in cattle (Newell and Hewinson, 1995).
3.2.1 Around 3 billion doses of BCG have been used since 1921 as a safe,
inexpensive, single-shot vaccine to protect people from tuberculosis, but the
overall efficacy remains somewhat controversial (Colditz et al., 1994; Roche
et al., 1995; Wilson, 2000; Fine, 2001). Over the years, many studies have
investigated the benefits of BCG and protective efficacies ranging from 80% to
less that 0% have been reported (Fine, 1995; Roche et al., 1995). Meta-
analysis of available published data indicated that BCG decreased the risk of
tuberculosis by 50% (Colditz et al., 1994). It is generally accepted that BCG
protects best against childhood and disseminated tuberculosis, but is less
effective against adult pulmonary tuberculosis, leading to a school of thought
that it protects better against internal, blood-borne spread than against initial
infection (Roche et al., 1995).
84
tuberculosis. The studies have been based either on vaccination followed by
challenge with virulent M. bovis (vaccine-challenge experiments; Table 1) or
on monitoring the effects of vaccination on field situations where cattle were
exposed to M. bovis (field studies; Table 2). While it is not always obvious
how individual studies should be ascribed, an attempt has been made in
Tables 1 and 2 to rationalize the major published information in a
chronological and geographical manner.
4.1.2 The first experiments with BCG in cattle were performed by Calmette
and Gurin (1911; 1920 and 1924). Doses of BCG, up to 200 mg, were given
intravenously and subcutaneously prior to challenge with M. bovis. At post
mortem examination, tuberculous lesions were limited in number or absent,
although guinea pig isolations were reported to be positive in some of the non-
lesioned cases. It was concluded that BCG conferred protection and
minimised lesion formation. The findings from subsequent French field trials
(Calmette and Gurin, 1920; Gurin et al., 1927) were also very encouraging,
with BCG vaccination reducing lesions or providing freedom from tuberculosis.
4.1.3 The results from the French investigations led to international interest in
the possibility of eradicating bovine tuberculosis by vaccinating cattle with
BCG. This was further stimulated by findings of an experiment in the Ukraine
(Tzeknovitzer, 1927) which concluded that BCG induced resistance to
tuberculosis in cattle.
4.1.5 An experimental study carried out in the 1930s in UK used BCG doses
of 5 and 50 mg (Buxton and Glover, 1939). Variable protection (between 0
and 50%) was reported, with the higher dose providing better results. As
reviewed by Francis (1958), in the 1930s there was also interest in the vole
bacillus (M. microti) as a potential vaccine strain. This was investigated in
calves and, after showing initial promise in inducing a relatively high degree of
immunity to M. bovis (Young and Paterson, 1949), it was ignored
subsequently due to concerns over virulence.
85
4.1.6 Zuckerman (1980) reviewed two trials which were carried out in UK in
the 1930s and 1940s, which were stated not to have been widely published.
The first trial was conduced in 4 herds infected with tuberculosis and lasted for
11 years. 47 animals were vaccinated at 6-month intervals. Ultimately, 25% of
these were found to have tuberculosis lesions, compared with 50% of their
contacts. The second trial involved more animals, but did not last as long due
to the advent of the national test-and-slaughter programme. In that case, 30%
of the vaccinated and 50% of the non-vaccinated animals were found to have
lesions.
4.1.7 Glover and Richie (1953) report on a UK trial carried out in 2 infected
areas. In that case, vaccination reduced the number of animals with lesions,
and there was an indication that vaccination was most successful if calves
were not subjected to early challenge. In another trial which was carried out
in an infected herd, it was found that considerable numbers of vaccinated
animals developed lesions, and it was concluded that test-and-slaughter was
a more realistic option (Doyle and Stuart, 1958). In other European trials,
however, more positive outcomes were reported. In two such programmes
carried out in Germany in the 1950s, tuberculosis was successfully
eradicated from herds which were known to have been infected (Schellner
and Gaggermeier, 1955; Rolle and Wiethe, 1956).
4.1.8 Considering the variable outcomes which had been reported for the use
of BCG in cattle up until the 1950s, an Expert Committee of the WHO/FAO
(1959) stated that: generally speaking, vaccination has no place in the
eradication of tuberculosis in cattle. This conclusion was based on a lack of
proven effect and the fact that BCG vaccination compromises the tuberculin
skin test.
86
4.2.1 The reports considered above provide a range of conclusions on the
potential of BCG to be used effectively against bovine tuberculosis. Among
the possible reasons for this variation, it is apparent that the studies were
performed under a great range of conditions, using different types of cattle
with different infection backgrounds, different vaccination strategies, different
methods of assessment and different criteria for success. It has been
recognised that improved animal models were needed to allow advancement
of tuberculosis vaccine development (Griffin, 2000), and, in the 1990s, Buddle
and co-workers modified the intra-tracheal method of experimentally infecting
cattle with M. bovis to allow a more controlled and appropriate assessment of
vaccines.
4.2.2 At that time in New Zealand, it was recognised that vaccination of cattle
was a possible option of addressing a tuberculosis problem confounded by
the presence of a reservoir of infection in possums. Furthermore, it had been
recognised that previous studies had vaccinated cattle with massive doses of
BCG, equivalent in many cases to in excess of 108 cfu (Skinner et al. 2001),
while it had been postulated that a low dose of BCG would provide more
effective protection by imprinting an appropriate pattern of immune response
(Bretscher, 1994; Griffin et al., 1999).
4.2.4 Further experiments were carried out in New Zealand to investigate the
effects of route of administration of BCG and compare BCG with an
alternative vaccine, killed M. vaccae (Buddle et al., 1995b). This study
confirmed the ability of BCG to reduce lesion formation in experimentally-
infected cattle, but detected no such effect for M. vaccae.
87
the subunit vaccine (based on culture filtrate proteins of M. bovis and IL-2)
was seen to enhance extrathoracic spread of infection compared to non-
vaccinates.
5.1 It has been demonstrated that vaccination with BCG can provide a
considerable degree of protection from the development of tuberculous
lesions following experimental challenge with M. bovis. However, this outcome
has not always been reflected in field trials. Indeed, attempts to utilise BCG to
control natural tuberculosis have often given disappointing results (OReilly
and Daborn, 1995; Buddle, 2001; Skinner et al., 2001). The reasons for this
overall lack of success in field situations are not clearly understood. A
number of factors have been proposed relating to either the vaccine or the
target cattle, and include:
5.2.1 Very large doses of BCG (up to 1010 cfu) were used in many field trials.
It is now considered that lower doses may induce more effective immunity
(Bretchner, 1994; Griffin et al., 1999).
5.2.2 Differing substrains of BCG were used in different trials. It has been
suggested that the lack of success in Malawi may relate to the use of BCG
Glaxo, which does not produce the dominant antigen MPB70 (C. Foster, 1992
cited by OReilly and Daborn, 1995). Interestingly, individual strains of BCG
have had very different efficacies in different trials against human tuberculosis
(Fine, 1995).
5.2.3 The viability of the BCG vaccine is difficult to ascertain. In some cattle
experiments, it has been shown that the BCG must be viable to induce
effective immunity (Haring et al., 1930). In some trials, particularly in difficult
situations, the conditions may not have been optimal for storage and
presentation of the vaccine.
88
5.3.2 Factors such as stress may affect development of effective immunity.
Griffin et al. (1999) have shown that modelling of stressful conditions by
treatment with dexamethasone has a devastating effect on development of
anti-BCG responses in deer. Other intercurrent infections may also have an
adverse effect on immuno-competence.
6. VACCINE DEVELOPMENT.
6.1 A lack of clear success for BCG along with the difficulty of addressing
some of the factors listed above, have provided impetus towards the
development of novel vaccines for bovine tuberculosis. This work has been
developing in parallel with major initiatives to develop new vaccines for human
tuberculosis and enormous potential for cross-discipline research has been
recognised.
6.2 Recent scientific advances will facilitate greatly the development of new
vaccines for bovine tuberculosis. For example, characterisation of the M.
bovis genome will provide great advantage in rational production of novel
vaccines such as sub-unit proteins, DNA vaccines, vector vaccines, M. bovis
auxotrophs and recombinant strains of BCG. Also, progress in the field of
bovine immunology will lead to greater understanding of protective immune
responses and development of tests to differentiate between vaccinated cattle
and those infected with M. bovis.
89
6.4 One major concern about vaccinating cattle with BCG has been that the
tuberculin skin test, which is often a pre-requisite for international trade, is
compromised (WHO/FAO, 1959). However, in the post-genomic era, it is
known that the process by which BCG evolved from M. bovis resulted in
deletion of defined stretches of DNA (Behr et al., 1999). This knowledge can
be utilised in the development of tests which can differentiate BCG-vaccinates
from cattle which have been exposed to M. bovis. Thus, only cattle which
have been exposed to the virulent organism will have responses to dominant
T-cell antigens such as ESAT-6 and CFP10, which are deleted from the
genome of all substrains of BCG (Pollock and Andersen, 1997; Buddle et al.,
1999; Vordermeier et al., 2002).
7. CONCLUSIONS.
7.1 As in human tuberculosis, BCG has many potential advantages for use
against tuberculosis in cattle. It is a safe, inexpensive vaccine for which there
is evidence of protective efficacy in experimental situations. However, a
number of factors, which are not fully understood, appear to compromise field
performance. Indeed, current expectations for BCG would probably fall well
short of the 90% efficacy which was indicated as necessary to provide
benefits in a mathematical model referred to by Krebs et al. (1997). It should
also be remembered that in experimental studies, the protective benefit
derived from BCG vaccination has often referred to limitation of lesions rather
than the prevention of infection. It is now generally stated that to have an
effective impact on bovine tuberculosis, a cattle vaccine must prevent
establishment and maintenance of infection. Indeed, the previous lack of
acceptable field performance for BCG may be a vindication of this current
standard.
90
8. ACKNOWLEDGEMENT.
The input of Dr Jim McNair (VSD, Belfast) in the production of this Appendix is
gratefully acknowledged.
9. REFERENCES.
Behr M.A., Wilson M.A., Gill W.P., Salamon H., Schoolnik G.K., Rane S.,
Small P.M. (1999). Comparative genomics of BCG vaccines by whole-
genome DNA microarray. Science, 284, 1520-1523
Berggren S.A. (1981). Field experiment with BCG vaccine in Malawi. British
Veterinary Journal, 137, 88-96.
Bretscher P.A. (1994). Prospects for low dose BCG vaccination against
tuberculosis. Immunobiology, 191, 548-554.
Brandt L., Feino Cunha J., Weinreich Olsen A., Chilima B., Hirsch P.,
Appelberg R., Andersen P. (2002). Failure of the Mycobacterium bovis BCG
vaccine: some species of environmental mycobacteria block multiplication of
BCG and induction of protective immunity to tuberculosis. Infection and
Immunity, 70, 672-678.
Buddle B.M., de Lisle G.W., Pfeffer A., Adwell F.E. (1995a). Immunological
responses and protection against Mycobacterium bovis in calves vaccinated
with a low dose of BCG. Vaccine, 13, 1123-1130.
Buddle B.M., Keen D., Thomson A., Jowett A.G., McCarthy A.R., Heslop J.,
de Lisle G.W., Standford J.L., Aldwell F.E. (1995b). Protection of cattle from
bovine tuberculosis by vaccination with BCG by the respiratory or
subcutaneous route, but not by vaccination with killed Mycobacterium vaccae.
Res Vet Sci., 59, 10-16.
Buddle B.M., Parlane N.A., Keen D.L., Aldwell F.E., Pollock J.M., Lightbody
K., Andersen P. (1999). Differentiation between Mycobacterium bovis BCG-
vaccinated and M. bovis-infected cattle by using recombinant mycobacterial
antigens. Clin Diagn Lab Immunol., 6, 1-5.
91
Calmatte A., Gurin C. (1911). Recherches exprimentales sur la defense
delorgganisme contre linfection tuberculose. Annuals of the Institute of
Pasteur, 25, 625-641.
Cheneau Y., Blancou J. (1975). Comparative values of live or killed BCG and
trypsinised Kochs bacillus in the immunisation of zebu against tuberculosis.
Rev. Elev. Md. Vt. Pays trop. 28, 1-7.
Colditz G.A., Brewer T.F., Berkey C.S., Wilson M.E., Burdick E., Fineberg
H.V., Mosteller F. (1994). Efficacy of BCG vaccine in the prevention of
tuberculosis. Journal of the American Medical Association, 271, 689-702.
Ellwood D.C. (1975). First results of the field use of BCG vaccine to control
bovine tuberculosis in Malawi. British Veterinary Journal, 131, 186-189.
Glover R.E., Ritchie J.N. (1953). Field trials with BCG for the immunisation of
calves against tuberculosis. British Veterinary Journal, 109, 411-427.
Griffin J.F.T., Mackintosh C.G., Slobbe L., Thomson A.J., Buchan G.S. (1999).
Vaccine protocols to optimise the protective efficacy of BCG. Tubercle and
Lung Disease, 79, 135-143.
92
Griffin J.F. (2000). Veterinary tuberculosis vaccine development. Clinical
Infectious Diseases, 30, S3, 223-228.
Harring C.M., Traum J., Hayes F.M., Henry B.S. (1930). Vaccination of calves
against tuberculosis with Calmette-Gurin culture, BCG. Hilgardia, 4, 307-
394.
Krebs J.R., Anderson R.M., Clutton-Brock T., Morrison W.I., Young D.,
Donnelly C.A. (1997). Bovine tuberculosis in cattle and badgers. Ministry of
Agriculture, Fisheries and Food (MAFF) Publications, London.
Larson W.P., Evans W.A. (1929). A two-year experiment with the Calmette
method of vaccination. Journal of the American Veterinary Medical
Association, 74, 580-585.
Li H., Ulstrup J.C., Jonassen T.O., Melby K., Nagai S., Harboe M. (1993).
Evidence for the absence of the MPB64 gene in some substrains of
Mycobacterium bovis BCG. Infection and Immunity, 61, 1730-1734.
Matsuo T., Matsumoto S., Ohara N., Kitaura H., Mizuno A., Yamada T.
(1995). Differential transcription of the MPB70 genes in two major groups of
Mycobacterium bovis BCG substrains. Microbiology, 141, 1601-1607.
Oettinger T., Jrgensen M., Ladefoged A., Haslv K., Andersen P. (1999).
Development of the Mycobacterium bovis BCG vaccine: review of the
historical and biochemical evidence for a genealogical tree. Tubercle and
Lung Disease, 79, 243-250.
93
OReilly L.M., Daborn C.J. (1995). The epidemiology of Mycobacterium bovis
infection in animals and man: a review. Tubercle and Lung Disease, 76, S1,
1-46.
Vordermeier H.M., Chambers M.A., Cockle P.J., Whelan A.O., Simmons J.,
Hewinson R.G. (2002). Correlation of ESAT-6-specific interferon production
in cattle following Mycobacterium bovis BCG vaccination against experimental
bovine tuberculosis. Infection and Immunity, 70, 3026-32.
Wedlock D.N., Vesosky B., Skinner M.A., de Lisle G.W., Orme I.M., Buddle
B.M. (2000). Vaccination of cattle with Mycobacterium bovis culture filtrate
94
proteins and interlukin-2 against bovine tuberculosis. Infection and Immunity,
68, 5809-5815.
Wiker H.G., Nagai S., Hewinson R.G., Russell W.P., Harboe M. (1996).
Heterogeneous expression of the related MPB70 and MPB83 proteins
distinguish various substrains of Mycobacterium bovis BCG and
Mycobacterium tuberculosis H37Rv. Scandinavian Journal of Immunology,
43, 374-380.
95
TABLE 1. OVERVIEW OF VACCINE CHALLENGE EXPERIMENTS
96
+ve. Protection 0-50% variation
protection with individual
6 7
Waddington & Ellwood Malawi BCG Galaxo used according to the 0.1mg S/C PM / H / B BCG appears to produce a
1972 manufacturer's instructions useful degree of resistance to
progression of TB
Ellwood & Waddington Malawi BCG Galaxo used according to 0.1-0.5mg PM / B Fewer lesions and BCG reduces the impact of
1972 manufacturer's instructions limited progression of virulent challenge. Greater
lesions in vaccine group protection in Zebu than Zebu
cross
Cheneau and Blancou 1975 Madaga- BCG 100mg S/C I/V Killed BCG and live BCG gave
scar slightly lower protection than
trypsin extract of Koch bacillus
(25.2%, 28.5% and 34.6%
respectively)
BCG, killed 250mg
Koch, 50mg
trypsin
extract
Novak and Suyubaeva 1985 USSR BCG In contact PM 53% developed lesions
BK Karkov In contact PM 15% developed lesions
Buddle et al 1995 New BCG 6 x 104 S/C 800 cfu I/T3 PM /H / B 20% vaccinated calves BCG at 6 x 104 or 106 induced
Zealand Pasteur cfu lesion +ve, 30% culture significant protection against
+ve; compared to 62.5% virulent challenge
controls
BCG 6 x 106 S/C 800 cfu I/T
Pasteur cfu
Buddle et al 1995 New BCG 2 x 105 S/C 2 x 103 cfu PM / H / B 37% of vaccinated Killed M. vaccae induced no
Zealand Pasteur cfu I/T calves were lesion and protection against virulent
culture positive challenge but BCG did
compared to 77% in the
M. vaccae group. 66%
of controls were
lesioned and culture
positive
97
BCG 2 x 103 S/C
Pasteur cfu
BCG 2 x 105 I/T
Pasteur cfu
M. vaccae, 2 x 109 I/D
killed cfu
Buddle et al 1999 New BCG 5 x 105 S/C 1 x 103 cfu PM / H / B Lesions found in BCG induced little protection in
Zealand Pasteur I/T vaccinated and control this study, possibly due to
calves previous exposure to
environmental mycobacteria
Wedlock et al 2000 New BCG 1 x 106 S/C 5 x 103 cfu PM / H / B 50% of vaccinated CFP-IL2 vaccination can reduce
Zealand Pasteur I/T calves lesion +ve. All the incidence of lesions but not
calves were bacteriology as much as BCG. High dose
positive. 100% non- CFP-IL2 can induce extra
vaccinates were lesion thoracic spread
positive
CFP-IL29 200g- S/C 75% of calves lesion
1mg +ve. All calves were
bacteriology positive.
Fewer lesions were
found in the vaccinated
calves compared to
controls
Superscripts:
1 Intra-venous
2 Sub-cutaneous
3 Intra-tracheal
4 Post Mortem
5 Guinea-Pig
6 Histopathology
7 Bacteriology
8 Colony forming unit
9 Culture filtrate protein-Interleukin-2
10 Intra-dermal
98
TABLE 2. OVERVIEW OF CONTROLED FIELD TRIALS BASED ON BCG VACCINATION
99
herd were lesioned. 15 cattle practical eradication policy than
with no visible lesions vaccination
where culture negative
Schellner & Gaggermeier Germany Strain P 28 infected Complete success was met with
1955 herds the Graub method (early
inoculation, segregation,
multiple vaccination)
Rolle and Wiethe 1956 Bavaria BCG 50mg S/C Infected TB was eradicated from a
herd severely infected herd over 7yrs
Ellwood 1975 Malawi BCG 2.6 x 109 S/C Infected Meat 11.9% of vaccinated BCG vaccination is an effective
Galaxo cfu6 herd inspection calves were lesioned, control measure for bovine TB in
17.8% non-vaccinated Malawi
were lesion positive
Moodie 1977 Malawi BCG 2.6 x 109 S/C Infected Meat Reduced numbers of BCG confers protection against
cfu herd inspection reactor cattle spread of TB
Berggren 1977 Malawi BCG 2.6 x 109 S/C Infected Meat With age matched BCG has no significant effect on
Galaxo cfu herd inspection vaccine and control the control of bovine TB nor
groups there was no does it reduce the incidence of
difference in the levels meat condemnations
of protection
Berggren 1981 Malawi BCG 2.6 x 109 S/C Infected PM / B Similar levels of lesion BCG did not reduce the rate of
Galaxo cfu herd positive cattle were infection nor the progression of
found in vaccine and lesions, gives little protection
non-vaccine groups against the Afro-Asian strain of
M.bovis
Sibgatullin 1982 USSR BCG Infected Over a five year period a herd
herd was declared free from TB
Superscripts:
1. Intra-venous
2. Sub-cutaneous
3. Post Mortem
4. Guinea-Pig
5. Bacteriology
6. Colony forming unit
100
APPENDIX 13.
John Bourne
1. INTRODUCTION.
1.1 The use of vaccines in either cattle or wildlife remains a potential policy
option, although this option offers prospects only in the medium to longer
term. A vaccine development programme is already in place. This involves a
number of international collaborations which harness a global resource which
includes a significant effort to develop a vaccine against the human form of
TB.
1.2 For the future while success cannot be guaranteed, if a vaccine policy is
to be pursued for either cattle or wildlife, it must be recognised that a
demanding research programme would have to be put in place to provide
proof principle that a vaccine is likely to be effective. But more importantly its
value in the field must be validated before the Sub-Committee can
appropriately advise.
1.3 There are I believe a number of important questions that need further
discussion. The purpose of this Appendix is to revisit some of the major
questions.
2.1 Introduction.
2.1.3 Any diagnostic test based upon detecting an immune response would
need therefore to distinguish immune responses generated following infection
from those elicited following challenge of a protected vaccinated animal. This
would be difficult to achieve. In addition to being highly sensitive such a test
101
would have to have a high level of specificity for it to be acceptable, since
false positive reactions would trigger a herd breakdown control response.
2.2 Are these aims realistic or are these too restrictive? We must consider:
2.2.1.1 The apparent level of induced protection likely to depend on the level
of challenge.
2.3 Also, we need to explore whether the use of a vaccine to limit cattle to
cattle spread of infection has any potential?
2.3.2 The only vaccine candidate that could be considered at the moment
would be BCG.
2.4.1 Experimental use of BCG in cattle suggests a 50% to 75% efficacy and
an average of 75% reduction in disease severity. Although vaccinated
animals remain bacteriologically positive it might be expected that vaccination
would reduce the opportunity for disease transmission.
2.4.1.2 Naturally infected (from wildlife or cattle) but vaccinated and protected
animals could not be distinguished on the basis of immunological tests.
102
2.5 Research requirements.
3.1 Introduction.
103
3.2.1.3.5 The influence of environmental Mycobacteria is unknown.
3.2.1.3.7 Some influence groups would argue that badgers dont need this.
3.2.2.2.2 The spatial relationship between infected badgers and cattle is not
known.
4. GENERAL ISSUES.
4.2 Vaccination is likely to be less effective than culling, and thus detecting
any effect on cattle TB would require a field trial of an extent and duration
comparable with the culling trial but with a smaller expectation of success.
4.4 Live vaccine in the environment may expose cattle and lead to spurious
breakdowns.
4.5 The effect of vaccine on already infected badgers is not known it could
promote shedding or be lethal (but there is no evidence for this in other
species).
4.7 Vaccinating badgers is not a quick fix that can be implemented outside
trial areas with any expectation of effectiveness in the medium or short term.
4.8 With current policy for controlling cattle TB based on the tuberculin test
vaccinating badgers has the potential for causing as many breakdowns as it
prevents.
104
4.9 The outcome of the culling trial will have a profound influence on the
expected success of any vaccination programme. Unless perturbation effects
are massive, vaccination is likely to be less effective than culling. The trial will
provide data that are essential if we are to provide informed scientific opinion.
5. NEXT STEPS.
5.2 Protection studies are needed. Facilities in GB are not available; can we
rely solely on studies that will take place in RoI which will encompass:
5.2.3 Using this model to reach point of proof principle of vaccine candidate.
5.3 If we are satisfied about the relevance of the RoI studies to the GB
situation we could move on to consider field experimental trials and field
validation.
105
CHAPTER 14.
Ivan Morrison
1. INTRODUCTION.
2.1 As discussed elsewhere, the only vaccine that is likely to be available for
use in the field over the next few years is BCG. Although vaccination of cattle
with BCG has been shown to reduce the severity of pathology following
challenge with virulent M. bovis, a significant proportion of the vaccinated
animals continue to harbour bacteria. Moreover, animals vaccinated with
BCG give a positive reaction in the tuberculin skin test, and hence cannot be
distinguished from infected animals. For these reasons, vaccination of cattle
with BCG is not a viable option at present.
3.1 For the last 50 years control of bovine TB in the UK and the rest of
Europe has relied on herd testing to identify and remove infected animals.
This strategy was originally adopted with the aim of eradicating the disease.
The only available vaccine, BCG, was not sufficiently effective for vaccination
to be considered as a primary strategy to achieve eradication, and BCG could
not be used in conjunction with herd testing because of interference with
interpretation of the skin test. Looking to the future, development of new
diagnostics and vaccines might allow alternative control strategies
incorporating vaccination to be considered:
106
to improve the efficiency of herd testing. It is likely that a gamma interferon
assay with similar or superior sensitivity to that of the skin test will be
developed over the next few years. If sensitivity can be achieved along with a
high level of specificity, serious consideration should be given to replacing the
skin test with the gamma IFN assay as the primary diagnostic assay for herd
testing. Such a laboratory-based assay would allow improved standardisation
of TB testing and require only one farm visit per test (as compared to 2 at
present).
3.3 A diagnostic assay based on the use of defined antigens would also
potentially allow the use of vaccines that did not contain the antigens used in
the diagnostic assay. Since many of the candidate diagnostic antigens are
absent from BCG but present in wild-type M. bovis, either live attenuated or
sub-unit vaccines could be considered. However, as discussed elsewhere
(see Appendices 1 & 12), the diagnostic assay would not only need to
distinguish infected from vaccinated animals but also infected from vaccinated
immune animals that have been exposed to challenge with M. bovis. The
latter may be difficult to achieve but is amenable to experimental investigation.
3.4 Vaccination without herd testing. Current resources for control of TB are
focused on identification of animals once they have become infected with the
causative organism. If wildlife are confirmed as a major source of infection
and if measures to control infection in wildlife prove to be impractical,
unacceptable or ineffective, this control strategy will have a limited impact on
the problem and will continue to consume a large amount of resource. An
alternative radical approach would be to use vaccination of cattle as the
primary means of control in affected regions, dispense with routine herd
testing and focus resources on detection of infected carcasses in
slaughterhouses. Such a strategy would require a highly effective vaccine,
which reliably prevented systemic infection and substantially reduced
pathology and bacterial excretion. The principal aim would be to protect
human health, by ensuring that vaccination prevented organisms reaching the
mammary gland, reduced bacterial excretion to a level that posed negligible
risk to humans in contact with the live animal and limited pathology to, at
most, a few small lesions in tissues that are discarded following slaughter.
This approach would probably require a vaccine with protective activity
superior to that of BCG.
107
APPENDIX 15
1.1 The Terms of Reference for the Sub-Committee were: to assist the ISG
in advising Defra Ministers on the feasibility for pursuing a TB vaccination
strategy for either cattle or wildlife. This should also include consideration of
future research requirements in addition to those already in place.
108
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Does it work?
Trials of the vaccine have been undertaken since it was first developed in the 1920s. The results have been
variable. About a third of the total trials have shown no protective effect. The remainders have shown
(*Protective efficacy is a measure of the proportion of people who would have got the disease had they not
had the vaccination. 80% protection means that 4 out of 5 individuals are protected. Efficacy for most
vaccines exceeds 95%. BCG is therefore a relatively weak protective vaccine.)
In summary
The reasons for variability are not fully understood. There have been a number of
1.Methodological. All studies varied slightly in the way they were designed
2.Different vaccines. The development of BCG has meant that strains vary according to the time at which
each has been developed. Different vaccine strains were used in the trials and are in use across the world
today.
3.Tuberculin status of subjects. Within trials some individuals in both control or vaccinated group may
have been tuberculin positive and therefore had natural protection. This may not have been accounted for
in some of the trials.
4.Different strains of M.tuberculosis. New molecular techniques have demonstrated that there are a large
number of different strains of the bacterium. It is possible that different areas of the world have different
strains, which may vary in virulence.
5.Genetic differences in population. There is variation in individual susceptibility to tuberculosis. This could
have caused disparity in results.
6.Intensity of infecting dose. Infection and susceptibility to disease may be affected by the quantity of
bacteria inhaled.
7.Nutritional differences. It is known that different nutritional states can vary susceptibility to disease. The
poorly fed individual is more susceptible.
8.Protection of controls by environmental mycobacteria. These free living mycobacteria which resemble
M.tuberculosis sometimes cause disease. They may be responsible for infecting individuals therefore
providing partial immunity to M.tuberculosis.
Studies carried out by the British Medical Research Council in the 1950s showed that BCG, when given to
teenage school children gave about 75% protection for 15 years.(1). Since 1953 it has been national policy
to vaccinate all children aged 12-13. Thus in theory the entire population receives protection from early
teenage years through to about the age of 30. The reason for choosing that age range was because in the
1950s cases rates were highest in young adults. The limited length of time for which BCG appeared to be
protective would therefore be maximal at the age when most people suffered from the disease. Secondly the
form of tuberculosis which pre-teenage children suffer from (primary) is not usually infectious, whereas the
form suffered by adults is infectious. Providing protection during early adult life therefore reduced
transmission.
In addition to the national policy for all teenagers, BCG is given at birth to those at
high risk of disease; those with a family history of tuberculosis and those from
minority ethnic groups.(see below)
No, mainly because of variation in trial results. Most countries give BCG at birth to
provide protection in the early years when infection can often lead to devastating
infected in very early life is high. Some countries such as the USA have chosen not
to use it because most trials there have not shown any protective effect.
In 1994 a metanalysis of all the trials was published. (2)This looked at a total of 1264 articles, 70 in depth,
14 prospective trials and 12 case-control studies. The authors found that seven trials show a protective effect
from death of 71%, five trials showed protection from meningitis of 64%, three, protection from disseminated
The authors concluded that geographical site of study explained 66% of variability.
They also found that on average BCG reduces risk of infection leading to disease
by 50%.
This is probably an erroneous conclusion, as the efficacy of BCG cannot be averaged. Trials show it to be
80% protective in one place and 20% in another. Average efficacy should not be taken.
Some workers believe that it is(3). This is because the BCG vaccine is continually being reproduced as part
of the manufacturing process and in common with other live organisms, which undergo this process, may be
becoming less virulent and therefore less able to provide immunity to those who are vaccinated.
In contrast sequential studies form the UK show that the 75% efficacy has been
http://www.priory.com/cmol/bcg.htm (3 of 8) [04/01/06 23:21:44]
FAQ about BCG
maintained (4,5)
Does giving BCG prevent the use of the tuberculin test in determining the
presence of infection with M. tuberculosis?
This is another area of controversy . BCG converts the tuberculin test from negative
to positive. Workers are split as to whether it is possible to tell the difference
between a positive test due to BCG alone and a positive test due to infection with
M.tuberculosis whether the individual has had previous BCG or not.
The importance of this is the decision to give preventive therapy for Latent Tuberculosis Infection (LTBI).
The USA has relied on prevention by determining whether infection (without disease) is present on the basis
of regular tuberculin testing for those at risk of infection such as health workers. BCG is not given as it is
believed to interfere with the interpretation of the tuberculin test. Other countries, such as the UK, do
give BCG but in cases where infection has occurred in addition to BCG and where
the risk of disease is appreciable, such as in co-householders of Sputum Smear
positive patients, preventive therapy can be given if the tuberculin test is strongly
positive.(7)
The probable answer to this is yes though evidence for this is necessarily sketchy. It
is probably more effective in preventing disease than providing preventive therapy to
those infected; a procedure for which there is no evidence of any efficacy at all. For
health care workers who may be exposed to drug resistant tuberculosis, even a low
protective efficacy of BCG would make vaccination worthwhile.
In a recent study of a mathematical model, BCG was preferred by small margin over
BCG should be considered for health care workers with risk of MDRTB
exposure.(8,9)
As rates of tuberculosis have declined the argument for continuing routine BCG to
the whole population becomes weaker. (10)For example if rates of disease are
5/100,00 and even if it is assumed that BCG gives 80% protection for 15 years then
A number of countries with very low rates of disease have stopped BCG vaccination, but due to the increase
of cases that has resulted at least one; the Check republic has restarted a routine BCG programme.
Conditions necessary to stop giving BCG include a good control programme, good
reporting especially of TB meningitis and the prevalence HIV and its possible impact
The result on TB cases is shown in the table below which shows rates of disease in
the Swedish and foreign born children at different percentage BCG cover.
BCG coverage
95 13 1.8
%
Incidence per 100,000 according to BCG Coverage:
Swedish 0.8 2.9 3.9
Foreign 2.6 13.2 39.4
In the present climate of rapidly increasing cases of disease world wide and mass
travel, the decision is probably not whether to stop BCG but whether to increase its
use.(13)
Arguments against use of BCG vaccine in a mass programme are not about efficacy but cost
effectiveness. (14)
Abscesses at the site of BCG injection are frequently reported. It is often assumed that this is due to bad
technique, as the injection should be given intra-cutaneaously and an accidental intramuscular injection may
result. Proximal lymph node swelling and abscess formation may rarely occur. If the injection is given at the
correct site, over insertion of Deltoid in the upper arm, the swelling will develop in the axillary lymph nodes.
immunocompromised infant. This is usually fatal. For this reason BCG should not be
In conclusion
Im glad I had my BCG
PDODavies.
References
1.Hart PD. Efficacy and applicability of mass BCG vaccination in tuberculosis control
BMJ 19677;1:587-592.
7.Rathus EM. The Heaf multiple puncture test compared with the Mantoux test in
epidemiological surveys.Med J. Aust 1956;1:696-8.
9.Stevens JP Daniel TMBCG immunization of health care workers exposed to MDRTB: a decision
analysisTubercle & Lung Dis. 1996;77:293-4.
10.Tala EO et al. Pros and Cons of BCG Vaccination in Countries with Low
Incidence of Tuberculosis.Infection Control and Hospital Epidemiology 1994;15:497-
499.
13.Cobelens GJ, van Deutekom H, Draayer-Jansen WE et al: Risk of infection with M.tuberculosis in
travellers to areas of high tuberculosis endemicity. Lancet 2000;356:461-65.
Further reading.
PGSmith and PEMFine BCG vaccination in Clinical Tuberculosis 2nd Editn Edit PDODavies, Chapman and
Hall, London 1998 pp417-434.
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Informe carrying out reference functions in the Region; (4) distribute and discuss regional
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1. cas amb malaltia confirmada per cultiu provocada pel complex M. tuberculosis.
2. cas amb frotis positiu per bacils acidoresistents (AFP) si no es disposa de
laboratoris de nivell II (que puguin processar mostres per al cultiu) o quan no es
pot esperar el cultiu rutinari d'espcies extretes de tots els casos.
Tamb s'han de notificar els casos "no definits", els quals han de complir les dues
condicions segents:
1. quan un clnic cregui que els signes i/o els smptomes clnics i/o radiolgics del
pacient sn compatibles amb la tuberculosi, i
2. quan un clnic decideixi tractar el pacient amb una terpia completa contra la
tuberculosi.
Els casos "definits" (i, quan sigui aplicable, els "no definits") de tuberculosi pulmonar
s'han de dividir en funci del resultat del frotis provocat o espontani en:
Variables essencials
Les variables essencials sn: informaci que descrigui el cas, incloent-hi el temps, el lloc i la
persona, com tamb els detalls de la localitzaci de la malaltia, l'estat bacteriolgic i el fet si el
pacient ha estat tractat anteriorment.
1. Persona afectada
Edat i sexe: La data de naixement, que permet calcular l'edat en el moment en qu es va iniciar
el tractament, i el sexe sn variables que s'han de saber de cada pacient.
El lloc de residncia. El lloc de residncia d'un pacient de tuberculosi s essencial per a l'acci
de la salut pblica. El lloc de residncia ha de ser el lloc on el pacient estava vivint en el moment
en qu es va iniciar el tractament. En el cas de persones sense llar, migrants, detinguts.., es pot
donar el lloc de residncia dins del pas durant els 3 mesos anteriors, o es pot buscar qualsevol
altra soluci que els pasos individualment considerin apropiada.
Localitzaci de la malaltia.
2. Localitzaci principal
3. Localitzaci menor
La localitzaci de la malaltia s'ha de recollir en tots els pacients. Ats que els pacients poden
tenir diverses localitzacions de malaltia, es recomana que es recullin com a mnim dues
localitzacions, una de principal i una de secundria (o menor), quan sigui aplicable. Ja que la
classificaci de la localitzaci de la malaltia pot variar a diferents pasos, es recomana que es
facin servir les localitzacions segents, perqu permetran fer les agregacions que siguin
necessries en un pas concret:
Tuberculosi extrapulmonar: Tuberculosi que afecta qualsevol altre lloc diferent dels que
afecta la pulmonar.
- Tuberculosi osteoarticular. Tuberculosi que afecta els ossos i/o les articulacions;
es subdivideix en:
1. tuberculosi espinal i
2. altres tuberculosis osteoarticulars que no siguin l'espinal.
1. meningitis tuberculosa i
2. una altra tuberculosi del sistema nervis central que no sigui la meningitis.
4. Estat bacteriolgic
resposta, la de la localitzaci secundria que hagi donat un resultat positiu (ex.: frotis
d'esput positiu, tuberculosi pulmonar confirmada per cultiu o frotis de bipsia negatiu,
tuberculosi limftica confirmada per cultiu).
- el resultat i la data:
- de l'examen microscpic directe (negatiu o positiu respecte dels bacils
acidoresistents, o examen no realitzat).
- del cultiu (negatiu o positiu respecte del complex M. tuberculosis, o examen no
realitzat).
- l'espcia identificada: M. Tuberculosis (MT), Mycobacterium bovis (MB), o
Mycobacterium africanum (MA),.
- L'examen histolgic amb evidncia de bacils acidoresistents hauria de
considerar-se com un examen microscpic positiu i, per tant, s'hauria de registrar
tamb aix.
Per als efectes de la salut pblica s essencial informar sobre tots els casos de tuberculosi que
hagin estat diagnosticats per metges. Per a l'epidemiologia, on les tendncies en la incidncia
sn d'especial inters, s molt important conixer si un cas notificat ha tingut o no tuberculosi
prviament. S'ha d'anar amb compte a l'hora d'assegurar-se que no es repeteixen els informes
dels casos crnics i dels pacients que van i vnen de forma intermitent. La resposta a les
preguntes d'aquest apartat hauria d'aclarir aquestes qestions:
6. El temps
L'ideal, per obtenir estimacions acurades de la incidncia de la malaltia, seria conixer la data
del seu comenament, per aix no acostuma a ser factible; tamb la data del diagnstic pot ser
difcil de fixar en el temps, per aix es recomana que la "data d'inici del tractament" ,
considerada una dada proxy se registri en tots els casos.
La data d'inici del tractament es defineix com la data en la qual el metge est prou
segur de la seva diagnosi i inicia el tractament adequat per a la tuberculosi. Per a la
tuberculosi pulmonar, aquesta acostuma a ser quan s'obt del laboratori un resultat de
frotis d'esput positiu o, en els casos de frotis d'esput negatiu, quan el metge ha reunit
proves clniques i/o radiolgiques suficients per a la diagnosi que justifiquen l'inici del
tractament. Quan no es pot disposar de la data d'inici del tractament, aquesta es pot
substituir per la data de notificaci del cas. I per als casos que no han rebut mai cap
tractament, com ara la diagnosi postmortem, aquesta ha de substituir la data del
diagnstic.
TB Publications @
Annual Report of RIT 2001-2003 (PDF file) (updated 05.12.20)
Newsletter from Kiyose No.21 (updated 05.12.07)
Organization & Activities (updated 05.10.24)
Department of Program Support, Department of Research, Mycobacterium Reference
Center
@@@@@@
@@@@
World TB Day
Cured TB patient stories
Updated 05/12/07
This page is provided for those interested in identifying research-related contacts. Please note multiple
entries, or any inappropriate entries, including questions, will be edited or erased at the sole discretion of
the Stanford Center for Tuberculosis Research. Use the Message Board for a more free discussion
format and for questions. If you have questions regarding personal treatment, follow the links provided
from our home page; there are many sources for general information on tuberculosis disease. Don't
neglect to talk to your health care provider!
Hi! I am yasir. I am intersted to do some thing for T.B patients, thats why I am keenly interested to
my Doc in this research. I have done Mphil(biotechnology).I have experienced all the molecular
biology techniques,PCR diagnostics, sequencing,Southern, Northern and westren analysis.Gel
documentation and cloning.
yasir-ul-Musawar <yasirawan@yahoo.com>
faisalabad, punjab Pakistan - Tue Dec 19 16:52:52 2000
working as general manager in a bulk drug manufacturing company. products being manufactured
are RIFAMPICIN, ETHAMBUTOL,PYRACINAMIDE,ISONIACIN HYDRAZIDE,. would be
interested in new molucules based on anti TB drugs. qualified as M.Sc (research) PhD (by
research).looking for assistanceship in development of new molucules.25 years of industrial
experience in product identification, development in lab , scaling up to pilot plant and finally to the
production stage. waiting for early reply.
DR RAJNIKANT VYAS <leenavyas@hotmail.com>
mumbai, maharashtrs india - Fri Dec 8 16:13:09 2000
working as a professional librarian in an engineering college. looking for some projects in field of
library and information science.qualified masters degree in library and information science.would
like to takeup some research projects with academic structures. waiting for the early reply.
LEENA R VYAS <leenavyas@hotmail.com>
MUMBAI, MAHARASHTRA india - Thu Dec 7 15:43:43 2000
working as a professional librarian in an engineering college. looking for some projects in field of
library and information science.qualified masters degree in library and information science.would
like to takeup some research projects with academic structures. waiting for the early reply.
LEENA R VYAS <leenavyas@hotmail.com>
MUMBAI, MAHARASHTRA india - Thu Dec 7 15:42:38 2000
I am trying to locate the final records of my grandmother who suppose -dly died of Tuberculosis in
1940, somewhere in Northern Illinois. Probably in Adams County, Illinois. I don't know where to
look for her records. Her name was Jennie Sue Cookson, nee Bushman, born in 1883.
Joseph A. Braun <jbraun636@msn.com>
Farmington, Missouri USA - Sun Dec 3 22:53:56 2000
i have just submitted my thesis. i am interested in the field of tuberculosis immunology especially in
the CMI response induce by proteins of M.tuberculosis. and how the macrophages of the contacts
of tb patients process antigens differently. i would like information of labs working on this aspect. i
amm also interested in proteomic analysis of such proteins which elicited a protective immune
rseponse in contacts as compared to the pateints
shobhita johari <joharishobhita@hotmail.com>
delhi, delhi India - Thu Nov 30 07:36:52 2000
Available schollarships for foreign students in Germany, France, Spain, Portugal, England, Irland,
Scotland, and all Southern America.
Ekaterina Belotsvetova <M.Kate@g23.relcom.ru>
Moscow, Russia - Tue Nov 21 21:09:29 2000
Schollarships for foreign students in Germany, France, Spain, Portugal, England, Irland, Scotland,
and all Southern America.
Ekaterina Belotsvetova <M.Kate@g23.relcom.ru>
Moscow, Russia - Tue Nov 21 21:07:53 2000
Curriculum Vitae Dear Sir/Madam, In reference to the position, I would like to be considered for
this position and have provided a CV and a brief list of the techniques I have used during the
course of my research. 1- Personal details, TITLE Holding PhD degree in Molecular Microbiology
From U.K NAME JAMSHID SURNAME RAHEB DATE OF BIRTH 17 / 3 /1962 PERMANENT
ADDRESS 19, Saviz, Ghiasvand, Dampezeshki, (Contact address) Tehran 13416, IRAN WORKE
ADDRESS National Research Center for Genetic Engineering and Biotechnology, P. O. Box: 14155-
6343 Tehran, IRAN TEL (HOME) (0098) 21 6039344 (Dr Jamshid Raheb) TEL (WORKE) (0098)
21 6413626 (Dr Jamshid Raheb) FAX (0098) 21 6419834 E-MAIL jamshid@nrcgeb.ac.ir HEALTH
no disability ENGLISH LANGUAGE Speaking fluently Listening fluently Reading fluently
Writing fluently NATIVE LANGUAGE Azeri & Persian 2- Higher education, Subject Degree
From To University Country Molecular PhD 1994 1998 The University U.K. ENGLAND
Microbiology of Warwick Bacteriology Ms.C 1987 1991 Tarbiat Modarres IRAN University
Microbiology Bs.C 1983 1987 Tehran University IRAN 3-Ph.D thesis For many years physiological,
morphological and particularly molecular studies on gliding bacteria were impossible due to the
lack of a suitable technique for the genetic manipulation of this group of bacteria including
Flexibacter chinensis. Our study has focused on the physiological and morphological changes in
molecular level in this organism during the transition from the exponential to stationary phase of
growth, and during long -term stress condition. Our data demonstrate that there is a dramatic
change in respiration activity and enzymes during the stationary phase which can not be seen in the
exponential phase. Parallel to this bacterial morphology changes with a particularly noticeable size
reduction in this usually filamentous bacterium. With the collaboration of Wisconsin University in
USA we have developed a method for the molecular study of this group of bacteria. We have
constructed two mutants for the genes which produce two novel sigma factors, KatF(sS) and
RpoH(s32), and have investigated the effect of these mutants with respect to cell size changes
during the transition from growth to starvation conditions and under heat stress. The mutants
were unable to change from the filamentous to coccoidal form and consequently were unable to
survive stress as effectively as the parental strain which could undergo morphological changes. Our
data have demonstrated the importance of cell division in Flexibacter chinensis for the survival of
this bacterium under stress conditions. 4- Research work. The Microbial sulfur-specific
transformation which selectively desulfurize organic sulfur compounds in fossil fuels, has been
identified. We have cloned a 4kb gene locus from Rhodococcus erytheropolis IGTS8 (4S pathway)
on a broad host range plasmid with integration ability in chromosome of gram negative bacteria.
This organized as one operon with three genes (dszA, dszB and dszC)under the control of single
promoter. The dsz gene has been cloned under control of tac promoter in different pseudomonas
solvent tolerant species. We have applied an industrial microorganism , with the ability in
biological desulfurization. In this way, using molecular and microbiological techniques we
successfully constructed a manipulated bacterium with two relevant industrial application, that is
biosurfactant production and desulfurization of fossil fuel. Further researches is in progress to find
out the influence of the biosurfactants on DBT desulfurization. This is the new alternatives to
commercialize the biodesulfurization of crude oil processes. 5- Work experiences I have at least
four years experiences in laboratory work in microbiology and molecular microbiology in full time
basis. I have learnt many techniques in this time including molecular cloning, DNA sequencing,
southern hybridisation, northern hybridisation, two dimentional gel electrophoresis, DNA
separation techniques, DNA cloning methods using different vectors including several suicide and
other vectors, general microbiology and relevant computer skills. 6- Skills I have had more than
four years laboratory experience and have used various techniques involved in the detection,
isolation and manipulation of nucleic acids and feel that I could make a significant contribution to
your program. I have made contributions to the field of molecular biology of bacteria, due to
working with a particularly difficult bacterial strain, Flexibacter, to manipulate using conventional
molecular biology techniques. I have learned many techniques in Warwick University in United
Kingdom and National Research Center for Genetic Engineering and Biotechnology, including
molecular cloning, polymerase chain reaction, DNA sequencing, southern hybridization, northern
hybridization, western blots, DNA separation techniques, two-dimensional gel electrophoresis,
general microbiology, DNA library, Over-expression of proteins, and computer skills. 7-Resarch
interests. Molecular Biology and Microbiology Research. 8- Publication and record Currently three
works for publication on the molecular biology and physiology of Flexibacter are being prepared
SOS FROM CHINA! My mother was burned by pulmonary tuberculosis, which was controlled
goodly for some time. Unfortunetely, the illness rebaddened recently, the tuberculosis ball has
formed, said by the doctor, but there is not effective medicine in China that can enter into the
tuberculosis ball to kill the bacteria. The only choice it operation, but it may bring some danger to
the patient. I am here to ask for a favor that whether there are some effective medicine in US. Your
assistance and advice is appreciated.
Yong Luo <luoqiyun@hotmail.com>
Chongqing, China - Wed Nov 8 23:11:50 2000
I would appreciate any information about collaboration in the field of BCG phylogeny and
comparative genomic studies of BCG Vaccines. Thank you in advance!
Tzvetelina Stefanova <tzvetelina_dimkova@hotmail.com>
Sofia, Bulgaria - Tue Oct 31 07:57:34 2000
I'm a market analyst. My interest is to keep informed of the latest medical research on TB.
Ms. Homa Christensen <homac@vhinc.com>
Valencia, CA U.S.A. - Mon Oct 30 22:36:39 2000
THIS SITE ROTTS! I DON'T LIKE IT MAN!!!!! BUILD A NEW ONE YOU FESTY POO!!!
Sorry, It's actually quite good!!!!@@@@ Man!
Nar CHo <lilgodfatherau@yahoo.com>
With only 2 people, This One Jamaica - Mon Oct 16 23:12:52 2000
have any information. At present i'm working with a reputed pharmaceutical co. in my own city as
a sr. microbiologist.my future plans are to go for research.
PINKAL DIWAN <pinnacle@netwala.com>
ahmedabad, gujarat india - Sun Oct 15 13:47:20 2000
I am interested in speaking with anyone who has information about the former Mt. Kipp
sanitorium located in Glen Gardner, New Jersey. I am writing a research paper on the institution
and how its role has changed.
Karin Gruss <nirakg@yahoo.com>
- Sat Oct 14 21:37:43 2000
Film research: writer needs accounts of patients, doctors, nurses, admin. workers associated with
tb sanitoriums in 1940s-50s. Also those involved with tb screening of US public schools. Many
thanks, patriciaroberts@home.com
patricia roberts <patriciaroberts@home.com>
toronto, ontario canada - Wed Oct 11 15:45:55 2000
Interested in it 2 much !
savita chauhan <chausavi@rediffmail.com>
Indore, MP INDIA - Tue Oct 10 17:42:14 2000
My department is advising the Swiss government on various international health issues. A recent
topic of concern and interest is the tuberculosis in penitentiary centers in countries of the former
Eastern Block and possibilities to control it. Nicolaus Lorenz MD, MSc Head of Department Swiss
Tropical Institute Swiss Centre for International Health Socinstrasse 57 P.O. Box CH-4002
Basel/Switzerland Tel. +41 61 284 8 125 Fax + 41 61 271 86 54
http://www.sti.unibas.ch/scih/scih.htm
Dr. Nicolaus Lorenz <nicolaus.lorenz@unibas.ch>
Basel, Switzerland - Wed Oct 4 12:23:00 2000
My theory is proven correct. One of my relatives complained of back pain. We thought maybe it
was muscle strain. We went to the doctor for a check up. After the check up she was given a
medicine which is for TB. Aha! So I asked my relative. Have you been lacking sleep. She said yes.
She said she was working a lot. Could not get much sleep because of a lot of worries. She does get
enough rest and sleep she says. But there is a difference between a genuine rest and sleep and just
closing your eyes and pretending to be asleep. When you worry don't do it while you are resting.
Start worrying once you wake up. When you rest, just free your mind of worries. And just
concentrate on sleeping. They said she was coughing and her back really hurts.She even skipped
one day of work because of it. So I told her that her lungs are strained. And that she should let it
expand. I told her about the "Ulcer Theory". And the next day she was working already. Had I not
told her about the "Ulcer Theory" she would be in a hospital coughing blood already. And now
she's fine.
Norman Greg <Pehpot@yahoo.com>
CA U.S.A. - Wed Sep 27 23:20:04 2000
Hello everybody, I shall highly appreciate if you send me detailed information on PCR based
diagnosis of TB and MDR-TB.I shall be happy to receive the details about the PCR protocols,
primer designs and information regarding detection kits and their reference. Thank you
Dr Nilanjan Das <dasnilanjan@hotmail.com>
Calcutta, West Bengal India - Wed Sep 27 18:47:45 2000
I have been working in the medical research center in Russia (Novosibirsk State medical
University).We are developing the project about dependence with hypertermia (temperature
increase) and pulmonary tuberculosis. I would highly appreciate if somebody could provide me the
information about it.(do you have an experience to treat a people with this type of treatment, what
kind of results were achieved) Or may be you know where can i find this information. I hope that
there is the possibility of fruitful cooperation. seeler@mail.ru
Elena <seeler@mail.ru>
Novosibirsk, RU Russia - Sat Sep 16 13:44:28 2000
I am presently researching on the history and statistics of tuberculosis. Hope you'll help me to
accomlish this research through giving addresss that are relevant to my research. Thanks
bernard <blue_svo@yahoo.com>
manila, philippines - Wed Sep 13 02:18:44 2000
Tuberculosis-Diagnosis-serology
Tsigeweini Asgedom <Tsigeweini.Asgedom@cih.uib.no>
Bergen, Bergen Norway - Fri Sep 8 13:46:20 2000
Seeking for Co-operation and Support -----a specific remedy for tuberculosis Now, a specific
tuberculosis remedy, which belongs to Traditional Chinese Medicine has been discovered. It's
named " Jiupin Baoling Pellet". According to the results of observation from more than 1,000
cases, this remedy has outstanding result in treating pulmonary tuberculosis, tuberculosis of lymph
nodes and bone tuberculosis. The curative rate may reach over 85%. This completely natural
remedy is adapted to pharmacopeia compatibility clo9sely. The intranasal usage enables the
effectiveconstituents exchange with qi and blood in lungs. According to Traditional Chinese
Medicine theory, tuberculosis is caused by infection of " certain worm ". People are attacked by
this worm at the state of deficiency of vital- qi and blood. Pulmonary tuberculosis occurred when
the worm existed in lungs. If the worm reached bone marrow from the blood circulation, bone
tuberculosis and tuberculosis of lymph node would form. Among the constituents of this pellet,
secretio bufonis has the functions of detoxification, analgesis, inducing insuscitationa and treating
the toxifying disease with poisonous agents: Unbelliferae can promote blood circulation to stop pain
and tonify the blood. If the course lasted too long, this chronic disease may demage qi and blood,
even cause stagnancy of qi and blood stasis. Deficiency of qi may prevent the folw of blood, and
deficiency of blood may do harm to channedl and collaterals. The symptoms of blood stasis and
stagnation of qi can be relieved by the use of umbelliferae in the remedy. Another component ---
horner nest can be used for eliminating wind and toxic material, stopping pain and even killing the
worm. Because of the cause of disease mentioned above, the use of hornet nest can achieve expected
results. With the rich clinical practice and hard research, the use of the components is efficient, and
the results are satisfied. According to outside body experience, the tuberculomyces which have
drug resistance to anti- tuberculosis drugs are sensitive to the remedy. In clinical use obvilus results
of treatment have been achieved especially for the patients with long lasting tuberculosis. All right
reserved by ZhaoDong. Any co-operations in research, development, investment and sale are
welcome.
ZhaoDong <dhc0@21cn.com>
- Fri Sep 8 13:08:53 2000
i'm reserching for the case of ashtma it's a disease that can kill and no one has found a cure for it
yet i have ben reserchen about it for over 18 years and still have not found the closes to it i have the
disease my self and believe me i have allmost died of it alot of times i would like to find something
that is close to it so i my self can have a good life to just like other people too. so if any one out there
can give me some pointers i would sped it where everyone will know that you have gave me infor.
and you will be in that book that i write about this killer disease and god will thatnk you too. i
know i would; thank you again; ms. june;;
june lopez <lopezjune@hotmail.com>
houston, tex. 77020 usa - Fri Sep 1 17:26:32 2000
Hi there!. I would like to know about tuberculosis diagnosis and antigen immunogenicity
evaluation, collaboration programs between institutions and MSc and PhD schollarships.
Jorge Luis Gonzalez Quintana <jlgonzalez@finlay.edu.cu>
Havana, Cuba - Thu Aug 17 18:45:44 2000
Deteriorating liver.
Tom Crowley <TomCrowley13@aol.com>
Shelby Twerp, MI USA - Wed Aug 16 04:56:44 2000
cool!
Jango <Jango@office.com>
- Fri Aug 11 10:49:52 2000
am a respiratory therapist..i have a case study report this tuesday about pleural effusion and
pulmonary edema and am having a hard time finding patient data,history etc.. please HELP! JAE
RRT
jae <jae718@yahoo.com>
manila, manila phillipnes - Sat Aug 5 06:27:36 2000
I have a sister who is a doctor, in her practice with patients with Tuberculosis she got the Potts
disease; I want to known a Medical Center in the Conus of U.S. which can help us to treat her as
aid for foreign patient with this disease; any help is welcome.
Enrique A. Posada <fam.posada@navegante.com.sv>
N.Cuscatlan, La Libertad El Salavdor - Tue Aug 1 04:32:09 2000
I am doing research in production and quatitative techniques in india and Looking for any
additional scholarships/sponserships by organisations to carry out studies.If U know any of the
organisations pls inform me.Thanks
jha T.K <tarun_kumar_jha@hotmail.com>
Ahmedabad, Gujrat india - Mon Jul 31 18:41:34 2000
I am doing research in production and quatitative techniques in india and Looking for any
additional scholarships/sponserships by organisations to carry out studies.If U know any of the
organisations pls inform me.Thanks
jha T.K <tarun_kumar_jha>
Great Site!
PageCrafters.net <sbt2@sendfree.com>
- Wed Jul 26 22:15:19 2000
Dear Sir, I am director of PPD providing in IRAN.I would be very pleased if I be in your mailling
list and have an opportunity to take higher education. Bye. With Best Wishes. Dr. Nader Mosavari
Nader Mosavari <nmosavari@rvsri.com>
Karaj, Tehran Iran - Tue Jul 25 06:41:07 2000
analyzing, designing, installment and teaching of the analog circuit and the digital circuit; Digital
imaging processingpattern recognition for developing the software in C, assemble language
Bao Susu <baosusu@scnu.edu.cn>
Guangzhou, Guangdong P.R.China - Mon Jul 24 13:24:09 2000
As I have read in one web page as a result of my web search. I can only wonder why it would need
a person to spend eight hours a day for six months or 24 hours a day for 2 months before he or she
gets infected with TB. I call it duplicating habits. It's when u acquire a persons habits. "TB is an
ulcer". An ulcer of the lungs. If u think u have TB, get plenty of rest and sleep. And relax ur body.
The less movement the better. Until you recover. "Getting enough rest and sleep expands the
lungs". Preventing it from shrinking or tightening up due to fatigue or lack of sleep. Shrinking or
tightening up of the lungs could cause one to spew blood. It's like twisting a wet towelette. Let ur
I'm looking for a current phylogenetic tree of Mycobacteria, as complete as possible, as well as a bit
of information on each species- whether or not it is free-living, and whether or not it has any
horizontal gene transfer. Any leads would be most appreciated. Thanks.
Hunter Fraser <hunter@mit.edu>
- Tue Jul 11 17:56:22 2000
Please check also my message on the message board. And don't forget to e-mail me. Thanks.
Ryan Mills <ten_f0ur@email.com>
Los Angeles, CA USA - Sun Jul 9 08:14:17 2000
Good air ventilation, a quiet surrounding and plenty of rest and sleep could cure TB. Pressures of
day to day life, not getting enough sleep and getting up early in the morning combined with an over
fatigued and tired body could lead to TB. Our lungs like our muscles could get over worked. To the
point that it's grinding itself. That it wants to spew blood. Children who lack sleep because of the
pressures of school could get TB. That is why the virue can't be cured by madicine. Because it is not
a virus and you don't need medicine to cure it. Maybe a drug or medicine to make the patient calm
and relaxed to have plenty of rest and sleep might help. E-mail me and let me know if I have a
point or not. The name I use is not my real name. Thanks
Ryan Mills <ten_f0ur@email.com>
Los Angeles, CA USA - Sun Jul 9 08:00:17 2000
I am looking for accounts/stories from people who spent time in tb sanitariums during the 1940 and
early 1950's. Any ideas on where to look? missgreer2u@yahoo.com
Julie Greer <missgreer2u@yahoo.com>
- Thu Jun 29 02:12:51 2000
I need information about History of Tuberculosisi in India . Web addresses will be helpful.
Dr. Irene Churruca <irenechu@teleline.es>
Barcelona , Barcelona Spain - Tue Jun 20 14:17:13 2000
I'm doing a paper on Tuberculosis, the history and how it began the "1health century" at the
beginning of the 21st century. If you have any information regarding any of these please send it to
me.
Rebecca <s.spears@usa.com>
New Hampshire United States - Wed Jun 14 17:39:54 2000
I'm doing a paper on Tuberculosis being the beginning of the health century, any information I can
get would be very helpful.
Rebecca <s.spears@usa.com>
Wilton, New Hampshire United States - Wed Jun 14 17:31:57 2000
i am doing a paper on Tuberculosis especially in the bones and articulations. Any information
would be helpful
alex s. <enemeno@hotmail.com>
Cali, Valle del Cauca Colombia - Tue Jun 6 22:27:00 2000
i am doing a paper on Tuberculosis especially in the bones and articulations. Any information
would be helpful
alex s.
Cali, Valle del Cauca Colombia - Tue Jun 6 22:26:35 2000
I am a student at UCLA and I was infected with TB about a year ago. I am now trying to do a
reseach paper on TB and I would really appreciate it if you could send me some information about
how TB started, what it is , and how to prevent and cure it.
Meital Amir <OOgigi>
santa monica , California - Sat May 20 17:47:52 2000
As an internist I am interested in the report of atypical mycobacterium as the causal agent for
extrapulmonary manifestation such as peripheral lymphadenitis or pleural effusion, which is
difficult to differentiate from mycobacterium tuberculosis complex. I hope some of you can share
your experience on how to diagnose in by current method such as molecular analysis or
immunologic method. Thanks.
Zuldahlan <zuldhln@bdg.centrin.net.id>
Bandung, Indonesia - Wed May 17 03:29:34 2000
Hey can you please send some names of some hospitals that help only in the healing of TB, I need a
list of hospitals for my Health class. Thank you very much, if you can email me back by April 27th.
luv to all.
Holly <Rbros@sigecom.NET>
Evansville, Indiana USA - Thu Apr 27 04:04:50 2000
Just passing through...very interesting site - I'll be back. Best wishes, Sheila
Digital-Price - Furniture
Boston, MA United States - Tue Apr 25 18:45:59 2000
I am originally from Turkey and very much interested to do any kind of research related with tbc.
I am an M.D. and prefer clinical or epidemiological researches.
Sukran Timbil <sukranti@yahoo.com>
Athens, GA USA - Mon Apr 10 22:20:33 2000
A recent breakout, this week, of TB has just happened in our community Jr. High. With a possible
infection of 200 - 250 kids I want to know in laymen's terms what TB is about, how it starts, it's
infectious rate, symptoms and incubation periods. This is a prime concern in our community right
now. Has a lot of parents scared, their children are being tested by school. Is this typically a good
thing to test so many students in such a short amount of time? Are the tests effective and what
treatments are available in the US? Thank you.
Mrs.Melanie Davis <melanie_davis@yahoo.com>
Hillsboro , OR USA - Tue Mar 28 08:34:17 2000
I have been looking for information on my paper due this Tuesday... This webpage was a great
place to look for info. I am a 6th grade student and Science is a great intrest of mine. Thanks alot
this webpage helped so much
Clay Dallas <HAWKSCTC140@Home.com>
Dallas, Texas USA - Thu Mar 23 02:10:18 2000
I'm looking for a sanitorium in Franklin County or somewhere around there called "Savilisville
Sanitorium" in the 1940's. Of course, it has been closed down for years. I'm loking for ANY
information what so ever. Thanks, Vicki G.
Vicki Gladfelter <Vickigladfelter@yahoo.com>
- Tue Mar 21 14:37:40 2000
send me addresses of women's/girls of South Delhi(India) based who are interested having sex at
any time. Thanks, Jassi
send me addresses of women's/girls who are interested having sex at any time. Thanks, Jassi
Arvind Jassi <jassi_110066@yahoo.com>
New Delhi(South), Delhi India - Wed Mar 15 08:29:16 2000
I am highly interested on the research been done on M. bovis. Molecular biology, gene expression
adn diagnosis.
ana maria zarraga <azarraga@uach.cl>
valdivia, chile - Tue Mar 14 01:11:26 2000
Can some one please tell me of a good web site where i can find out about Teberculosis. I am from
Scotland and a family member of my boy friend here has it. PLease suggest a web site for me!
Thank you
Clara <heeps_2000@yahoo.com>
Amsterdam, Netherlands Holland - Wed Feb 23 12:35:35 2000
I'm a high school student doing some reasearch on antibiotic resistance for my senior Bio class.
Any suggestions?
Andi G <shambala@maytheforcebewithyou.co.uk>
- Fri Feb 11 22:26:51 2000
Hi, biological research has always been of great interest to me. I am especially interested in how
bilogical pathogens effect cultural patterns. I have a B.A. from Binghamton University (S.U.N.Y) in
theAnthropological Sciences... I am currently pursuing a second B.A. in Biology...Please contact me
if you have any research availability in the New York City area. Thank You, Ian C. Lord
clinical aspects
sandeep saluja <drsaluja@hotmail.com>
new delhi, DELHI india - Sat Feb 5 23:46:10 2000
A research about serum A.D.Alevel in pulmonary T.B.If you have iny interest or idea please
contact.
Dr.HAKIM <anooshi@whatmail.com>
TEHRAN, IRAN - Wed Feb 2 22:06:17 2000
I am a highschool student interested in holistic medical research and development for a future
profession and I am looking for any suggestions to any colleges dealing with this field,
Suggestions??
Lindsey Nero <Kacey26@Worldnet.Att.net>
Mt.Holly, NJ USA - Fri Jan 28 21:27:35 2000
I'm a graduate student and would like to obtain new full text articles on Mycobacteriophage.
Wendell O. Junia <wenesis@hotmail.com>
Manila, Philippines - Fri Jan 28 11:08:47 2000
I'm a Medical Resident and I'm making a paper on the Incidence of Lung Ca in patients presenting
as PTB. I've seen a # of patients who have been treated as PTB but on biopsy or pleural fluid
studies showed CA.
Joseph E. Poblacion, MD <jopobsmd1@hotmail.com>
Cebu City, Philippines - Sun Jan 9 06:18:54 2000
We are interested in molecular characterization and drug sensitivity of Mtb strains. Also,
serodiagnosis of infection by Mtb is of our interest.
Angel Gustavo GUEVARA PhD <labinves@hcjb.org.ec>
Quito, Pichincha Ecuador - Wed Dec 22 16:05:23 1999
TB.Microbiology $ Epidemiology
Mir.Mohammad Ziaei <mmziaei@hotmail.com>
Tabriz, East Azerbaijan Iran - Mon Dec 13 19:54:18 1999
Too big of words. I don't understand it. Please use smaller words, or maybe hyperlinks to the
definations of big words. Thank you. tammi
Tammy <sporkypunk@aol.com>
Bremerton, WA USA - Sat Nov 27 21:44:55 1999
I am a student completely fascinated with molecular biology and genetics. I have performed
research on transgenic mice in embryonic develpoment at the EIB/NCI/NIH, the most incredible
experience I have gained yet. My interests mainly include the following: the human genome
research project, cancer research, and anything affiliated with genetics.
Leana Movsessian <HyeLeana@aol.com>
Germantown, Maryland USA - Mon Nov 22 20:26:03 1999
I am a student completely fascinated with molecular biology and genetics. I have performed
research on transgenic mice to decode all genes coding for embryonic develpoment and the
EIB/NCI/NIH. My interests mainly include the following: the human genome research project,
cancer research, and anything affiliated with genetics.
Leana Movsessian <HyeLeana@aol.com>
Genetics, Molecular biology, research in cancer cells, human genome project, etc
Leana Movsessian <HyeLeana@aol.com>
Germantown, Marylan USA - Mon Nov 22 20:22:18 1999
I'm italian. I'm going to finish my PhD at the end of 1999. The subject of my thesis is: Tuberculosis
in human fetal brain: microglia infection with M. tuberculosis and different strains of M. avium. I
studied mycobacterial effects on microglia cell cultures (cytokines expression and production,
chemokines expression) I'm looking for a post-doc in California to study tuberculosis. I have a
strong background in immunocytochemistry, human fetal neurons cell cultures. If you have any
ongoing projects in this area please contact me.
Monica Curto <curto@vaxca1.unica.it>
- Mon Nov 1 08:14:14 1999
I am a Masters student (history) at San Diego State researching the social effects of Tuberculosis in
Mexico and the border region. Any help is appreciated.
Christine Moore <cmoore@aznet.net>
Oceanside, Ca USA - Thu Oct 28 16:08:46 1999
Another TB positive person. Have been told never, repeat never, to get another TB test again. As
far as I know, I have no symptoms. Have been positive for 30+ years. Just sharing this with you.
I am a Medical doctor with a Master's degree in Biostatistics. I'm interested in current research on
multidrug resistance and current evaluation of the DOTS programme.
Dr Alexander Quarshie <quarshiea@hotmail.com>
- Thu Oct 7 22:39:44 1999
I am a Medica doctor with a Master's degree in Biostatistics. I'm interested in current research on
multidrug resistance and current evaluation of the DOTS programme.
Dr Alexander Quarshie <qurshiea@hotmail.com>
- Thu Oct 7 22:38:43 1999
I am a student conducting research on the controlling of TB. Although I have only begun my
research, I will be conducting and submitting information regarding the testing of a particular
drug and its derivatives. Any information about TB research is greatly appreciated as I am just
getting started.
Amber Garcia <a_garcia@po.bethanywv.edu>
Bethany, WV USA - Tue Oct 5 00:32:22 1999
I hold Ph.D. degree in Vet.Public Hlth from U.K. I am an assiss.Prof. at dep. Microbiol., Col. Vet.
Med. Baghdad previousely, now am looking for a job in Jordan. I used to supervise many M.Sc.
and Ph.D. research projects and I worked on many types of Bacteria, mainly Campylobacter,
Salmonella, Moraxella, S.aureus, Streptococci ( esp. Enterococci), Pasteurella, E.coli, Klebsiella
and I was always interested to work on T.B. because it is widely distributed in our country and in
many other countries, and more important, my wife was suffering from bone T.B. and is being
treated since February 1999, until and her condition improved quite well on an intensive course of
INH-Ethambutol-Rifampicin. I used to work in a private human clinical lab. and I was extremely
efficient in preparing acid-fast smears and I did some improvements on the routine methods under
use by most laboratories. I shall be very glad to keep in continuous touch with you. Thank you.
Dr. Amir S. Rahim Al-Obaidi <wave-gang@usa.net>
I am a pulmonary physician working in the Centre for Tuberculosis &Chest Diseases since 1990.I
hold two diplomas in Tubercular &Chest Diseases from Pakistan.My spheres of interest are
MULTIDRUG RESISTANCE IN TB,SERODIAGNOSIS OF TB AND REVIEWING THE
EFFICACY OF BCG VACCINE.Iam particularly distressed at the re emergence of this great killer
disease and needs a global effort to combat this trend.Iwould be indebted if I am in anyway able to
contribute towards the research in TB.Iwelcome anyone with similiar concern to get in touch with
me.
DR. SYED FASIHUDDIN <sfasih@awalnet.net.sa>
MAKKAH, SAUDI ARABIA - Sun Oct 3 10:24:22 1999
I am a pulmonary physician working in the Centre for Tuberculosis &Chest Diseases since 1990.I
hold two diplomas in Tubercular &Chest Diseases from Pakistan.My spheres of interest are
MULTIDRUG RESISTANCE IN TB,SERODIAGNOSIS OF TB AND REVIEWING THE
EFFICACY OF BCG VACCINE.Iam particularly distressed at the re emergence of this great killer
disease and needs a global effort to combat this trend.Iwould be indebted if I am in anyway able to
contribute towards the research in TB.Iwelcome anyone with similiar cocern to get in touch with
me.
DR. SYED FASIHUDDIN <sfasih@awalnet.net.sa>
MAKKAH, SAUDI ARABIA - Sun Oct 3 10:19:04 1999
What is tuberculosis.
Lori Palmer <lp3acres@earthlink.net>
Doswell, VA USA - Fri Oct 1 13:20:42 1999
Epidemiology
Jill Mengel <JL_Mengel@acad.fandm.edu>
Lancaster, PA Lancaster - Thu Sep 30 01:24:08 1999
I would like if I can receive some posters I can use for Health education.
Boubker Naouri <Boubker_Naouri@doh.state.fl.us>
Kissimmee, Fl USA - Fri Sep 17 19:15:57 1999
mycobacteria, membrane proteins, detergent soluble and water soluble ones, molecular biology
test
test
- Mon Aug 30 19:11:37 1999
Dear sir, Here I attached a personal resume to apply for a post doctor research in new drug
research and development.I hope you will read it carefully and reply me. your sincerely, Jie Yang
JIe Yang <tbrg@public.km.yn.cn>
kunming, yunnan P. R. China - Mon Jul 26 02:38:13 PDT 1999
Drugs Resistance.
Guillermo A. Paredes <gapmd@ix.netcom.com>
Martinez, CA USA - Tue Jul 20 21:30:12 PDT 1999
Interest: Social History of Tuberculosis in Australia; specifics re people who came to colonial
Australia 'for their health', i,.e. the cure for 'consumption'.
Lois Baglin <baglin@alphalink.com.au>
East Brighton, Victoria Australia - Mon Jul 19 22:08:36 PDT 1999
Extrapulmonary tuberculosis
Anna Marie G. Pato <docanna@cebu.pw.net.ph>
Cebu, Cebu Philippines - Fri Jul 16 06:19:17 PDT 1999
I'm a surgical resident and is interested in the management of extrapul- monary tuberculosis, since
we still have a high incidence of tb in our country we still see and treat patients with
extrapulmonary tb.
Jose Roy Z. Gregorio, M.D. <joeygmaninistis@yahoo.com>
Quezon City, Philippines - Sat Jul 3 01:00:28 PDT 1999
I have a bachelor's degree (honors) in Molecular, Cellular, and Developmental Biology and will be
studying infectious diseases as a graduate student. I would like to volunteer either in clinical or
laboratory environments - I have experience in both areas. Please contact me if you would like
assistance and are located in the SF area.
Kiersten Israel-Ballard <kiersten_ballard@hotmail.com>
Santa Cruz, CA USA - Tue Jun 29 21:28:37 PDT 1999
I want to volunteer in your research project. I am a medical doctor and already had one year
clinical experience (internship in Internal medicine at New York Hospital ).Want to volunteer
while waiting for residency.I hope to hear from you soon.
Roeliza Ebbah-Pascua <roelizapascua@hotmail.com>
San Jose, California - Tue Jun 29 09:58:07 PDT 1999
Spatial epidemiology of TB
Phil Atkinson <p.atkinson@cdsc.nthames.nhs.uk>
London, UK - Tue Jun 8 09:10:42 PDT 1999
Bovine TB, molecular epidemiology, RFLP, spoligotyping, PFGE, VNTR, AFLP, virulence,
transmissibility, stability, genomics, direct detection, PCR
Robin Skuce <skucer@dani.gov.uk>
Belfast, Northern Ireland - Tue Jun 8 06:42:57 PDT 1999
tuberculosis diagnosis, prevention, treatment We will be interested to know whether a case where
M.tb. has been isolated twice on two different days by Bactec and confirmed by use of TMA of
Gene Probe should be treated or not. General consesus is not people who are infected as the above
case should not be treated. Why. Are they not in danger to themselved in future ? How does one get
extrapulmonary tuberculosis such as renal, bone or meningitis, or lymphadenitis. Are these
infected people also dangerous to other. Would appreciate to form and be part of discussion group
on this type of matter. I am new web learner and would appreciate reply by e-mail.
Dr.Suresh Amin <suamin@pi.zaverchand.com>
Baroda, Gujarat India - Sun Jun 6 19:02:22 PDT 1999
I am interested to conduct an evaluation study on the TB Program of our local government. Are
there available research literature in this area?
Dr. Jocelyn C. Kintanar, <joycorki@iname.com>
Cebu, Cebu Philippines - Mon May 31 05:56:10 PDT 1999
I am researching the effects and damage caused by bacterial infections following surgical
procedures within major hospitals. I am interested in hearing from anyone who following infection
has tested positive for Tuberculosis, Mycomplasma, Toxomplasma, Luekemia, Cytomegolivirus.
My research interest is in particular to women who have had caesarian section.
Liani Simpson <liani@powerup.com.au>
Brisbane, Queensland Australia - Thu May 20 21:07:49 PDT 1999
I'm a graphic designer and i've been assigned a project to create a stamp collection related to
Tuberculosis and its history. I need all the visual information i can get about subjects, people linked
to this disease and pictures of the bacteria itself. Websites with good pictures related with TB will
help very much. This work will help ANTDR (Associacao Nacional de Tuberculose e Doencas
Respiratorias) in its fight against this plague. Any help i could get would be very important.
Thanks in advance.
Antonio Manuel Silva <antonio@mrnet.pt>
Lisbon, Portugal - Thu May 20 13:31:50 PDT 1999
DNA based methods for diagnosis of tubersulosis and molecular epidemiology. Interested in
collaborations.
Dr Madhu Goyal <m.goyal@herts.ac.uk>
Hatfield, U.K - Mon May 17 06:13:41 PDT 1999
I'm doing a science report on tuberculosis and I really, Really,REALLY need pictures of the
tuberculosis microbe. Katrina
Katrina Howe <thowe@ideafamilies.org>
Fairbanks, AK USA - Fri Apr 30 13:22:55 PDT 1999
i am a post graduate student doing my thesis work on mycodot LAM test efficacy in diagnosing TB
Vibrio cholerae, Population Genetics, Molecular Evolutionary Genetics, Pulsed Field Gel
Electrophoresis, Bacterial Diversity.
Diego Riao <mao9823@usa.net>
Santaf de Bogot D. C., Cundinamarca Colombia - Sun Mar 28 18:58:55 PST 1999
I would like to know more about the diagnostic aspect of tb. especiallly the modern methods. Is
there any association for tuberculosis?
Elizabeth Anne Scicluna <elizabet@mail.global.net.mt>
Malta - Sat Mar 20 12:38:44 PST 1999
Hi, We would like to inform you that our Singapore Anti-Tuberculosis Association (SATA) website
has changed its homepage address from Http://rs.nic.net.sg/virtuoucity/sata to
Http://home2.pacific.net.sg/~satakat/index.html but our Email address remains the same as
Satakat@pacific.net.sg. Please update or help to link our new webpage address to your site. Thank
you. Regards SATA
Henry <satakat@pacific.net.sg>
- Fri Mar 12 19:50:17 PST 1999
Susceptibility of man to bovine tuberculosis - Koch stated, most medical men believed the intestins
would suffer first. "I myself," he wrote, "have seen primary tuberculosis of the intestines only
twice. ...at Charity Hospital in Berline, only ten cases in five years. Primary TB of intestine w/o
lungs and bronchia never occured, in 933 cases. Biedart found only 16 cases in 3104 postmortems
on tubercuar children. So how then can we accunt for the inter-transmissibility of human and
bovine tuberculosis?" (Koch) The solution? The very tiny dark particles within each of the diseased
cells are actually plasmids. They are far too small to be clearly identified with an ordinary
microscope. Note also, plasmids are the microorganisms that transfer genes between various stains
of bacteria. it is not only tuberculosis that produces plasmids. The same microorganism(s) also
transfer genes, DNA, or drug resistant modlues between drug resistant bacteria. Hence, the very
dark, tiny particles within each cancer cell, turn out to be the same thing - plasmids. The plasmid
transfers into a weakened cell, and it resets the genes. Some plasmid are self-transferable. All are
self replicating. Hence, this well-hidden genetic altering mechanism is what produces tuberculosis,
as well as all kinds of cancers and tumors. Onces the new gene(s) are transplanted, the newly
completed genetic material functions completely FROM INSIDE THE IMMUNE
SURVEILLANCE SYSTEM OF THE HOST. Hence, this explains the subtle inheritance patterns
found in many disease, such as TB, MS, MD, Diabetes, Leprosy - and any of these, as well as
cancers and tumors are only PSEUDO-GENETIC in the orgin. Would you agree with these
statements, or not? Please let me know.
Bruce D McKay, Bio Epistemologist <jeferson@gte.net>
Tampa, FL USA - Fri Mar 5 00:23:09 PST 1999
I am conducting a study on the toxic elements in hair analysis of both patients diagnosed with TB
and family members that don't have the disease. I need information or research done on the effects
or lack of of nutrients and toxic elements in TB. I work in Hospital Santa Clara, the most
important hospital for TB in South America and we are in great need for help and support.
John E. Bastidas M.D. <fmoser@cable.net.co>
Bogot, Colombia - Fri Feb 12 04:16:37 PST 1999
I have an interesting case on tuberculosis of gall bladder. I need some references regarding the
tuberculosis of Gall Bladder
Dr. O. P. Sudrania <opsudrania@usa.net>
Siliguri, West Bengal India - Wed Feb 10 03:28:40 PST 1999
I'm doing and investigation about tuberculosis, Immunology, Genetics, diagnostic in LCR I would
like to have some information about this, if you please by able to send me these information
victor Minera <oscargal@mail.concyt.gob.gt>
Guatemala, Guatemala Guatemala - Tue Feb 9 10:16:03 PST 1999
tuberculosis
Olga Malyscheva <ok_mal@usa.net>
moscow, mo RF - Sun Feb 7 07:33:12 PST 1999
I am the student of medicine faculty of Cerrahpaa and 1 year left to be a doctor.I just want to
learn more about every patience and especially about tuberculosis because of the fact that
tuberculosis is a very important patience in my country.
Ozan Karata <okaratag@hotmail.com>
stanbul, Trkiye - Sat Feb 6 08:00:34 PST 1999
Me: TB epidemiologist at the World Health Organization (but applying to medical school, hoping
to be able to go back to California!). In the meantime, my research interests include TB and
gender, particularly gender-based differences in the delivery of TB care (a common problem in the
developing world), among other things...
Suzanne K. Scheele <ScheeleS@who.ch>
Geneva, Switzerland - Tue Feb 2 07:00:02 PST 1999
Ihave a 5 month old patient with tuberculous meningitis&cavitary lesions.How frequent we see
cavitary tuberculosis in children?
Soner Sarmask <mehmetsoner@.superonline.com>
Istanbul, Turkiye - Wed Jan 27 11:51:43 PST 1999
Looking for more info about the guidelines on testing positive on the Manatoux test when the BCG
was given over 22 years ago.
Shelagh Taylor <Oscaig@aol.com>
Great Lakes, IL USA - Fri Jan 22 07:28:41 PST 1999
develop this method of diagnosis for different diseases, the foundation being in immunological
reactions, registered with the help of the immuno-bio-chemo-luminescence naturally present in the
body, and stimulated in the acidic agent hydrogen peroxide. With the use of standard methods of
testing as a control I compared them for many years with this method of analysis and it has proved
extremely accurate.
Yakuba Nataliya <frolke@ibm.net>
Toronto, Ontario Canada - Thu Jan 21 02:43:01 PST 1999
Any research findings on TB in immigrants to developing countries. Are they responsible for
transmission to the indeginous peoples or is the reverse true?
Kenneth <kennethm@epid.lan.mcgill.ca>
Montreal, Quebec Canada - Mon Jan 18 15:07:02 PST 1999
Any research findings on TB in immigrants in developing countries. Are they responsible for
transmission to the indeginous peoples or is the reverse true?
Kenneth <kennethm@epid.lan.mcgill.ca>
Montreal, Quebec Canada - Mon Jan 18 15:05:23 PST 1999
I want to know about multiresistant tuberculosis, any information or link will be useful. Thank
Katherine Hernandez <bartleyjames@hotmail.com>
Lima, Lima Per - Mon Jan 18 14:51:49 PST 1999
Research on Active TB in adults who have had no sympotoms, negative skin tests and negative
chest Xrays negative smears, but does have positive culture of liquid from a washing of the lungs
due to a broncochope as result of a chronic non-productive cough for years..
Kay <kdddalga@ocsonline.com>
Dalton, GA USA - Sun Jan 10 22:54:04 PST 1999
Portable TB Isolation Systems For Healthcare and other needs eliminates most respirator use
Ted Arts <isosys@localnet.com>
Buffalo, NY USA - Wed Jan 6 06:48:34 PST 1999
We want to express several recombinant proteins from M.tuberculosis. Where can we get the
corrseponding DNA or cDNA?
Werner Schmitz <wschmitz@biozentrum.uni-wuerzburg.de>
I am a school nurse, our District TB policy was to conduct mass PPD skin testing on the 7th grade
students. I have found a 30% conversion rate with a 2nd PPD test, in those students that had only
redness (no induration) with the 1st PPD test. I would be interested in any research or information
regarding the signifecance of redness only reaction to a PPD skin test and its correlation to TB
infection in this or any age group. please contact me at Lannalyn@aol.com thank you L. Lee
RN,BSN
Lynn Lee <Lannalyn@aol.com>
Brownsville, Texas USA - Thu Nov 26 19:02:35 PST 1998
I am a 3 rd year Bsc student and my final year project is a kit review of Gen Probe MTB kit. I am
intrested to hear from any one else who has used this kit so that we can share useful information or
anyone who can provide useful links. THANKS
Latham Yates <latham_yates@yahoo.com>
Weymouth , Dorset England - Wed Nov 25 10:28:05 PST 1998
I am in my final year (BSc hons applied biological sciences), my final project involves Heminested
inverse PCR for rapid identification of M.tb strains. I would be grateful for any information or
links to information you can provide. Thanks
Elaine Connor <elaine.connor@iki.fi>
Manchester, England - Wed Nov 25 07:10:19 PST 1998
MDR TB
MARCIA SEISCENTO <600@apm,.org.br>
so paulo, so paulo brazil - Tue Nov 17 12:41:31 PST 1998
Tuberculosis,Fibreoptic Bronchoscopy,treatment of TB
DR BHARAT GOPAL;MD <engee@nda.vsnl.net.in>
delhi, delhi india - Sat Nov 7 01:06:06 PST 1998
Was there any Clinincal trials done in using morhine or heroin in treating Tuberculous or any lung
diseases?
Helena Bonner <Helena@physio.unr.edu>
coleraine, N.Ireland - Thu Nov 5 04:39:52 PST 1998
I am interested in all aspects related to molecular drug resistant mechanisms employed by TB.
Eric T. Y. Leung <eric@hkusua.hku.hk>
- Wed Nov 4 21:58:54 PST 1998
I am interested in any reported case dealing with Mycobacterium tuberculosis infection leading to
Interstitial lung disease or pulmonary fibrosis or any new treatment modalities for tuberculosis
infection or disease.
Emilina Montero-Luz <vinlyn@compass.com.ph>
Manila , Philippines - Mon Nov 2 21:47:43 PST 1998
I am interested in research about susceptibility genetic and TB or others topics about Molecular
Genetic in this disease
Paula Andrea Granda Carvajal <agranda@mailexcite.com>
Medelln, Antioquia Colombia - Wed Oct 14 14:42:59 PDT 1998
I'd really apreciate if anyone could send me any file rellated with tuberculosis treatment. Chemical
aspects of the drugs, farmacology, etc. Any kind of information would be usefull. Thanks!
Julian Catalan <julian@crb.org.br>
Blumenau, SC Brasil - Tue Oct 13 15:52:29 PDT 1998
Please include infor regarding epidimiology of TB within the Asian population in America.
Christine Nguyen <christine112.hotmail.com>
san jose, california U.S.A - Tue Oct 13 12:54:44 PDT 1998
I'm a biologist working at the hygiene institut in Morocco I'm unteresting in huomoral response to
mycobateium tuberculosis,SDS PAGE.
LARBI BAASSI <baassilarbi@mailcity.com>
Rabat, Morocco - Fri Oct 9 08:57:21 PDT 1998
Interest in PCR of gene probe. The local distributer claims that we can do sensitivity by PCR. Is it
true ?
Dr Suresh Amin <suamin@pi.zaverchand.com>
Baroda, Gujarat india - Sun Oct 4 17:09:13 PDT 1998
So nice a site. I would like to continue studying on TB. I am looking for some hard workers to do
research. The world is my country. It does not matter to me where to work. Waiting for you!
Babak Shokouhi <Mesri@me.ut.ac.ir>
Tehran, Iran - Sat Sep 19 14:24:56 PDT 1998
I'm a medicine student from Brasil and I need some information in order to apply in my research
:epidemiology of pleural tuberculosis and diagnosis statistics of ADA and citological analysis of
pleural effusion.
Juliana Ferreira de Oliva <Oliva@iron.com.br>
Santos, So Paulo Brasil - Wed Sep 16 10:54:20 PDT 1998
I am a 5th year medicine student in Colombia. The incidence of TBC is very high down here since
this is a third world nation. I am planning on doing my thesis about the efficiency of the ADA
(Adenosine Deaminase) test in patients with pleural effusion due to TBC. I would be interested in
any information or previous studies that have been done about this theme. My mailing address is:
Federico Castellanos Arango Calle 80 No. 55-22 Apto. 7A Barranquilla, COLOMBIA I am very
thankful for all the information you can provide me.
Federico castellanos Arango <fedecaste@hotmail.com>
Barranquilla, Atlantico Colombia - Thu Aug 13 20:24:52 PDT 1998
Dear colleagues I am very interesting to develop relations with researchers and organisations
involved in study of immunology and genetics of tuberculosis. I am representing the group of
azerbaijanian scientists from the Institute of Lung Diseases and TB. We are also very interesting in
investigation of efficacy of BCG vaccination and new forms of prevention of tuberculosis. We'll
appreciate any interest and suggestions to us. Looking forward to hearing from you.
In February of this year, my 6-year-old son was diagnosed with TB meningitis. This in turn caused
hydrocephalus, which caused several strokes to his mid- brain. We were told he had 1 week--1
month to live. If by some chance he did live he would be a vegetable. Right now he is at Methodist
Hospital in Indianapolis and is learning how to talk and walk all over again. What I'm looking for
is statistics on the survival of children who have been diagnosed with this disease and the possibility
of more strokes (what are the odds of him having more). I would also like to know if there is a
chance for him to recover completely. Please e-mail to me any information on TB Meningitis so I
can know what would be reasonable expectations for me to have. Thank you for your time and
efforts.
Holly M. Gimenez <miracleboy@hotmail.com>
Muncie, IN USA - Fri Jul 31 12:35:56 PDT 1998
I am interested in information on the spread of TB in Russia since the fall of the Soviet Union.
Thank you. genise ghee
Genise O. Ghee <gheego@mcmail1.marshall.adsn.int>
- Wed Jul 29 06:10:11 PDT 1998
Iam a professor of Biochemistry of the school of medicine, our proyect is is RFLP of multiresistant
strain of Mycobacterium Tuberculosis here in the valley of Mexicali the incidence of tb is around
49 per 100,000 we have around 650 new cases of tb per year reported by the Helth department the
number or multiresistant strains (2 or more antifimic drugs) is almost 30%. Multidrug resistant
strain,RFLP,IS6110,Inmunological response anti-tb DNA probes
Acosta-Valle Hector <acosta@csiam1.mxl.uabc.mx>
Mexicali, Baja California Mexico - Mon Jul 27 13:53:09 PDT 1998
kindly send me updates on pott's disease (journals, etc..) thru e-mail. i will highly appreciate it if
you could send it by tuesday next week because i have a case presentation re: pott's disease on
friday, thanks in advance. more power! dr. abner m. hornedo department of pediatrics de los
santos medical center quezon city, philippines
abner m. hornedo, m.d. <hornedomd@hotmail.com>
quezon city, philippines - Fri Jul 24 21:37:32 PDT 1998
What kind of fish are in the picture of Peter Small? Did he really catch them?? How many are
there?? What did they weigh??
Lizzie
- Sun Jul 19 07:15:16 PDT 1998
I would appreciate any information about all forms of TB throughout history in New York state
especially sanitoriums>Thank-you
Rebecca Guthrie <Beks1@aol.com>
- Wed Jul 1 20:56:10 PDT 1998
Clinical Tuberculosis, Chapman and Hall London, 1998. Why is the AIDS conference in Geneva
not telling the world that the commonest cause of death in AIDS patients is tuberculosis?
Peter Davies <p.d.o.davies@liverpool.ac.uk>
Liverpool, UK - Mon Jun 29 04:01:49 PDT 1998
I am in need of information about TB to be used as a teaching tool for children and parents in a
pediatric hospital in Boston
Ed Gilbert <ejg51@yahoo.com>
Evertt , MA. U.S.A. - Wed Jun 24 16:34:26 PDT 1998
Rapid mycobacterial identification by PCR-Restriction Enzme Analysis (hsp65 gene) How to make
it more practical for use in heavy burden clinical laboratories?
O. Kaya Koksalan <koksalan@escortnet.com>
Istanbul, Turkey - Mon Jun 22 11:35:22 PDT 1998
Medical Air Technology Corporation provides leading edge Air Purification systems for hospital,
correctional and long term care facilities. We work closely with infection control personnel,facility
management,safety officers, engineers and architects to provide individually designed rooms that
are GUARANTEED and CERTIFIED in writing to meet or exceed all present CDC guidelines and
OSHA regulations. For more information on TUBERCULOSIS / AIRBORNE INFECTION
CONTROL for the 21st century visit our website www.medair.com Thank you
Jeff Olarte <medairjeff@aol.com>
mission viejo, ca usa - Thu May 28 09:32:11 PDT 1998
Medical Air Technology Corporation provides leading edge Air Purification systems for hospital,
correctional and long term care facilities. We work closely with infection control personnel,facility
management,safety officers, engineers and architects to provide individually designed rooms that
are GUARANTEED and CERTIFIED in writing to meet or exceed all present CDC guidelines and
OSHA regulations. For more information on TUBERCULOSIS / AIRBORNE INFECTION
CONTROL for the 21st century visit our website www.medair.com Thank you
I am a student of medice at the UIA in Costa Rica, I am working about multidrug resistant
tuberculosis and management. I would appreciate any input in this matter.
Andres Obando Valverde <aobando@hotmail.com>
Cartago, Costa Rica - Mon May 25 23:03:46 PDT 1998
I am working at mycobacterial laboratory which is a top national referral center for the country.
We examined about 100 samples per day, almost one third of them got MDR. I would like to share
the data and learn more from TB experts in Stanford as well as other institute in USA
Dr. Tjandra Yoga Aditama SpP(K) DTM&H DTCE <doctjand@link.net.id>
Jakarta, Jakarta Indonesia - Wed May 20 07:11:27 PDT 1998
Differentiate between MOTT and M.TB in extra pulmonary specimens. regards, Bela Oza
Bela Oza <fabritex.haho@medusa.sprintrpg.ems.vsnl.net.in>
Vadadora, Gujarat India - Tue May 19 19:49:25 PDT 1998
Mycobacterium Avian Intracellular Complex, Pan Sinisitus, Pneumonia > 3 + Fx. Ribs < coughing
since 10/97 -- 4/15/98. Associated with Herpes Simplex I and systemic yeast--infections recently
diagnosed--Possible Occupational Exposure ?? HIV possible. Pet dog uthanized & checked for
above. Mother & friend also spent time w/ me checked for TB. What experience or info do you
have on this subject ? Thank You, jrstutts@sprynet.com
J. Stutts <jrstutts@sprynet.com>
White Plains, NY USA - Sun May 10 14:34:43 PDT 1998
complex " interested molecular mechanisms granuloma formation, mycobacterial virulence and
impaired macrophage function. other interest include Rheumatoid arthriris, Stroke and cancer. Dr
Vinayak D Kanade, Dept of Microbiology and Cell Biology, Indian Institute of Science, Bangalore
560012, Karnataka State, INDIA.
Dr Vinayak D Kanade <vinay@mcbl.iisc.ernet.in>
Bangalore , Karnataka INDIA - Sun May 3 09:57:15 PDT 1998
tb anything
Jeff Bauer <jeff_bauer1@hotmail.com>
New york, New york U.S.A - Fri May 1 18:18:36 PDT 1998
I am doing a term paper for Anatomy. I am a junior in high school. I am very interested in the
study of this disease. if applicable, please send me any info. Thanks.
H. Khan <h-man@thegrid.net>
- Tue Apr 28 19:15:15 PDT 1998
Isoniazid, Serodiagnosis, Newer drugs, Culture methods, Slow release preparations of antiTB
drugs
Dr.Rajesh M.Ballal <clintech@mailexcite.com>
Nagpur, Maharashtra India - Tue Apr 28 04:01:16 PDT 1998
(M. bovis)Tuberculin production, quality assurance, potency assay Animal (domestic and
exotic)tuberculosis diagnosis
Dr. Elizabeth Rohonczy <Rohonczyl@em.agr.ca>
Nepean, Ontario Canada - Fri Apr 24 09:53:44 PDT 1998
Found the web-site very useful in researching a project on TB Trends in Dudley, UK. Keep up the
good work everybody.
Simon Round
Wolverhampton, UK - Wed Apr 22 01:25:05 PDT 1998
Found the web-site very useful in researching a project on TB Trends in Dudley, UK. Keep up the
good work everybody.
Simon Round
Wolverhampton, UK - Wed Apr 22 01:24:34 PDT 1998
Found the web-site very useful in researching a project on TB Trends in Dudley, UK. Keep up the
good work everybody.
Simon Round
I'm a senior at Richard Stockton College of New Jersey. I'm working on a research paper for my
Molecular Genetics class I found MDR-TB to be a very interesting topic. I would appreciate any
input in this matter. Anything to do with Molecular Bio will be an asset.
Sunil Daniel <stk2846@loki.stockton.edu>
Absecon, NJ USA - Sun Apr 19 19:40:09 PDT 1998
userdata 128.249.49.110
mo <mg690770@bcm.tmc.edu>
- Thu Apr 16 21:38:08 PDT 1998
I am a doctor working at the National Research Hematological center. We are interested whether
you had got clinical cases of association of tuberculosis with pure red cell aplasia. We have just had
a patient who had been suffering for a long time of chronic lymphocytic leukemia ( T-cell origin).
research on: 1. new drugs 2. new vaccines (for primary disease and adult disease) 3. treatment
failures
Dr. Gina S. Itchon <jprcm@xu.edu.ph>
Cagayan de Oro, Philippines - Thu Apr 2 17:56:25 PST 1998
I want to have information about IgA determination by ELISA test ,usefull for diagnosis in
children tuberculosis.Also I can provide some results of research in Extrapulmonary tuberculosis,
and trends of bacteriological resistance in pacients from all the cities in Bolivia.
mirtha camacho <inlasa@caoba.entelnet.bo>
La Paz, La Paz. Bolivia - Thu Apr 2 15:18:09 PST 1998
Hi... I'm writing a paper on paleopathology (New World) concerning tuberculosis from a zoonotic
perspective. Do you have any information concerning mammoth/elephant, bison, etc (pleistocene)
tb-man transmission? Thank you...Tammy
Tammy Grady <tegrady@acs.ucalgary.ca>
Calgary, Alberta Canada - Wed Mar 25 12:06:24 PST 1998
I am a high school student I'd like some information about TB i can use in my research paper can
you help me?please?
Carrie Childers but its my dad's comp name <kf4owd@naxs.com>
gray, tn usa - Mon Mar 23 18:55:25 PST 1998
Need information on engineering and environmental controls for airborne infection isolation rooms
incidence and statistics on tb cases in the US and the world mdr tb statistics
jonel p. saludes <sotera.g@ustcc.ust.edu.ph>
manila, philippines - Thu Mar 12 02:46:10 PST 1998
I'm doing a research paper on Native American Health Services, I understand American Indians
have a history with the disease 'Tuberculosis'. Please write to me if there is any further
information. Sincerely, Lucynda Gorman
Lucynda Gorman <lcgorman@rocketmail.com>
Tempe, AZ US - Tue Mar 10 05:24:00 PST 1998
information on extrapulmonary tuberculosis especially the female reproductive system bone joints
Eroica Chmura <mailto:eroica.chmura@marymount.edu>
- Mon Mar 9 10:28:49 PST 1998
i am a 8th grade student doing a report on tb and i would be glad if you would help me out and
send me info whenever it is possible. thank you very much billy
Billy Stewart <c3e@hotmail.com>
dearborn hts., michigan united states - Sun Mar 8 20:02:26 PST 1998
I'm giving a speech on Tuberculosis on 3-11-98 and would like any information you might have on
case studies or any statistics regarding TB.
JoKasta McMillen <mpayne@remc.11.k12.mi.us>
Bridgman, MI USA - Fri Mar 6 11:23:56 PST 1998
I am doing a GNVQ and need research on TB and the people it effects.ASAP please.
Hannah Aylward <tony.aylward@MCmail.com>
London, England - Thu Mar 5 04:50:41 PST 1998
Molecular interactions between MTB and human macrophage. MTB gene expression pattern
Francesca Mariani <mariani@utovrm.it>
Rome, Italy - Thu Feb 19 01:58:30 PST 1998
I went to the gulf in 90/91. In March of 1997, I found out I was TB Positive after a positive skin test.
I completed the regimen of six months isoniazid. If you need someone for post treatment study, I'd
like to volunteer, and I'm in the area. Jonathan L. Hopwood
Jonathan L. Hopwood <hopwood@hoover.stanford.edu>
Menlo Park, CA US - Sat Feb 14 14:54:14 PST 1998
TUBERCULOSIS CUTANEAS
PRESEDO JULIO <JULPRE@CIUDAD.COM.AR>
BUENOS AIRES, ARGENTINA - Sun Feb 8 20:50:28 PST 1998
Data concerning incidence of suspect/confirmed infectious Tb in the long-term health care setting
(e.g. skilled nursing and assited living facilities).
Chris Davis <chris_davis@manorcare.com>
Gaithersburg, MD - Wed Feb 4 08:53:19 PST 1998
I'm in the 8th grade and doing a Science Fair Prject on TB. Please provide me with any
information possible by the end of the week.
FL Department of Corrections Office of Health Services, Environmetal Health 2601 Blair Stone RD
Tallahassee, FL 32399-2500
Gregory S. Redmon <redmon.gregory@mail.dc.state.fl.us>
Tallahassee, FL US - Fri Jan 23 06:43:38 PST 1998
Recurrence How would TB be identified if it were to recure? Ten years post can TB re-appear, the
patient followed the TB drug program and no further problems related to TB. Currently there
appears to be a small spot on the lung. Not able to preform biopsy. Could it be TB?
Eliot Bernstein <alps1@pacbell.net>
CDM, CA usa - Wed Jan 21 08:24:15 PST 1998
TB infection control public health issues worker exposures conversion rates in general population
Teresa A. Caruthers <tcaruthers@afscme.org>
Washington, DC US - Wed Jan 21 08:05:36 PST 1998
I'm innterested in "Tuberculosis" and I would like to have more inforamtion on it. If it's possible
plese send a couple of pages I don't mind Martin Ronnig
Martin Ronning <Faconnable@usa.net>
Brussels, Belgium - Mon Jan 19 01:57:36 PST 1998
Patient education, college health issues, promotion of skin testing, skin testing results and
medications used.
Jo Buczko <jabuczko@paccd.cc.ca.us>
Pasadena, CA USA - Sun Jan 18 11:34:40 PST 1998
Patient education, college health issues, promotion of skin testing, skin testing results and
medications used.
Jo Buczko <jabuczko@paccd.cc.ca.us>
Pasadena, CA USA - Sun Jan 18 11:34:22 PST 1998
Epidemiology of tuberculosis
Prikazsky Vladimir, M.D. <prikjr@mbox.vol.cz>
Prague 10, Czech Republic - Sun Jan 18 08:40:58 PST 1998
Interested in finding a position as a research assistant for Summer 98 in San Francisco area. I am
currently attending Bryn Mawr College' s postbaccalaureate pre-medical program and have some
additional reasearch/lab experience. I graduated from Princeton University in 1996, and I am
entering Jefferson Medical College in the fall. Would love suggestions from those already immersed
in research as to how they found their wonderful positions. Thanks.
Laurie Gustafson <lgustafs@brynmawr.edu>
- Mon Jan 12 12:36:37 PST 1998
international opportunities- I am a 2nd year veterinary student who would like to help with
research abroad (preferably epidemics in impoverished countries) during the summer months of
1998
Lena Gutberlet <lgutberl@mail.vt.edu>
Blacksburg, VA usa - Mon Jan 12 09:18:16 PST 1998
international opportunities- I am a 2nd year veterinary student who would like to help with
research abroad (preferably epidemics in impoverished countries) during the summer months of
1998
Lena Gutberlet <lgutberl@mail.vt.edu>
Blacksburg, VA usa - Mon Jan 12 09:17:46 PST 1998
international opportunities- I would like to help with research abroad during the summer months
of 1998
Lena Gutberlet <lgutberl@mail.vt.edu>
Blacksburg, VA usa - Mon Jan 12 09:05:57 PST 1998
I would be grateful for any information relating to the instance of TB in Ireland, past and present,
general information on TB would be likewise valuable. Thanking you, in anticipation....
Edel <Ge94323861@ailm.may.ie>
Co.Kildare, Ireland - Mon Jan 12 05:31:13 PST 1998
Hey, cool page here. Yah, well THAT'S ALL hahahahahahaha yelling's DUMB!!!
Ben Jones <banjones@hotmail.com>
Pitwomen, New Jersey USA - Sun Jan 11 14:55:46 PST 1998
MDR Tuberculosis
Dr. S. Martnez-Selmo <martnez.selmo@codetel.net.do>
Santo Domingo, Distrito Nacional Dominican Republic - Sat Jan 10 18:47:49 PST 1998
Dear Sirs: Be very pleased of directing me you with motive of requesting informacion on the
disease called granuloma tuberculosis or tumor endumedular, the request is due to that I have to a
relative with that disease and wanted to know of the fact that is tried and which isyour cure. From
already I thank your time, and I wait prompt response.
Please inform me if my newborn is at risk of contracting TB. My uncle has TB that recently
became active again after being dormant for a number of years. If my baby comes in contact with
him, is it likely, or possible, that it will infect my son? Please reply as I am very concerned and will
keep my son away from my uncle if I have to. Thank-you.
Traci Lizotte <lizotte@uniserve.com>
Chilliwack, BC Canada - Mon Jan 5 20:11:41 PST 1998
I would like to know about tuberculosis on the skin, because two years ago I had that problem. I
need to know if I'm going to have more problems when Ill decide to become mother.I finish my
treatment, but sometimes I have some little samples of Tb.
Lucia Diaz <lucy@fenix.ifisicacu.unam.mx>
Mexico, D.F Mexico - Fri Jan 2 14:00:57 PST 1998
tuberculosis of urogenital tract the evolution prognosis and treatment i am doing research on these
topics and would be thankful if you can guide me to obtain some information thank you and a
happy new year
bafiq nizar <bafiq@gmb.ro>
constanta, constanta romania - Fri Jan 2 04:51:04 PST 1998
I need informations about the transmission of TB.Ihad some cases in my family and i would like to
i like your web page it was very helping to me in my TB reort thanks a lot . keep trying to find a
cure and update this site asap . thank you so much , dominkue
dominikue
whitehaven , pa usa - Mon Dec 29 15:58:36 PST 1997
I'm interested in contacts study of tbc patients. Do you have any protocol? QP of contacts in tbc
resistant cases (INH,...)
Neus Camps Cura <fcodina@grn.es>
Girona, catalonia spain - Mon Dec 22 11:51:43 PST 1997
I am very intersted in the system regerding the care of TB patients especially highly infectious Pts.
in USA. Do most of hospitals have isolation wards or how to isolate these pts from other
immunocompromised pts?
Shuji kurane, M.D. <skurane@nms.ac.jp>
Tokyo, JAPAN - Sun Dec 21 10:01:21 PST 1997
I need info.
Andrew Rosenthal <jarosen@chicago.avenew.com>
TB and homelessness
Theresa Butler <theresa.butler@metrokc.gov>
- Wed Dec 10 12:24:51 PST 1997
Diagnostics
Maria Scully <mktg@feiltd.com>
Buffalo, NY USA - Wed Dec 10 05:44:15 PST 1997
I would appreciate any information on TB possible. Especially pictures dealing with the bacteria
and patients
Abigail Nickel <atn6037@acs.tamu.edu>
College Station, Texas USA - Wed Dec 10 02:08:43 PST 1997
Encapsulated TB
Melody Becker <chloe@bellsouth.net>
Whitehouse, TN USA - Mon Dec 8 12:08:26 PST 1997
I am pregnant and I saw that having lupus could affect my pregnancy. I don't know of having
lupus and I don't know much about it. I was trying to find out how you get tested for it.
Brandi Donley <jfoerch@remc8.k12.mi.us>
Grand Rapids, Michigan U.S.A. - Mon Dec 8 09:39:00 PST 1997
Any expert information pertaining to the residual effects of pneumo-throax treatments on the heart
muscle. Please respond. This information would be very important to me and my family.
Forrest Stephanian <Woodmannn@AOL.com>
- Sun Dec 7 19:07:01 PST 1997
I like your homepage! Good design! If you have time, come to our german homepage. Hallo,
herzlichen Glckwunsch zur gelungenen Homepage. Ausgesprochen gutes Design. Auf jeden Fall
eine Bereicherung frs Netz. Hoffentlich kommen noch viele Besucher vorbei. Mit einem
freundlichen Gru aus Deutschland!
Erich
Berlin, DDR - Wed Dec 3 17:46:39 PST 1997
Hi I am a child from I.E Weldon I am doing a project on Tuberculosis My Grandma has the
disease I was wondering if any of you could e-mail me with some websites or information on the
disease at Jo.Frost@sympatico.ca Thank you
Brad Frost <Jo.frost@sympatico.ca>
Norwood, Ontario Canada - Mon Dec 1 10:25:41 PST 1997
I am doing a report on tuberculosis and would like to find some more information. especially
primary sources, like people that had the disease or that live with it today.
Lmeister <Lmeister@ix.netcom.com>
Minneapolis, Minnesota USA - Thu Nov 27 11:51:44 PST 1997
-We are interested in pharmacokinnetics of tuberculostatic drugs in AIDS patients. -Also, we are
researching in DOT prophylaxis in drug users with isoniazid twice weekly.
j. portilla <portilla@san.gva.es>
alicante, spain - Mon Nov 24 16:52:18 PST 1997
TB fascinates me!!!! I am a second year medical student at Mayo Medical School. I am currently
seeking a position with a team researching TB in an endemic area. I am a hard worker and very
committed. Please contact me if you are aware of any potential projects. Thank you!!! Sue
Susan Kearney <Kearney.Susan@mayo.edu>
- Sun Nov 23 14:32:00 PST 1997
We've reported three of the first short course tratment reports of TB/HIV in Peru, case control
study. We need more information about local experiencies with 6 months/four drugs/short course
TB treatment
Oswaldo Jave Castillo <gjave@rcp.net.pe>
Lima, Lima Peru - Tue Nov 18 13:33:25 PST 1997
Looking for info about how M.Tuberculosis escapes the immune system and develops into TB
disease
Margarida Monteiro <mmam@students.si.fct..unl.pt>
Almada, Portugal - Sat Nov 15 11:09:02 PST 1997
I'm doing my BSc Genetics and biochemistry at the university of Wales, Aberystwyth. I am
interested in the treatment to TB and in its future research into new treatments for MDR-TB.
Karen Barker <kab5@aber.ac.uk>
Ceredigion, Wales UK - Fri Oct 31 08:42:37 PST 1997
I have an uncle who is diabetic and was diagnosed lately to have potts disease. Is potts disease
curable in this case? Or is it more likely to spread through the rest of the body? Thanks in advance.
Mostafa Afifi <the_afifis@hotmail.com>
I'm spanish from Barcelona. I'm working in Tuberculosis recombinant vaccine. I'm very interested
to work in New york city the next year 1998, due to my wife's work. I 've got a grant, then the
economic source is already solved for next year 1998. Please contact with me if you are interested in
my collaboration. Thank you very much. All together will fight against tuberculosis.
Dr. Juan Joseph Munne MD PhD in Medicine <mil-garc@uniandes.edu.co>
Barcelona, Catalunya Spain - Thu Oct 30 16:03:23 PST 1997
I'm spanish from Barcelona. I'm working in Tuberculosis recombinant vaccine. I'm very interested
to work in New york city the next year 1998, due to my wife's work. I 've got a grant, then the
economic source is already solved for next year 1998. Please contact with me if you are interest in
my collaboration. Thank you very much. All together will fight against tuberculosis.
Dr. Juan Joseph Munne MD PhD in Medicine <mil-garc@uniandes.edu.co>
Barcelona, Catalunya Spain - Thu Oct 30 15:57:02 PST 1997
M. avium complex drug therapy...My aunt has developed complications from miliary TB and
M.avium complex, and cannot tolerate the current drug therapy...please send any information on
any and all options for treating this terrible disease.
Connie Koch <Sillyme@aol.com>
Arden, NC USA - Wed Oct 22 07:29:21 PDT 1997
I am in need of information about diagnostics for hydatidosis and statistics about hydatidosis in
Peru. And some epidemiology, please. Thank you.
Alfonso Barnechea <gasbarn@telematic.edu.pe>
Lima, Lima Peru - Wed Oct 15 15:47:34 PDT 1997
DNA fingerprinting (by RAPD) of Mycobacterium tuberculosis strains to determine if MTB strains
corelate with epidemiological groups in patients which would assist in successfully seeking TB
contacts.
Cynthia B Fisher <Fisher.Cynthia@bay_pines.va.gov>
Bay Pines, FLorida USA - Fri Oct 10 09:28:56 PDT 1997
RFLP, virulence, resistance. Molecular Mecanisms of Mtb resistance. Methods for detection
Jose C. Palomares <folia@cica.es>
Seville, Spain - Sat Oct 4 14:01:03 PDT 1997
Veterinarian with canine patient with avian tuberulosis. Interested in any information on canine
tuberculosis.
Kirsten Leach <kirsten@reap.org.nz>
Taupo, New Zealand - Sat Sep 20 16:12:11 PDT 1997
I am a nursing student who is concerned with 2 fellow class mates that have tested positive on a
PPD test several years ago, one was tested twice and had a severe reaction. They were told various
things form they cannot take meds, to the meds will make their hair fall out, to they are healthy
enough they should be okay. Each is in mid 20s early 30s. Any information would be helpful.
Sarah Lieberenz <GROUCHOMAES@msn.com>
Midland, Texas USA - Thu Sep 11 22:20:38 PDT 1997
We are interested to start a pilot study concerning the treatment of tuberculosis in the county of
Iasi (Romania). We have already obtained the support of the WHO. Dr Traian Mihaescu Clinic of
Pulmonary Diseases 30 Dr I Cihac St Iasi 6600 Romania tel:+40.32.214406 fax:+40.32.213532
Traian Mihaescu <mihaescu@sigma.tuiasi.ro>
Iasi, Romania - Sun Sep 7 03:58:45 PDT 1997
tuberculoma
flora samwel <killpests@raha.com>
dar es salaam, tanzania - Sun Aug 31 05:48:23 PDT 1997
-all aspects of TB, currrently invloved in Community Health program at the Ubniversity of Natal
as a medical Student
Naeem Sader <sadern@med.und.ac.za>
Durban, KwaZulu/Natal South Africa - Sat Aug 23 09:48:19 PDT 1997
I am interested in communicating with anyone who has treated TB-meningitis or has suffered from
it. Please contact me at jgelfand@uci.edu or 714-824-4971
I am involved in a project which deals with the effect of UV light on the nosocomial transmission of
MTB and would like information related to the topic.
Tracey <Kestingt@med.und.ac.za>
Durban, Natal South Africa - Mon Aug 11 06:18:09 PDT 1997
I work in the area of image processing/rcognition and I am very interested in acquiring a large
dataset of slides or digitised images from slides of both ZN-stained and auramine-stained TB bacilli
in sputum.
Colin Campbell <C.Campbell@bris.ac.uk>
Bristol, Avon England - Mon Aug 11 02:43:26 PDT 1997
I might have TB and need to knnow more info about the disease.
Debbie Taillon <cnightmare@ibm.net>
Stittsville, Ontario Canada - Fri Aug 1 09:17:59 PDT 1997
I am looking for a suitable post-doc position. Have extensive experience in the field of tuberculosis
for the past 10 years. Have experience in Immmunology, Microbiology, Mol. Biology &
Biochemistry. Have developed Immunodiagnostic tests for tuberculosis.
Dr. Mythili Kameswaran <rmc@rmc.ernet.in>
Bombay, Maharastra India - Mon Jul 28 00:16:08 PDT 1997
I major in clinical pathology, especially microbiology. In korea, patients with active tuberculosis
are about 1% of all population. So, I have a great interest in tuberculosis. I have studied the
usefulness of TB PCR for the diagnosis of tuberculous meningitis. I would like to exchange opinions
on molecular diagnosis and epidemiologic studies.
Jae-Seok Kim, M.D. <SNUKJS@hitel.net>
Seoul, Korea - Sun Jul 27 05:26:34 PDT 1997
Diagnosis, prevention and treatment of tuberculosis. Identification of species and strain specific
DNA sequences. Methods for isolation of mycobacteria from clinical samples.
Lakshmi Kantham <lkantham@amrad.com.au>
Hawthorn East, Vic 3123 Australia - Thu Jul 24 22:39:15 PDT 1997
I am currently doing research on therapy for MDR-TB resistant to the usual triple Anti-Koch's.
Any form of help is highly appreciated. Thanks!
Dr. Leonard Lao <lllao@aimonline.org>
Caloocan, Philippines - Tue Jul 22 05:44:51 PDT 1997
This is a Very Nice Site!...Come visit us at World Association of Persons with Disabilities [WAPD]-
The Sleeping Giant is waking up! HELP you give TODAY is HELP you get Tomorrow..... BE A
PARTNER!
George Kerford, President/CEO [WAPD] <thehub@wapd.org>
San Antonio, Texas USA - Sat Jul 19 13:59:00 PDT 1997
I am from Pakistan and working with tuberculosis for last four years. Ihave worked both with
immunology and molecular pathology of mycobacteria. I have optimized the diagnosis of
extrapulmonary tuberculosis from blood and have successfully applied the techniqu to the
diagnosis of 120 clinical isolates (paper in preparation) Besides this I have also done molecular
epidemiology of tuberculosis using both Is6110 and Is 1081 for the differentiation of organism
within tuberculosis compelex and for the differentiation between M.bovis and Mtuberculosis.
Currently Iam working with the Mtp40 gene. Iam intrested in doing my Phd and persuing my
work in the same field. I am intrested in looking at the intracellular signalling followed by
phagocytosis of tubercel bacillie. If you have any ongoing projects in the related areas please
contact me.
Shaper Mirza <Mirza_Shaper@micro.microbio.uab.edu>
birmingham, Alabama united States - Fri Jul 18 14:39:07 PDT 1997
especially multiresistant tuberculosis strains in Balkans I'm from the European part of Turkey
I would like to receive information on BCG revaccination and protection against tuberculosis BCG
revaccination tuberculosis immunity tuberculosis and vaccines
Reinaldo de Menezes Martins <reinaldo@unikey.com.br>
Rio de Janeiro, RJ Brazil - Tue Jul 8 19:18:36 PDT 1997
Actually I am researching in multiresistent patients with TB treatment. I would like to receive any
information about this.
Carlos Manuel Young <balanya@c.net.gt>
Guatemala, Guatemala Guatemala - Tue Jul 8 14:35:39 PDT 1997
Im a student of medicine, I have to make a paper of TBC, epidemiolgy, drug resistance, and terapy
of TBC (PAHO protocol )
Juan Gallegos Flores <hugoga@mail.cosapidata.com.pe>
Arequipa, Per - Sat Jun 28 11:25:16 PDT 1997
I am a physician at the childrens infectious hospital in St. Petersburg, Russia. I specialize in TB &
minengitis. I would like to discuss surgery applications for the treatment of TB. I am in San
Francisco, CA from July 7-16th and from July 30 to Aug 9, 1997. I would like to discuss surgical
treatment of TB with you. I have had several succesful cases and I would like to discuss & share
this information with you. In CA my telephone number is 415-592-1397. I would like very much to
visit Stanford and view your facility. Best regards Lioudmila Klotchkova
Lioudmila klotchkova <lexas@russiamail.com>
Belmont, CA USA - Fri Jun 27 15:19:24 PDT 1997
growing mycobacteria
Jaime Esteban <fjdmicro@microb.net>
Madrid, Spain - Thu Jun 26 05:45:13 PDT 1997
More zero band strains of M.tb exists in South India. DR probe has been found to be the ideal
probe for molecular typing of M.tb. Key words: Mycobacterial virulence genes, promoters,
intracellular survival.
Dr. R. Sahadevan <sahadevan@hotmail.com>
Madras, Tamil Nadu India - Sat May 31 04:43:56 PDT 1997
Study Results of UV Light Technologies, Management of DOT & DOPT, Community Healthcare
Epidemiology Issues
Kevin A. Gritzke <jjmce@ixnetcom.com>
St. Louis, MO USA - Tue May 27 17:35:25 PDT 1997
EthnoBios S.R.L. is a small biotech company located in Bolivia working with medicinal plants that
have a history of traditional usage. At this time we are working with the sap of a plant that has a
history in treating TB, rheumatoid arthritis annd verruges. Studies have suggest that this product
induces differnt effects on sveral phases of the immune response which may be compatible with the
reported capacity to resolve the TB process. In addition, these effects (stimulation of splenocytes
and modulation of the marcrophages activity) lead to consider this substance as a promising
candidate to further studies and application as an immunomodulatory product. We have another
that is just as interesting but I have already writen more than a "few lines." Sorry. If anyone is
interested please contact me at lipena@wara.bolnet.bo We lack funding to continue our studies so
any info. would be apprecialted. Thanks, Joseph C. Traini
Lic. Joseph C. Traini <lipena@wara.bolnet.bo>
La Paz, La Paz Bolivia - Tue May 27 12:10:02 PDT 1997
Louisiana Office of Public Health employee in Tuberculosis Control Program interested in learning
more about TB diagnosis and treatment.
Richard Adams <RWadams@msn.con>
New Orleans, LA USA - Sun May 18 20:35:21 PDT 1997
I'm a graduate student who is prepareing a paper on the resurgence of TB and it's effects on the
community. Any information that can be obtained would be very much appreciated
Leslie F. Dowers <Sansouci22>
Rosedale, New York U.S.A. - Sun May 18 19:19:33 PDT 1997
I would like to receive the lattest news about tuberculosis and the co-infection with AIDS. Im a
brasilian pulmonologist that work with TB/AIDS. Thank you for your help
Enio Pires Studart <enio@openlink.com.br>
rio de janeiro, RJ Brasil - Sat May 17 15:33:18 PDT 1997
Use of HPLC for species identification of mycobacteria, susceptibility testing and epidemiology.
David Fett <keon@prof.slh.wisc.edu>
Gene expression of Mycobacteria. analysis of limiting amounts of RNA using novel techniques.
Microarray hybridization to study gene expression patterns.
Joe Mangan <jmangan@sghms.ac.uk>
London, England - Wed May 14 08:22:48 PDT 1997
I am a PhD student in Economics at the University of York. analysis of the spread and control of
tuberculosis in developing countries (case study: South - Africa), mathematical models of
population dynamics, rural-urban migration (** edited for length **)
Doriana Delfino <dd109@york.ac.uk>
York, UK Europe - Mon May 12 11:32:32 PDT 1997
I work as Lecturer in Preventive and Social Medicine in Government Medical College, Nagpur,
INDIA. My interests are DOTS and epidemiologic models of tuberculosis.
Hemant Kulkarni <h-kulkarni@usa.net>
Chapel Hill, North Carolina USA - Sat May 10 13:20:44 PDT 1997
My academic unit has a growing program of TB research (Adult and pediatric) both in London
and in Central Africa. The work encompasses immunology, epidemiology, immunotherapy and
pathology. Keywords: TB, Adult, Pediatric, Central Africa, London, Epidemiology, immunology,
microbiology
Dr.Alimuddin Zumla PhD.MD.FRCP <a.zumla@ucl.ac.uk>
London W1P 6DB, United Kingdom - Sat May 10 06:04:35 PDT 1997
I am a 16 year-old high school student from Denver who is interested in learning about TB and the
reasons for its resurgence in the past ten years, as well as multi-drug resistant tuberculosis. If
anyone has information on this topic, it would be much appreciated.
Merrill Abrams <abramsjl@texaco.com>
Denver, CO USA - Mon May 5 13:34:05 PDT 1997
I am particularly interested in multi-drug resistant TB, DNA based assay for rapid detection of
multidrug-resistant TB or rifampin resistant strains, molecular aspects of TB also ,,,and possibly
virulence
Ma. Sheila Mangalonzo-de Jesus <enteng@pusit.admu.edu.ph>
Cupang, Muntinlupa City, 1771 Philippines - Mon May 5 07:43:34 PDT 1997
Main interests: National TB Programmes, DOTS, TB and NGOs, training health workers. Visit the
DOTS,TB/HIV-AIDS,TB researches,
Petchawan Pungrassami ,M.D. <petch@t-rex.hatyai.inet.co.th>
Hatyai District, Songkla Province THAILAND - Tue Apr 29 08:36:21 PDT 1997
Looking for info on the recovery time from TB in insulin dependent diabetes.
Nancy Conner <nanna@mindspring.com>
Birmingham, AL US - Tue Apr 29 08:23:27 PDT 1997
Dept. of Biochem., Baylor college of Medicine. Interests: pathogenesis, virulence. Have isolated and
characterized the oligomeric state and chaperone activity of the 16 kDa antigen from M. tb.
Todd P. Primm <tp034588@bcm.tmc.edu>
Houston, Texas USA - Mon Apr 28 11:07:36 PDT 1997
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Vaccine Home
Vaccine
BCG Vaccine - for prevention of TUBERCULOSIS BCG
DPT
Oral Polio
Background and General Guidelines
Varicella
Measles
BCG, or bacille Calmette-Gurin, is a vaccine for tuberculosis (TB)
disease. BCG is used in many countries, but it is not generally Hepatitis-A
recommended in the United States because of the low risk of Hepatitis-B
infection with M. tuberculosis, the variable effectiveness of the BCG
Typhoid Fever
vaccine against pulmonary TB, and the vaccines interference with
tuberculin reactivity. MMR
Haemo Influenza-B
BCG vaccines are live vaccines derived from a strain of TT (Tetanus)
Mycobacterium bovis that was attenuated by Calmette and Guerin at Surgeries/Procedures
the Pasteur Institute in Lille, France (29). BCG was first administered
Obstestrics and Gyneac
to humans in 1921. Many different BCG vaccines are available
worldwide. Although all currently used vaccines were derived from Orthopeadic
the original M. bovis strain, they differ in their characteristics when General Surgeries
grown in culture and in their ability to induce an immune response to Urological
tuberculin. These variations may be caused by genetic changes that
occurred in the bacterial strains during the passage of time and by Gastrointestinal
differences in production techniques. The vaccine currently available Other Operations
for immunization in the United States, the Tice strain, was developed ENT
at the University of Illinois (Chicago, Illinois) from a strain originated
Eye
at the Pasteur Institute. The Food and Drug Administration is
considering another vaccine, which is produced by Connaught Pathology
Laboratories, Inc., for licensure in the United States. This vaccine Dental
was transferred from a strain that was maintained at the University Laparoscopic/Endoscopic
of Montreal (Montreal, Canada).
News/Articles
Incinerator for TPH
BCG vaccination does appear to lower the risk of serious
complications of primary TB in children. But in the United States, the New Facility for
consideration of BCG vaccination is recommended only for children Sr.Citizen
who have negative tuberculin skin test results, and who cannot be A New lease of life
given treatment for latent TB infection but are at high risk for TPH rises from Ashes
continuous exposure to infectious TB or to TB that is resistant to
isoniazid and rifampin. BCG is no longer recommended for health ETech. in eye surgery
care workers or other adults who are likely to be exposed to TB. New Annexe for TPH
However, vaccination of health care workers should be considered on Case Studies
an individual basis in settings in which
Gynaec tumor surgery
(1) a high percentage of TB patients are infected with M. tuberculosis A typical delivery case
strains resistant to both isoniazid and rifampin, Remedy from Squint
(2) transmission of such drug-resistant M. tuberculosis strains to
Other Links
health care workers and subsequent infection are likely, and
(3) comprehensive TB infection-control precautions have been Best Indian Hospitals
implemented and have not been successful. Jamshedpur hospitals
Dhanbad hospitals
Furthermore, BCG should not be given to persons who are Ranchi hospitals
immunosuppressed, such as persons who are infected with HIV. It
Ranchi Nursing homes
should not be given to pregnant women, even though no harmful
effects of BCG vaccination on the fetus have been observed. Community/Health
Family Welfare
Interpreting Tuberculin Skin Test Results in BCG-Vaccinated Persons Bagbera Dispensary
Lafarge OHC
In persons vaccinated with BCG, sensitivity to tuberculin is highly Tariffs
variable, depending upon the strain of BCG used and the group Bed charges
vaccinated. The presence or size of a postvaccination tuberculin skin-
test reaction does not predict whether BCG will provide any Operations charges
protection against TB disease. Working Hours
General working hours
Furthermore, the size of a tuberculin skin-test reaction in a BCG- Clinical working hours
vaccinated person is not a factor in determining whether the reaction Immunizational clinics
is caused by M. tuberculosis infection or the prior BCG vaccination.
ICU/Trauma center
Tuberculin skin testing is not contraindicated for persons who have ICU
been vaccinated with BCG, and the skin-test results of such persons Trauma center
are used to support or exclude the diagnosis of M. tuberculosis
infection. T C John center
Health Care
A diagnosis of M. tuberculosis infection and the use of treatment of Patient's Feedback
latent TB infection should be considered for any BCG-vaccinated
person who has a tuberculin skin-test reaction of >=10 mm of
induration, especially if any of the following circumstances are
present:
The vaccinated person is a contact of another person who has
infectious TB, particularly if the infectious person has transmitted M.
tuberculosis to others;
vaccinated persons who are infected with HIV and who are at risk for
M. tuberculosis infection if they have a tuberculin skin-test reaction
of >= 5 mm induration.
Tinplate Hospital
P.O.Golmuri, Jamshedpur
Phone: +91-0657-2340512, EPABX: 2340713-720
Site Developed by MSD(TCIL)
Turberculosis
"TB"
"MDR-TB" (multi-drug resistant TB)
This is part of a series on Opportunistic Infections ("OIs"). Please note that --
1. This Page Is Just A Starting Point: GIS is a great place for you to find overview
information about HIV and opportunistic infections, but it is not a substitute for getting
medical advice from a doctor who specializes in treating HIV.
2. Finding The Latest Information: Advances in treating opportunistic infections can
happen at any time, so the material on this page may be outdated. Some links in the see
also section at the bottom of this page are actually special database links. They may
contain information published after this page was written.
Classification
Infection with Mycobacterium tuburculosis
Description
Infection: TB is transmitted when a person with active TB coughs or sneezes, releasing
microscopic particles into the air. These particles, also called droplet nuclei, contain live
tubercle bacteria, and may result in infection when inhaled by another person. Once
infected by TB, most people, remain healthy and develop only latent infection. People with
latent infection are neither sick nor infectious. However, they do have the potential to
become sick and infectious with active TB. (GMHC)
An earli OI: Active TB often occurs early in the course of HIV infection, often months or
years before other OIs. In fact, TB may be the first indication that a person is HIV-infected.
TB also causes disease outside the lungs of HIV-infected people, particularly in the later
stages of AIDS. (NIH)
Multi-drug Resistant TB: Of particular concern for people with AIDS is multi-drug-
resistant TB (MDR-TB). MDR-TB occurs when patients fail to take their TB medicine for
the prolonged periods necessary to destroy all parts of the TB organism and it becomes
resistant to the drugs. These resistant organisms can be spread to other people. Even with
treatment, for individuals coinfected with HIV and MDR-TB, the death rate may be as high
as 80 percent, as opposed to 40 to 60 percent for people with MDR-TB alone. The time
from diagnosis to death for some patients with HIV and MDR-TB may be only months as
they are sometimes left with no treatment options. (NIH)
In about half of the HIV+ people with TB, the infection involves more than just the lungs.
Other targets include the lymphatic system.
Symptoms include: cough, fever, night sweats, weight loss, fatigue.
Diagnosis is usually made with a skin test.
The US Centers For Disease Control considers TB an AIDS-defining condition.
Danger Zone
TB is more frequent for those with CD4+ cells less than 200/mm but can occur at any
CD4+ count.
NOTE: If you are undergoing treatment that has increased your CD4+ levels, see the important
note on Naive T-Cells. There is some evidence that you should use the lowest CD4+
level you ever had when considering your risk for some opportunistic infections.
Prevention
The US CDC recommends treatment for any HIV+ person with latent (inactive, no
symptoms) M. tuberculosis. That diagnosis is made using skin tests.
Prophylaxis (prevention) is usually isoniazid.
Outside the US, BCG vaccination has been used for the prevention of TB.
NOTE: Many HIV experts stress that it is important that anyone newly diagnosed as being HIV-
positive be given a "TB with anergy" test. That is a test for TB, mumps, and candida. Those with
severely damaged immune systems can show false negative results on the TB test.
1. If you test positive for TB, you are infected with TB.
2. If you test negative for TB but positive for mumps or candida, you do not have TB. This is
the result you want! Those with functioning immune systems will test positive for mumps,
candida, or both ... so a positive result on these tests means the negative TB test can be
trusted.
3. If you test negative for all three, then you have anergy, which means your immune system
is to damaged to respond to common antigens.
Treatment
Treatment usually includes multiple drugs: isoniazid, rifampin, pyrazinamide,
ethambutol (or streptomycin).
Some mutations of TB are resistant to some of the common drugs. There are
susceptibility tests that can show which drugs will work on a particular strain.
The US CDC recommends DOT (directly observed therapy) -- where a nurse
watches each drug dose being taken. The biggest reason for TB treatment
failure is a failure to take the medicines.
Some with late-stage AIDS have trouble absorbing the drugs. Doctors can
sometimes run tests to see if malabsorption is a problem.
See Also...
GIS Knowledgebase: TB Drugs
GIS Knowledgebase: TB Clinical Trials
GIS Knowledgebase: AIDSline TB Articles
This information is designed to support, not replace, the relationship that exists between you and your doctor.
1998. AEGIS.
TB is at the lowest rate of increase since it's emergence in the 1980's according to the CDC.
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