BVGH Global Health Primer 2009

BVGH Global Health Primer
August 2009
Building Biotech Solutions for Diseases of the Developing World

BVGH Global Health Primer
August 2009

Founded Board of Directors Acknowledgements
2004 Robert B. Chess, Chairman BVGH thanks Anna Schoenfelder for her assistance
Chairman, Nektar Therapeutics in writing, editing, and designing the 2009 edition
Supporters Christopher D. Earl, PhD of the Global Health Primer and Joanna Lowell
Bill & Melinda Gates Foundation President & CEO, BIO Ventures for for overseeing the entire project. The Primer
Global Health benefited from feedback from Jaya Banjeri
Biotechnology Industry Organization
and Anna Wang of MMV; Lew Barker and Peg
The Rockefeller Foundation Carl B. Feldbaum Willingham of Aeras; Asmita Bavre and Anna Upton
President Emeritus, Biotechnology of the TB Alliance; Lisa Beyer and Ulysee Huling III
Industry Leaders
Industry Organization (BIO) of IAVI; Debbie Burgess of the Bill & Melinda Gates
James C. Greenwood Foundation; Esther Butler, Cynthia Roberts, and
Corporate Leadership Council
President, BIO Duncan Steele of PATH; Tim Cooke, formerly of
Alnylam Pharmaceuticals
Avant Therapeutics; Sally Ethelston of MVI; Joan
Anacor Pharmaceuticals Vaughn M. Kailian
Fahy of LSTM; Alan Fairlamb of the University of
Covington & Burling LLP General Partner, MPM Capital
Dundee; Beatrice Gordis of FIND; Larry Hale of
Exelixis, Inc. Melinda Moree, PhD WRAIR; James Hickman and Susan Lynch of iOWH;
Genzyme Corporation Former Director, Clem Lewin of Novartis; Richard Mahoney of PDVI;
Goodwin Procter LLP Malaria Vaccine Initiative Curt Malloy of IDRI; Jim McKerrow of the Sandler
Kleiner Perkins Caufield & Byers
J. Leighton Read, MD Center; Jean-Pierre Paccaud of DNDi; Mark Riddle
OSI Pharmaceuticals
General Partner, Alloy Ventures of NMRC; Holly Seltzer of IPM; Lee Schoentrup of
Vertex Pharmaceuticals
SBRI; Jaco Smith of Sanofi-Pasteur; Amit Srivastava
The Winkler Foundation George Rupp, PhD
of Children’s Hospital, Boston; Richard Tidwell
President & CEO, The
of the University of North Carolina; and Irene
International Rescue Committee
Thuo of SVI. Special thanks are owed to Anastasia
Semienko and Leighland Feinman for their help
with past editions of the Primer, without which
this document would have been significantly
more difficult to produce. Finally, BVGH gratefully
acknowledges the Bill & Melinda Gates Foundation
for their financial support.
cover photo: Julien Harneis

Message to Readers Message to Readers
Dear Reader:
How can biotech participate in solving the great unmet medical needs of this century?
BVGH exists, in part, to answer this question. The amazing capabilities of the biotech
industry—the financial resources, technology, and expertise—have the potential to make
a powerful impact on the diseases that primarily affect the poor in developing countries.
We seek out and define opportunities to apply those capabilities. By doing so, we can
encourage more companies to participate in global health and meet those medical needs.
This primer is focused on defining the global health needs for those in the life sciences
who want to understand the neglected diseases of the developing world. In addition,
information is provided for those in the global health community who want to
understand the progress being made in the development of new drugs, vaccines, and
diagnostics that could help them in the daily struggle against deadly and debilitating
diseases of poverty.
Our approach in this volume is scientific, yet conveys the urgency of these issues.
We have done all we can to be precise and accurate in the information we have
assembled. We quantify the emergence of an unprecedented array of candidate
vaccines, drugs, and diagnostics to treat developing world diseases, as well as
highlight increasing commitment from the public and private sectors to invent ways
to end the cycle of ill health and poverty that are prevalent in developing countries.
But research and development (R&D) for neglected diseases remains woefully
underfunded. We have the tools to create new drugs, vaccines, and diagnostics, but
the process remains difficult, lengthy, and exceedingly expensive. Even though the
investment is far greater than a decade ago, it’s far less than what’s needed. BVGH plays
two parts in this fight. We highlight the untapped scientific opportunities and we make
the argument for investment in R&D and incentives that will attract the brightest minds
and most powerful technologies. New technologies paired with an increasing investment
in health systems offer hope for defeating age-old diseases and offering better health and
well being to all.
Sincerely yours,
Melinda Moree, PhD

Interim CEO
BIO Ventures for Global Health
3 BVGH Global Health Primer BVGH Global Health Primer 3

List of Abbreviations
ACT . . . . . . . . . . . . . . . . artemisinin-based combination therapy
Aeras . . . . . . . . . . . . . . Aeras Global TB Vaccine Foundation
AMC. . . . . . . . . . . . . . . . Advance Market Commitment
BCG. . . . . . . . . . . . . . . . Bacille Calmette-Guerin tuberculosis vaccine
BIO. . . . . . . . . . . . . . . . . Biotechnology Industry Organization
BVGH. . . . . . . . . . . . . . BIO Ventures for Global Health
CDC. . . . . . . . . . . . . . . . Centers for Disease Control and Prevention (United States)
CPDD. . . . . . . . . . . . . . Consortium for Parasitic Drug Development
DALY. . . . . . . . . . . . . . . Disability Adjusted Life Year
DFID. . . . . . . . . . . . . . . Department for International Development (United Kingdom)
DNDi. . . . . . . . . . . . . . . Drugs for Neglected Diseases initiative
EMEA. . . . . . . . . . . . . . European Medicines Agency
EPI. . . . . . . . . . . . . . . . . Expanded Program on Immunization (WHO)
ETEC. . . . . . . . . . . . . . . Enterotoxigenic Escherichia coli
FIND. . . . . . . . . . . . . . . Foundation for Innovative Diagnostics
FDA. . . . . . . . . . . . . . . . Food and Drug Administration (United States)
FNIH. . . . . . . . . . . . . . . Foundation for the National Institutes of Health (United States)
GAVI Alliance. . . . . . Formerly Global Alliance for Vaccines and Immunisation
Global Fund. . . . . . . The Global Fund to Fight AIDS, TB and Malaria
IAVI. . . . . . . . . . . . . . . . International AIDS Vaccine Initiative
ICDDR,B . . . . . . . . . . . International Center for Diarrheal Disease Research, Bangladesh
IDRI. . . . . . . . . . . . . . . . Infectious Disease Research Institute
IFFIm . . . . . . . . . . . . . . International Financing Facility for Immunization
iOWH. . . . . . . . . . . . . . Institute for OneWorld Health
IPM . . . . . . . . . . . . . . . . International Partnership for Microbicides
IVI. . . . . . . . . . . . . . . . . . International Vaccine Institute
MDR-TB. . . . . . . . . . . . multidrug-resistant tuberculosis
MMV. . . . . . . . . . . . . . . Medicines for Malaria Venture
MVI. . . . . . . . . . . . . . . . Malaria Vaccine Initiative
NGO . . . . . . . . . . . . . . . non-governmental organization
NIAID. . . . . . . . . . . . . . National Institute for Allergy and Infectious Diseases (United States)
NIH . . . . . . . . . . . . . . . . National Institutes of Health (United States)
OECD. . . . . . . . . . . . . . Organisation for Economic Co-operation and Development
PAHO. . . . . . . . . . . . . . Pan American Health Organization
PATH. . . . . . . . . . . . . . . Formerly Program for Appropriate Technology in Health
PDP. . . . . . . . . . . . . . . . product development partnership
PEPFAR. . . . . . . . . . . . President’s Emergency Plan for AIDS Relief (United States)
PMI . . . . . . . . . . . . . . . . President’s Malaria Initiative (United States)
R&D. . . . . . . . . . . . . . . . research and development
SBRI. . . . . . . . . . . . . . . . Seattle Biomedical Research Institute
TB Alliance . . . . . . . . Global Alliance for TB Drug Development
TDR. . . . . . . . . . . . . . . . Special Programme for Research and Training in Tropical Diseases
UNDP. . . . . . . . . . . . . . United Nations Development Program
UNICEF. . . . . . . . . . . . United Nations Children’s Fund
USAID. . . . . . . . . . . . . . United States Agency for International Development
WHO. . . . . . . . . . . . . . . World Health Organization
XDR-TB . . . . . . . . . . . . extensively drug-resistant tuberculosis
Contents
BVGH Fact Sheet. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
The Global Disease Burden. . . . . . . . . . . . . . . . . . . . . 9
Bridging the Innovation Gap . . . . . . . . . . . . . . . . . . 10
The Role of Biotechnology . . . . . . . . . . . . . . . . . . . . 12
The Need for Incentives. . . . . . . . . . . . . . . . . . . . . . 12
Why the Global Health Primer? . . . . . . . . . . . . . . . 14
Key Global Health Players. . . . . . . . . . . . . . . . . . . . . 16
Select Companies Working in Global Health. . . . . 25
Highlights in Global Health R&D. . . . . . . . . . . . . . . 26
Disease Sheets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Chagas Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Cholera. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Dengue Fever (DF). . . . . . . . . . . . . . . . . . . . . . . . . 36
Enterotoxigenic E. coli (ETEC) . . . . . . . . . . . . . . . 39
Human African Trypanosomiasis (HAT). . . . . . 42
Human Hookworm Infection . . . . . . . . . . . . . . . 46
Human Immunodeficiency Virus (HIV). . . . . . . 49
Japanese Encephalitis (JE) . . . . . . . . . . . . . . . . . . 53
Leishmaniasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Lymphatic Filariasis (LF) . . . . . . . . . . . . . . . . . . . 60
Malaria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Pneumococcal Disease. . . . . . . . . . . . . . . . . . . . . 68
Rotavirus Gastroenteritis. . . . . . . . . . . . . . . . . . . 71
Schistosomiasis. . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Shigellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Tuberculosis (TB) . . . . . . . . . . . . . . . . . . . . . . . . . 80
M essage to R eaders
BVGH Impact
Our accomplishments are
measured by the growing
numbers of companies who are
committing their best scientists
and technologies to solving
pressing public health needs
across the globe.
Incentives
Leading efforts to ensure successful
implementation of the new Priority
Review Voucher program and helping
product developers take advantage of
the new incentive
Worked with the G8 and multilateral

organizations to help design a novel
advance market commitment for
BIO Ventures for Global Health, a non-profit organization, pneumococcal vaccines, launched in
harnesses the resources of the biotechnology industry to create February 2007
new medicines for neglected diseases of the developing world.

Innovation
Published Closing the Global Health
Over the past 30 years, biotechnology has revolutionized medicine Innovation Gap, which defines
how industry-based drug discovery
in the developed world. In the developing world, however, platforms can be applied to neglected
tropical diseases
millions of patients die each year from diseases of poverty
because we don’t yet have modern medicines to prevent, treat Defined a viable, untapped global
market for TB vaccines, published
and diagnose deadly pathogens. Biotechnology can make major in our report Tuberculosis Vaccines:
The Case for Investment, leading to
inroads in treating neglected diseases — and offer hope for the new industry investment and R&D
partnerships
development of drugs, vaccines, and diagnostics in our lifetimes.
Partnering
BVGH breaks down barriers that hinder industry initiatives in global Catalyzed partnerships between
health product development. We foster collaboration among biotechnology companies and
public-sector innovators to address
stakeholders in industry, philanthropy, academia, and government, diverse opportunities for drugs,
vaccines, and diagnostics.
and we catalyze industry investment through the creation of new
Convened meetings enabling
market-based incentives. diverse stakeholders to develop new
collaborations, including the first
Partnering for Global Health Forum
in March, 2008, attracting over 500
attendees from all sectors of industry
and global health
7 BVGH Global Health Primer

“There are lots of interesting projects that
can be done by small biotech companies in
global health... My prediction is that we’re
right at the beginning of the global health
work by biotechnology companies.”
C l e m e n t L e w i n , H e a d , S t r a t e g i c Imm u n i z a t i o n P l a n n i n g ,
Nova rti s Vacci nes and D iag nost ic s
W h y the G lobal H ealth P rimer ?
The Global Disease Burden
New vaccine, drug, and diagnostic technologies have helped to add almost
a decade to Americans’ average life expectancy since 1950. 1 But these
innovations have yet to realize their true promise for all the world’s citizens:
life expectancy for those living in sub-Saharan Africa has actually dropped
over the past thirty years.2
The billions of people living on less than $2 per day continue to suffer from
an array of acute and chronic infectious diseases. Every year, as many as
seventeen million people — most of them children — die from such infectious
diseases as tuberculosis, malaria, and HIV/AIDS, as well as diarrheal diseases
and respiratory infections. Other, lesser-known chronic infections, including
lymphatic filariasis and schistosomiasis, debilitate rather than kill, striking
people in the prime of life, affecting entire families’ productivity and quality
of life, and trapping successive generations in poverty.
This century’s successes
The diseases chronicled in this Global Health Primer
in defeating smallpox and continue to devastate bodies, lives, communities, societies,
and governments and drastically limit the potential for
potentially polio through economic growth. Diseases of the developing world affect
not just individuals’ life expectancy and productivity, but
universal vaccination offer also the planet’s economic, political, and social stability.
The health of the global community depends on our
hope to impoverished millions success in fighting the diseases of poverty.
who today suffer from myriad We know we can conquer diseases through better medicines,
improved care, and prevention. This century’s successes in
pathogens unknown in the defeating smallpox and potentially polio through universal
vaccination offer hope to impoverished millions who today
developed world. suffer from myriad pathogens unknown in the developed
world. But the fight can’t be won without a new generation
of drugs, vaccines, and diagnostics to prevent and treat neglected diseases.
Right now, however, the R&D pipeline that generates those technologies is
too meager to ensure that ten years from now, health care providers will have
the tools they need to roll back the most devastating diseases of poverty.
1 National Center for Health Statistics, Health, United States, 2007 (Hyattsville, Md., 2007),
Table 27. Life expectance at birth for men born in 2004 in the United States was almost
ten years longer than men born in 1950. Life expectancy for women born in 2004 was
more than nine years greater than for women born in 1950.
2 United Nations, “Life Expectancy in Sub-Saharan Africa Is Lower Now Than 30 Years Ago:
UN Index,” press release, November 9, 2006, Accessed online 04/01/09 at: http://www.
un.org/apps/news/storyAr.asp?NewsID=20548&Cr=human&Cr1=develop.

Bridging the Innovation Gap
Over the past decade, global health pioneers such as the Bill & Melinda
Gates Foundation have established unmistakably that global health problems
can be solved; the world can no longer turn a blind eye to the suffering
from these diseases. Tremendous progress has been made in improving
the delivery of existing drugs, vaccines, and diagnostics through programs
such as the Global Fund, the World Health Organization (WHO), the GAVI
Alliance (GAVI), and the U.S. President’s Emergency Plan for AIDS Relief
(PEPFAR). Better access to today’s drugs, vaccines, and diagnostics, however,
only accentuates the inadequacy of available treatments for such afflictions
as tuberculosis, malaria, worms, and human African trypanosomiasis.
Current investment in R&D for neglected diseases is only a fraction of

what is needed to move promising discoveries from academic laboratories
to clinical trial. According to the George Institute for International Health’s
2008 G-FINDER survey, $2.5 billion was invested in R&D to create new
products to treat diseases of poverty in 2007. While
that may seem sizeable, the majority of that funding was Today there are more
dedicated to HIV/AIDS, with a lesser amount for malaria
and tuberculosis. Many other devastating neglected compelling ideas for
diseases lack the most minimal research funding.
R&D than there are
BVGH terms this lack of investment in R&D the
“innovation gap.” Compared to the developing world’s dollars to fund them.
staggering unmet medical needs, the funding for new
solutions is dreadfully insufficient. Today there are more compelling ideas
for R&D than there are dollars to fund them. The innovation gap is further
compounded by the near-absence of private sector innovators that have led
the field in making new medicines to treat patients in wealthy countries.
We know we can find new ways to prevent and treat diseases of poverty. The
invention of recombinant DNA technology in 1973 spurred a revolution in
the science of drug and vaccine discovery. Breakthroughs in genomics and
biochemistry have given us the tools to understand and harness the molecular
mechanisms that underlie human disease. These advances have led to the
invention of entirely new classes of drugs, vaccines, and diagnostics for
cancer, cardiovascular disease, and HIV/AIDS. There’s no scientific reason
why technological advances that have revolutionized health care for the
affluent cannot transform the course of diseases afflicting the poor.

photo: Christopher D. Earl/BVGH
Sleeping Sickness: The Case for New R&D
If
diseases could be classified as cruel and unusual, human For a patient diagnosed with late-stage sleeping sickness, treatment
African trypanosomiasis, also known as “sleeping sickness,” options are few. The drug most commonly used, melarsoprol, was
would be near the top of the list. Spread via the bite of tsetse developed in 1949. A derivative of arsenic, it kills roughly 5% of
flies, the disease attacks the brain, causing patients to hallucinate people who are injected with it, fails to cure 1/3 of patients, and
and fall into a coma. According to The New York Times writer Donald can burn the veins of those who survive. A newer drug, eflornithine,
McNeil Jr., “[Patients] have been known to chase neighbors with requires intravenous (IV) infusions four times a day for two weeks in
machetes, throw themselves into latrines, and scream with pain at large volumes. Since most patients live far from hospitals or nurses
the touch of water. Only at the end do they lapse into a lassitude so able to insert an IV line, eflornithine is not an option in the remote,
great that they cannot eat, followed by coma and death.” rural areas where sleeping sickness takes the greatest toll.
This scenario plays out in the poorest communities in central Africa Clearly, drugs that are effective, safe, and easy to administer are
every day. Tens of thousands of people, mostly the rural poor, die desperately needed, as are simple, point-of-care diagnostics that
each year from the disease, while hundreds of thousands more detect early- and late-stage disease. Yet currently there is only
become infected. In some regions, sleeping sickness claims more a single new drug in clinical trials for sleeping sickness. This is in
lives than HIV/AIDS. sharp contrast to the 270 drugs in development for colon cancer,
which kills roughly the same number of people in the United
African sleeping sickness is treatable if diagnosed in its early stages. States as sleeping sickness does in Africa. Creating important new
But its symptoms — headache and fever — are often overlooked. compounds to combat sleeping sickness is only possible with a
There are no simple, point-of-care diagnostic tests that would significant investment today in innovative drug discovery.
identify the disease before it progresses. Once the disease has
advanced, diagnosis can be made only by examining the spinal fluid
extracted via lumbar puncture.
BVGH Global Health Primer 11

The Role of Biotechnology
In October 2007, BVGH published Closing the Global Health Innovation Gap,
the first in a series of reports that explore how biotechnology can solve urgent
global health problems. Our report showed that the biotechnology industry —
which today is the principal source for new therapeutics for developed world
diseases — has the means to take on the fight against neglected diseases.
A core insight from our report is that biotechnology companies organize

drug discovery around specific classes of molecular targets, some of which
underpin multiple diseases. Companies develop therapeutic technologies
to attack these targets, typically specific classes of disease-related enzymes,
molecular messengers, or cell-surface proteins.
They then apply their technology opportunistically Establishing a clear
to the most relevant diseases. In many cases, those
targets are also present in the pathogens that cause business case is essential
neglected diseases. This creates a largely untapped
opportunity to turn the biotechnology arsenal against if companies are to commit
the problems of global health.
millions of dollars to
The biotechnology industry offers strength in its
diversity. With more than 4,400 companies and developing products for
over 200 products approved by the FDA, the
biotechnology industry has the size and scope to patients who have little or
take on the fight against neglected diseases. Biotech
CEOs are entrepreneurs who are willing to take on no money to pay for them.
risk and who are single-minded in pursuit of their
goals. Several thousand biotechnology companies means several thousand
different approaches to solving problems, hundreds of unique technology
platforms, and a corps of scientists who know how to develop drugs, vaccines,
and diagnostics. Competition is critical when the answers aren’t clear. Solving
problems that haven’t been addressed before requires diverse ideas, different
methods, and competition to select the winning solutions.
The Need for Incentives
While the scientific and medical basis for action is clear, the financial
argument is more challenging. Establishing a clear business case is essential
if companies are to commit millions of dollars to developing products for
patients who have little or no money to pay for them. For most companies,
the reality of the marketplace and the need to turn a profit forces them to
focus on established world markets. But as this primer illustrates, where
the business case can be made, companies will follow. On pg. 25, we list
the biotechnology and pharmaceutical companies already committed to
producing medicines that address needs in the developing world.

Incentives for Innovation
P
atients that will benefit from new products to treat by getting drugs to market faster. Estimates of the value of a PRV
neglected diseases live on less than two dollars a day. In the range from $50 million to $500 million — enough to offset the risk
developed world, that is not enough to buy a single bottle and investment required for research and development. BVGH has a
of aspirin, let alone a regime of tuberculosis treatments lasting Web site — prvinfo.org — dedicated to information on PRVs.
several months. Developing world patients lack the purchasing
power of consumers in the developed world — power that impels AMCs are designed to enhance the value of insufficient developing
biotechnology and pharmaceutical companies to spend billions on world markets. Under AMCs, donors commit to guaranteed,
developing the next lifestyle drugs to treat baldness and premature preferential prices for a certain number of vaccines sold to the
wrinkles. Without this financial motivation, it is necessary to seek poorest countries. In return, manufacturers agree to lower their
different ways to spur companies into action. We at BVGH believe prices substantially after an agreed-upon period. This ensures
companies need an array of incentives and up-front funding to long-term access for countries with patients most in need. BVGH
allow them to deploy their scarce resources on new opportunities published a report in May of 2006 with recommendations for
in neglected diseases. AMCs. We worked with the World Bank and the Global Alliance for
Vaccines and Immunizations to incorporate many of the report’s
BVGH is active in the area of incentives —we develop and advocate recommendations in the first AMC pilot. This pilot, launched in 2007,
for key funding models like the priority review vouchers (PRVs) and has commitments from seven donors and is being implemented.
advanced market commitments (AMCs). We are also working to Donors pledged $1.5 million to guarantee a market in developing
develop new incentives that will spur industry to action. countries for new pneumococcal vaccines to prevent deadly
respiratory infections in children.
The PRV program awards a voucher to companies that develop
drugs for neglected tropical diseases (NTD). This voucher grants More is still needed, both in up-front funding and downstream
the company faster review of a future drug of their choosing once rewards for successful developments. Today, BVGH is assessing
the NTD drug is approved by the U.S. Food and Drug Administration novel incentive mechanisms that will encourage small, early-
(FDA). The speedier review process can shave between four and stage companies to join in the fight against diseases of the
twelve months off the standard review, saving companies millions developing world.

Where markets in the developing world are lacking, the most powerful
approach to stimulating innovation is to design, legislate, and fund incentives
that reward the creation of novel medicines for global health. Rewards that
are received only upon success are attractive to innovators and efficient
for donors. Effective incentive mechanisms encourage companies to invest
resources in developing products, instead of depending solely on grants
and contracts provided by the global health funders. At BVGH, we actively
advocate for novel incentives that can replicate the power of the marketplace
in driving investment in new R&D.
Why the Global Health Primer?
President Obama noted in a recent statement on global health, “We cannot

simply confront individual preventable illnesses in isolation. The world is
interconnected, and that demands an integrated approach to global health.”
BVGH’s Global Health Primer forges connections between expertise in developing

world diseases and the cutting-edge technologies that are the foundation of
new vaccines, drugs, and diagnostics. It is a resource for innovators in the
biotechnology and global health communities to learn how
At BVGH, we actively best to focus efforts. The Primer lists the major global health
organizations focused on R&D, including international
advocate for novel incentives non-governmental organizations, government agencies, and
academics. It highlights the companies that have committed
that can replicate the power to global health and progress made in the past year. Using a
common framework for presenting our research, the Primer
of the marketplace in driving describes the unmet needs for 16 diseases and summarizes
current pipelines for vaccines, drugs, and diagnostics, while
investment in new R&D. pointing out critical gaps that need to be addressed.
Our hope is that the Primer will foster innovative R&D to grow the pipeline
for neglected diseases. Millions in poor countries are suffering from diseases
that devastate their livelihoods. Solutions are within reach, and the time has
come to take transformative action.

photo: Pierre Holtz /Unicef
K e y G lobal H ealth P la y ers
Key Global Health Players
P roduct D evelopment P artnerships ( P D P s )
Aeras Global TB Vaccine n Leading the effort to develop a new vaccine for tuberculosis (TB); working on both
Foundation — Aeras “prime” and “booster” candidate vaccines in prime-boost regimens with improved BCG
www.aeras.org and several delivery systems for subunit vaccines; lead products in Phase II clinical
Focus: Vaccines for tuberculosis trials in South Africa
n Partnering with GlaxoSmithKline (GSK), Crucell, Intercell, Sanofi-Pasteur,
Oxford University, and Statens Serum Institute to develop novel TB vaccines
n Partnering with multiple research institutions to develop clinical trials sites in
South Africa, India, Uganda, and Kenya
n Has received over $300 million in funding, principally from the Bill & Melinda
Gates Foundation and also from bilateral donors such as the Netherlands
Ministry of Foreign Affairs and the Research Council of Norway
Drugs for Neglected n Founded in 2003 by four publicly funded research institutes from Malaysia,
Diseases initiative — India, Kenya, and Brazil along with Institut Pasteur and Médecins Sans
DNDi Frontières
www.dndi.org n Working in partnership with industry, academia, and non-governmental
Focus: Drugs for leishmaniasis, organizations (NGOs), DNDi has the largest ever R&D portfolio for the
human African trypanosomiasis, kinetoplastid diseases and currently has two post-registration, five clinical, and
Chagas disease, and malaria four preclinical projects, along with a wide variety of discovery activities
n In 2007-2008, delivered two new fixed-dose antimalarial products: ASAQ
(artesunate-amodiaquine) with Sanofi-Aventis, and ASMQ (artesunate-
mefloquine) with Farmanguinhos/Fiocruz
n By mid-2008, announced formation of drug discovery partnerships with GSK
and Anacor, as well as with Institute Pasteur Korea, Institut de Recherche pour
le Développement, Eskitis Institute in Brisbane, and the University of North
Carolina
n Secured over $75 million in funding from public and private sectors
Foundation for Innovative n The only PDP to focus on diagnostics—initial focus on TB expanded to malaria
New Diagnostics — FIND and human African trypanosomiasis
www.finddiagnostics.org n Partnering with Cepheid, ImmPORT, Tyrian Diagnostics, Hain Lifesciences,
Focus: Diagnostics for Roche Diagnostics, Becton, Dickinson and Company, Cellestis, BioMérieux,
tuberculosis, malaria, and human Eiken Chemical, Zeiss, and many others
African trypanosomiasis n In September 2007, announced funding of $62 million over five years for TB
diagnostics

Global Alliance for TB n Not-for-profit PDP developing new drugs for TB; founded in 2000
Drug Development — n Conducting Phase III trials of moxifloxacin in combination with other drugs; a
TB Alliance new compound, PA-824, is in Phase II trials; multiple discovery projects in early
www.tballiance.org pipeline
Focus: Drugs for tuberculosis n Partnering with Bayer, GSK, Novartis, Sanofi-Aventis, BG Medicine, the
University of Auckland, the University of Illinois at Chicago, the University of
Pennsylvania, Texas A&M University, Yonsei University, the Infectious Disease
Research Institute (IDRI), Korea Research Institute of Chemical Technology,
Beijing Tuberculosis and Thoracic Tumor Institute, Rutgers University, and the
Institute of Materia Medica in China
n Has raised over $200 million from donors such as the Bill & Melinda Gates
Foundation, the Rockefeller Foundation, Irish Aid, UK Department for
International Development (DIFD), the Netherlands Ministry of Foreign Affairs,
and the US Agency for International Development (USAID)
Institute for OneWorld n Not-for-profit focused on drugs for neglected diseases; founded in 2000
Health — iOWH n Paromomycin IM Injection was approved for use in India in 2006 for the
www.iowh.org treatment of visceral leishmaniasis. In May 2007, it was designated by the WHO
Focus: Drugs for neglected for inclusion on its Model List for Essential Medicines.
diseases in developing countries n In partnership with Amyris, Sanofi-Aventis, and the University of California,
Berkeley, formed the Artemisinin Project to develop semisynthetic artemisinin,
derivatives of which are a key component in first-line malaria treatments
n Entered into a collaboration with Roche to access its proprietary compound
library to identify new diarrheal disease treatments
n Has obtained over $140 million in grants, principally from the Bill & Melinda
Gates Foundation
International AIDS n Leading global partnership for the development of an HIV/AIDS vaccine; founded
Vaccine Initiative — IAVI in 1996 and operational in 24 countries
www.iavi.org n Conducted human trials with six vaccine candidates in 11 countries on four
Focus: Vaccines for HIV/AIDS continents—Asia, Africa, Europe, and North America
n Partnered with more than 40 academic, biotechnology, pharmaceutical, and
governmental institutions
n Received over $569 million in contributions since 1996; current annual budget
nearly $113 million
International Partnership n Leading partnership to develop vaginal microbicides to prevent transmission of

for Microbicides — IPM HIV; founded in 2002
www.ipm-microbicides.org n Has one candidate product currently in clinical trials and several others in
Focus: Microbicides for preclinical development
prevention of HIV/AIDS n Partnering with Gilead Sciences, Merck, Imquest Biosciences, Pfizer, Tibotec,
transmission Bristol-Myers Squibb, and Locus, among others
n Has raised over $350 million from the Bill & Melinda Gates Foundation, the
Rockefeller Foundation, DIFD, and other sources

Medicines for Malaria n Leading organization developing new drugs and combination therapies for
Venture — MMV malaria; founded in 1999
www.mmv.org n Lead products are Coartem® Dispersible, a pediatric formulation of artemether-
Focus: Drugs for malaria lumefantrine, registered with Swiss Medic in January 2009; Eurartesim®,
dihydroartemisinin-piperaquine, which has completed Phase III and now is
being prepared for filing with EMEA and US FDA; and Pyramax®, pyronaridine-
artesunate, currently in Phase III clinical trials
n Partnering with GSK, Novartis, Broad-Genzyme, Advinus, and many others on
the discovery and development of new anti-malarials
n Has received funding and pledges totaling $318 million from the Bill & Melinda
Gates Foundation, Wellcome Trust, governments, and other sources
PATH — Formerly n Largest of the Bill & Melinda Gates-funded non-profit organizations;
Program for Appropriate founded in 1977
Technology in Health n Home to the PATH Malaria Vaccine Initiative, the PATH Enteric Vaccine
www.path.org Initiative, and other large initiatives including the Meningitis Vaccine Project and
Focus: Sustainable, culturally the PATH Rotavirus Vaccine Program
relevant solutions to improve n Developing medical devices, diagnostics, and vaccines that are appropriate
health and well-being in the for developing countries; also working to improve health care delivery and
developing world individual and community behaviors
n Responsible for over 30 products that have helped solve global health problems,
including single-use syringes, malaria tests, and chemically active stickers that
detect heat-damaged vaccines
n Piloting introduction of cervical cancer vaccines and meningococcal vaccines into
the developing world
n Has received more than $1.4 billion in funding from foundations, the US
government, other governments, multilateral agencies, corporations, and
individuals
PATH Enteric Vaccine n Founded in 2007 as a project of PATH

Initiative — EVI n Advancing the development of safe, effective, and affordable vaccines to protect
www.path.org/projects/enteric_ infants and young children in the developing world against Enterotoxigenic E.
vaccine coli (ETEC) and Shigella
Focus: Vaccines against leading n In 2008, announced partnerships with Ace Biosciences and EndoBiologics
bacterial causes of diarrheal n Received $50 million start-up grant from the Bill & Melinda Gates Foundation
disease
PATH Malaria Vaccine n Created in 1999 as a global program of PATH

Initiative — MVI n RTS,S, the most clinically advanced vaccine candidate in MVI’s portfolio, has
www.malariavaccine.org been developed in partnership with GSK Biologicals; it is expected to enter Phase
Focus: Vaccines for malaria III clinical trials soon
n Partnered with Sanaria Inc., Walter Reed Army Institute of Research (WRAIR),
GenVec Inc., Seattle Biomedical Research Institute (SBRI), and many others
n Has raised nearly $468 million in funding, chiefly from the Bill & Melinda Gates
Foundation

Pediatric Dengue Vaccine n Mission is to accelerate the development, evaluation, and introduction of
Initiative — PDVI affordable dengue vaccines; conceived in 2001 and formally established at the
www.pdvi.org International Vaccine Institute in 2003
Focus: Vaccines against dengue n Current projects include supporting innovative research on diagnostics and
infection assays; assisting companies to develop vaccines; developing multipurpose field
sites; collaborating with partners on regulatory issues; and preparing models of
vaccine introduction and use
n Partners include seven vaccine companies in Brazil, Europe, India, and
the United States; a number of leading academic research centers; several
government agencies and the WHO
n As of mid-2008, donations of over $60 million from the Bill & Melinda Gates
Foundation, the Rockefeller Foundation, and the Government of Korea
SVI Human Hookworm n A major program of the Sabin Vaccine Institute (SVI), dedicated to accelerating
Vaccine Initiative — the development of safe, affordable vaccines against hookworm infection and
SVI-HHVI schistosomiasis
http://sabin.org/programs/hhvi/ n The Na-ASP-2 Human Hookworm Vaccine is currently in a Phase I clinical
index.html testing in a hookworm endemic region of Brazil
Focus: Vaccines for hookworm n The Sm-TSP-2 Schistosomiasis Vaccine has completed manufacturing process
infection and schistosomiasis development
n Partners include George Washington University, the Oswaldo Cruz Foundation,
the London School of Hygiene and Tropical Medicine (LSHTM), the Queensland
Institute of Medical Research, Instituto Butantan, and the Institute of Parasite
Diseases at the Chinese Center for Disease Control and Prevention
n Currently, grants from the Bill & Melinda Gates Foundation support the
development of the human hookworm vaccine; Private donors have provided
seed funding for the development of the schistosomiasis vaccine

I nternational and M ultilateral O rgani z ations and I nitiatives
Bill & Melinda Gates Launched in 2000, the foundation supports work in the areas of global health,
Foundation
global development, and US public education. Current endowment is $29.7 billion,
and grant commitments to date total $19.8 billion. In 2009, the foundation will
www.gatesfoundation.org
disburse $3.8 billion, a figure which includes a portion of the 2006 bequest of $31
billion from Warren Buffett.
Department for The aid and development arm of the British government. Aims to reduce world
International Development poverty through long-term programs that tackle its underlying causes. A major
— DFID supporter of Advanced Market Commitments (AMCs) and other programs to
www.dfid.gov.uk improve health in the developing world. Its annual budget is roughly $6 billion.
Foundation for the Founded in 1996, FNIH was established by the NIH as a flexible funding
National Institutes organization to support pioneering biomedical research. In partnership with the
of Health — FNIH Bill & Melinda Gates Foundation, the Wellcome Trust, and the Canadian Institutes
www.fnih.org of Health Research, FNIH administers the Grand Challenges in Global Health
initiative, a $436.6 million program to develop cost-effective, simple-to-use,
inexpensive, health tools for the developing world.
International Center ICDDR,B is an international health research institution that conducts research,
for Diarrheal Disease training, and program-based activities in collaboration with partners from academic
Research, Bangladesh — and research institutions throughout the world. In 2007, the organization received
ICDDR,B almost $29 million, with large portions from USAID, DFID, and the government of
www.icddrb.org Bangladesh.
International Finance IFFIm is a financing facility backed by a coalition of governments to finance

Facility vaccine commitments. These commitments are floated on the international
for Immunisation bond market in order to “front-load” predictable funding to GAVI for enhanced
Company — IFFIm vaccination programs. IFFIm provided $800 million, or 90 percent, of GAVI’s 2007
www.iffim.com expenditures.
International Vaccine The IVI, established by the United Nations Development Program with the support
Institute of 35 countries and the WHO, supports collaborative research to accelerate the
(UN Program hosted by introduction of new vaccines into developing countries. The IVI’s focus includes
Korea) — IVI basic and applied laboratory research, product development, training, and technical
www.ivi.org assistance. The Pediatric Dengue Vaccine Initiative (PDVI) is hosted by the IVI.
GAVI Alliance — An alliance between the public and private sector, GAVI has raised more than $3.5
Formerly Global Alliance billion for the purchase and distribution of vaccines to children in the developing
for Vaccines and world. GAVI’s funding comes from national governments and a 15-year, $1.5
Immunisation billion grant from the Gates Foundation. GAVI estimates its efforts have prevented
www.GAVIalliance.org 2.9 million deaths since 2000.
The Global Fund to Fight Since 2002, the Global Fund has directed global financing for the prevention and
AIDS, TB and Malaria — treatment of HIV/AIDS, tuberculosis, and malaria. As of April 2009, the Global
Global Fund Fund has approved $15.6 billion to support programs in 136 countries and
www.theglobalfund.org disbursed $7.3 billion.

National Institute for Part of the National Institutes of Health (NIH), NIAID provides support for research
Allergy and Infectious into infectious, immunologic, and allergic diseases. NIAID is the leading arm of the
Diseases — NIAID US government that promotes research into preventions and cures for HIV/AIDS,
www.niaid.nih.gov influenza, and infectious diseases of the developing world.
Pan American Health PAHO is an international public health agency working to improve health and
Organization — PAHO living standards of the countries of the Americas. It serves as the WHO’s Latin
www.paho.org America regional office and is the main purchaser of vaccines in Latin America.
President’s Emergency PEPFAR aims to dramatically scale up HIV/AIDS prevention, diagnosis, and
Plan for AIDS Relief — treatment in 15 target countries. Currently the program supports the treatment
PEPFAR of 1.7 million patients, most of whom live in sub-Saharan Africa. President Bush
www.pepfar.gov signed a bill to reauthorize PEPFAR in 2008, pledging up to $48 billion in funding
over five years, more than tripling the $15 billion spent from 2003-2008. The
reauthorization includes over $9 billion to fight malaria and tuberculosis.
President’s Malaria Begun in 2005, the PMI was reauthorized in 2008 to increase malaria funding to $5
Initiative — PMI billion over five years through bilateral programs worldwide. The PMI is working
www.pmi.gov with multiple public and private sector partners in programs to distribute bed nets,
drugs, and insecticides.
The Rockefeller Established in 1913, the foundation has more than $4 billion in assets that support
Foundation programs in health, globalization, arts and culture, agriculture, housing, and
www.rockfound.org education. Many of today’s largest product development partnerships (PDPs) were
founded with seed financing from the foundation.
Special Programme for TDR, an independent program established by the WHO, supports R&D through
Research and Training grants and partnerships to combat 10 of the most devastating tropical diseases.
in Tropical Diseases — It coordinates worldwide efforts in discovery research for neglected diseases,
TDR emphasizing support for research in developing countries.
www.who.int/tdr
United Nations The UNDP is the United Nation’s principal provider of advice, advocacy, and grant
Development Program — support to foster development initiatives.
UNDP
www.undp.org
United Nations Children’s UNICEF provides long-term humanitarian and developmental assistance to children
Fund — UNICEF and mothers in developing countries. UNICEF is the global leader in vaccine
www.unicef.org procurement, reaching 40 percent of the world’s children. In 2008, UNICEF
vaccinated 700,000 women to prevent neonatal tetanus.
United States Agency for USAID is the US government’s foreign aid and development organization. With field
International Development offices all over the world, USAID strives to advance US foreign policy objectives by
— USAID supporting economic growth, agriculture, trade, democracy, conflict prevention,
www.usaid.gov humanitarian assistance, and global health. USAID administers PEPFAR, PMI, and
other disease-targeted programs.

The Wellcome Trust The Wellcome Trust is the largest funder of biomedical research in the United
www.wellcome.ac.uk Kingdom, investing £600 million annually. The Trust has a strong interest in
infectious disease and has devoted significant resources to neglected diseases. The
Trust is increasingly funding “translational” efforts to invent new therapeutics based
on fundamental discoveries made in academic laboratories—the organization is
unusual in its willingness to fund private sector R&D. The Trust helped pioneer the
use of the antimalarial artemisinin outside of China.
World Health Organization The WHO is the agency of the United Nations that acts as a coordinating authority
— WHO on international public health. Its major aim is to combat disease, especially
www.who.int/en infectious diseases, and to promote the general health of the peoples of the world.

N otable R esearch I nstitutions and academic consortiums
The Broad Institute of MIT n A biomedical research institute investigating all aspects of human disease;
and Harvard
launched in 2004
n Collaborating with MMV, Genzyme, and Advinus to identify new malaria
www.broad.mit.edu
therapeutics
Focus: Malaria and tuberculosis
n Helped decode the extensively drug resistant (XDR) form of the M. tuberculosis
genome in 2007
n Received $600 million in gifts from Eli and Edythe Broad
Infectious Disease n A non-profit biotechnology organization committed to developing products to

Research Institute — IDRI prevent, detect, and treat infectious diseases of poverty; founded in 1993
www.idri.org n Lead product is a vaccine against leishmaniasis, currently in Phase I & II clinical
Focus: Vaccines, diagnostics, trials in India, Latin America, and Africa
and drugs for leishmaniasis, n World-class platforms in antigen discovery and development, adjuvant
tuberculosis, malaria, leprosy, and formulation and delivery, therapeutic molecule target discovery, and biomarker
other infectious diseases discovery for diagnostics
n Funded by the Bill & Melinda Gates Foundation, the NIH, the American Leprosy
Missions, and the M.J. Murdock Charitable Trust; IDRI also engages in public-
private partnerships with such companies as Eli Lilly & Company and GSK
Sabin Vaccine Institute n Working to develop and deliver vaccines to the developing world for nearly
www.sabin.org two decades
Focus: Vaccine research, n Home to the Human Hookworm Vaccine Initiative, the Global Network for
development, and advocacy Neglected Tropical Disease Control, and several other advocacy efforts
n Has supported symposia for rotavirus, pneumococcal diseases, and other global
health threats
n Funded by the Gates Foundation, Geneva Global, GSK, Wyeth, Merck, and
other private donors
Seattle Biomedical n Independent research institute focused on infectious diseases, particularly

Research Institute — SBRI malaria, HIV/AIDS, tuberculosis, human African trypanosomiasis, leishmaniasis,
www.sbri.org and Chagas disease; founded in 1976
Focus: Malaria, tuberculosis, HIV/ n Currently establishing, in collaboration with MVI, the Malaria Clinical Trials
AIDS, trypanosomal diseases, Center, devoted to testing the safety and efficacy of malaria vaccines
toxoplasmosis, candida, and n Annual budget of approximately $40 million
other infectious diseases n $30.6 million awarded by NIH to fund Seattle Structural Genomics Center for
Infectious Disease

University of California, n A simulated pharmaceutical R&D division in which academic groups are
San Francisco Sandler combined with managers from industry
Center n Maintains open-access “Low Hanging Fruit” Web site; a database of
www.sandler.ucsf.edu FDA-approved drugs that have shown activity against T. brucei, L. donovani, and
Focus: Parasitic diseases S. mansoni
n Developed high throughput anti-parasitic screens; partnered with over 20
companies to identify drug leads for neglected tropical diseases
n One candidate for Chagas disease in IND-enabling studies and three in lead
optimization
n Supported by $20 million from the Sandler Foundation
University of Dundee n A translational research and drug discovery center targeting human African
Tropical Disease Initiative trypanosomiasis and other neglected diseases
www.drugdiscovery.dundee. n Phenotypic and target-based screening capabilities; multiple projects in hit
ac.uk/tropical/overview validation and hits-to-leads phase
Focus: Parasitic diseases n Aims to have at least one drug candidate ready for entry in formal preclinical
development by 2011
n £15 million in funding over five years from the Wellcome Trust, the Wolfson
Foundation, and other agencies
University of North n Developed pafuramidine, an oral drug for early-stage human African
Carolina Consortium for trypanosomiasis that failed in Phase III clinical trials in 2008; new compounds
Parasitic Drug for late-stage human African trypanosomiasis and visceral leishmaniasis are in
Development — CPDD preclinical stage
Focus: Human African n Consortium members include the University of North Carolina, Georgia State
trypanosomiasis, leishmaniasis, University, the Swiss Tropical Institute, the London School of Hygiene and
and malaria Tropical Medicine, Ohio State University, the University of South Florida, the
University of Glasgow, Gorgas Memorial Institute (Panama), Kenya Agricultural
Research Institute, and Immtech Pharmaceuticals
n Has received over $60 million in funding from the Gates Foundation

Select Companies Working in Global Health

Highlights in Global Health R&D: New Incentives and Initiatives
Market Incentives n Priority Review Vouchers (PRVs): In September 2008, the FDA’s new PRV program went
into full effect. Sponsors obtaining FDA approval for a new biologic or chemical entity for
a neglected tropical disease are awarded a transferable PRV that reduces the FDA review
period for any other subsequent application to approximately six months. In April 2009,
Coartem®, an antimalarial drug launched by Novartis and MMV, received the first PRV.
n Advanced Market Commitment (AMC): In June 2009, the governments of Italy,

the United Kingdom, Canada, Russia, Norway, the Bill & Melinda Gates Foundation, and
GAVI Alliance partners World Bank, UNICEF, and the World Health Organization formally
launched the first AMC program. $1.5 million was pledged in October 2007 to encourage
industry investment in much-needed vaccines for the developing world. The first project
will focus on pneumococcal disease, which effects 1.6 million people each year.
US Government n National Institutes for Health’s Therapeutics for Rare Diseases Program:
Initiatives In May 2009, the National Institutes for Health (NIH) announced a $120 million, five-year
program to advance pre-clinical research for rare and neglected diseases. The program
will enhance the drug development pipeline by absorbing some of the risk of early stage
development and encouraging new public-private partnerships.
n New Funding for NTDs: In February 2008, President Bush announced the formation of
a new, five-year, $350 million initiative to fund the control of seven key neglected tropical
diseases (six parasitic worm infections and trachoma).
n PEPFAR: In July 2008, the President’s Emergency Program for AIDS relief (PEPFAR) was
reauthorized by Congress for $48 billion over five years.
photo: Pierre Holtz /Unicef

New Financial n Grand Challenges Explorations: In October 2007, the Gates Foundation announced
Support for R&D the new five-year, $100 million initiative to spur innovation in global health research.
$100,000 grants are awarded on the basis of a 2-page application; successful projects have
the opportunity to receive additional funding of $1 million or more. 104 Round 1 winners
were announced in October 2008. In May 2009, an additional 81 grants were announced.
Among the awardees were three biotech firms: Cupron, Inc., Osel and Sangamo BioSciences.
n Enteric Vaccine Initiative (EVI): In October 2007, PATH received $50 million from the
Gates Foundation to form EVI, a public-private partnership aimed at developing new anti-
diarrheal vaccines.
New Private n GlaxoSmithKline Patent Pool: In March 2009, GSK announced the creation of a
Sector Initiatives “patent pool” to provide third parties with access to GSK Intellectual Property. To catalyze
new efforts in R&D, GSK is providing access to small molecule pharmaceuticals to treat the
16 neglected diseases identified by the FDA.
n Celgene Global Health: In February 2009, Celgene announced the creation of Celgene
Global Health, a new group formed to apply Celgene’s science, technology, resources and
expertise towards developing solutions for major health problems in underdeveloped
countries.
n Vertex Global TB Network: In mid-2008, Vertex Pharmaceuticals announced the

formation of a global collaboration aimed at advancing early-stage research into new
approaches for the treatment of tuberculosis. To date, Vertex has engaged the commitment
of multiple TB research organizations and over 60 researchers around the globe.
n Novartis Vaccines Institute for Global Health: In February 2008, the non-profit
initiative was launched in Siena, Italy with the goal of discovering and developing vaccines
for the developing world. The institute’s initial focus will be on diarrheal diseases. Novartis
will pay for staff and running costs, and will seek additional external funding to cover
project costs.
New Research n HIV Neutralizing Antibody Center: In September 2008, IAVI and the Scripps Research
Centers Institute announced the establishment of a $30 million research center to develop
neutralizing antibodies, seen as a key component of an effective HIV preventative vaccine.
n Human Challenge Center: In March 2008, SBRI and MVI announced that they will open a
new $4.8 million center devoted to testing the safety and efficacy of malaria vaccine candidates
in humans. The first trial at the center is expected to take place in the summer of 2009.
n Seattle Structural Genomics Center for Infectious Disease: In December

2007, SBRI received a $30 million federal contract to house the bioinformatics center
aimed at determining the structure of significant pathogen proteins in vaccine, drug and
diagnostic design.

D isease B ackgrounders
Disease Sheets

Chagas Disease
B ackgr o u nd nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is Chagas Disease?
Chagas disease, also called American trypanosomiasis, is a parasitic disease that through chronic infection causes
damage to the nervous system, digestive tract, and the heart. Humans contract the disease when the infected feces
of the insect vector enter the body, typically by scratching the insect bite.
Global Burden
It is estimated that 8 million to 9 million people are currently infected,
with 750,000 new cases and 14,000 deaths occurring each year. An
additional 25 million people are at risk of infection.
Geographic Distribution
Chagas disease is prevalent in 18 countries within the Americas, ranging
from Mexico to Argentina.
Causative Agent/Transmission
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi.
It is transmitted to humans through the feces of blood-sucking insects
Countries endemic for Chagas disease (WHO, 2008)
known as triatomine bugs (also called “assassin” or “kissing” bugs).
Transmission may also occur congenitally or via breast milk or blood transfusion. In its human host, the parasites
invade and replicate inside many cell types. Pet dogs are an alternate mammalian host, whose proximity to humans
thwarts efforts to break the chain of transmission. Chagas disease is most prevalent in rural areas and is linked to
substandard housing. Thatched roofs and mud walls are especially prone to infestation by the insect vector. T. cruzi
is related to the trypanosomes that cause human African trypanosomiasis and leishmaniasis.
Presentation
Chagas disease can be classified as acute or chronic.
The acute phase of the disease begins several days after infection. Most acute infections are asymptomatic, but some
produce fever and swelling of the lymph nodes, spleen, liver, and the site of infection. The hallmark of the acute
phase of Chagas disease is the swelling of the eyelids or the side of the face near the bite wound (Romaña’s sign).
The chronic phase can last from months to decades and may also
remain asymptomatic for long periods of time. Damage can eventually
occur to the nervous system, the digestive system, and the heart.
Cardiomyopathy, or damage to the heart’s muscle structure, is the
leading cause of death.
Trends
The number of deaths per year has decreased slightly in recent years.
The WHO launched an eradication campaign in 2007.
Triatomine bugs often infest rural, substandard

housing (photo: CDC/WHO)

C hagas D isease
E x isting P r o d u cts nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Drugs Vaccines Diagnostics
There is no treatment for chronic n None Current diagnostics cannot reliably detect
infections. chronic disease or monitor effects of
n Nifurtimox & Benznidazole treatment.
– Cures at least 50 percent of n TcF-ELISA
acute and short-term chronic – Sensitive and specific
infections principally in children, – Low occurrence of leishmaniasis
but has little to no impact on cross-reactions
long-term chronic infections n UBI MAGIWEL™ ELISA
– Frequently causes side effects, – Detects antibodies (IgG) to T. cruzi
which can be severe in human serum or plasma
– Limited access n Chembio Chagas STAT-PAK™
– High cost of treatment – Detects antibodies to T. cruzi
– Shows signs of resistance – Rapid test, no refrigeration required
N ew P r o d u ct N eeds nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n Effective against chronic disease n Preventive: long-term protection n Able to differentially diagnose the
n Oral formulation against infection presence and stage of disease
n Short course of therapy n Therapeutic: treat the chronic phase n Test of cure
n Pediatric formulations
P ipe l ine nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Pre- Clinical- Clinical- Clinical-
Drugs Discovery Clinical Phase I Phase II Phase III
DNDi/LAFEPE/University of Liverpool (pediatric benznidazole) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
DNDi/Eisai/Federal University of Ouro Preto (ravuconazole) nnnnnnnnnnnnnnnnnnnnn
Sandler Center/NIAID/SRI International (cysteine protease inhibitors) nnnnnnnnnnnnnnnnnnnnn
Schering-Plough Research Institute (posaconazole) nnnnnnnnnnnnnnnnnnnnn
DNDi/GSK/STI (4[1H] pyridones and cysteine protease inhibitors) nnnnnnnn
DNDi/CDCO/Epichem/Murdoch University (Chagas lead optimization consortium) nnnnnnnn
DNDi/STI/Fiocruz and many others (nitroimidazoles) nnnnnnnn
DNDi/Institut de Recherche pour le Développement (canthin-6-one alkaloids ) nnnnnnnn
Genzyme/Fiocruz (target identification and screening) nnnnnnnn
M arket Opp o rt u nities nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

n This is primarily a disease of the poor and will require donor support to encourage innovation.

C hagas D isease
D eve l o pment I ss u es nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

n Clinical trials are likely to n Clinical trials are likely to n No biomarkers exist to
be complicated by the slow be complicated by the slow detect chronic disease
progression of the disease progression of the disease n Troponin, a marker for cardiac
n In the chronic stage, organisms are damage that is elevated in late-
difficult to detect and damage occurs chronic-stage disease, cannot
over many (more than 15) years differentiate between “no disease”
and the early chronic stage
A dditi o na l I nf o rmati o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

General Disease Links
n World Health Organization (WHO) ~ www.who.int/topics/chagas_disease/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/chagasdisease
Key Organizations
n Drugs for Neglected Diseases initiative (DNDi) ~ www.dndi.org
n Special Programme for Research and Training in Tropical Diseases (TDR) ~ www.who.int/tdr
Important Papers
n Bustamante, JM, et al. Drug-induced cure drives conversion to a stable and protective CD8+ T central memory
response in chronic Chagas disease. Nature Med 14:542-50 (2008)
n De Souza, W. From the cell biology to the development of new chemotherapeutic approaches against
trypanosomatids: Dreams and reality. Kinetoplastid Biol Dis 1:3 (2002)
n El-Sayed, NM, et al. The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science
309:409-15 (2005)
n El-Sayed, NM, et al. Comparative genomics of trypanosomatid parasitic protozoa. Science 309:404-9 (2005)
n Hucke, O, et al. The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs
against Chagas disease. J Med Chem 48:5415-18 (2005)
n Tarleton, RL, et al. The challenges of Chagas disease—grim outlook or glimmer of hope? PLoS Med 4:e332 (2007)

Cholera
What Is Cholera?
Cholera is an acute bacterial intestinal infection with a short incubation
period, typically one to five days. Cholera causes watery diarrhea and
vomiting that can lead to severe dehydration and death in less than 24
hours if not treated promptly. In areas where cholera is endemic, the
disease mainly affects children.
Global Burden
In 2004, the WHO reported that 101,383 cases of cholera occurred in
56 countries resulting in 2,345 deaths. Case-fatality rates in epidemic
conditions can exceed 40 percent, making cholera prevention a major
Countries with reported endemic cholera cases, public health objective.
2004-2007 (WHO, 2008)
The majority of cases currently occur in sub-Saharan Africa and Southeast Asia, but distribution varies. During 2004,
major outbreaks occurred in Cameroon, Chad, Guinea, Mali, Niger, Senegal, and Zambia.
Cholera is caused by ingestion of food or water contaminated with the bacterium Vibrio cholerae. Most sudden, large
outbreaks are linked to a contaminated water supply. Rarely, cholera can be transmitted by direct person-to-person
contact. Until 1992, the only known cholera agent was Vibrio cholerae O1, but in that year a new serogroup, O139, was
observed and found to be the cause of several epidemics in Asia.
Presentation
V. cholerae produces an enterotoxin that induces the intestine to release
fluid, causing abundant, watery diarrhea that can quickly lead to
severe dehydration. Frequent vomiting can exacerbate dehydration. If
the dehydration is not addressed, cholera can be fatal. Most healthy
people have the ability to fight a cholera infection without manifesting
symptoms; however, about 10 percent of those infected develop severe
disease.
Trends
holera remains a global threat and one of the key indicators of low
C
Vibrio cholerae serogroup O1
(photo: CDC/Janice Carr)
development level. It is a particularly dangerous problem in places with
limited access to clean water. Most developing countries are at risk for
cholera outbreaks.
Current vaccines do not protect against O139. The Institut Pasteur cautioned in 2003 that this new strain “may well
become the origin of an eighth cholera pandemic.”

C holera

n Palliative Care n First-Generation Vaccines n Rapid diagnostic dipstick test
− Oral rehydration therapy is (including Dukoral®) − Relies on immunochromatography
used to treat symptoms − Oral delivery to detect the presence of O1 and
− Antibiotics and intravenous fluids − Protection ranges from three O139 lipopolysaccharides
are sometimes given in severe cases months to two years
− Some require multiple doses for
efficacy; efficacy can be as low as
61 percent
− Licensed in some countries but
mainly available to travelers
− Ineffective against O139 strain
new P r o d u ct needs nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

n High-potency antibiotic n Single-dose, oral vaccine n Ability to differentiate between
n Bivalent against O1 and O139 cholera cholera and other diarrheal pathogens
n Provides long-term protection n Rapid test to ensure quick
(more than 2 years) to infants response in an epidemic
and young children

Vaccines Discovery Clinical Phase I Phase II Phase III
IVI/National Institute of Cholera & Enteric Diseases, India/ nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Shantha Biotechnics/VaBiotech (ORC-Vax®: oral, killed, bivalent)

Celldex/IVI (CholeraGarde®: oral, live, attenuated) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Finlay Institute, Cuba (strain 638: oral, live, attenuated) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Celldex/NIAID (oral, cholera-ETEC combination vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

n Potential commercial opportunities for vaccines through military and travelers’ applications.

n Need to overcome antibiotic resistance n Difficulties in conjugate development n None
n Specifications for travelers’
and military markets may differ
from endemic markets

C holera

n World Health Organization (WHO) ~ www.who.int/topics/cholera/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/ncidod/dbmd/diseaseinfo/cholera_g.htm
Key Organizations
n International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) ~ www.icddrb.org/pub
n WHO Initiative for Vaccine Research (IVR) ~ www.who.int/vaccine_research/en
Important Papers
n Lucas, MES, et al. Effectiveness of mass oral cholera vaccination in Beria, Mozambique. NEJM 352:757-67 (2005)
n Mahalanabis, D, et al. A randomized, placebo-controlled trial of the bivalent killed, whole-cell, oral cholera
vaccine in adults and children in a cholera endemic area in Kolkata, India. PLoS One 3:e2323 (2008)
n Sack, DA, et al. Cholera. Lancet 363:223-33 (2004)

Dengue Fever (DF)
What Is Dengue Fever?
Dengue fever (DF) is a viral, mosquito-borne disease that can cause
severe, flu-like symptoms with high fever and extreme muscle and joint
pain. Dengue hemorrhagic fever (DHF), a more dangerous form of the
disease associated with increased blood vessel permeability, can be fatal.
Global Burden
There are an estimated 50 million new dengue infections each year, and
more than 2.5 billion people are at risk for the disease. Approximately
500,000 cases of DHF require hospitalization each year, the majority of
whom are children, resulting in more than 20,000 deaths. Without proper
Countries with areas of dengue risk (WHO, 2007) treatment, DHF case fatality rates can exceed 20 percent.
DF is endemic in 100 countries throughout the Americas, Southeast Asia, the Western Pacific Islands, Africa, and the
eastern Mediterranean. Southeast Asia and the Western Pacific are most seriously affected. Dengue cases have also
been reported in Hawaii, Texas, and Puerto Rico.
The dengue virus is a member of the family Flaviviridae, which includes the viruses that cause yellow fever, Japanese
encephalitis, and West Nile disease. There are four known serotypes. The viruses are transmitted by Aedes aegypti
mosquitoes, subgenus Stegomyi.
Presentation
DF is a severe, incapacitating, flu-like illness that affects infants,
young children, and adults, but seldom causes death. In older children
and adults, DF symptoms include sudden onset of high fever, severe
headache, muscle and joint pain, and rash. With palliative care, these
symptoms typically resolve within weeks, but complete convalescence
may require additional time.
Less than 1 percent of patients infected with dengue develop DHF, which
is characterized by low platelet counts and blood iron imbalance that
may be accompanied by bleeding, enlarged liver, and circulatory failure.
Aedes aegypti, the vector for dengue fever Without proper treatment, DHF case fatality rates can exceed 20 percent.
(photo: CDC/James Gathany/Frank Collins)
However, modern intensive supportive therapy such as intravenous fluid
replacement can reduce case fatality rates to less than 1 percent.
Exposure to one dengue serotype provides permanent immunity against that serotype, but subsequent infections by
a different serotype increase the likelihood that the patient will develop DHF.
Trends
Due to the deforestation, development, and urbanization of tropical regions, breeding grounds for A. aegypti have
expanded. As a result, human-vector contact has increased, and infection rates are on the rise.
The A. aegypti habitat is not limited to the developing world, and dengue cases have recently occurred in Puerto
Rico, Singapore, Hawaii, and the southern United States.
A dengue epidemic in Brazil that started in early 2008 caused over 55,000 infections over four months in Rio de
Janeiro alone.

D E N GDUengue
E F E V EFRever
(DF)

n Palliative Care n None n PanBio Rapid Tests
– Intravenous fluid replacement − Dengue Duo Cassette and Dengue
can be used for rehydration Duo IgM and IgG Rapid Strip Test
− Acetaminophen can be used (For differentiation between primary
to manage pain and fever and secondary dengue infection)
n PanBio ELISAs
− Dengue IgG Indirect ELISA (For
detecting past/active dengue infection)
− Dengue IgM and IgG Capture
ELISAs (For diagnosis of
primary and secondary dengue
infection, respectively)

n Oral formulation n Single- or two-dose tetravalent n Ability to diagnose initial
n Rapid-acting n Provides extended protection stage of disease, to distinguish
n Ameliorates symptoms n Safe and effective in young children between serotypes, and to
n Prevents DHF n Effective against all four serotypes distinguish from other fevers

Novartis Institute for Tropical Diseases (inhibitors of viral and host targets) nnnnnnnn
SIGA (ST 981, ST 610, ST 689, and ST 562) nnnnnnnn

Acambis/Sanofi-Pasteur (ChimeriVax™-Dengue: live, chimeric tetravalent) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
GSK/WRAIR (live, attenuated tetravalent) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
NIAID/JHU/Biologics(E)/Panacea/Butantan nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
(monovalent, live, attenuated intertypic chimeric)
GenPhar/NMRC (flavivirus-based recombinant DNA vaccine, tetravalent) nnnnnnnnnnnnnnnnnnnnn
InViragen/Shantha Biotechnics/CDC/PDVI nnnnnnnnnnnnnnnnnnnnn

(DENVax: live, attenuated chimeric tetravalent)
Hawaii Biotech/PDVI (recombinant protein, tetravalent) nnnnnnnnnnnnnnnnnnnnn
WRAIR (whole virus, inactivated) nnnnnnnnnnnnnnnnnnnnn

n Potential markets for travelers to endemic regions and for people living in developed world areas where A. aegypti
can be found. The range of dengue is expanding into areas such as Singapore and the southern United States.
n Military market; biodefense vaccines can qualify for FDA fast-track approval.
n Largest market for dengue vaccines is in the endemic areas of the tropics (over 4 billion people at risk in Latin
America, Asia, and perhaps Middle East/Africa).

E N G U E F ever
D engue EVER (DF)

n Developing an antiviral that is n Developing a tetravalent vaccine n Serologic tests only detect antibodies
effective once infection has occurred effective against all four serotypes to dengue late in infection

n World Health Organization (WHO) ~ www.who.int/topics/dengue/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/ncidod/dvbid/dengue
Key Organizations
n Genome Institute of Singapore and Novartis Institute for Tropical Diseases ~ http://dengueinfo.org/NITD/
n Pediatric Dengue Vaccine Initiative (PDVI) ~ www.pdvi.org
n WHO Initiative for Vaccine Research (IVR) ~ www.who.int/vaccine_research/en
Important Papers
n Blaney, JE, Jr., et al. Recombinant, live-attenuated tetravalent dengue virus vaccine formulations induce a
balanced, broad, and protective neutralizing antibody response against each of the four serotypes in rhesus
monkeys. J Virol 79:5516-28 (2005)
n Edelman, R. Dengue and dengue vaccines. J Infect Dis 191:650-3 (2005)
n Guirakhoo, F, et al. Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax™-DEN2) vaccine:
Phase I clinical trial for safety and immunogenicity: Effect of yellow fever pre-immunity in induction of broad
neutralizing antibody responses to all 4 dengue serotypes. Human Vaccines 2:60-7 (2006)
n Monath, TP. Dengue and yellow fever—challenges for the development and use of vaccines.
NEJM 357:2222-5 (2007)
n Wilder-Smith, A, and Schwartz, E. Dengue in travelers. NEJM 353:924-32 (2005)

Enterotoxigenic E. coli (ETEC)
What Is Enterotoxigenic E. coli?
Enterotoxigenic E. coli (ETEC), a virulent strain of the bacterium Escherichia coli, is a major cause of severe diarrhea
leading to hospitalization. Infection by this bacterium is a leading killer of children in the developing world.
Global Burden
Each year an estimated 300 million to 400 million new infections of ETEC
result in 400,000 to 500,000 deaths. Ninety percent of these deaths occur
in lower income countries. ETEC is a major cause of childhood diarrhea;
most fatal cases occur in children under the age of two. ETEC is also the
leading cause of travelers’ diarrhea.
ETEC cases are reported worldwide; incidence rates are highest in Central
and South America, Africa, and Southeast Asia.
Countries at high risk for travelers’ diarrhea Causative Agent/Transmission

(CDC, 2007) E. coli is a bacterium with numerous serotypes, most of which normally
inhabit the human intestinal tract with little ill effect. Several strains,
however, secrete toxins that act on the intestinal lining and cause disease. E. coli that cause diarrheal illness can be
broken down into four categories based on virulence mechanism: enterotoxigenic (ETEC), enteropathogenic (EPEC),
enteroinvasive (EIEC), and enteroaggregative (EAggEC). ETEC is transmitted through food or water contaminated with
human or animal feces.
Presentation
Toxins released by gut-colonizing ETEC cause water and salts to be lost
into the intestine, resulting in watery diarrhea, abdominal cramping,
fever, and vomiting. Death is caused by extreme dehydration.
Trends
The disease burden associated with ETEC and other diarrheal infections
remains enormous across all developing countries. ETEC is also a
concern for travelers visiting the developing world.
Although ETEC can be treated with antibiotics, the most effective drugs
One strain of E. coli (photo: CDC/Janice Carr) are prohibitively expensive. Misuse of antibiotics has led to drug-
resistant ETEC strains.

EN
nteroto
TEROTOX
x Iigenic
GENIC E. C
coli
OLI (ETEC)

n Palliative Care n Dukoral® is a cholera vaccine that n None
− Oral rehydration therapy can has shown 60 percent short-term
be used to treat symptoms efficacy against travelers’ diarrhea
− Antibiotics and intravenous fluids n No product exists to vaccinate
are sometimes given in severe cases people in endemic regions

n High-potency antibiotic n Oral delivery n Ability to differentiate between
n Multivalent ETEC and other causes of
n Provide extended protection to diarrhea, including protozoa
infants and young children

Intercell (LT transcutaneous patch) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Center for Vaccine Development at University of Maryland nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(CVD 1208: oral, attenuated Shigella expressing ETEC antigens)
Ace BioSciences/PATH Enteric Vaccine Initiative nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(Ace527: live, attenuated recombinant E. coli expressing LTB)
Celldex/NIAID (attenuated cholera expressing CTB and ETEC antigen CFA/I) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MIDRP (SC608: attenuated S. flexneri w/ETEC Cfab component of CFA/I and LTB) nnnnnnnnnnnnnnnnnnnnn
NICHD/Robbins (O-LT/ST: LT-ST toxoid conjugated to O antigen) nnnnnnnnnnnnnnnnnnnnn
Göteborg University (killed, whole-cell ETEC expressing CFA/I, CS1-5, and rCTB-LTB) nnnnnnnnnnnnnnnnnnnnn
MIDRP (fimbrial tip adhesion antigens) nnnnnnnnnnnnnnnnnnnnn
Emergent Europe (Spi-VEC ETEC: S. typhi vector expressing LTB nnnnnnnnnnnnnnnnnnnnn

and other ETEC antigens)

n Surveys indicate that individuals across low- and middle-income countries would be willing to pay one-half to
one day’s wage for a vaccine on the private market.
n Moderate financial case for investment:
– Market may be sufficient to attract innovators (nearly $400 million peak annual)
– Market driven by travelers, military, and middle-income populations
– More robust travelers’ market could boost revenue an additional $200 million per year

E N T E R OETnteroto
OXIGENIC E . C O L I E(.Ecoli
x igenic TEC)

n Need to overcome antibiotic resistance n Multiple strains make it difficult n None
to design a multivalent vaccine
with sufficient coverage
n Certain major cell-surface markers
are not immunogenic, making them
poor candidates for vaccines

n World Health Organization (WHO) ~ www.who.int/vaccine_research/diseases/e_e_coli/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/ncidod/dbmd/diseaseinfo/etec_g.htm
Key Organizations
n International Centre for Diarrheal Disease Research, Bangladesh (ICDDR,B) ~ www.icddrb.org/pub
n PATH Enteric Vaccine Initiative (EVI) ~ www.path.org/projects/enteric_vaccine
Important Papers
n Qadri, F, et al. Enterotoxigenic Escherichia coli in developing countries: Epidemiology, microbiology, clinical
features, treatment, and prevention. Clin Microbiol Rev 18:46-83 (2005)
n Qadri, F, et al. Reduced doses of oral killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine is
safe and immunogenic in Bangladeshi infants 6-17 months of age: Dosing studies in different age groups.
Vaccine 24:1726-33 (2006)
n Walker, RI. Considerations for development of whole-cell bacterial vaccines to prevent diarrheal diseases in
children in developing countries. Vaccine 23:3369-85 (2005)

Human African Trypanosomiasis (HAT)
What Is Human African Trypanosomiasis?
Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by a single-celled parasitic
protozoan called a trypanosome and is transmitted by tsetse flies. The disease progresses from fever and fatigue to
severe neurological conditions. Untreated HAT results in death.
Global Burden
There are 60 million people at risk worldwide. Each year, there are an
estimated 10,000 to 50,000 deaths.
HAT is found in 36 countries in sub-Saharan Africa, but the vast majority
of cases occur in just three countries: Angola, the Democratic Republic of
the Congo, and Sudan.
HAT is caused by Trypanosoma brucei, a protozoan parasite transmitted to
(Simarro et al. PLoS NTD5:e55 [2008]) humans by the bite of an infected tsetse fly. There are several subspecies
of T. brucei; T.b. gambiense, found in Central and West Africa, causes
chronic disease, and T.b. rhodesiense, present in South and East Africa, causes acute disease. The cattle reservoir
for T.b. rhodiense has proved to be a barrier for disease control. T. brucei is related to the trypanosomes that cause
Chagas disease and leishmaniasis.
Presentation
T. brucei parasites first develop in the blood, lymph, and peripheral organs (stage 1) and then cross the blood-brain
barrier and enter the central nervous system (stage 2). Stage 2 is characterized by severe neurological disorders
including extreme fatigue, major disturbances to patients’ sleep cycle
(hence “sleeping sickness”), and coma. Without treatment, the disease is
always fatal.
Trends
By the 1960s, aggressive surveillance and programs to eradicate tsetse
flies resulted in the near disappearance of the disease. Subsequently,
control measures were relaxed, tsetse populations recovered, and HAT
rebounded. Since the WHO made HAT a priority in 1995, improved HAT
control has caused a 68 percent reduction in cases, as of 2006.
T. brucei parasites in a patient’s blood smear

(photo: CDC/Myron Schultz)

H uman A frican T r y panosomiasis HUMAN A F R I C AAN
H uman T R Y P A TNrOySpanosomiasis
frican OMIASIS (HAT)

Current treatments have variable efficacy, n None There are no rapid, easy-to-use, serological
are prohibitive to deliver (pentamidine point-of-care diagnostic tests available.
is delivered by parenteral injection; all As a result, patients are not typically
others are administered intravenously), diagnosed until the late stage of the
and can be highly toxic. disease.
n Pentamidine n Case Detection
– Treats stage 1 T.b. gambiense infection – Blood smear for T.b. rhodesiense
(ineffective against stage 2 HAT) (sensitive) or T.b. gambiense
– Side effects are rare (less sensitive)
n Suramin – Card indirect agglutination test
– Treats stage 1 T.b. rhodesiense (CATT) for T.b. gambiense
infection (ineffective n Staging
against stage 2 HAT) – Microscopy on cerebral spinal
– Side effects can be severe fluid following lumbar puncture
n Melarsoprol (arsenic derivative)
– Treats stage 2 HAT
– Side effects are frequent and severe;
results in reactive encephalopathies
in 5 to 10 percent of treated cases
– Showing evidence of resistance
n Eflornithine (DFMO)
– Treats stage 2 HAT; effective only
against T.b. gambiense infection
– Side effects are numerous
and can be severe
– Requires hospital administration
– Highly effective, but costs are
high and supply is unreliable

n Reduced toxicity n Vaccines not targeted n Distinguishes between stage 1 and
n Efficacy against T. gambiense stage 2 disease (treatment choice
and T. rhodesiense depends on whether or not there is
n Efficacy against stage 1 central nervous system involvement)
and stage 2 disease n Test of cure
n Must cross blood-brain barrier in
order to eliminate central nervous
system infection in stage 2 disease

H uman
U M A N A frican
FRICAN Tr
RyY panosomiasis
PANOSOMIASIS (HAT)

Discovery Pre- Clinical- Clinical- Clinical-
Drugs Clinical Phase I Phase II Phase III
DNDi/Epicentre/MSF/Democratic Rep. of the Congo/Rep. of the Congo/STI nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
(nifurtimox-eflornithine) (completed 11/2008)
DNDi/Accelera/STI/Axyntis/Covance/Aptuit/KARI (fexinidazole) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Consortium for Parasitic Drug Development (DB series) nnnnnnnnnnnnnnnnnnnnn
Dafra Pharma (DF-051) nnnnnnnn
DNDi/Scynexis/Pace University (HAT consortium for lead optimization) nnnnnnnn
DNDi/STI/Fiocruz and many others (nitroimidazoles) nnnnnnnn
DNDi/Epichem/Murdoch University (microtubule inhibitors) nnnnnnnn
DNDi/GSK/STI (4(1H) pyridones and cysteine protease inhibitors) nnnnnnnn
DNDi/Kitasato Institute (screening: natural products) nnnnnnnn
DNDi/Central Drug Research Institute (screening) nnnnnnnn
DNDi/Eskitis Institute (screening: natural products) nnnnnnnn
University of Dundee Tropical Disease Initiative (screening) nnnnnnnn
Sandler Center (kinase inhibitors) nnnnnnnn
Discovery Preclinical Clinical

Diagnostics
Nucleic acid detection
FIND/Murdoch University/Obihiro University/Eiken Chemical Corp nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(loop-mediated isothermal amplification of DNA)
Antibody or antigen detection
FIND/MicroCoat (serologic dx: T. b. gambiense) nnnnnnnn
FIND/University of Technology (Germany) (RNA aptamers) nnnnnnnn
FIND/SBRI (optimized antibody probes) nnnnnnnn
FIND/University of Brussels (nanobodies) nnnnnnnn
Disease staging
FIND/Inst. of Tropical Medicine/Royal Tropical Institute nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(IgM quantification; ‘dri-dot’ single format test)
FIND/Aberdeen University (blood markers) nnnnnnnn
FIND/University of Geneva/Inst. of Tropical Medicine/Makerere Univ. (biomarkers) nnnnnnnn

n Primarily a disease of impoverished rural communities and will require donor support to encourage innovation.

H uman A frican T r y panosomiasis HUMAN A F R I C AAN
H uman T R Y P A TNrOySpanosomiasis
frican OMIASIS (HAT)

n Eradication of central nervous system n T. brucei undergo extensive antigenic n Serum biomarkers that correlate
infection is difficult to confirm variation, which presents significant with stage 2 disease have only
(only a few residual organisms are obstacles to vaccine development recently been identified
needed for infection to recur)
A dditi o na l I nf o rmati o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

n World Health Organization (WHO) ~ www.who.int/topics/trypanosomiasis_african/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/trypanosomiasis
Key Organizations
n Drugs for Neglected Diseases Initiative (DNDi) ~ www.dndi.org
n Foundation for Innovative New Diagnostics (FIND) ~ www.finddiagnostics.org
n University of Dundee, Tropical Disease Initiative ~ www.drugdiscovery.dundee.ac.uk/tropical/overview/
Important Papers
n Berriman, M, et al. The genome of the African trypanosome Trypanosoma brucei. Science 309:416-22 (2005)
n Legros, D, et al. Treatment of human African trypanosomiasis—present situation and needs for research and
development. Lancet Infect Dis 2:437-40 (2002)
n Njiru, ZK, et al. Loop mediated isothermal amplification (LAMP) method for rapid detection of Trypanosoma brucei
rhodesiense. PLoS NTD. 2:e147 (2008)
n Renslo, AR, and McKerrow, JH. Drug discovery and development for neglected parasitic diseases. Nature Chemical
Biology 2:701-10 (2006)
n Simarro, P, et al. Eliminating human African trypanosomiasis: Where do we stand and what comes next? PLoS
Med 5:e55 (2008)

Human Hookworm Infection
What Is Human Hookworm Infection?
Human hookworm infection is a parasitic disease caused by soil-dwelling nematodes. Whereas light infections may
be asymptomatic, heavy infections may cause anemia, diarrhea, abdominal pain, weight loss, and loss of appetite.
Global Burden
An estimated 576 million people are infected with hookworm, and
approximately 3 billion people are at risk for acquiring the infection.
The largest number of cases occurs in impoverished rural areas of
sub-Saharan Africa (198 million cases), Southeast Asia (59 million), India
(71 million), and tropical regions of the Americas (50 million).
Hookworm infection is caused by the parasitic nematodes Necator
Countries with areas endemic for hookworm americanus and Ancylostoma duodenale. N. americanus is found in the
infection (SVI, 2005) Americas, sub-Saharan Africa, Southeast Asia, China, and Indonesia and
is the more prevalent cause of infection; A. duodenale is geographically
restricted to the Middle East, North Africa, and India. Hookworms hatch in soil and mature through three larval
stages. Upon contact with humans, larvae penetrate the skin, enter the blood stream, and eventually migrate into
the lung trachea, where they are swallowed into the stomach. They then travel through the digestive tract to the
small intestine where, over five to nine weeks, they feed on blood components and mature into adult worms that
are approximately one centimeter in length. Adult females lay eggs, which are released in feces into the
environment, reinitiating the cycle of infection.
Presentation
To feed, hookworms attach to the walls of the small intestine, resulting
in host blood loss and injury to the mucosa. In children, chronic disease
causes iron-deficiency anemia, which impairs physical and cognitive
development. In expectant mothers, severe infection results in adverse
outcomes for both mother and child, including low birth weight,
impaired milk production, and increased risk of death.
Trends
Currently, human hookworm infection is treated by deworming with the
drugs, and deworming programs are a crucial component of hookworm
A hookworm in its immature, noninfectious stage
control programs. Many control programs, however, are school-based,
(photo: CDC)
which limits their ability to reach adults and the elderly. Also, drug
treatment has variable efficacy, and with frequent and repeated use, there are concerns that drug resistance may
develop. Moreover, re-infection occurs rapidly post-treatment, especially in areas of high transmission where it can
occur within four to 12 months.

H uman H ookworm I nfection

n Albendazole, mebendazole, n None commercially available n Microscopic examination
or pyrantel pamoate of feces for eggs
– Low efficacy (mebendazole),
rapid reintroduction,
resistance, limited access
N ew P r o d u ct N eeds nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n New class of drugs to counter n Prevent hookworm disease due to n Low-cost, simple test on feces to
inevitable rise of resistance infection with Necator americanus, the diagnose hookworm infection
n Drugs that offer long-lasting most prevalent hookworm worldwide
protection in order to break
the chain of transmission

Vaccines Clinical Phase I Phase II Phase III
SVI-HHVI (Na-ASP-2 hookworm vaccine: recombinant antigen) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
SVI-HHVI (Na-APR-1 hookworm vaccine: recombinant antigen) nnnnnnnnnnnnnnnnnnnnn

n Because hookworm occurs almost exclusively among the estimated 2.7 billion people who survive on incomes
of less than $2 per day, there is no commercial market for a vaccine targeting hookworm. To be effective, such
a vaccine must be manufactured and distributed for less than $1 a dose, and possibly even much less. The
SVI-HHVI has developed a unique Global Access Strategy to ensure that an eventual vaccine is made available to
those affected at extremely low cost.

n New targets have not been defined n A highly efficacious vaccine that n Potential cross-reactivity with
protects against a multicellular other helminth infections
organism has never before been made
n Access to adjuvants to
increase immunogenicity

H uman H ookworm I nfection

n World Health Organization (WHO) ~ www.who.int/vaccine_research/diseases/soa_parasitic/en/index2.html
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/hookworm
Key Organizations
n SVI-Human Hookworm Vaccine Initiative (SVI-HHVI) ~ http://sabin.org/programs/hhvi/index.html
Important Papers
n Asojo, OA, et al. X-ray structures of Na-GST-1 and Na-GST-2 two glutathione s-transferase from the human
hookworm Necator americanus. BMC Structural Biology 7:42 (2007)
n Bethony, J, et al. Antibodies against a secreted protein from hookworm larvae reduce the intensity of hookworm
infection in humans and vaccinated laboratory animals. FASEB J 19:1743-5 (2005)
n Bethony, JM, et al. Randomized, placebo-controlled, double-blind trial of the Na-ASP-2 hookworm vaccine in
unexposed adults. Vaccine 26:2408-17 (2008)
n Diemert, DJ, et al. Vaccines: Hookworm vaccines. Clin Infect Dis 46:282-8 (2008)
n Loukas, A, et al. Vaccination with recombinant aspartic hemoglobinase reduces parasite load and blood loss after
hookworm infection in dogs. PLoS Med 2:e295 (2005)
n Loukas, A, et al. Hookworm vaccines: Past, present, and future. Lancet Infect Dis 6:733-41 (2006)

Human Immunodeficiency Virus (HIV)
What Is HIV?
HIV is a retrovirus that causes acquired immunodeficiency syndrome (AIDS), a syndrome characterized by
progressive deterioration of the immune system. HIV/AIDS patients are at risk for opportunistic infections because
of their diminished immune function, which may eventually lead to their death.
Global Burden
At the end of 2007, it was estimated that 33.2 million people worldwide
were infected with HIV. There were approximately 2.1 million AIDS
deaths, and another 2.5 million people were newly infected with HIV.
Young people between the ages of 15 and 24 now account for almost half
of all the new infections. Young women are especially vulnerable, with
prevalence rates being as high as four times those for young men of the
same age.
HIV/AIDS is a worldwide pandemic. Nearly two-thirds of those living
HIV affects countries all over the world (WHO)
with HIV/AIDS are located in sub-Saharan Africa. Southern Africa has
been hardest hit; in several countries, the prevalence of HIV exceeds 30 percent of the adult population. Although
the prevalence of HIV in South and Southeast Asia is much lower than in Africa, its huge population makes it
second to Africa in terms of the total number of individuals infected.
HIV is spread by exposure to infected body fluids including blood, semen, and breast milk. The major routes of
transmission are by sexual contact, through contaminated needles, and from infected mother to child in utero, at
birth, or through breastfeeding.
HIV mutates rapidly, and today patients are infected by many different
strains. Most broadly, HIV can be classified as HIV-1 or HIV-2. HIV-1 is
more virulent than HIV-2, causes the majority of infections, and can be
divided into several distinct groups, which are themselves divided into
subtypes, or clades, that display distinct geographic infection patterns.
Treatment is more complicated in regions where more than one clade is
circulating because hybrid strains can arise.
Presentation
Clinical diagnosis of HIV infection is complicated by the lack of specific
symptoms. Two to four weeks after infection, patients may display
The tiny spheres in this micrograph are the HIV flu-like symptoms accompanied by a rash and fever. However, many
virus budding from the surface of a lymphocyte
patients are initially asymptomatic. Although the incubation period
(photo: CDC/C. Goldsmith)
between infection and onset of AIDS is often cited as seven to 10 years,
disease course is accelerated in low- and middle-income countries due to environmental factors including burden
of disease and nutrition. Once a patient develops AIDS (as defined as a CD4 lymphocyte count of <200 cells/µL), the
disease is characterized by decreased immune functioning and an extreme susceptibility to opportunistic infections.
Trends
The HIV/AIDS epidemic has spread rapidly and is now considered a global pandemic. More than 95 percent of all
new infections occur in people living in low- and middle-income countries. There is some good news—since 2000,
worldwide, the percentage of people living with HIV/AIDS has stabilized. Due to the success of antiretroviral (ARV)
treatment programs in prolonging life combined with new infections, however, the total number of individuals
infected with HIV continues to rise. Resistance to ARVs is common and transmission of HIV strains resistant to one
or multiple drugs has been documented and appears to be increasing.

H uman I mmunodeficienc y V irus ( H I V )

n Combination and Highly Active n None Current technologies do not provide an
Antiretroviral Therapy (HAART) inexpensive point-of-care test by which
− Composed of a combination to direct treatment.
of anti-HIV drugs n HIV Enzyme Immunoassay
− There are three major groups of & Western Blot Assay
anti-HIV drugs, consisting of more − Detects antibodies to HIV in serum,
than 20 approved medications plasma, oral fluid, dried blood, or urine
− Side effects and drug resistance n OraQuick® ADVANCE™
can be significant issues HIV-1/2 Antibody Test
− Although older, less expensive − First oral fluid rapid HIV test
antiretrovirals are increasingly − Can be used on oral fluid, plasma,
available, the latest treatments fingerstick, and venipuncture
remain out of reach for many whole blood specimens
in the developing world n Chembio STAT-PAK™ & SURE CHECK®
− Current drugs reduce viral load, Assays and Dipstick Tests
but do not cure the disease and − Simple, sensitive, and specific
must be taken indefinitely − Room-temperature storage

n New fixed-dose combinations n Preventative vaccine that offers long- n Test to diagnose infection in infants
n Specific pediatric formulations term protection against multiple clades less than 18 months of age
n Low-cost, effective, easy-to-use n Point-of-care test that quantifies
first- and second-line treatments viral load and CD4 count and
n Combinations that could be used indicates when to start treatment
for pre-exposure prophylaxis and when to switch treatment
in children and adults

P ipe l ine * nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Sanofi-Pasteur/ANRS (ALVAC-vCP1521: canary pox vector) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
GeoVax/NIAID (prime: Gag, Pol, Env DNA, boost: MVA expressing Gag, Pol, Env) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Bavarian Nordic (MVA-BN® multiantigen) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
EuroVacc Foundation/GENEART (DNA-C + NYVAC-C) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Muhimbili University/Karolinska Institute/Swedish Institute for Infectious nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

Disease Control/Vecura/USMHRP (prime: HIVIS DNA, boost: MVA-CMDR)
Aaron Diamond AIDS Research Center/IAVI and others (ADVAX and TBC-M4) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
GSK (recombinant prophylaxis) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
St. Jude’s/NIH (PolyEnv1, EnvDNA, EnvPro) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
GenVec/NIH (VRC-HIVADV014-00-VP) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Crucell/NIAID (Ad26.ENVA.01) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
WRAIR (MVA-CDMR) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
South African AIDS Vaccine Initiative (DNA C-2) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
St. George’s University, London, and others (HIV gp140 + adjuvants) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
University of Pennsylvania (PENNVAX-B; DNA plasmids) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
University of South Wales (prime: pHIS-HIV-AE; boost: rFPV-HIV-AE ) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Moscow Institute of Immunology (VICHREPOL with adjuvant) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Wyeth/NIAID (various DNA and peptide vaccines) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Guangxi CDC (multiclade HIV-1 DNA vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
AlphaVax/NIAID (multigene) nnnnnnnnnnnnnnnnnnnnn
Novavax (VLP HIV-1) nnnnnnnnnnnnnnnnnnnnn
Novartis/NIH (preventive vaccine) nnnnnnnnnnnnnnnnnnnnn

Microbicides Discovery Clinical Phase I Phase II Phase III
Indevus/MRC/DFID (PRO 2000) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
CAPRISA/USAID/LIFElab/Gilead/FHI/CONRAD (tenofovir gel) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
NIAID/Indevus/ReProtect (PRO 2000 and BufferGel®) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
StarPharma/NIAID/NICHD (VivaGel®) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
IPM (TMC120: dapivirine gel) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
NIAID (ethanol in emollient gel) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
CONRAD/NIAID/UCLA/CDC/Thailand Ministry of Health (UC-781) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
*This is not an exhaustive listing of all HIV vaccines and microbicides currently in development or clinical trials and excludes HIV drugs and
preclinical microbicides.


n The worldwide market for HIV/AIDS products is rising because of several factors, including increasing HIV
prevalence, drug resistance, and poor patient compliance with existing regimens.
n Efficacious HIV drugs and vaccines, especially if affordable, will find markets in both the developed and
developing worlds. By one estimate, annual sales of HIV/AIDS drugs are expected to grow from $7.1 billion in
2005 to more than $10.6 billion by 2015.
n Donor commitment to fighting HIV/AIDS includes the President’s Emergency Plan for AIDS Relief (PEPFAR),
funded at $15 billion for 2003-2008 and reauthorized for $48 billion for 2008-2013.

n Continued need for high- n Vaccines need to overcome wide n CD4 and Viral Load Diagnostics
potency, less-costly drugs variability of virus strains, both in In infants, it is difficult to obtain
n Resistance is a growing issue single patients and across populations sample volume adequate for
n The development of a vaccine detection; also presence of maternal
that induces humoral, cell- antibodies can complicate diagnosis
mediated, and mucosal immunity
has proven challenging

n World Health Organization (WHO) ~ www.who.int/topics/hiv_infections/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/hiv
n National Institute for Allergy and Infectious Diseases (NIAID) ~ www.niaid.nih.gov/factsheets/hivinf.htm
Key Organizations
n AIDS Vaccine Advocacy Coalition (AVAC) ~ www.avac.org
n Alliance for Microbicide Development ~ www.microbicide.org
n Global Fund to Fight AIDS, Tuberculosis and Malaria ~ www.theglobalfund.org/en
n HIV InSite ~ http://hivinsite.ucsf.edu
n HIV Vaccine Trials Network (HVTN) ~ www.hvtn.org
n International AIDS Vaccine Initiative (IAVI) ~ www.iavi.org
n International Partnership for Microbicides (IPM) ~ www.ipm-microbicides.org
Important Papers
n AIDS Epidemic Update 2007 ~ http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf
n Aledort, JE. Reducing the burden of HIV/AIDS in infants: The contribution of improved diagnostics. Nature S1,
19-28 (2006)
n Barouch, DH. Challenges in the development of an HIV vaccine. Nature 455:613-9 (2008)
n Duerr, A, et al. HIV vaccines: New frontiers in vaccine development. Clin Infect Dis 43:500-11 (2006)
n Gallo, RC. The end or the beginning of the drive to an HIV-preventive vaccine: A view from over 20 years. Lancet
366:1894-8 (2005)
n Lederman, MM, et al. Microbicides and other topical strategies to prevent vaginal transmission of HIV. Nat Rev
Immunol 6:371-82 (2006)
n Markel, H. The search for effective HIV vaccines. NEJM 353:753-7 (2005)

Japanese Encephalitis (JE)

What Is Japanese Encephalitis?
Japanese encephalitis (JE) is a viral disease transmitted by mosquitoes that causes fever and flu-like symptoms. In
severe cases, JE results in inflammation of the brain (encephalitis). Death may result if the symptoms are not treated.
Global Burden
JE is the leading cause of viral encephalitis and neurological infection in
Asia. Annually, 50,000 new cases are recorded, resulting in 15,000 deaths
and a 75 percent JE-related disability rate; however, these numbers may
not reflect the true disease burden due to underreporting. Over 3 billion
people live in areas endemic for JE.
JE is endemic in Asia, ranging from the islands of the Western Pacific in
the east to the Pakistani border in the west, and from Korea in the north
to Papua New Guinea in the south. JE distribution is linked to irrigated
Countries with seasonal or year-round transmis-
rice production combined with pig rearing.
sion of Japanese encephalitis in 2003 (WHO, 2008)
The JE virus belongs to the family Flaviviridae, along with the viruses responsible for dengue fever, yellow fever,
and West Nile disease. Mosquitoes belonging to the Culex tritaeniorhynchus and Culex vishnui groups, which breed in
flooded rice fields, transmit JE. Because Culex mosquitoes prefer to feed on animals, the virus circulates in birds and
pigs, spilling into human populations only when Culex populations increase dramatically over a short period of time.
Presentation
Most JE virus infections are mild (fever and headache) or asymptomatic. Approximately one in 300 infections results
in severe disease characterized by rapid onset of high fever, headache, neck stiffness, disorientation, coma, seizures,
spastic paralysis, and death. In these cases, JE affects the brain or the membranes around the brain (meninges). Of
those who survive severe JE, 30 percent suffer lasting damage to the
central nervous system. In areas where the JE virus is common,
encephalitis occurs mainly in young children because older children and
adults have acquired immunity through prior exposure.
Trends
Large outbreaks of JE in India and Nepal have highlighted the continuing
expansion of the geographic range of the disease in recent years.
JE virus particles (photo: picture library of

Sanofi Pasteur)

JA PANESE EN
apanese CEPHALITIS (JE)
ncephalitis

n Palliative Care n Inactivated Vaccine (JE-VAX®) An inexpensive, field-ready technology
− Intravenous fluid replacement − Derived from infected mouse brain (MAC DOT) has been developed but not
can be used for rehydration − Expensive commercialized.
− Acetaminophen can be used − Requires three doses n Plaque Reduction
to manage pain and fever − Offers short-term protection Neutralization Assay (PRNT)
− Reports of neurological and − Time intensive and costly
hypersensitivity reactions − High biosafety-level requirements
following vaccination n Hemagglutination Inhibition (HI)
n Live, Attenuated Vaccine − Low specificity
− Inexpensive − High level of cross-reactivity
− Used in China, but not widely available with other flaviviruses
− Currently being developed under n ELISA
improved GMP conditions − Simple and sensitive
− Some cross-reactivity with
other flaviviruses
− Not currently suitable for
point-of-care testing

n Drug therapy not targeted n Second-Generation Vaccine n No cross-reactivity with other
− Safer flaviviruses
− Requires fewer doses
− Should be compatible with
the WHO EPI schedule

Intercell/Novartis/Biologics E (Ixiaro®) FDA approved 03/2009 nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
(IC51: inactivated Vero cell-grown SA14-14-2 strain)
Acambis/Sanofi Pasteur nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(ChimeriVax-JE: live, chimeric derived from SA14-14-2 strain)
Biken/Kaketsuken (inactivated Vero cell-grown Beijing strain) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

n Significant opportunity in travelers’ and military markets.
n One company estimates a global market of over $300 million.

n Difficult to develop therapeutic n Evaluation of efficacy of JE n Important to detect disease in
antivirals vaccines against virus strains for early stages of infection, when
different geographic regions intervention may be beneficial

J A P AJNapanese
E S E E N C EEPncephalitis
HALITIS (JE)

n World Health Organization (WHO) ~ www.who.int/vaccine_research/diseases/japanese_encephalitis/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/ncidod/dvbid/jencephalitis
Key Organizations
n International Vaccine Institute, Japanese Encephalitis Program ~ http://www.ivi.org/program/tr_je_program.html
Important Papers
n Anonymous. RNA sequence restrains fatal encephalitis. Focus Online (2006)
n Konstantin, V, et al. Chimeric vaccines against Japanese encephalitis, dengue and West Nile. New Generation
Vaccines, 3rd ed. Chapter 47. Eds. M Levine, JB Kapper, R Rappuoli, MA Liu, and MF Good. New York and Basel:
Marcel Dekker (2004)
n Monath, TP, et al. Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): Phase II
clinical trials for safety and immunogenicity, effect of vaccine dose and schedule, and memory response to
challenge with inactivated Japanese encephalitis antigen. J Infect Dis 188:1213-30 (2003)
n Solomon, T. Flavivirus encephalitis. NEJM 351:370-78 (2004)
n Tauber, E, et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: A
non-inferiority, phase III, randomised controlled trial. Lancet 370:1847-53 (2007)

Leishmaniasis
What Is Leishmaniasis?
Leishmaniasis is a widespread parasitic disease that affects the skin, mucosa, and internal organs, resulting in
severe disfigurement, disability, or death.
Global Burden
Worldwide there are 12 million people infected with Leishmania parasites.
An estimated 350 million people are at risk for infection. There are
approximately 1.7 million new cases and 45,000 deaths each year.
Leishmaniasis is found in 88 countries, 72 of which are low-income
countries.
More than 90 percent of all cases of cutaneous leishmaniasis, the most

common form of the disease, are found in Afghanistan, Brazil, Iran, Peru,
Countries with areas of visceral and cutaneous Saudi Arabia, and Syria. Approximately 90 percent of all cases of visceral
leishmaniasis risk. Leishmaniasis epidemiological leishmaniasis, a less common but deadlier form of the disease, occur in
information has serious gaps. (WHO, 2003) Bangladesh, India, Nepal, Sudan, and Brazil.
The leishmaniases are caused by approximately 20 different species of protozoa that belong to the genus Leishmania.
The parasites are transmitted by the bite of the female phlebotomine sandfly. Within the vertebrate host, parasites
invade and replicate inside white blood cells such as macrophages and inside dendritic cells. Leishmania are related
to the trypanosomes that cause human African trypanosomiasis and
Chagas disease.
Presentation
Leishmania diseases can be classified into one of four forms: (1) visceral
leishmaniasis (VL), commonly known as Kala-azar, which is fatal if
left untreated; (2) cutaneous leishmaniasis (CL), the most common
form, which is marked by a proliferation of self-healing skin lesions
that produce significant scarring; (3) mucocutaneous leishmaniasis
(MCL), which is an ulcerative Leishmania infection that results in
destruction of the mucosal membranes of the nose and mouth; and
Protozoan parasites cause leishmaniasis (CDC) (4) diffuse cutaneous leishmaniasis (DCL), the most difficult Leishmania
manifestation to treat, which causes chronic ulcers and skin lesions
resulting in severe disfigurement.
Trends
There is a profound need for safe, effective therapeutics and vaccines to combat the leishmaniases. Indeed, over
the last 10 years, regions endemic for leishmaniasis have been growing, and there has been a sharp increase in the
number of recorded cases of the disease. It is likely that a substantial number of cases are never recorded because
declaration is compulsory in only 32 of the 88 countries affected by the disease.

L eishmaniasis L eishmaniasis

n Miltefosine (Impavido®) There are no modern vaccines against n Direct Agglutination Test (DAT)
− Approved in 2003 for use in India for VL leishmaniasis. with freeze-dried antigen
and in 2005 for use in Colombia for CL n In some endemic regions, to protect − First-line diagnostic
− Has shown a 95 percent response against CL, a controlled lesion is − Highly sensitive and specific
rate when used against VL created in an area of the skin normally − Does not require special equipment
− Currently the only effective covered by clothing, via inoculation of n Dipsticks rK39/RK26
oral treatment live parasite. While this lesion is active, − rK39 for serological diagnosis
− Contraindicated in pregnancy the individual is protected from lesions − Based on a recombinant
n Paromomycin (aminosidine, on more visible parts of the body. This antigen of L. chagasi
Humatin®) process is called leishmanization. − Requires cold storage
− Approved in 2006 for use in India for VL − Reduced sensitivity in
− Granted “orphan drug” status HIV-positive patients and in
− Injected certain genetic backgrounds
n Amphotericin B n Katex (Latex Agglutination Test)
− Liposomal amphotericin B − Used to detect L. donovani
(AmBisome®) is first-line treatment antigen in urine samples
of VL in United States. − Requires cold storage
− Severe side effects associated n Skin Snip
with non-liposomal forms − Test of cure
− Injected
n Pentavalent Antimonials:
sodium stibogluconate (Pentosam®),
meglumine antimoniate (Glucantime)
− Predictable, but reversible side effects
− Resistance has emerged
in certain areas
− Injected
n Pentamidine, Ketoconazole
N ew P r o d u ct needs nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n Oral formulation n High-efficacy recombinant n Detection of early-stage,
n Shorter course of treatment subunit vaccine systemic disease
n Safer than current treatments n Prophylactic and therapeutic n Perform satisfactorily in East Africa
n High efficacy against all n Effective against multiple n Less invasive test of cure
leishmania species leishmania species

L eishmaniasis

DNDi/iOWH/multiple East African partners (paromomycin) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
DNDi and multiple Indian partners (combination therapies) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
DNDi and multiple East African partners (Ambisome®) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Banaras Hindu University (amphomul) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
DNDi/BioDelivery Sciences International (Bioral™: amphotericin B) nnnnnnnnnnnnnnnnnnnnn
DNDi/Advinus/Drugabilis/University Seins Malaysia, LSHTM (buparvaquone) nnnnnnnnnnnnnnnnnnnnn
DNDi/Imperial College/London School of Pharmacy/LSHTM nnnnnnnnnnnnnnnnnnnnn

(amphotericin B polymer)
ICO Therapeutics (iCo-009: oral reformulation of amphotericin B) nnnnnnnnnnnnnnnnnnnnn
Consortium for Parasitic Drug Development (DB series) nnnnnnnnnnnnnnnnnnnnn
Dafra Pharma/Max Planck Institute (oleylphosphocholine) nnnnnnnn
DNDi/Advinus/CDRI (VL consortium for lead optimization) nnnnnnnn
DNDi/STI/Fiocruz and others (nitroimidazoles) nnnnnnnn
DNDi/GSK/STI (4[1H] pyridones and cysteine protease inhibitors) nnnnnnnn
DNDi/Institute Pasteur Korea (visual high-throughput screening) nnnnnnnn

IDRI/GSK (leish-111f + MPL-SE) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

n Potential military market; CL has been reported in hundreds of troops stationed in Iraq. The problem has become
widespread enough that the CDC has advised soldiers returning from Iraq to wait a year before donating blood to
prevent the spread of the parasite.

n None n Leishmanization (see existing n Regional differences in population
products, above) suggests can influence the strength of
vaccination is possible but long- the immune response to certain
lasting immunity may be difficult to diagnostic test antigens
achieve with a recombinant vaccine

L eishmaniasis L eishmaniasis

n World Health Organization (WHO) ~ www.who.int/topics/leishmaniasis/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/leishmania
Key Organizations
n Drugs for Neglected Diseases initiative (DNDi) ~ www.dndi.org
n Institute for OneWorld Health (IOWH) ~ www.oneworldhealth.org
n Infectious Disease Research Institute (IDRI) ~ www.idri.org
Important Papers
n Coler, RN, and Reed, SG. Second-generation vaccines against leishmaniasis. Trends in Parasitol 21:244-9 (2005)
n Davies, CR, et al. Leishmaniasis: New approaches to disease control. BMJ 326:377-82 (2003)
n Hailu, A, et al. Visceral leishmaniasis: New health tools are needed. PLoS Med 2:e211 (2005)
n Ivens, AC, et al. The genome of the kinetoplastid parasite, Leishmania major. Science 309:436-42 (2005)
n Peacock, CS, et al. Comparative genomic analysis of three Leishmania species that cause diverse human disease.
Nature Genetics 39:839-47 (2007)

Lymphatic Filariasis (LF)
What Is Lymphatic Filariasis?
Lymphatic filariasis (LF), also known as elephantiasis, is caused by parasitic worms and leads to severe
disfigurement of the extremities. While not directly life-threatening, LF is among the world’s leading causes of
permanent and long-term disability. Those infected are disabled in their most productive stage of life, resulting in
an economic and psychosocial burden on afflicted individuals, families, and communities.
Global Burden
More than 120 million people are infected with LF; over 40 million are
seriously disfigured by the disease. It is estimated that 1.3 billion people
are at risk for the disease.
LF is endemic in 83 countries. One-third of the people infected with LF
live in India, and one-third live in Africa. Most of the remaining cases are
distributed throughout South Asia, the Pacific, and the Americas.
Countries endemic for lymphatic filariasis The thread-like, parasitic worms Wuchereria bancrofti and Brugia malayi
(WHO, 2006) cause lymphatic filariasis. Adult worms lodge in the lymphatic system,
where they live for four to six years and produce millions of immature microfilariae (minute larvae) that circulate in
the blood. The parasites are transmitted to a mosquito vector when its blood meal includes microfilariae. Inside the
mosquito, over the course of one to thee weeks, the larvae mature to the infective stage and are transmitted to a
new human host during a subsequent blood meal.
Presentation
The worst symptoms of the chronic disease generally appear in adults. Elephantiasis of an entire leg, arm, the vulva,
or the breast—swelling up to several times normal size—is common. In endemic communities, some 10 to 50
percent of men suffer from genital damage, especially formation of hydrocoeles (fluid-filled balloon-like
enlargements of the sacs around the testes) and elephantiasis of the
penis and scrotum. Once hydrocoele formation has begun, the most
effective way to deal with it is generally surgery, but this solution is too
expensive for the majority of people affected by the disease.
Trends
The Global Programme to Eliminate Lymphatic Filariasis has targeted
elimination of LF by 2020. Results from the program’s first eight years
(2000-2007) are encouraging. Yearly, single-dose mass drug adminstration
has reached 570 million individuals in 48 LF-endemic countries,
protecting an estimated 9.5 million people with subclinical disease from
LF pathogen Wuchereria bancrofti in a blood smear. progressing to clinical disease and preventing disease in 6.6 million
The worm is in the microfilariae stage newborns.
(CDC/Mae Melvin)

L y mphatic F ilariasis ( L F )

n Combination Treatment— n None n Microscopy
Albendazole with − Difficult because the parasites often
Diethylcarbamazine (DEC) have a “nocturnal periodicity” that
or Ivermectin restricts their appearance in the blood
− Use of single doses of two drugs to the hours between 10 p.m. and 2 a.m.
administered concurrently is 99 − Inexpensive reagents
percent effective in removing n Binax nOW® Filariasis Test
microfilariae from the blood for − Antigen detection test
a full year after treatment − Rapid; requires 10 minutes
− Does not kill adult worms − Detects antigens of W. bancrofti in
− Current standard of care is to whole blood, serum, or plasma
treat children annually for five − Simple, very sensitive, and specific
years to prevent disease and − Expensive to use; generally used
break the chain of infection to identify populations at risk
− Treatment with DEC can cause serious rather than individual diagnosis
side effects if onchocerciasis is also
present, as occurs in certain African
countries; ivermectin is used as an
alternative in these regions

n Kills adult worms (macrofilaricidal) n Prevents establishment of n Further development of diagnostics
and reduces swelling infection by microfilariae for B. malayi
n Decreases necessity of repeated, n Adapt existing serologic assays to
annual treatment; inhibits work with oral fluids or urine
microfilariae production


Anti-Wolbachia Consortium: Liverpool School of Tropical Medicine/ nnnnnnnn
CombinatoRx/New England Biolabs, and others (anti-Wolbachia treatments)

n The critical issues for LF are delivery into remote, endemic areas and maintenance of treatment over many years
to reduce adult disease and break the chain of transmission. Currently, all drugs used to treat LF are donated.
n Many current LF treatments are also effective against other diseases common in the developing world; new
drugs might likewise have multiple markets.

n Recent evidence (June 2007) suggests n Lack of an in vitro culture n The major challenge is to reduce
that ivermectin resistance is emerging system for filariae cost of each diagnostic to below $1
in onchocerciasis (a filarial worm n Absence of tools for easy
disease); this observation reinforces genetic manipulation
the need for new drugs in the n Need for improved animal models
event resistance appears in LF

n World Health Organization (WHO) ~ www.who.int/topics/filariasis/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/lymphaticfilariasis
Key Organizations
n Anti-Wolbachia Consortium ~ www.a-wol.net
n The Carter Center ~ www.cartercenter.org
n The Global Alliance to Eliminate Lymphatic Filariasis ~ www.filariasis.org
Important Papers
n Galvez Tan, JZ. The elimination of lymphatic filariasis: A strategy for poverty alleviation and sustainable
development—perspectives from the Philippines. Filaria Journal 2:12 (2003)
n Johnston, KL, and Taylor, MJ. Wolbachia in filarial parasites: Targets for filarial infection and disease control. Curr
Infect Dis Rep 9:55-9 (2007)
n Molyneux, D. Lymphatic filariasis (elephantiasis) elimination: A public health success and development
opportunity. Filaria Journal 2:13 (2003)
n Ottesen, EA, et al. The global program to eliminate lymphatic filariasis: Health impact after 8 years. PLoS NTD
2:e317 (2008)
n Perera, M, et al. Neglected patients with a neglected disease? A qualitative study of lymphatic filariasis. PLoS NTD
1:e128 (2007)
n Towards a strategic plan for research to support the global program to eliminate lymphatic filariasis: Summary
of immediate needs and opportunities for research on lymphatic filariasis. Supplement 5 to AJTMH 71 (2004)

Malaria
B ackgr o u nd nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn`
What Is Malaria?
Malaria is a parasitic disease transmitted by infected mosquitoes. It can be categorized as either uncomplicated or
severe. Symptoms of uncomplicated malaria include fever, chills, body aches, nausea, headache, vomiting, and
diarrhea. Severe disease can cause anemia, acute respiratory distress syndrome, coma, and death.
Global Burden
Half of the world’s population is at risk for malaria. In 2006, there were
an estimated 246 million malaria cases and nearly 1 million deaths. Over
90 percent of malaria deaths occur in Africa; 85 percent of deaths were
in children under the age of five. In Africa, malaria has been estimated
to result in more than $12 billion in lost annual gross domestic profit;
malaria control would cost a fraction of this sum.
Malaria is endemic in more than 100 countries in tropical and subtropical
regions of Africa, Asia, and Central and South America.
Countries with areas of malaria transmission
(WHO, 2003) Causative Agent/Transmission
Malaria is caused by four species of protozoa of the genus Plasmodium: P. falciparum, P. vivax, P. ovale, and P. malariae.
P. falciparum causes the most severe and deadly form of the disease. P. vivax is less deadly, but worldwide, is the
most prevalent Plasmodium parasite and is the cause of the most morbidity. Transmission of all species occurs via
the bite of an infected female Anopheles mosquito.
Presentation
Once in the bloodstream, parasites migrate to the liver, invade hepatocytes, and undergo multiple rounds of
replication. Following this asymptomatic period (which lasts anywhere from a week to months depending on the
species of Plasmodium), parasites are released from the hepatocyte and infect red blood cells (RBCs). During this
blood or erythrocytic stage, parasites replicate several times inside the RBCs, eventually causing them to burst and
thereby freeing the parasites to infect new RBCs. The symptoms of uncomplicated disease are associated with the
erythrocytic stage. The destruction of RBCs may also cause jaundice and anemia. Severe disease may result in
kidney failure, seizures, or coma.
Trends
Increasingly, Plasmodium are resistant to existing antimalarials. Use of
combination therapies and the development of new drugs and vaccines
are strategies being pursued to guard against drug resistance.
Several Anopheles vector species are exhibiting pesticide resistance, even

to the powerful pesticide DDT.
A red blood cell harboring many P. vivax parasites

(photo: CDC/Mae Melvin)

M alaria

The leading drugs used in the developing n None n Light Microscopy
world, chloroquine and sulfadoxine- − High sensitivity and specificity when
pyrimethamine (SP/Fansidar®), are performed under optimal conditions
increasingly ineffective across wide − Labor-intensive and requires
areas because of resistant parasites. New skill to read slides
artemisinin-based combination therapies n Rapid Diagnostic Tests (RDTs)
(ACTs) are currently the best treatments − More expensive than microscopy
but are up to ten times as costly. − Vulnerable to high temperatures
n Chloroquine and humidity
− Affordable and widely available − Can be highly sensitive and specific
− Now ineffective in most malaria − Cannot distinguish severe disease,
endemic areas due to resistance active disease, and background
n Sulfadoxine-pyrimethamine parasitemia from one another
(SP/Fansidar®) − Binax NOW® test is the only rapid
− Resistance increasing rapidly test approved in the United States
n Artemisinin-based Combination
Therapies (ACTs)
− Currently the best treatment
− Only one ACT (Coartem®) is licensed
for use in the United States; many
other ACTs are available overseas
− More expensive than chloroquine or SP
Other, more expensive drugs are available

in the developed world and are used
prophylactically

n Inexpensive (in tens of cents) n Vaccine for infants with delivery n Requires minimal training
n Easy to manufacture tied to EPI schedules n Distinguishes between severe
n Significant shelf life n Effective for at least two years and uncomplicated malaria
n Simple, regular, and short dosing n Demonstrated non-interference n Distinguishes malaria from other
regimen (one to three days) with EPI vaccines causes of acute febrile illness
n Effective against malaria caused by
all major species of Plasmodium

M alaria M alaria
P ipe l ine ( S e l ect items o n l y ) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

MMV/Novartis (Coartem® Dispersible) (launched 01/2009) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Sigma-Tau/WRAIR (Nuartez®: intravenous artesunate for adults) (in registration) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MMV/Sigma-Tau/Chongqing Holley (Eurartesim®: dihydroartemisinin piperaquine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MMV/U. of Iowa/Shin Poong Pharma, Korea (Pyramax®: pyronaridine-artesunate) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Pfizer Inc. (Zithromax®-chloroquine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Ranbaxy (RBx 11160: arterolane malate-piperaquine phosphate) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Sanofi-Aventis (artesunate-ferroquine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MMV/University of Tübingen (intravenous artesunate for children) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Sanofi-Aventis (SAR 97276: choline uptake inhibitor) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MMV/GSK (tafenoquine for P. vivax) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MMV/GSK (GSK 932121A and prodrug: 4-pyridones) nnnnnnnnnnnnnnnnnnnnn
Sanofi-Aventis (SAR 116242: trioxaquine) nnnnnnnnnnnnnnnnnnnnn
MMV/Univ. Nebraska/Monash Univ./STI nnnnnnnnnnnnnnnnnnnnn

(OZ439: next-generation synthetic peroxide)
MMV/Merck (MK4815) nnnnnnnnnnnnnnnnnnnnn
MMV/Treague (non-racemic RS(+) mefloquine: AD 452) nnnnnnnnnnnnnnnnnnnnn
MMV/WRAIR (mirincamycin) nnnnnnnnnnnnnnnnnnnnn
MMV/Biotec/LSHTM/Monash University (DHFR inhibitors) nnnnnnnn
MMV/Novartis Institute for Tropical Diseases (quinazoline derivatives) nnnnnnnn
MMV/Novartis Institute for Tropical Diseases (natural product) nnnnnnnn
MMV/UT Southwestern/U. Washington/Monash University nnnnnnnn

(dihydroorotate dehydrogenase (DHODH) inhibitors)
MMV/Novartis Institute for Tropical Diseases (screening and lead optimization) nnnnnnnn
MMV/Broad Institute/Genzyme/Advinus (screening and lead optimization) nnnnnnnn
MMV/GSK (screening and lead optimization) nnnnnnnn
MMV/Eskitis Institute (screening: natural products) nnnnnnnn

M alaria

MVI/GSK/WRAIR (Mosquirix; RTS,S AS01/AS02) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Oxford University (FP9/MVA, ME-TRAP) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Mymetics/Pevion Biotech (PeviPRO™ - PEV3a) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
NIAID/Univ. of Bamako/Univ. of Maryland/GSK/USAID/WRAIR (AMA1/ASO2A) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
NMRC/USAID/MIDRP/CDMRP (M3V-Ad-PfCA) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Sinobiomed/WHO (PfCP2.9) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MVI/LaTrobe University (MSP2-C1 ISA720) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Crucell/NIAID (AdHu35: adenovirus vector+CSP) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MVI/MVDB/NIAID/NIH (AMA1-C1 ISA720) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Oxford University/Okairòs/Wellcome Trust (PlaMaVax: adenovirus vector) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
WRAIR/GSK/USAID (FMP010 ASO1B) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
SSI/EMVI (GMZ2: Glurp and MSP3) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MVI/Sanaria (radiation-attenuated sporozoites) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MVI/ICGEB (P. vivax; PvRII) nnnnnnnnnnnnnnnnnnnnn
Pharmexa/NIH (EP1300) nnnnnnnnnnnnnnnnnnnnn
MVI/Monash University (MSP4) nnnnnnnnnnnnnnnnnnnnn
MVI/GenVec/NMRC (multivalent: adenovirus vector) nnnnnnnnnnnnnnnnnnnnn

n A highly efficacious vaccine, marketed to travelers and the military as well as to the developing world, could
yield a positive return on investment for its developer, provided the public sector is willing to support the
purchase for resource-poor countries.
n Because malaria is such an overwhelming burden to African societies, donor funding for malaria prevention
and treatment is expected to be a priority for many years to come and is likely to support the development,
manufacture, and delivery of a highly efficacious vaccine.

n Resistance may make new drugs n No correlates of protection n In areas highly endemic for
obsolete quickly n No predictive animal models P. falciparum malaria, due to
n A highly efficacious vaccine that acquired immunity, not all people
protects against a eukaryote infected with parasites will be
has never before been made sick with malaria disease

M alaria M alaria

n World Health Organization (WHO) ~ www.who.int/topics/malaria/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/malaria/
Key Organizations
n Medicines for Malaria Venture (MMV) ~ www.mmv.org
n Multilateral Initiative on Malaria (MIM) ~ www.mimalaria.org
n PATH Malaria Vaccine Initiative (MVI) ~ www.malariavaccine.org
n Roll Back Malaria ~ www.rbm.who.int
Important Papers
n Águas R, et al. Prospects for malaria eradication in Sub-Saharan Africa. PLoS ONE 3:e1767 (2008)
n Alonso, PL, et al. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in
young African children: Randomised controlled trial. Lancet 364:1411-20 (2004)
n Alonso, PL, et al. Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum
disease in Mozambican children: Single-blind extended follow-up of a randomised controlled trial. Lancet
366:2012-8 (2005)
n Anonymous. Disease watch – focus: Malaria. Nature Rev: Microbiol 2:276-7 (2004)
n Carlton, JM, et al. Comparative genomics of the neglected human malaria parasite Plasmodium Vivax. Nature
455:757-63 (2008)
n Defining and defeating the intolerable burden of malaria III: Progress and perspectives. Supplement 6 to AJTMH
77 (2007)
n Gardner, MJ, et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498-511
(2002)
n Greenwood, BM, et al. Malaria. Lancet 365:1487-98 (2005)
n Moody, A. Rapid diagnostic tests for malaria parasites. Clin Microbiol Rev. 15:66-78 (2002)
n Rafael, ME, et al. Reducing the burden of childhood malaria in Africa: The role of improved diagnostics. Nature
S1, 39-48 (2006)
n WHO-FIND report: Malaria RDT Performance: Results of WHO product testing of malaria RDTs: Round 1 (2008)
n World Malaria Report (2008) ~ www.who.int/malaria/wmr2008/malaria2008.pdf

Pneumococcal Disease
What Is Pneumococcal Disease?
Pneumococcal disease is a collection of maladies caused by the
bacterium Streptococcus pneumoniae. The infection commonly manifests as
pneumonia, meningitis, sepsis, and middle ear infection. S. pneumoniae is
one of the most important pathogens of infants in the developing world;
the elderly and the immunocompromised are also at high risk.
Global Burden
Pneumococcal disease is estimated to be responsible for the deaths of
nearly 1 million children under the age of five, 90 percent of whom live
in the developing world.
Pneumococcal disease is pandemic (WHO)
Pandemic; pneumococcal disease is found in all countries.
Streptococcus pneumoniae (“pneumococcus”), the cause of pneumococcal disease, is a Gram-positive, encapsulated
bacterium. Due to differences in composition of its polysaccharide capsule, there are at least 90 S. pneumoniae
serotypes; 11 common serotypes account for 75 percent of invasive disease globally. The nasopharynx of young
children is the major reservoir of the bacterium; infection is transmitted person-to-person by inhalation of
respiratory droplets.
Presentation
The onset of pneumonia, a potentially fatal form of pneumococcal
disease, begins with fever, chills, and headache. Other symptoms include
cough and difficulty breathing due to the buildup of liquid in the lung
alveoli.
Two other invasive S. pneumonia infections are prevalent: 1) infection
of the bloodstream may lead to sepsis, an overwhelming inflammatory
response resulting in death; and 2) infection of the outer layer of the
brain and spinal cord (meningitis) may result in paralysis, neurological
effects, and death.
Scanning electron micrograph of S. pneumoniae
(CDC/Janice Carr/Richard Facklam)
Trends
In the United States, the introduction in 2000 of the seven-valent
pneumococcal conjugate vaccine (Prevnar®) has been remarkably effective at reducing pneumococcal disease in
young children. Moreover, due to herd immunity, vaccination of children reduces pneumonia in adults. Prevnar®,
however, does not protect against serotypes 1 and 5, both of which are highly prevalent in the developing world.
Because of the twin issues of serotype coverage and replacement, there is growing interest in protein vaccines and
protein-polysaccharide combination vaccines.

n Antibiotics n Prevnar® (PCV7): 7-valent n BinaxNOW pneumococcal
– Penicillin, amoxicillin, cephalosporins, pneumococcal conjugate vaccine urinary antigen (PNAG) test
erythromycin, azithromycin, (for children under age five)
clarithromycin, fluoroquinolones n PPV23, a 23-valent polysaccharide
vaccine (for adults over 65 and
other high-risk persons)

P neumococcal D isease

n Overcome antibiotic resistance n Efficacy in children under five n Differentially diagnose the cause
n Efficacy against regionally of a fever of unknown origin (e.g.
prevalent serotypes bacterial pneumonia or malaria)
n Efficacy that is independent n Distinguish bacterial and
of capsular serotype, ensuring viral pneumonias to aid in
widest possible coverage treatment decisions

GSK (Synflorix®: 10-valent conjugated vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
(EDMA approval in 01/2009)
Wyeth (13vPnC: 13-valent conjugated vaccine) (in registration) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
GSK (S. pneumoniae adult recombinant conjugated vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Sanofi-Pasteur (single antigen; meningitis & pneumonia in infants) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Intercell/PATH (protein subunit vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Ace BioSciences/SSI (S. pneumoniae vaccine) nnnnnnnnnnnnnnnnnnnnn
Sanofi-Pasteur (multivalent meningitis & pneumonia in infants) nnnnnnnnnnnnnnnnnnnnn
PATH/Children’s Hospital Boston (killed whole cell vaccine) nnnnnnnnnnnnnnnnnnnnn
PATH/Genocea/Children’s Hospital Boston (Geno 002: protein subunit vaccine) nnnnnnnn

n A significant market for pneumococcal vaccines exists in the developed world. Additionally, a $1.5 billion
Advanced Market Commitment (AMC) has been established to create a market for pneumococcal vaccines in the
developing world.

n Antibiotic resistance n At least 90 serotypes exist n Many children are nasopharyngeal
n Non-conjugated polysaccharide carriers of S. pneumoniae, hampering
vaccines exhibit poor immune the ability to use polysaccharides
response in children under age two excreted in urine as diagnostic of
and in immunocompromised people infection as can be done for adults
n Protein subunit vaccines—identifying
an efficacious cocktail


n World Health Organization (WHO) ~ www.who.int/topics/pneumococcal_infections/en/
n Centers for Disease Control and Prevention ~ http://www.cdc.gov/ncidod/dbmd/diseaseinfo/streppneum_t.htm
Key Organizations
n GAVI Alliance ~ www.gavialliance.org
n PATH ~ www.path.org/projects/pneumococcal_protein_vaccine_project.php
n PneumoADIP ~ www.preventpneumo.org/index.cfm
Important Papers
n Briles, DE, et al. Pneumococcal diversity: Considerations for new vaccine strategies with emphasis on
pneumococcal surface protein A (PspA). Clin Micro Reviews 11:645-57 (1998)
n Lim, YW, et al. Reducing the global burden of acute lower respiratory infections in children: The contribution of
new diagnostics. Nature S1:9-18 (2006)
n Malley, R, et al. Intranasal immunization with killed unencapsulated whole cells prevents colonization and
invasive disease by capsulated pneumococci. Infect Immun. 69:4870-3 (2001)
n Scott, JAG, et al. Pneumonia research to reduce childhood mortality in the developing world. J Clin Invest
118:1292-300 (2008)
n UNICEF, Pneumonia: The forgotten killer of children (2006) ~ www.unicef.org/publications/files/Pneumonia_The_
Forgotten_Killer_of_Children.pdf

Rotavirus Gastroenteritis
What Is Rotavirus Gastroenteritis?
Rotavirus gastroenteritis is a viral infection predominantly affecting
infants and young children that causes severe diarrhea, vomiting,
and fever. Because of the rapid dehydration that results from the
combination of diarrhea and vomiting, the disease can be fatal.
Global Burden
Rotavirus is the most common form of severe diarrhea in infants and
children. Each year, rotavirus is responsible for an estimated 527,000
deaths (85 percent of deaths occur in developing countries) and over 2
million hospitalizations.
Rotavirus infects nearly all young children and in-
fants worldwide, but mortality rates vary widely. Geographic Distribution
Pandemic; rotavirus is found in all countries.
Rotavirus is a non-enveloped, double-stranded RNA virus that is transmitted by the fecal-oral route via person-to-
person contact or, less frequently, via contaminated food, water, or objects. Upon ingestion, the virus infects
epithelial cells lining the small intestine, inside of which it replicates manyfold, causing cells to excrete fluids,
which results in profuse, watery diarrhea. Once released, virus particles can infect neighboring cells, reinitiating the
cycle of infection. Rotavirus exists in multiple serotypes, is stable in the environment and is highly contagious;
improved sanitation has little effect on disease control.
Presentation
Symptoms include fever, vomiting, and severe diarrhea leading to rapid
dehydration. Symptoms appear two to three days after exposure and last
three to eight days.
Trends
By age three, nearly all children have been exposed to rotavirus. In
developing countries, 75 percent or more of children have their first
infection by 12 months of age. The availability of highly efficacious
vaccines is expected to have a major impact on diarrheal disease in
infants and young children.
Scanning electron micrograph of rotavirus virions
and a number of smaller, unknown 29 nm virion
particles (CDC/Erskine Palmer)

R otavirus G astroenteritis

n Palliative care Currently, there are two FDA-approved There are several commercially available
n Oral rehydration therapy rotavirus vaccines on the market: diagnostic assays to detect rotavirus in
n RotaTeq™: oral, 3-dose, live, patient stool
pentavalent human-bovine n ELISA, Latex agglutination,
reassortant vaccine (Merck) immunochromatographic strips

n Rotarix®: oral, 2-dose, live,
attenuated vaccine (GSK)

In addition, the Chinese government has
licensed LLR, a lamb-derived monovalent,
live, attenuated, 1-dose oral vaccine

n Not currently targeted n Must provide protection to infants n Robust, reliable, and simple “bedside”
n Must act on relevant serotypes diagnostics for point-of-care use

Bharat Biotech International* (ORV 116E: live, natural reassortant vaccine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Bhutantan (Brazil), Serum Institute of India (India), Shantha Biotechnics* (India), nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
and Wuhan Institute* (China) (human bovine (UK) reassortant vaccine)
Murdoch Children’s Research Institute* (Australia) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(RV3: naturally attenuated neonate strain)
International Medica Foundation/Biovirx (rhesus assortant oral vaccine) nnnnnnnnnnnnnnnnnnnnn
Lanzhou Institute of BioMedical Products (multivalent lamb rotavirus vaccine) nnnnnnnnnnnnnnnnnnnnn
*Supported by PATH.

n The market in the developed world for a rotavirus vaccine is estimated to be up to $1 billion annually. The GAVI
Alliance is committed to purchasing rotavirus vaccines for the developing world.

n None n No increased risk of intussusception n None
n EPI schedule-compatible

R otavirus G astroenteritis R otavirus G astroenteritis

n World Health Organization (WHO) ~ www.who.int/topics/rotavirus_infections/en/
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/rotavirus/
Key Organizations
n GAVI Alliance ~ http://www.gavialliance.org/
n PATH Rotavirus Vaccine Program ~ http://www.path.org/projects/rvp.php
Important Papers
n Glass, RI. New hope for defeating rotavirus. Sci Am 294:46-55 (2006)
n Ruiz-Palacios G, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. NEJM
354:11-22 (2006)
n Vesikari, T, et al. Safety and efficacy of a pentavalent human–bovine (WC3) reassortant rotavirus vaccine. NEJM
354:23-33 (2006)

Schistosomiasis
What Is Schistosomiasis?
Parasitic worms that infect blood vessels cause schistosomiasis. Symptoms of early infection include blood in urine
or stool, and over time the infection leads to urinary tract or liver damage. Death can result from bladder cancer or
from an internal hemorrhage.
Global Burden
Schistosomiasis is endemic in 74 developing countries, infecting more
than 200 million people in rural agricultural and peri-urban areas.
Twenty million may suffer from severe disease, while approximately 120
million are thought to experience chronic debilitating symptoms such as
anemia and impaired cognitive development. An estimated 779 million
people worldwide are at risk for the disease.
More than 80 percent of people infected with schistosomiasis live in
sub-Saharan Africa. The disease is also prevalent in the Middle East and
Countries endemic for schistosomiasis (WHO, 2007) can be found in parts of Southeast Asia and Latin America.
Schistosomiasis is caused by trematode flatworms of the genus Schistosoma. Schistosoma eggs are expelled in the
feces or urine of infected individuals. When humans come in contact with contaminated water, schistosome larvae,
which initially develop in freshwater snails, penetrate the skin and enter the bloodstream. The parasites migrate
through the lungs to the liver where they mature, mate, and migrate
together to blood vessels near either the intestine (S. mansoni) or bladder
(S. haematobium). Over the next five years, a female worm lays 200 to
2,000 eggs daily. About half the eggs produced are excreted in the feces
or urine; the remainder become trapped in body tissues and organs,
where they can cause severe damage, particularly to the liver. The
parasite itself causes little damage to the human body.
Presentation
Schistosomiasis can take two forms—urinary and intestinal. In urinary
schistosomiasis, urination becomes painful and urine turns blood red.
Schistosoma are named for their split (schisto) There is progressive damage to the bladder, urine ducts, and then
body. In this photo, a pair is shown on the left, kidneys. In intestinal schistosomiasis, there is progressive enlargement
while the separate male and female are shown to of the liver and spleen and hypertension of the abdominal blood vessels.
the center and right, respectively (photo: CDC)
Eggs breaking through from blood vessels into the intestine leads to
blood in stools. In advanced cases, the functioning of organs such as liver, spleen, and kidneys becomes impaired.
Death can result from bladder cancer or renal failure (S. haematobium) or bleeding from varicose veins in the
esophagus or gastrointestinal tract (S. mansoni).
Trends
Older estimates of the burden of schistosomiasis failed to adequately take into account the full range of symptoms,
sequelae, and chronic nature of the disease. More recent analysis has revealed that it is among the most serious
tropical diseases. Schistosomiasis often goes undiagnosed in children and is associated with stunting, vitamin
deficiency, and developmental and cognitive problems. Children under 14 are especially vulnerable to severe
infection leading to progressive disease and early death.

S chistosomiasis S chistosomiasis

n Praziquantel (Distocid®, Biltricide®) n None n Dipstick (S. haematobium)
− Standard of care − Detection of blood in urine
− Safe and highly effective in n Microscopy (S. mansoni)
curing an infected patient − Examine stool for eggs
− Does not prevent reinfection − Most practical method for diagnosis
− Off patent and inexpensive; − Inefficient; requires laboratory,
costs as low as $0.20/dose multiple analyses
n Others - Oxamniquine, Metrifonate − Poor sensitivity; does not
− Difficult to obtain catch early infections
− Do not work on all forms of the disease n Antibody Detection
− Sensitivity and specificity vary widely
n ELISA
− Highly sensitive; species can be
determined by immunoblot

n Effective against multiple species n Requires few doses n For S. mansoni, control programs
n Long-lasting n Extended protection need more sensitive diagnostics
n High immunogenicity

UCSF Sandler Center (K11777 cysteine protease inhibitor) nnnnnnnnnnnnnnnnnnnnn
Illinois State University/NIH (oxadiazoles) nnnnnnnn

Fiocruz (S. mansoni Sm14) nnnnnnnnnnnnnnnnnnnnn
SVI-HHVI (Sm-TSP-2) nnnnnnnnnnnnnnnnnnnnn

n This is primarily a disease of the very poor. Donor support will be required to encourage innovation.

n None n Need for further research n Diagnostic tests need to be
into target antigens adapted to point-of-care formats
n A highly efficacious vaccine that
protects against a multicellular
organism has never before been made

S chistosomiasis

n World Health Organization (WHO) ~ www.who.int/topics/schistosomiasis/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/ncidod/dpd/parasites/schistosomiasis
Key Organizations
n Sabin Vaccine Institute (SVI) ~ http://sabin.org/index
n Schistosomiasis Control Initiative (SCI) ~ www.schisto.org
Important Papers
n Chitsulo, L, et al. Disease watch – focus: Schistosomiasis. Nature Rev: Microbiol 12:12-3 (2004)
n Fenwick, A. New initiatives against Africa’s worms. Trans. Royal Soc Trop Med Hyg 100:200-7 (2006)
n Pearce, EJ. Progress towards a vaccine for schistosomiasis. Acta Tropica 86:309-13 (2003)
n Sayed AA, et al. Identification of oxadiazoles as new drug leads for the control of schistosomiasis. Nature Med
14:407-12 (2008)

S chistosomiasis
Shigellosis
What Is Shigellosis?
Shigellosis is an infection by bacteria of the genus Shigella that causes
severe abdominal symptoms, including diarrhea, dysentery, abdominal
cramps, fever, and rectal pain. Shigellosis can result in death. The
disease is more dangerous than other gut pathogens because it can
penetrate the lining of the intestine and cause severe inflammation of
the intestine and systemic complications.
Global Burden
Worldwide there are approximately 165 million cases of shigellosis
annually, causing over 1.1 million deaths. Nearly 70 percent of all
Prevalent Shigella species vary by geographic area episodes and approximately 60 percent of all deaths attributable to
(WHO)
shigellosis involve children under five years old.
S. sonnei is the most common species in the United States and other industrialized countries. S. flexneri is endemic to
the developing world. S. boydii is common only in India. S. dysenteriae type 1 is associated with epidemic outbreaks
of shigellosis in confined populations such as can occur following natural disaster or political unrest.
Shigellosis is caused by bacterial infection by one of four species of Shigella: S. dysenteriae, S. flexneri, S. boydii, and S.
sonnei. Transmission occurs via consumption of food and water contaminated by human waste.
Presentation
Shigella bacteria multiply within the epithelial cells of the colon, cause cell death, and spread laterally to infect and
kill adjacent epithelial cells, resulting in mucosal ulceration, inflammation, and bleeding. Shigella dysenteriae serotype
1 produces severe disease and may be associated with life-threatening complications. Symptoms of shigellosis
include diarrhea and/or dysentery with frequent mucoid bloody stools,
abdominal cramps, and tenesmus. In some children, shigellosis causes
seizure. Adults can experience Reiter’s Syndrome as a result of the
disease, leading to eye and joint inflammation and reactive arthritis.
Trends
Diarrheal diseases including shigellosis represent an enormous disease
burden across all developing countries. Shigellosis is also a concern for
travelers.
Although shigellosis can be treated with antibiotics, the most effective

drugs are expensive. Antibiotic misuse has led to the emergence of drug-
Shigella bacteria may penetrate the intestinal
resistant Shigella strains.
mucosum (CDC/Eugene Gangarosa/Sam Formal,
WRAIR)

S higellosis

n Palliative Care n No FDA-approved vaccine exists n Standard clinical microbiology
− Oral rehydration therapy can n In China, a recombinant, live, n No commercially available
be used to treat symptoms oral Bivalent FS (S. flexneri, S. molecular tests
− Antibiotics and intravenous fluids sonnei) vaccine, which has shown
are sometimes given in severe cases 60 percent efficacy in adults, is
available (Lanzhou Institute of
Vaccines and Biological Products)

n High-potency antibiotic n Single- or 2-dose product n Ability to differentiate between
n Oral delivery shigellosis and other gut infections
n Effective for at least two years such as those caused by ETEC
n Multivalent and diarrhea-causing protozoa

NICHD/Robbins (O-specific polysaccharide conjugate) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
WRAIR (Invaplex 50: S. flexneri 2a) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Institut Pasteur (SC599: live, attenuated S. dysenteriae 1a) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
CVD at University of Maryland (CVD 1208: Shigella) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
CVD at University of Maryland (CVD 1208S: Shigella) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
CVD at University of Maryland (Hybrid CVD 1208S: Shigella + ETEC) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MIDRP/Venkatesan (WR Ss1: live, attenuated S. sonnei) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MIDRP/Venkatesan (WR Ss2 & Ss3: live, attenuated S. sonnei) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
MIDRP/Venkatesan (WR Sd2: live, attenuated S. dysenteriae) nnnnnnnnnnnnnnnnnnnnn
MIDRP/Venkatesan (WR Sf2 & Sf3: live, attenuated S. flexneri) nnnnnnnnnnnnnnnnnnnnn
Aridis (live, attenuated typhoid vector expressing nnnnnnnnnnnnnnnnnnnnn

S. sonnei, S. dysenteriae, and S. flexneri 2a O-PS)
Celldex (live, attenuated cholera vector [Peru 15] expressing S. sonnei O-PS) nnnnnnnnnnnnnnnnnnnnn
Endobiologics/PATH Enteric Vaccine Initiative (O-specific polysaccharide) nnnnnnnnnnnnnnnnnnnnn
Bird-C (bacterial ghosts; S. flexneri 2a) nnnnnnnnnnnnnnnnnnnnn
GlycoVaxyn AG (O-specific biconjugate) nnnnnnnnnnnnnnnnnnnnn

S higellosis S higellosis

n Potential opportunity in travelers’ and military markets may improve global market opportunity.

n Antibiotic resistance n Multiple strains make it difficult n Key issue is the rapid identification
to design a multivalent vaccine of all serotypes from fecal material
with sufficient coverage
n Certain major cell-surface markers
are not immunogenic, making them
poor candidates for vaccines

n World Health Organization (WHO) ~ http://www.who.int/vaccine_research/diseases/diarrhoeal/en/index6.html
n Centers for Disease Control and Prevention (CDC) ~ http://www.cdc.gov/ncidod/dbmd/diseaseinfo/
shigellosis_g.htm
Key Organizations
n International Center for Diarrheal Disease Research, Bangladesh (ICDDR,B) ~ www.icddrb.org/pub
n PATH Enteric Vaccine Initiative (EVI) ~ www.path.org/projects/enteric_vaccine
Important Papers
n Von Seidlein, L, et al. A multicentre study of Shigella diarrhoea in six Asian countries: Disease burden, clinical
manifestations, and microbiology. PLoS Med 3:e359 (2006)
n Walker, RI. Considerations for development of whole cell bacterial vaccines to prevent diarrheal diseases in
children in developing countries. Vaccine 23:3369-85 (2005)

Tuberculosis (TB)
What Is Tuberculosis?
Tuberculosis (TB) is a pandemic bacterial disease that most commonly affects the lungs (pulmonary TB). In
otherwise healthy individuals, most infections are latent and therefore asymptomatic. About 10 percent of people
infected with TB will develop disease. In immunocompromised patients such as those with HIV, active TB disease is
extremely common.
Global Burden
One-third of the global population—2 billion people—is infected with
the mycobacterium that causes TB; between 5 and 10 percent of those
infected will develop active TB disease. In 2006, the WHO estimated that
9.2 million people became sick with TB and 1.7 million died. TB is the
leading killer of HIV-positive patients.
TB is a worldwide problem, but 80 percent of the global burden is borne
by only 22 countries. One-third of those infected live in India and China.
Tuberculosis is a global threat
TB incidence in 2006, by WHO region, were as follows: Africa (2,807,688),
the Americas (330,724), Eastern Mediterranean (569,703), Europe (433,261), Southeast Asia (3,100,355), and the
Western Pacific (1,915,285).
TB is caused by Mycobacterium tuberculosis (MTB) and is spread via an aerosol route; when people with active
pulmonary TB exhale, cough, sneeze, or even talk, they release tiny droplets containing bacteria that can be inhaled
by others. Once inside the lung, MTB invades and replicates within macrophages. The host’s immune response may
result in the formation of granulomas that contain the infection. Alternatively, MTB may escape control by the
granuloma and replicate within the lung and/or disseminate to tissues throughout the body. In contrast to many
bacteria, MTB is extremely slow-growing (~20- to 24-hour doubling time
in log phase), a fact that has important implications on the course of
treatment.
Presentation
Symptoms of active pulmonary TB include a cough lasting more than
two weeks, coughing up blood, fatigue, fever, chills, night sweats,
and weight and appetite loss. Latent TB is neither contagious nor
symptomatic. If a carrier’s immune system is compromised, the chance
that he or she will develop active TB increases dramatically.
Trends
Micrograph of M. tuberculosis under a magnifica-
TB is a leading cause of death in the developing world. The recent
tion of over 15000X (CDC/Janice Carr/Ray Butler)
increase in TB deaths stems from a multitude of factors including
pandemic HIV, drug resistance, war, and increasing poverty (which reduce treatment compliance). The incidence
of multidrug-resistant TB (MDR-TB) is rising at an alarming rate (an estimated 500,000 cases in 2006) and is not
restricted to the developing world. Moreover, recent WHO data has revealed the existence of “super strains” of
MDR-TB: 79 percent of such MDR-TB strains are resistant to three of the four first-line drugs. MDR-TB that is also
resistant to certain second-line drugs is known as extensively drug-resistant TB (XDR-TB) and has recently been
identified in HIV-positive populations and others. Active TB is the primary cause of HIV-related death in Africa.

T uberculosis ( T B ) T uberculosis ( T B )

Current TB therapies are delivered as n BCG (Bacille Calmette-Guerin) Diagnostics for active case detection:
combinations of antibiotics over six − Most widely administered n Stained Sputum Smear
to nine months. Serious problems of vaccine in the world − Microscopic first indicator of the
efficacy and toxicity reduce compliance − Safe and inexpensive presence of mycobacteria
and increase the generation of resistant − Targeted at newborn − Provides physician with a preliminary
bacteria. infants only, per WHO confirmation of the diagnosis
n Rifampicin − Not used in the United States, − Only 50 percent sensitivity; less
− Introduced in 1963 Canada, or parts of Europe, but in HIV-positive patients
n Isoniazid, Pyrazinamide, common in the developing world − Difficult to perform in children
Streptomycin & Ethambutol − Variable and limited efficacy n Culture
− Introduced in 1940s–60s − Appears to reduce risk of severe − Gold standard for diagnosis
− Most frequently used in three- childhood TB disease, but, − Common in reference labs only
and four-drug combinations provides limited or no long-term − Needed for drug susceptibility testing
− Treatment often causes protection against pulmonary TB in to diagnose MDR- and XDR-TB
toxic side effects adolescents or adults; this subject n Nucleic acid Amplification
n Ethionamide, Para-Amino Salicylate is controversial with numerous − Rapid, sensitive
(PAS), Cycloserine, Amikacin, studies providing conflicting results − Used mainly in research
Kanamycin, Fluoroquinolones − Too expensive for use in
− Second-line drugs developing countries
− Generally less potent and more n QuantiFERON-TB Gold &
toxic (except fluoroquinolones) T-SPOT.TB Antigen Tests
− Used to treat drug-resistant TB − Detects immune response
(interferon) to antigens unique to MTB
Diagnostics to detect latent TB:

n Purified Protein Derivative (PPD)
Skin Test, a.k.a. Mantoux Test
− Nonspecific; can be misleading
due to prior BCG vaccination
− Does not work in HIV-positive patients
There are no rapid, point-of-care

diagnostics to distinguish latent from
active disease.

n Rapid acting (courses of two months n Safe to administer to HIV-positive New products for active case detection:
or less) infants and to adolescents n Rapid and easily performed
n Can be co-administered with n At least 70 percent efficacy n Specific and sensitive
antiretrovirals against TB disease n Able to distinguish latent

n Safer than existing treatments n At least as safe as BCG TB from active disease
n Effective against MDR-TB and XDR-TB n Effective in HIV-positive
n Highly potent patients and in children
n Unaffected by prior BCG vaccination

T uberculosis ( T B )
P ipe l ine ( S e l ect items o n l y ) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

OFLOTUB consortium/EU/TDR/IRD/Lupin (gatifloxacin) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
TB Alliance/Bayer/University College London/British MRC (moxifloxacin) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Tibotec/Johnson & Johnson (TMC 207: diarylquinolines) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
TB Alliance (PA-824: nitroimidazole) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Otsuka (OPC-67683: nitroimidazole) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Sequella/NIH (SQ-109: diamine) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Lupin Pharmaceuticals (LL-3858: pyrrole) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
TB Alliance/KRICT/Yonsei University (TBK-613: quinolone) nnnnnnnnnnnnnnnnnnnnn
Sequella (SQ-609: dipiperidine) nnnnnnnnnnnnnnnnnnnnn
Eli Lilly drug discovery partnership/ nnnnnnnnnnnnnnnnnnnnn

Microbial Chemistry Research Foundation (CPZEN-45)
Eli Lilly drug discovery partnership/Summit plc. (anti-TB compounds) nnnnnnnn
Dafra Pharma (DF-152) nnnnnnnn
FASgen (FAS20013: synthase inhibitor) nnnnnnnn
Sequella (SQ-641: capuromycin) nnnnnnnn
Vertex (kinase inhibitors) nnnnnnnn
TB Alliance/University of Auckland/University of Illinois, Chicago nnnnnnnn

(nitroimidazole analogs)
TB Alliance/University of Auckland/Colorado State University nnnnnnnn

(multifunctional molecules)
TB Alliance/GSK (mycobacterial gyrase inhibitor) nnnnnnnn
TB Alliance/GSK (InhA inhibitors) nnnnnnnn
TB Alliance/GSK/Texas A&M (malate synthase inhibitor) nnnnnnnn
TB Alliance/Institute of Materia Medica/BTTTRI (riminophenazines) nnnnnnnn
TB Alliance/University of Pennsylvania/University of Illinois, Chicago nnnnnnnn

(energy metabolism inhibitors)
TB Alliance/University of Illinois, Chicago (phenotypic screening) nnnnnnnn
TB Alliance/IDRI (protease inhibitors) nnnnnnnn
TB Alliance/Novartis Institute for Tropical Disease (various projects) nnnnnnnn
TB Alliance/Rutgers (RNA pol inhibitors) nnnnnnnn
TB Alliance/IMCAS (natural product screening) nnnnnnnn
AstraZeneca (screening and target identification) nnnnnnnn

T uberculosis ( T B ) T uberculosis ( T B )

Oxford University/Emergent BioSolutions/Aeras (MVA-85A/AERAS-485) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
GSK/Aeras (GSK M72) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Crucell/Aeras (Crucell Ad35/AERAS-402) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
SSI/Intercell/Sanofi-Pasteur/Aeras (HyVac 4/AERAS-404) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
SSI/Intercell/TBVAC (Hybrid 1: 85B-ESAT-6) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Aeras (AERAS-405: double stranded RNA nucleocapsids encoding Mtb antigens) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Aeras (AERAS-407: rBCG) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Vakzine Projekt Management/Max Planck Institute (VPM1002: rBCG: ΔureC-Hly) nnnnnnnnnnnnnnnnnnnnn
Albert Einstein College of Medicine (live, attenuated Mtb derivatives) nnnnnnnnnnnnnnnnnnnnn
Institut Pasteur/University of Zaragoza (live, attenuated Mtb ΔphoP/R) nnnnnnnnnnnnnnnnnnnnn
UCLA/NIAID (rBCG30ARMF, rBCG(MtbB)30, rBCG-hIFN-g) nnnnnnnnnnnnnnnnnnnnn
Karolinska Institute (Nas L3/Htk BCG) nnnnnnnnnnnnnnnnnnnnn
Karolinska Institute (Nas L3/AM85B conjugate) nnnnnnnnnnnnnnnnnnnnn
Institut Pasteur/INSERM/TB-VAC (heparin-binding haemagglutin protein nnnnnnnnnnnnnnnnnnnnn

purified from M. bovis BCG)
ImmunoBiology/Aeras (HspC™ TB vaccine) nnnnnnnnnnnnnnnnnnnnn
Discovery Preclinical Clinical

Diagnostics
Nucleic acid detection
FIND/Cepheid/UMDMJ (GeneXpert System TB) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
FIND/Eiken Chemical (LAMP-based dx) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
FIND and partners (urinary NAAT) nnnnnnnn
Antibody or antigen detection

FIND/Tauns Co. Ltd. (Capilia TB test) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Sequella (transdermal TB patch) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Tyrian Diagnostics/Becton-Dickinson/FIND nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

(TB DiagnosticIQ™: rapid antigen-based)
FIND and partners (Mycobacterial lipoarabinomannan [LAM] nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

antigen detection in urine)
ChemBio/IDRI (serologic rapid TB test using Dual Path Platform [DPP™]) nnnnnnnn
FIND and partners (dipstick antibody test) nnnnnnnn

T uberculosis ( T B )

n According to the Global Alliance for TB Drug Development (TB Alliance), the current TB drug market is estimated
at $450 million and is projected to reach $700 million by 2010.
n With 9 million new cases each year, and manyfold greater new latent infections, there is a very large target
patient population.
n BVGH estimates the peak annual market for a TB vaccine is over $750 million for a booster vaccine and over
$400 million for a BCG replacement vaccine, with most of these revenues coming from developed and emerging
economies.
n Despite potentially profitable developed and emerging country markets, donor support will still be needed for
delivery to the neediest patients.

n Latent infection is difficult to n Lack of immune correlates of n New diagnostics will require
clear with standard antibiotics protection or surrogate markers that the discovery of TB-specific
n Non-replicating, persistent MTB predict clinical efficacy of a vaccine serum biomarkers
are often minimally affected n Development and maintenance
by standard antibiotics of clinical trial site capacity

n World Health Organization (WHO) ~ www.who.int/tb/en
n Centers for Disease Control and Prevention (CDC) ~ www.cdc.gov/nchstp/tb/default.htm
Key Organizations
n Aeras Global TB Vaccine Foundation ~ www.aeras.org
n Global Alliance for TB Drug Development ~ www.tballiance.org
n Stop TB Partnership ~ www.stoptb.org
Important Papers
n Andries, K, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.
Science 307:223-7 (2005)
n Gandhi, NR, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with
tuberculosis and HIV in a rural area of South Africa. Lancet 368:1575-80 (2006)
n Keeler, E, et al. Reducing the global burden of tuberculosis: The contribution of improved diagnostics. Nature S1,
49-57 (2006)
n Reichman, LB, and Tanne, JH. Timebomb: The Global Epidemic of Multi-drug Resistant Tuberculosis. New York:
McGraw-Hill (2002)
n Skeiky, YAW, and Sadoff, JC. Advances in tuberculosis vaccine strategies. Nature Rev: Microbiol 4:469-76 (2006)
n The Stop TB Strategy ~ www.who.int/tb/publications/2006/who_htm_tb_2006_368.pdf
n Tuberculosis Vaccines: The Case for Investment ~ www.bvgh.org/documents/
BVGHTBVaccineReport10-6FINAL.pdf
n WHO Report 2008: Global Tuberculosis Control ~ www.who.int/tb/publications/global_report/2008/
pdf/fullreport.pdf

BIO Ventures for Global Health Phone: +1 202-312-9260

1225 Eye Street, NW, Suite 1010 Fax: +1 443-320-4430
Washington, DC 20005 USA www.bvgh.org

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BVGH Global Health Primer

Building Biotech Solutions for Diseases of the Developing World

Building Biotech Solutions for Diseases of the Developing World

cover photo: Julien Harneis

Melinda Moree, PhD

3 BVGH Global Health Primer BVGH Global Health Primer 3

The Global Disease Burden. . . . . . . . . . . . . . . . . . . . . 9

Bridging the Innovation Gap . . . . . . . . . . . . . . . . . . 10

The Role of Biotechnology . . . . . . . . . . . . . . . . . . . . 12

The Need for Incentives. . . . . . . . . . . . . . . . . . . . . . 12

Why the Global Health Primer? . . . . . . . . . . . . . . . 14

Key Global Health Players. . . . . . . . . . . . . . . . . . . . . 16

Select Companies Working in Global Health. . . . . 25

Highlights in Global Health R&D. . . . . . . . . . . . . . . 26

Dengue Fever (DF). . . . . . . . . . . . . . . . . . . . . . . . . 36

Enterotoxigenic E. coli (ETEC) . . . . . . . . . . . . . . . 39

Human African Trypanosomiasis (HAT). . . . . . 42

Human Hookworm Infection . . . . . . . . . . . . . . . 46

Human Immunodeficiency Virus (HIV). . . . . . . 49

Japanese Encephalitis (JE) . . . . . . . . . . . . . . . . . . 53

Lymphatic Filariasis (LF) . . . . . . . . . . . . . . . . . . . 60

Worked with the G8 and multilateral

new medicines for neglected diseases of the developing world.

7 BVGH Global Health Primer

The Global Disease Burden

9 BVGH Global Health Primer BVGH Global Health Primer 9

Bridging the Innovation Gap

Current investment in R&D for neglected diseases is only a fraction of

10 BVGH Global Health Primer

Sleeping Sickness: The Case for New R&D

BVGH Global Health Primer 11

The Role of Biotechnology

A core insight from our report is that biotechnology companies organize

The Need for Incentives

12 BVGH Global Health Primer

Incentives for Innovation

BVGH Global Health Primer 13

Why the Global Health Primer?

President Obama noted in a recent statement on global health, “We cannot

BVGH’s Global Health Primer forges connections between expertise in developing

14 BVGH Global Health Primer

Key Global Health Players

P roduct D evelopment P artnerships ( P D P s )

16 BVGH Global Health Primer

International Partnership n Leading partnership to develop vaginal microbicides to prevent transmission of

BVGH Global Health Primer 17

PATH Enteric Vaccine n Founded in 2007 as a project of PATH

PATH Malaria Vaccine n Created in 1999 as a global program of PATH

18 BVGH Global Health Primer

BVGH Global Health Primer 19

I nternational and M ultilateral O rgani z ations and I nitiatives

International Finance IFFIm is a financing facility backed by a coalition of governments to finance

20 BVGH Global Health Primer

BVGH Global Health Primer 21

22 BVGH Global Health Primer

N otable R esearch I nstitutions and academic consortiums

Infectious Disease n A non-profit biotechnology organization committed to developing products to

Seattle Biomedical n Independent research institute focused on infectious diseases, particularly

BVGH Global Health Primer 23

24 BVGH Global Health Primer

BVGH Global Health Primer 25

n Advanced Market Commitment (AMC): In June 2009, the governments of Italy,

26 BVGH Global Health Primer

n Vertex Global TB Network: In mid-2008, Vertex Pharmaceuticals announced the

Pre- Clinical- Clinical- Clinical-