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Rotavirus infection Professor Timo Vesikari: Rotavirus vaccine development Cervical Cancer Prophylactic HPV vaccination for young adult women Inuenza The inuenza A (H1N1) 2009 pandemic: the end of the rst inuenza pandemic of the 21st century

VOLUME 4 / ISSUE 4 / 2010

GEN-2010-021

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the copyright owner. No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, through negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the Publisher recommends that independent verication of diagnoses and drug dosages should be made. Opinions expressed in this publication are those of the original authors and do not necessarily reect those of the Publisher, the sponsor, or the editors. The Publisher assumes no liability for any material published herein.

Editor-in-chief
Professor David J. Weber, MD, MPH Professor of Medicine, Pediatrics and Epidemiology Schools of Medicine and Public Health University of North Carolina Associate Chief of Staff University of North Carolina Health Care Chapel Hill, NC USA

Immunization programs Herd immunity: a critical factor to consider in immunization

Rotavirus infection

International Editorial Board Members

Associate Professor Lance C Jennings, QSO, FRCPath, PhD Canterbury Health Laboratories & Pathology Department, University of Otago Christchurch New Zealand Professor Fred N. Were, MD, PhD Department of Pediatrics and Child Health University Of Nairobi Kenyatta National Hospital Kenya Professor Fred Zepp, MD Childrens Hospital Johannes Gutenberg University Mainz Germany Bernd Benninghoff, PhD Dirk Poelaert, MD Global Medical Affairs GSK Biologicals Rixensart Belgium

Professor Timo Vesikari: Rotavirus vaccine development News 12 Vaccine uptake is also affected by culture Scientists have successfully cloned the human cytomegalovirus offering new hope for the treatment of potentially life-threatening diseases Cervical Cancer 14 Prophylactic HPV vaccination for young adult women Inuenza 18 The inuenza A (H1N1) 2009 pandemic: the end of the rst inuenza pandemic of the 21st century Abstracts 22 High hepatitis A virus (HAV) vaccination coverage has nearly eliminated transmission of HAV infection in Alaska Study revealed no increased risk of autism associated with thimerosal-containing vaccines Travel related diseases Hajj pilgrims and vaccination requirements 24

Varicella 28 Varicella vaccines and traditional vaccination schedules ISSN 1784-1275 Misconceptions Misconceptions about vaccinations Congress Calendar 32

Publisher
Med@Consulting BVBA Zonneweeldelaan 25 b 19 3600 Genk Belgium E-mail: publisher@advances-in-vaccinology.com

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This journal is funded entirely by GlaxoSmithKline Biologicals, SA. All articles appearing in the journal have been written on behalf of or by GlaxoSmithKline Biologicals.

CONTENT
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Herd immunity: a critical factor to consider in immunization

Summary Herd immunity can be dened as: "The reduction of infection or disease in the unimmunized segment as a result of immunizing a proportion of the population". Herd immunity is a collateral benet for all national immunization programs.

Vaccines provide direct protection to vaccinated individuals, but may also provide benets to unvaccinated individuals by reducing transmission of the pathogen and thereby lowering the risk of infection.1 Herd immunity is the basis on which all national immunization programs are designed. It is the concept that not everybody in a population has to be immunized to protect everyone in that population. As long as a sufcient number of children are immunized against each disease for which there is a vaccine, protection against that disease will be conferred to their wider community.

In 1927, Kermack and McKendrick predicted that there should exist a critical threshold level for the fraction of susceptible individuals below which introduction of infection can only lead to minor outbreaks.2 The epidemiological theory proposed by Kermack and McKendrick explains why it is possible to eradicate an infectious agent without achieving complete vaccine coverage.3-4 The herd immunity theory proposes that, in diseases passed from person-to-person, it is more difcult to maintain a chain of infection when large numbers of a population are immune.

Figure 1. Herd immunity is dened as: "The reduction of infection or disease in the unimmunized segment as a result of immunizing a proportion of the population".

IMMUNIZATION PROGRAMS
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Herd immunity: a critical factor to consider in immunization

Herd immunity threshold

Although no vaccine offers 100% protection, the spread of disease from person-to-person is much higher in those who have not been vaccinated.5 Scientists have found that when a certain percentage of a population is vaccinated, the spread of the disease is effectively stopped. This critical percentage of the population that must be immunized, called the herd immunity threshold, depends on three factors: the infectivity of the disease, the vulnerability of the population, and environmental factors (Table 1).6 Table 1. Estimated herd immunity thresholds for vaccine preventable diseases.7
Disease Herd immunity threshold (estimated) 85% 83 94% 75 86% 92 - 94% 80 - 86% 80 85% 83 85%

inuenzae type b (Hib), major serotypes of Streptococcus pneumoniae, and Neisseria meningitidis serogroup C.8-9 Selective vaccination of schoolchildren against seasonal inuenza results in the indirect protection of other age groups, such as adults and elderly, with reduced incidence of the disease. Children play an important role in the transmission of inuenza within families, schools and communities.10 In Russia, a mass vaccination campaign in children 3 to 17 years of age signicantly reduced inuenza-like illness in children and in unvaccinated elderly adults.11

Herd immunity and public perception of vaccination

Despite the fact that wide use of vaccination has produced substantial achievements in the control of vaccine-preventable diseases, some parents decide not to immunize their children. As vaccination coverage spreads through a community, it reaches a point at which those who are unvaccinated are highly unlikely to catch a disease because of the herd immunity effect. Therefore, as a result of previous vaccination efforts the incidence of a disease can be minimal. In this scenario parents may choose not to vaccinate their child as they do not understand the rationale for vaccinating against a disease that poses a low risk of infection. If enough parents decide not to have their children vaccinated, more cases will start to appear and then the entire population is at risk. To achieve herd immunity it is important that health professionals and the public are educated about the importance of continuing immunization to prevent infection.12 On average, to achieve 100% protection against measles in the United Kingdom the uptake of immunization must be about 95%. A decade ago, health scares

Diphtheria Measles Mumps Pertussis Polio Rubella Smallpox

Herd immunity has long been recognized as an important benet of vaccines. Vaccines against diphtheria poliovirus, varicella, rubella, measles, hepatitis B virus and Bordetella pertussis have important herd immunity effects.7 Largely unanticipated at the time of vaccine introduction, the herd immunity effect of the bacterial polysaccharide conjugate vaccines has been a major contributor to the successful control of invasive and noninvasive disease due to Haemophilus

References
John TJ, Samuel R. Herd immunity and herd effect: new insights and denitions. Eur. J. Epidemiol. 2000; 16 (7): 601-606. Kermack WO, McKendrick AG. Contribution to the mathematical theory of epidemicsI. 1927. Bull. Math. Biol. 1991; 53: 33-55. Fine P. Herd immunity: History, theory, practice. Epidemiol Rev. 1993; 15: 265-302. Anderson RM, May RM. Infectious diseases of humans: Dynamics and control. Oxford: Oxford University Press (1991): 757 p. Jamison DT, Breman JG, Measham AR (editors). Chapter 4: Vaccine-preventable diseases. Priorities in Health: Disease Control Priorities Companion Volume. World Bank Publications 2006. 6. Begg NT, Gay NJ. Theory of infectious disease transmission and herd immunity. In: Balows A, Sussman M, eds. Topley and Wilson's microbiology and microbial infections. Vol 3. 9th ed. London: Edward Arnold, 1997. 7. CDC. History and epidemiology of global smallpox eradication. Available at: http://www.bt.cdc.gov/agent/smallpox/training/overview/pdf/eradicationhistory.pdf (Accessed on 15 September 2010). 8. Makwana N, Riordan FA. Bacterial meningitis: the impact of vaccination. CNS Drugs 2007; 21 (5): 355-366. 9. McVernon J, Ramsay ME, McLean AR. Understanding the impact of Hib conjugate vaccine on transmission, immunity and disease in the United Kingdom. Epidemiol. Infect. 2008; 136 (6): 800-812. 10. Glezen WP. Emerging infections: pandemic inuenza. Epidemiol. Rev. 1996; 18: 64-76. 11. Ghendon YZ, Kaira AN, Elshina GA. The effect of mass inuenza immunization in children on the morbidity of the unvaccinated elderly. Epidemiol. Infect. 2006; 134: 71-78. 12. Berger A. How does herd immunity work? BMJ 1999; 319: 1462-1467. 13. Health Protection Agency Epidemiological Data Measles, Mumps, Rubella. Available at: http://www.hpa.org.uk/hpr/infections/immunisation.htm (Accessed on 15 September 2010). 14. Jansen VA, Stollenwerk N, Jensen HJ, et al. Measles outbreaks in a population with declining vaccine uptake. Science 2003; 301: 804. 1. 2. 3. 4. 5.

IMMUNIZATION PROGRAMS
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about the measles, mumps, and rubella vaccine (MMR vaccine) contributed to a signicant drop of the MMR immunization rates in the UK. The MMR coverage dropped from 92% in 1995-1996 in England to 80% in 2003-2004, a percentage below the herd immunity threshold of measles.13 As a direct consequence, outbreaks of measles and mumps occurred throughout the UK.14

Professor Timo Vesikari: Rotavirus vaccine development

References
1. Parashar UD, Gibson CJ, Bresse JS, Glass RI. Rotavirus and severe childhood diarrhea. Emerg Infect Dis 2006;12 (2): 304-306. 2. WHO. Detailed Review Paper on Rotavirus Vaccines. To be presented to the WHO Strategic Advisory Group of Experts (SAGE) on Immunization, April 2009. Available at: http://www.who.int/immunization/sage/3_Detailed_Review_Paper_on_Rota_Vaccines_17_3_2009.pdf (Accessed August 30, 2009). 3. Glass R, Parashar U, Bresee J, et al. Rotavirus vaccines: current prospects and future challenges. Lancet 2006; 368: 323-332. 4. WHO. Report of the meeting on the future directions for rotavirus vaccine research in developing countries. Geneva; 2000. WHO/V and B/.00.23. 5. Mrukowicz J, Szajewska H, Vesikari T. Options for the prevention of rotavirus disease other than vaccination. J Pediatr Gastroenterol Nut 2008; 46 Suppl 2: S32-37. 6. Dennehy PH. Rotavirus vaccines an update. Vaccine 2007; 25: 3137-3141. 7. CDC. Intussusception among recipients of rotavirus vaccine - United States, 1998-1999. MMRV 1999; 48: 577-581. 8. Simonsen L, Viboud C, Elixhauser A, et al. More on RotaShield and intussusception: the role of age at the time of vaccination. J Infect Dis 2005; 192 (Suppl 1): S36-S43. 9. Vesikari T. Rotavirus vaccines. Scand J Infect Dis 2008; 40: 691-695.

Rotavirus infection is the most common cause of severe diarrheal disease in infants and young children worldwide and continues to have a major global impact on childhood morbidity and mortality.1 Rotavirus infects nearly every child before the age of 3 years. The median age of a primary rotavirus infection is younger in developing countries, ranging from 6 to 9 months (80% occur among infants <1 year old). Developing countries often exhibit one or more periods of more intense rotavirus circulation against a background of year-round rotavirus transmission and a great diversity of rotavirus strains. In contrast, the median age of primary infection is older in developed countries, ranging from 9 to 15 months (65% occur among infants <1 year old) caused by 4 to 5 common rotavirus strains.2 Rotavirus is transmitted by the fecal-oral route and a small infectious dose (< 100 virus particles) facilitates spread from person to person or possibly via airborne droplets. First infections in children 3 to 24 months of age most often lead to vomiting, then watery diarrhea that is sometimes accompanied by fever. In temperate climates, rotavirus has a distinct peak in the cooler winter months when it is the predominant pathogen causing up to 70% of hospital admissions for diarrhea.4

Figure 1. Professor Timo Vesikari (University of Tampere, Finland).

Rotavirus vaccine development was identied as a priority

During the past two decades, discussions among many groups including the World Health Organization (WHO), the Institute of Medicine and the Global Alliance for Vaccines and Immunization (GAVI) have identied rotavirus vaccines as a priority for development.4 This decision has been based primarily on the enormous toll of rotavirus disease. It is estimated that each year

more than 500,000 children under ve years of age die of rotavirus gastroenteritis, more than two million are hospitalized and 25 million require an outpatient visit.1 In poor countries approximately one child in every 250 will die of rotavirus disease by ve years of age. Control measures such as clean water initiatives and improvements to personal hygiene have led to dramatic declines in bacterial and parasitic gastroenteritis infections across the world, but rates of rotavirus infection and illness among children in industrialized

ROTAVIRUS INFECTION
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Professor Timo Vesikari: Rotavirus vaccine development

and less-developed countries remain similar. Hygienic measures are unlikely to lead to corresponding declines in rotavirus burden.5 Longitudinal studies have demonstrated that naturally acquired rotavirus infections provide protection against rotavirus disease upon reinfection, and that protection is greatest against the most severe disease outcomes. Although children can be infected with rotavirus several times during their lives, initial infection after age 3 months is most likely to cause severe diarrhea and dehydration. A realistic goal for a rotavirus vaccine is to duplicate the degree of protection against disease that follows natural infection. Therefore, vaccine program objectives include the prevention of moderate to severe disease but not necessarily of mild disease associated with rotavirus.6 Effective rotavirus vaccines are most needed in developing countries where mortality associated with rotavirus is high.

RotaShieldTM: the rst licensed rotavirus vaccine

The rst multivalent live oral reassortant vaccine developed was RotaShieldTM (a rhesus rotavirus tetravalent [RRV-TV] vaccine). This tetravalent vaccine contained a mixture of four virus strains representing the most commonly seen G types, G1 to G4. The licensure of RotaShieldTM in the USA in 1998 was a truly remarkable event, as it also marked the acceptance of the concept of rotavirus vaccination in general. Unfortunately, the vaccine had to be withdrawn less than one year later, after about 100 cases of intussusception had been reported in close temporal proximity to the administration of RotaShieldTM.7 Most cases were in infants to whom the rst dose of vaccine had been given in the so-called catch-up program between ages 3 and 9 months of age.8 The mechanism of this association has never been elucidated, and the exact risk, which was judged to be about one case of intussusception in 10,000 vaccine recipients, remains controversial. The risk of intussusception was evaluated in large clinical trials for the currently available rotavirus vaccines (RotarixTM and RotaTeqTM). In December 2008 The Global Advisory Committee on Vaccine Safety (GACVS) reviewed safety data from clinical trials with RotarixTM and RotaTeqTM and surveillance data from the manufacturer of RotaTeqTM. The GACVS concluded that these data did not indicate an increased risk of intussusception following vaccination compared to background rates. An intussusception risk of the order of that which had been associated with RotaShieldTM can be ruled out with condence but further post-marketing surveillance with RotarixTM and RotaTeqTM is necessary.

Figure 2. Rotavirus infects nearly every child before the age of 3 years.

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Two licensed oral rotavirus vaccines

The two live attenuated oral rotavirus vaccines were licensed in 2006 for prevention of severe acute gastroenteritis in children: RotarixTM (GSK), a human rotavirus vaccine with G1P[8] serotype characteristics and RotaTeqTM (Merck), a bovine-human reassortant vaccine expressing human G 1- 4 and P[8] antigens.9 RotarixTM is a live vaccine containing the attenuated G1, P[8] human rotavirus strain, and is recommended to be orally administered in 2 doses beginning at 6 weeks of age, with an interval of at least 4 weeks between the rst and second dose, and with series completion by 24 weeks of age. RotaTeqTM is a live attenuated, bovinehuman reassortant rotavirus vaccine containing the most common rotavirus antigens seen in humans (G1, G2, G3, G4, and P[8]), and is recommended to be orally administered in 3 doses, starting at 6 to 12 weeks of age, with the subsequent doses administered at 4- to 10-week intervals, and the third dose administered before 32 weeks of age. Both vaccines have been demonstrated in clinical trials using European, North American, and South American populations to be 90 to 100% effective in preventing severe rotavirus gastroenteritis and 74 to 85% effective in preventing rotavirus infection of any severity. Clinical trial data have shown both vaccines to have clinically acceptable safety proles.

Recent data from clinical trials with RotarixTM and RotaTeqTM in developing countries (e.g. South Africa, Malawi, Nicaragua, El Salvador) translated into a lower efcacy than in earlier trials in Europe and in North and South America. Vaccine safety continues to be clinically acceptable in all settings studied. The public health impact of rotavirus vaccine introduction may be greater in Africa and Asia compared with other regions of the world due to higher background rates of rotavirus disease and the potential for higher numbers of prevented cases.2 Based on the results of these clinical trials the World Health Organization (WHO) has recommended that rotavirus vaccination should be included in all national immunization programs. The new recommendation by WHO's Strategic Advisory Group of Experts (SAGE) extends an earlier recommendation made in 2005 on vaccination in the Americas and Europe, where clinical trials had demonstrated clinically acceptable safety proles and efcacy in populations with low and intermediate mortality. New data from clinical trials, which evaluated vaccine efcacy in countries with high child mortality, has led to the recommendation for global use of the vaccine. Although many programmatic and nancial challenges face the global use of rotavirus vaccines, these vaccines and new candidates in the pipeline hold promise to make an immediate and measurable effect to improve child health and survival from this common burden affecting all children. Post-marketing surveillance studies are needed to monitor the vaccine impact on circulating viral strains recovered from stools in order to test possible vaccine selection pressure and potential strain replacement.

ROTAVIRUS INFECTION
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News ...

Vaccine uptake is also affected by culture

According to a study published in the Journal of Advanced Nursing, the cultural beliefs of the elderly population inuence their likelihood of choosing to be vaccinated against inuenza (Figure 1). Inuenza is a highly infectious viral disease that attacks the human respiratory tract. Elderly people are especially vulnerable to severe complications of inuenza, which may result in hospitalization and death. Vaccination is the most effective measure to help prevent the complications of inuenza. However, vaccine uptake rates for aging populations in many countries still remain below the WHO recommended rate of 75% to be achieved by the year 2010. Researchers from Hong Kong explored the factors that can inuence the vaccine preferences of the elderly and uptake of the inuenza vaccine in nine countries (South Korea, Canada, the United Kingdom, Greece, Brazil, Turkey, China, Nigeria and Indonesia) with a variety of cultures, economic status and vaccination coverage. The researchers who developed a framework for understanding vaccination behavior identied ve themes (Figure 1). Vaccine preferences were guided by peoples behavioral beliefs in vaccination. There are a number of factors considered, including the perceived susceptibility to and severity of inuenza, vaccine effectiveness, vaccine cost, health-care and social costs. Uptake of vaccination was likely to be more concentrated in countries where the benet of vaccines had become a normative belief in favor of vaccination. The researchers said healthcare providers that help in educating elderly people to understand the benets of vaccinations, as well as providing encouragement, will be more successful in increasing vaccine uptake.
Enid Wai-yung Kwong, Samantha Mei-che Pang, Pin-pin Choi et al. Inuenza vaccine preference and uptake among older people in nine countries. Journal of Advanced Nursing 2010; 66 (10): 2297-2308.

Scientists have successfully cloned the human cytomegalovirus offering new hope for the treatment of potentially life-threatening diseases
Human cytomegalovirus (HCMV) is a clinically important herpes virus that causes congenital malformations worldwide. The development of new treatments against HCMV has been hampered, as scientists have been unable to stably replicate HCMV outside the human body. Dr Richard Stanton (School of Medicine, Cardiff University, UK) and his team have successfully cloned the HCMV: HCMV has by far the largest genome of all viruses affecting humans. Consequently it was technically difcult to clone this virus in an intact form in the laboratory. Cloning a copy of the virus has enabled us to identify the genes causing the instability of the virus outside the body. Following the identication of these genes, we have successfully developed cells in which we can grow HCMV that corresponds to that which exists in the human body. Cloning HCMV for the rst time will help virologists develop antivirals and vaccines against this virus. Dr Richard Stanton added: HCMV has been designated as the highest priority vaccine target by the US Institute of Medicine. When developing vaccines or anti-viral agents, it is crucial to work with a virus that accurately represents the virus present in patients. For the rst time our work has enabled us to create an exact copy of HCMV outside of the body offering a vital step forward in the developments of new treatments.
Richard J. Stanton, Katarina Baluchova, Derrick J. Dargan, et al. Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication. Journal of Clinical Investigation 2010; 120 (9): 3191-3208.

Susceptibility to and severity of inuenza

Vaccine effectiveness

Vaccine cost

Healthcare cost

Social cost

Probability calculation

Utility calculation

Behavioral beliefs Cultural values, health beliefs

Preference for vaccination

Vaccination uptake

Figure 1. Hypothetical framework of vaccine uptake among older people.

Indigenous health practices Normative beliefs in vaccination Cues to action Availability Accessibility Affordability

(reprinted with permission)

NEWS
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Prophylactic HPV vaccination for young adult women

References
1. National Cancer Institute. Understanding cancer series: HPV vaccine [Online] Available from:http://www.cancer.gov/cancertopics/understandingcancer/HPV-vaccine/allpages [Accessed date: January 2010] 2. World Health Organization. Expert Committee on Biological Standardization. Guidelines to assure the quality, safety and efcacy of recombinant Human Papillomavirus viruslike particle vaccines, accessed on 27/3/2009 at http://screening.iarc.fr/doc/WHO_vaccine_guidelines_2006.pdf 3. Muoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classication of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348: 518-527. 4. Bosch X, Burchell A, Schiffmann M et al. Epidemiology and Natural History of Human Papillomavirus Infections and Type-Specic Implications in Cervical Neoplasia. Vaccine 26S (2008) K1K16 5. de Sanjose S, Quint W, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010; 11: 1048-1056. 6. Stanley M.Immune responses to human papillomavirus. Vaccine 2006,Vol24S1/16-22 7. Viscidi RP, Schiffman M, Hildesheim A, et al. Seroreactivity to human papillomavirus (HPV) types 16,18 or 31 and risk of subsequent HPV infection: results from a population-based study in Costa Rica. Cancer Epidemiol. Biomarkers Prev. 2004; 13: 324-327. 8. Mayrand M, Coutle F, Hankins C, et al. Detection of human papillomavirus type 16 DNA in consecutive genital samples does not always represent persistent infection as determined by molecular variant analysis. J. Clin. Microbiol. 2000; 38 (9): 3388-3393. 9. Safaei A, Khanlari M, Momtahen M, et al. Prevalence of high-risk human papillomavirus types 16 and 18 in healthy women with cytologically negative pap smear in Iran. Indian J. Pathol. Microbiol. 2010; 53 (4): 681-685. 10. Ferlay J, Bray F, Pisani P, Parkin DM. Globocan 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancerbase No. 5. Version 2.0, IARCPress, Lyon, 2004.Available at: www.depdb.iarc.fr/globocan/GLOBOframe.htm 11. World Health Organization. Initiative for Vaccine Research. http://www.who.int/vaccine_research/diseases/hpv/en/ Accessed on October 8, 2010. 12. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55: 74-108. 13. Gravitt PE, Jamshidi R. Diagnosis and management of oncogenic cervical human papillomavirus infection. Infect. Dis. Clin. North Am. 2005; 19: 439-458. 14. Brown DR, Shew ML, Qadadri B, et al. A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J. Infect. Dis. 2005; 191: 182-192. 15. Bosch FX, de Sanjose S. Chapter 1: Human papillomavirus and cervical cancer--burden and assessment of causality. J. Natl. Cancer Inst. Monogr. 2003; 3-13. 16. Wright TC, Van Damme P, Schmitt HJ, et al. Chapter 14 : HPV vaccine introduction in industrialized countries. Vaccine 2006; 24 Suppl 3: S122-S131. 17. Castle PE, Schiffman M, Herrero R, et al. A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste,Costa Rica. J. Infect. Dis. 2005; 191: 1808-1816. 18. Muoz N, Mndez F, Posso H, et al. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian womenwith normal cytological results. J. Infect. Dis. 2004; 190 (12): 2077-2087. 19. Szarewski A. 9th International Multidisciplinary Congress of the European Research Organisation on Genital Infection and Neoplasia. Monte Carlo,Monaco, February 17-20 2010. Abstract. 20. Huh W, Paavonen J, Naud P, et al. Efcacy of the HPV-16/18 AS04-adjuvanted vaccine in women according to their initial DNA and serostatus: Patricia end-ofstudy results. 13th Biennial Meeting of the International Gynaecologic Cancer Society 2010. Prague, Czech Republic, October 23-26, 2010. Abstract 1782. 21. Olsson S, Kjaer S, Sigurdsson K, et al. Evaluation of quadrivalent HPV 6/11/16/18 vaccine efcacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection. Human Vaccines 2010; 5 (10): 696-704.

Summary Prophylatic cervical cancer vaccines have the potential to help prevent cervical cancer caused by certain oncogenic human papillomavirus (HPV) types. These vaccines help protect against: incident and persistent infections, cytological abnormalities, cervical intraepithelial neoplasia (CIN) and precancerous lesions (CIN 2, CIN 3 and adenocarcinoma in situ). The primary target population for HPV vaccination to date is the non-sexually active, pre-adolescent girls. However, latest data of a large clinical trial shows that sexually active girls/women between 15 and 26 years also benet from HPV vaccination.

What is cervical cancer?

Cervical cancer is almost exclusively caused by a virus called human papillomavirus (HPV) which is transmitted through sexual activity including intimate skin contact.1 There are about 100 known types of HPV2, of which at least 15 can cause cervical cancer.3 HPV types 16 and 18 are the most common cancer causing virus types and are found in for over 70 percent of all cervical cancer cases worldwide.4 Globally, HPV types 16, 18, 31, 33, 35, 45, 52, and 58 are the eight most frequent cancer-causing HPV types, which are responsible for about 91% of all cervical cancer.5 HPV is a particularly challenging virus as it is able to evade detection by the bodys natural immune system. As a purely mucosal virus which does not enter the bloodstream and does not kill the cells it infects, HPV avoids sending out the usual signals that trigger the

The global burden of cervical cancer

Worldwide, cervical cancer kills on average one woman in the world every two minutes10 and is the second biggest cause of female cancer mortality.11 Globally, cervical cancer is estimated to affect 510,000 women each year.11 In addition, women who survive cervical cancer sometimes are left infertile by radical surgery to remove the cancerous tissue.

50

40

Persistence (%)

30

20

10

0 <25 25-34 35-44 Age group (years) 45-54 55-64 65

Figure 1. Persistence of the oncogenic human papillomavirus (HPV) by age group.17

CERVICAL CANCER
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immune system.6 Thus, the natural immune response following infection appears not to be strong enough to protect against initial or subsequent infection with only a small number of subjects experiencing some partial protection.6, 7, 8, 9

Prophylactic HPV vaccination for young adult women

The risk of infection

Every sexually active woman is at risk of oncogenic HPV infection.12,13 It is estimated that up to 50-80 % of women will acquire an HPV infection in their lifetime, and up to 50 % of those infections will be with an oncogenic HPV type.14,15 Although the peak of HPV infection occurs in women aged less than 25 years old, incident and prevalent infection can continue throughout adult life due to subsequent infection by oncogenic types.16 There is evidence that infections among older women (over 35) are more likely to be persistent than those in younger women, and therefore older women may be at increased risk for development of cervical cancer (Figure 1).17

In a cohort trial 1,610 HPV-negative women (1585 years) with normal cytological results at baseline were monitored every 6 months for an average of 4.1 years. 18 The oncogenic HPV incidence was 5/100 woman-years. The 5-year cumulative risk of acquiring any HPV infection remained at 30% in women 25 to 29 years old and 22% in women 30 to 44 years old. The cumulative risk of HPV infection declined to 12% in women > 45 years old. A small increase in the incidence of oncogenic HPV infection was also seen in this cohort after the age of approximately 40, peaking at around age 50. These results conrm that a signicant risk of newly acquired HPV infections remains in sexually active women of all ages.

100

80

(95% CI, 94.3-99.8)

98.5%

(95% CI, 92.7-99.3) (95% CI, 13.2-98.0)

97.2%

81.1%

60 Persistence (%)

40

20

0 Seronegative for HPV 16/18 Irrespective HPV 16/18 serostatus Seropositive for HPV 16 and/or 18

Figure 2. Vaccine efcacy (%)(*) against CIN2+ associated with HPV 16/18 in women aged 15 to 25 years, with or without evidence of previous exposure. 20
(*) Vaccine efcacy reported in total vaccinated cohort = women receiving > 1 dose with Type Assignment Algorithm: assigns probable HPV causality in lesions with multiple HPV types.

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Preventing cervical cancer through vaccination

Current HPV vaccines do not have a therapeutic effect and do not prevent the development of CIN in women already infected with a given HPV type prior to vaccine administration. It is not a surprise that from a public health perspective, the primary target population for HPV vaccination is non-sexually active, pre-adolescent girls. The girls in this population generally have not been exposed to any of the vaccine-targeted HPV types. New data has shown, however, that the majority of young adult women potentially could benet from vaccination. The AS04- adjuvanted HPV-16/18 vaccine against HPV was shown to be highly efcacious against pre-cancerous lesions (CIN 2+) associated with HPV16/18 in women aged 15- 25 years with evidence

Conclusion
The priority of routine vaccination programs with HPV vaccines should be the primary target population of pre-adolescent girls and young women; however, new data in women aged 15 to 25 years with the AS04- adjuvanted HPV-16/18 vaccine has shown efcacy against CIN2+ associated with HPV-16/18 even in women with evidence of a previous infection (seropositive). 19-20

CERVICAL CANCER
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The use of HPV vaccinations should be in accordance with ofcial recommendations and the approved product information in your country.

of a previous infection (seropositive for HPV-16 and/ or -18).19-20 The study has shown that women aged 15 -25 years currently infected (DNA positive) with one vaccine HPV type were protected against the other vaccine type, if DNA negative for that type (Figure 2).20 Similar results were obtained with the quadrivalent HPV vaccine (HPV types 6/11/16/18) in subjects with serological evidence of prior vaccine type HPV infection.21

The inuenza A (H1N1) 2009 pandemic: the end of the rst inuenza pandemic of the 21st century

Summary On 11 June 2009 the World Health Organization (WHO) declared the start of the rst inuenza pandemic of the 21st century.1 More than one year later, on 10 August 2010 Margaret Chan, the Director-General of the WHO, announced that the world has moved into the post-pandemic period.2 How might we prepare for a future inuenza pandemic? The lessons that have been learned during the rst inuenza pandemic of this century could help in answering this important question.

Virology
Instead of the H5N1 avian inuenza virus, a swine-origin H1N1 inuenza virus was responsible for the start of the inuenza A (H1N1) 2009 pandemic. This virus contained a combination of gene segments that had previously not been reported in swine or human inuenza viruses.3 Its genome is the result of a reassortment and contains genes from triple-reassortant North American swine virus and Eurasian swine virus lineages. No expert expected the emergence of this pandemic H1N1 virus (Figure 1). The majority of pandemic inuenza A (H1N1) 2009 viruses analyzed to date are antigenically and genetically

closely related to the recommended vaccine virus A/California/7/2009.4 As a consequence of increasing concern following the Hong Kong H5N1 outbreak in 1997, and subsequent events with associated human infections, pandemic preparedness planning has been a focus of WHOs global inuenza strategy. During a brieng on 29 April 2009 Margaret Chan, the Director-General of the WHO, stated: The world is better prepared for an inuenza pandemic than at any time in history. Preparedness measures undertaken because of the threat from H5N1 avian inuenza were an investment and we are now

1. 2. 3. 4. 5. 6. 7. 8.

HA NA PA PB1 PB2 NP M NS

Classic swine, North American lineage Eurasian swine lineage Avian, North American lineage Human seasonal H3N2 Avian, North American lineage Classic swine, North American lineage Eurasian swine lineage Classic swine, North American lineage

Figure 1. Gene segment composition of the pandemic inuenza A (H1N1) 2009 virus.6

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The inuenza A (H1N1) 2009 pandemic: the end of the rst inuenza pandemic of the 21st century

beneting from this investment. For the rst time in history, we can track the evolution of a pandemic in real time.5

from inuenza virus infection. Inuenza in pregnancy is associated with an increased risk of adverse pregnancy outcomes, such as spontaneous abortion, preterm birth, and fetal distress.11

Epidemiology
Contrary to what had been expected, North America, and not South East Asia, was the epicenter of the rst inuenza pandemic of the 21st century. The novel H1N1 virus was rst detected in a widespread outbreak in Mexico in March-April 2009.7 Within weeks, the virus that was causing the epidemic in Mexico was identied in many other countries worldwide. On 11 June 2009, the WHO raised the phase of pandemic alert to level 6. The pandemic inuenza A (H1N1) 2009 virus has been shown to affect all age groups. Rapid spread has been observed in some communities, especially in crowded places such as schools. In school outbreaks in the UK, around 30% to 50% of students have been infected.8 A proportion of older adults may have had a degree of cross protection conferred by pre-existing neutralising antibodies directed against other inuenza A viruses.9 In certain disadvantaged groups, including indigenous populations of North America and the Australasia-Pacic region, rates of severe A (H1N1) 2009 inuenza virus infection have been increased.10 To date, the epidemiology of pandemic A (H1N1) 2009 virus infection indicates that children and young adults have had the highest attack rates.11 The risk factors for severe disease from pandemic A (H1N1) 2009 virus infection reported are considered not disimilar to those risk factors identied for complications from seasonal inuenza (Table 1).11 Pregnant women, especially those with co-morbidities, are at increased risk for complications

Table 1. Groups at increased risk of severe disease from pandemic H1N1/09 virus infection.11 1. Infants and young children, in particular below 2 years; 2. Pregnant women; 3. Persons of any age with chronic pulmonary disease (e.g., asthma, COPD); 4. Persons of any age with chronic cardiac disease (e.g., congestive cardiac failure); 5. Persons with metabolic disorders (e.g., diabetes); 6. Persons with chronic renal or hepatic disease, certain neurological conditions, haemoglobinopathies, or primary or secondary immunosuppressive conditions; 7. Children receiving chronic aspirin therapy; 8. Persons above 65 years.

Clinical features
Most people with pandemic inuenza A(H1N1) 2009 virus infection have had self-limiting uncomplicated illness. Symptoms were generally mild and closely resembled seasonal inuenza. The most commonly reported symptoms included cough, fever, sore throat, muscle

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Treatment and vaccination

Pandemic inuenza A (H1N1) 2009 virus is currently susceptible to the neuraminidase inhibitors oseltamivir and zanamivir, but resistant to the M2 inhibitors amantadine or rimantadine. Antiviral therapy was recommended by the WHO to patients considered to be at higher risk of developing severe or complicated illness and who had complicated illness due to conrmed or

References
1. World Health Organization. Transcript of statement by Margaret Chan, Director-General of the World Health Organization, 11 June 2009. Available at: http://www.who.int/mediacentre/inuenzaAH1N1_presstranscript_20090611.pdf. (Accessed on 15 September 2010). 2. World Health Organization. Transcript of statement by Margaret Chan, Director-General of the World Health Organization, 10 August 2010. Available at: http://www.who.int/mediacentre/vpc_transcript_joint_2010_08_10.pdf. (Accessed on 15 September 2010). 3. Garten RJ, Davis CT, Russell CA, et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) inuenza viruses circulating in humans. Science 2009; 325: 197-201. 4. World Health Organization. Weekly virological update on 12 August 2010. Available at: http://www.who.int/csr/disease/swineu/laboratory13_08_2010/en/index.html (Accessed on 15 September 2010). 5. World Health Organization. Transcript of statement by Margaret Chan, Director-General of the World Health Organization, 29 April 2009. Available at: http://www.who.int/mediacentre/news/statements/2009/h1n1_20090429/en/index.html (Accessed on 15 September 2010). 6. Trifonov V, Khiabanian H, Rabadan R. Geographic dependence, surveillance, and origins of the 2009 inuenza A (H1N1) virus. N. Engl. J. Med. 2009; 361: 115-119. 7. Lpez-Cervantes M, Venado A, Moreno A, et al. On the spread of the novel inuenza A (H1N1) virus in Mexico. J. Infect. Dev. Ctries 2009; 3 (5): 327-330. 8. Mathematical modelling of the pandemic H1N1 2009. Wkly Epidemiol. Rec. 2009; 84: 341-348. 9. Hancock K, Veguilla V, Lu X, et al. Cross-reactive antibody responses to the 2009 pandemic H1N1 inuenza virus. N. Engl. J. Med. 2009; 361: 1945-1952. 10. Louie JK, Acosta M, Winter K, et al. Factors associated with death or hospitalization due to pandemic 2009 inuenza A(H1N1) infection in California. JAMA 2009; 302: 1896-1902. 11. World Health Organization. Clinical management of human infection with pandemic (H1N1) 2009: revised guidance. http://www.who. int / csr / resources / publications / swineu / clinical_management_h1n1.pdf. 12. Health Protection Agency. Pandemic H1N1 2009 clinical practice notemanaging critically ill cases (28 July 2009). Available at: http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1248854036293 (Accessed on 15 September 2010). 13. Centers for Disease Control and Prevention. Update on inuenza A (H1N1) 2009 monovalent vaccines. MMWR 2009; 58:1100-1101. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5839a3.htm. (Accessed on 15 September 2010). 14. European Medicines Agency. Pandemic inuenza (H1N1) website. Available at: http://www.emea.europa.eu/inuenza/vaccines/home.htm. (Accessed on 15 September 2010). 15. World Health Organization. Director-General's opening statement at virtual press conference. 10 August 2010. Available at: http://www.who.int/mediacentre/news/statements/2010/h1n1_vpc_20100810/en/index.html (Accessed on 15 September 2010). 16. Simpson CR, Ritchie LD, Robertson C, et al. Vaccine effectiveness in pandemic inuenza - primary care reporting (VIPER): an observational study to assess the effectiveness of the pandemic inuenza A (H1N1)v vaccine. Health Technol. Assess. 2010; 14 (34): 313-346

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aches, malaise, and headache. Some patients reported gastrointestinal symptoms (nausea, vomiting, and/or diarrhea).6 However, for some severe complications occurred such as pneumonia resulting in respiratory failure, acute respiratory distress syndrome (ARDS), multi-organ failure and death.12

strongly suspected inuenza virus infection.11 Inactivated- and live attenuated monovalent vaccines containing the recommended vaccine virus strain A/California/7/2009 (H1N1) have been approved by the FDA, European Medicines Agency (EMA) and other regulatory bodies.13-14 Many countries reported good vaccination coverage, especially in high-risk groups, and this coverage further increases community-wide immunity.15 Evidence from an observational study to assess the effectiveness of the pandemic inuenza A (H1N1) 2009 vaccine demonstrated a high degree of protection in the vaccinated high-risk populations (e.g. pregnant women, children, health-care workers, patients with at-risk comorbidities) against the inuenza strain.16

Abstracts

High Hepatitis A Virus (HAV) vaccination coverage has nearly eliminated transmission of HAV infection in Alaska
Hepatitis A is a highly contagious liver infection. It is one of the several types of hepatitis viruses that cause inammation, affecting the liver's functionality. Alaska has previously experienced cyclic hepatitis A epidemics, and the rate among Alaska Native people was signicantly higher than among other racial and ethnic groups. Hepatitis A vaccines were licensed in the US in 1995 and recommended by the Advisory Committee on Immunization Practice (ACIP) for routine vaccination of US children in populations with high rates of hepatitis A virus (HAV). Populations include those found in American Indian and Alaska Native communities throughout the United States. Rosalyn Singleton et al. evaluated the impact of universal childhood vaccination, initiated in 1996, on HAV epidemiology in Alaska by analyzing HAV cases reported to the State of Alaska. HAV incidence in all age groups declined 98.6% from 60.0/100,000 in 19721995 to 0.9/100,000 in 20022007. The largest decrease (99.9%) was in Alaska Native people, whose incidence (0.3%) in 20022007 was lower than the overall US 2007 rate (1.0%) (Figure 1). The decrease (99.8%) among children aged 0 to14 years was the largest. Routine childhood vaccination has nearly eliminated HAV infection in Alaska.
Rosalyn J. Singleton, Sarah Hess, Lisa R. Bulkow, et al. Impact of statewide childhood vaccination program in controlling hepatitis A virus infection in Alaska. Vaccine 2010; 28: 6298-6304.

Study revealed no increased risk of autism associated with thimerosal-containing vaccines

From the 1930s to the early 2000s, many routinely administered childhood vaccines contained very tiny amounts of thimerosal as preservative. Thimerosal is an organic mercury containing compound having 49.55 per cent mercury by weight, and is initially metabolized to ethylmercury and thiosalicylate. Ethylmercury exposure from the preservative thimerosal had been hypothethized as a possible risk factor for autism or other ASDs (autism spectrum disorders). In 1999, as a precautionary measure, the American Academy of Pediatrics and the US Public Health Service published a joint statement which included a request that manufacturers eliminate or reduce as expeditiously as possible the mercury content in their vaccines. Many vaccines recommended for children 6 yr of age subsequently were made available in thimerosal-free or thimerosal-reduced formulations. Most previous research has not revealed an increased risk of autism associated with thimerosal-containing vaccines (http://www.cdc.gov/vaccinesafety/concerns/ thimerosal/index.html). In a recent study, US researchers conducted a case-control study in 3 managed care organizations of 256 children with ASD and 752 controls. This new study revealed no increased risk of ASD associated with receipt of thimerosal-containing vaccines. No increased risk was found for subtypes of ASD, including ASD with regression, and prenatal exposure was also not associated with a risk of ASD.
Cristofer S. Price, William W. Thompson, Barbara Goodson, et al. Prenatal and infant exposure to thimerosal from vaccines and immunoglobulins and risk of autism. Pediatrics 2010; published online Sep 13, 2010.

Figure 1. Hepatitis A virus infection rate per 100,000 by year, 19722007, among Alaska Native and non-Native Alaska persons.
2000 1800 Rate per 100,000 1600 1400 Rate per 100,000 1200 1000 800 600 400 200 0 1972 1975 1978 1981 1984 1987 1990 Year 1993 1996 1999 2002 2005

Native Non-native

10 9 8 7 6 5 4 3 2 1 0 96 97 98 99 00 01 02 Year 03 04 05 06 07

(reprinted with permission)

ABSTRACTS
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Hajj pilgrims and vaccination requirements

References
1. Memish ZA. The Hajj: communicable and non-communicable health hazards and current guidance for pelgrims. Euro Surveill. 2010; 15 (39): 19671. 2. Memish ZA, et al. Establishment of public health security in Saoudi Arabia for the 2009 Hajj in response to pandemic inuenza A H1N1. Lancet 2009; 374: 1786-1791. 3. Shek LP, Lee BW. Epidemiology and seasonality of respiratory tract virus infections in the tropics. Paediatr. Respir. Rev. 2003; 4 (2): 105-111. 4. El Bashir H, Haworth E, Zambon M, et al. Inuenza among U.K. pilgrims to hajj, 2003. Emerg. Infect. Dis. 2004; 10 (10): 1882-1883. 5. International consultation on infectious disease prevention and control for Umra and the Hajj: Technical meeting report, Jeddah, Kingdom of Saudi Arabia, 5-7 Rajab 1430H/28-30 June 2009. Available at: http://www.emro.who.int/csr/h1n1/pdf/infectiousdiseases_hajj_umra.pdf (Accessed on 15 September 2010). 6. World Health Organization. Health conditions for travellers to Saudi Arabia for the pilgrimage to Mecca (Hajj). Wkly Epidemiol. Rec. 2009; 46 (84): 477484. 7. Al-Mazrou YY, Al-Jeffri MH, Abdalla MN, et al. Changes in epidemiological pattern of Meningococcal disease in Saudi Arabia; Does it constitute a new challenge for prevention and control? Saudi Med. J. 2004; 25: 1410-1413. 8. World Health Organization. Health conditions for travellers to Saudi Arabia for the pilgrimage to Mecca (Hajj). Wkly Epidemiol. Rec. 2006; 81 (44): 422-423 9. Gatrad AR, Sheikh A. Hajj and risk of blood borne infections. Arch. Dis. Child. 2001; 84: 375 10. Memish ZA, Venkatesh S, Ahmed QA. Travel epidemiology: the Saudi perspective. Int J Antimicrob Agents 2003; 2: 96-101. 11. Memish ZA. Health conditions for travelers to Saudi Arabia for (Hajj) for the year 1431H/2010. J. Infect. Publ. Health 2010; 3: 92-94.

Summary The Hajj pilgrimage in Mecca (Saudi Arabia) is currently the largest annual congregation in the world. Extended close contact, shared accommodation and overcrowding are all associated with an increased risk of infection. Possible outbreaks of disease at the Hajj include respiratory tract infections including inuenza and pneumococcal pneumonia, invasive meningococcal disease, blood-borne diseases, and skin infections.

Figure 1. The Kaaba is a cube-shaped building in Mecca and it is the most sacred site in Islam. During the Hajj, pilgrims walk around the Kaaba seven times in a counter-clockwise direction.

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The Hajj is the annual pilgrimage to Mecca, Saudi Arabia and is currently one of the largest annual mass gatherings. The Hajj is one of the ve pillars of Islam. It is a religious duty that must be carried out at least once in their lifetime by every Muslim who can afford to do so. In 2009, over 2.5 million pilgrims visited Mecca and the vast majority being international travellers. The pilgrims usually arrive two months before the Hajj takes place. Camps consisting of ats and tents are provided by

the Ministry of Hajj.1 The Hajj takes place between the 8th and 13th day of the last month of the Islamic lunar calendar and therefore Hajj falls 10 to 11 days earlier each year. In 2010, the dates for the Hajj fell between the 14 to the 18 November. During this period, extreme congestion of this geographically diverse population amplies health risks, particularly infectious diseases.1

Hajj pilgrims and vaccination requirements

Vaccination requirements
While pilgrimage to Mecca was the context for severe cholera outbreaks in the 19th century, the health situation for pilgrims has greatly improved.2 The Ministry of Health (MoH) of Saudi Arabia takes the health security very seriously and each year gives appropriate immunization requirements and advice. Inuenza As Saudi Arabia is in the tropical sphere, inuenza is expected to occur in two different peaks corresponding to the winter seasons of northern and southern hemispheres.3 The attack rate of inuenza during the Hajj is reported to be as high as 38% despite vaccination.4 Before the start of the inuenza A (H1N1) 2009 pandemic the Ministry of Health of Saudi Arabia recommended that pilgrims particularly those with pre-existing conditions (e.g. elderly, patients with chronic heart disease or with cardiac, hepatic or renal failure) be vaccinated against inuenza before arrival. The inuenza A (H1N1) 2009 pandemic imposed extra concerns regarding public health during Hajj 2009. The Ministry of Health of Saudi Arabia organized together with the World Health Organization (WHO) a consultation process to develop recommendations to mitigate the effects of the inuenza pandemic during the 2009 Hajj.5 Special entry visa requirements and recommendations for the Hajj were issued by the Ministry of Health of Saudi Arabia. During the pandemic, people at high risk were advised to postpone their participation in the Hajj. Additionally, it was advised that all pilgrims be vaccinated against seasonal and pandemic inuenza.6

Meningococcal meningitis Until the year 2000, bivalent (serogroups A, C) meningococcal vaccination was recommended for all pilgrims to the Hajj areas. During the Hajj pilgrimages of 2000 and 2001, there was an epidemiological shift from serogroup A disease to serogroup W135 disease together with an increase in incidence in younger age groups.7 As a result, the quadrivalent (ACWY135) meningococcal polysaccharide vaccine was introduced in 2001 by the Ministry of Health for all pilgrims. All Hajj pilgrims are required to submit proof of vaccination with the quadrivalent (ACWY 135) meningococcal vaccine as part of the Hajj visa application.Vaccination with quadrivalent polysaccharide vaccines has proved successful and has quelled meningococcal disease since 2002. Polio Although poliomyelitis is close to eradication, all pilgrims are advised to ensure their poliomyelitis vaccination is up to date. If the last dose of poliomyelitis vaccine was more than 10 years ago a booster with trivalent tetanus, diphtheria and poliomyelitis vaccine should be given. The Ministry of Health of Saudi Arabia recommends that all people aged less than 15 years travelling to Saudi Arabia from polio-affected countries show proof of vaccination with oral poliomyelitis vaccine 6 weeks prior to application for their entry visa.1 Irrespective of previous immunization history, children aged less than 15 years arriving in Saudi Arabia will also receive one oral poliomyelitis vaccine dose at border points on arrival in Saudi Arabia.8 All pilgrims regardless of age and vaccination status coming from Afghanistan, India, Nigeria and Pakistan the countries that never

26

Figure 2. The tent cities in Mina provide temporary accommodation to millions of visiting pilgrims.

completely interrupted the transmission of the polio virus should receive one dose of oral poliomyelitis vaccine.1 Hepatitis B As part of the rites of Hajj, men shave their heads although trimming the hair is also acceptable; women also cut a lock of their hair. Communal use of razors or blades carries the risk of blood borne infections such as hepatitis B, hepatitis C or HIV, especially considering that many pilgrims will come from regions where such infections are now endemic.9 To minimize this risk the Saudi Arabia Ministry of Health advises pilgrims to avoid unlicensed barbers and to seek licensed barber facilities at the Hajj premises. However, many pilgrims will have their heads shaved by unlicensed barbers, often reusing the razor blades.1 Memish et al. estimated that about 10% of the barbers in the Kingdom of Saudi Arabia are carriers of hepatitis C and 4% carry hepatitis B, over a tenth of whom are in active carrier stage.10 The Ministry of Health of Saudi Arabia encourages all pilgrims to receive hepatitis B

vaccination prior to their travel.1 The standard schedule for administering the hepatitis B vaccine in adults 20 years and older calls for three doses of vaccine at zero, one, and six months. An accelerated schedule consists of vaccination at zero, one, and two months, with a booster given 12 months after the rst dose. Yellow fever All travellers arriving from countries where there is a risk of yellow fever transmission must present a valid yellow fever vaccination certicate in accordance with the International Health Regulations. In the absence of such a certicate, the person will be vaccinated upon arrival and placed under strict surveillance for 6 days from the day of vaccination or the last date of potential exposure to infection, whichever is earlier.6 Aircraft,ships and other means of transportation arriving from areas infected with yellow fever are requested to submit a certicate indicating that it applied disinfection in accordance with methods recommended by WHO.11

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Varicella vaccines and traditional vaccination schedules

Figure 1. Break-through varicella infection is varicella disease that occurs more than 42 days after vaccination following exposure to wild-type varicella zoster virus and usually results in mild illness. Nonetheless, breakthrough varicella is contagious and can lead to transmission of virus to those unvaccinated.

Summary
Given the highly transmissible nature of varicella, low vaccination coverage rates generally achieved with targeted varicella vaccination in susceptible adolescents or high-risk groups are unlikely to induce substantial herd immune effects or inuence the epidemiology of varicella disease. Accumulating evidence from countries that have implemented routine varicella vaccination of infants shows a dramatic reduction in the morbidity and mortality from varicella.

The currently marketed varicella vaccines are based on the "Oka" strain of the varicella-zoster virus (VZV), which has been modied through sequential propagation in different cell cultures. Various formulations of such live, attenuated vaccines have been tested extensively and are approved for use in most countries.1 Initial clinical trials with the Oka VZV strain were initiated in Japan by Takahashi in the early 1970s. A thermostable formulation of the rst varicella vaccines (storage at 2-8C for 2 years) has been available for more than 10 years now. Following a single dose of the above-mentioned vaccines, seroconversion is seen in about 95% of healthy children but effectiveness levels can be markedly lower.1,2,3 With regards to duration of protection, children remained seropositive for at least 7 years in clinical studies. In a study of 1,164 healthy children 1 to 12 years of age originally enrolled in clinical studies, an estimated vaccine efcacy of 93.8 to 94.6% was reported during a 7-year period, as assessed by comparing the observed average annual breakthrough rate with the age adjusted expected annual incidence rate of varicella in unvaccinated children.4 Furthermore an efcacy rate of 88.5% was observed in vaccinated individuals exposed to varicella in the household, based on an historical comparison with exposed, unvaccinated susceptible individuals.4 From a logistic as well as an epidemiological point of view, the optimal age for varicella vaccination is 12 to 24 months. In Japan and several other countries 1 dose of the vaccine is considered sufcient, regardless of age. However, other countries such as the U.S. now recommend 2 doses of vaccine for all children, adolescents and adults. Small studies show that when the vaccine is administered within 3 days after exposure to VZV, a post exposure protective efcacy up to 80%

Current varicella vaccination recommendations

The majority of countries with a national recommendation for varicella vaccination promote targeted vaccination in susceptible adolescents or highrisk groups, such as seronegative women at childbearing age, healthcare workers, susceptible individuals with immunosuppressed close contacts, daycare personnel and teachers (Table 1).6 The WHO recommends that routine childhood immunization may be considered in countries where the disease is a relatively important public health and socioeconomic problem, where the vaccine is affordable, and where high (85%-90%) and sustained vaccine coverage can be achieved. Childhood immunization with lower coverage could theoretically shift the epidemiology of the disease to older persons and increase the number of severe cases in older children and adults.1 In addition the WHO recommends that the vaccine may be offered in any country to individual adolescents and adults without a history of varicella, in particular to those at increased risk of contracting or spreading the infection. This use in adolescents and adults entails no risk of an epidemiological shift, as childhood exposure to VZV remains unaffected. The strategy of targeted varicella vaccination in susceptible adolescents or high-risk groups does not have the potential to interrupt viral transmission and, in the past, has been far less effective in achieving high coverage rates when compared with childhood programmes.7

VARICELLA VACCINES
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may be expected.5 Varicella in persons who have received the vaccine (break-through varicella) is substantially less severe than the disease in unvaccinated individuals (Figure 1).

Varicella vaccines and traditional vaccination schedules

Conclusion and future

Individual varicella vaccination will provide patients with the benets associated with vaccination. The introduction of routine vaccination against varicella will reduce the varicella case numbers, hospitalizations and deaths due to varicella. Moreover, two doses of varicella vaccine will achieve a better individual protection - most strikingly against mild disease - and a better disease control in the long term. Varicella routine vaccination using a one-dose schedule was introduced in the USA in 1995.8 The Advisory Committee on Immunization Practices (ACIP) decided in June 2006 to increase the number of varicella doses from one to two, with the ofcial recommendations published in June 2007.9

A second dose of vaccine given universally to children may be necessary to maximise protection against varicella by increasing the proportion of children with protective antibody titres and improving cell-mediated immune responses. Indeed, a two-dose varicella vaccination schedule for children is reported to be associated with a higher vaccine efcacy and a threetimes lower risk of breakthrough disease than among individuals who received one dose (2.2% over 10 years compared with 7.3%, respectively, p<0.001).10, 11 Educational activities are needed in order to raise awareness among policy makers and healthcare professionals as to the benets of universal routine vaccination against varicella.

Table 1. Varicella vaccination recommendations in different countries.6 Country Austria Current Varicella Vaccination Recommendations Seronegative girls/women at childbearing age Seronegative healthcare workers (especially in pediatric institutions) High-risk children (e.g. children with forthcoming transplantation or chemotherapy or immunosuppression; before immunosuppression) Seronegative family members of high-risk children Seronegative day-care personnel and teachers Routine childhood immunization, administered at 18 months of age, with catch-up at 1013 yr of age High-risk patients Universal childhood vaccination with 2 doses: rst dose at 15 months of age; second dose at 46 yr of age (Brazilian Pediatric Society and Brazilian Immunization Society) Routine vaccination for individuals 12 months of age who are susceptible to varicella Susceptible groups of adults, e.g. healthcare workers, teachers, day-care workers, household contacts, and other close contacts of immunocompromised individuals Susceptible individuals at high risk of severe varicella disease or its complications Childhood immunization from the age of 13 months onwards On an individual named patient basis

Australia Belgium Brazil Canada

Cyprus Finland

30

France

High-risk groups: post exposure vaccination in adults (> 18 yr) without previous varicella infection; students studying medicines and paramedicines; seronegative close contacts of immunosuppressed Administered according to a 2-dose schedule to all children at 1114 months and 1523 months of age when combined with MMR (MMRV) Routine vaccination for healthy children at the age of 1218 months and for all susceptible children is recommended by the National Vaccinations Committee, but not yet ofcially endorsed by the Ministry of Health (National Vaccination Committee) (Personal communication) On an individual named patient basis Recommendation for UMV in children through Health Maintenance Organizations, but not yet part of the routine childhood immunization schedule All susceptible individuals (national vaccination program) Priority to all susceptible adults and adolescents, and then all children living in regions able to reach high coverage rates (> 80%) in the short-term Sicily: Universal childhood vaccination in second year of life and catch-up in 12-yr-olds with no history of varicella Voluntary vaccination from 12 months of age Recommendation for UMV in children, but not yet part of the routine childhood immunization schedule None, but considering introducing recommendations for childhood immunization to be administered with rst dose of MMR vaccine Recommended for all susceptible individuals Routine childhood immunization, compulsory at 12 months of age No ofcial recommendation, but childhood immunization from the age of 1218 months and catch-up vaccination of susceptible adolescents at 1112 yr recommended by the Spanish Association of Pediatrics High-risk groups Seronegative healthy children > 12 yr and adults who have not had varicella Seronegative adolescents aged 1115 yr Catch-up for persons with no history of varicella Routine childhood vaccination at 12 months of age

Germany Greece

Hungary Israel Italy

Japan Lithuania Malta Poland Qatar Spain

Sweden Switzerland Taiwan

The United Kingdom Nonimmune healthcare workers Healthy close contacts of immunosuppressed patients On an individual named patient basis The United States of America All children < 13 yr of age administered routinely 2 doses of varicella-containing vaccine (rst dose at 1215 months and second dose by the age of 46 yr (with at least 3 months between doses) Second dose catch-up for children, adolescents, and adults who previously received 1 dose Routine childhood vaccination

Uruguay

References
1. World Health Organization. Varicella vaccines. WHO position paper. Wkly Epidem. Rec. 1998; 73: 241-248. 2. Miron D, Lavi I, Kitov R, et al. Vaccine effectiveness and severity of varicella among previously vaccinated children during outbreaks in day-care centers with low vaccination coverage. Pediatr. Infect. Dis. J. 2005; 24 (3): 233-236. 3. Galil K, Lee B, Strine T, et al. Outbreak of varicella at a day-care center despite vaccination. N. Engl. J. Med. 2002; 347 (24): 1909-1915. 4. Vessey SJ, Chan CY, Kuter BJ, et al. Childhood vaccination against varicella: persistence of antibody, duration of protection, and vaccine efcacy. J. Pediatr. 2001; 139: 297-304. 5. Arnedo-Pena A, Puig-Barbera J, Aznar-Orenga MA, et al. Varicella vaccine effectiveness during an outbreak in a partially vaccinated population in Spain. Pediatr. Infect. Dis. J. 2006; 25: 774-778. 6. Vesikari T, Sadzot-Delvaux C, Rentier B, et al. Increasing coverage and efciency of measles, mumps, and rubella vaccination and introducing universal varicella vaccination in Europe. Pediatr. Infect. Dis. J. 2007; 26: 632-638. 7. Sengupta N, Booy R, Schmitt HJ, et al. Varicella vaccination in Europe: are we ready for a universal childhood programme? Eur. J. Pediatr. 2008; 167: 47-55. 8. Centers for Disease Control and Prevention. Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Centers for Disease Control and Prevention. MMWR 1996; 45: 136. 9. Advisory Committee on Immunization Practices. Meeting of the Advisory Committee on Immunization Practices. June 2930, 2006. Available at: http://www.cdc.gov/vaccines/recs/acip/downloads/min-jun06.pdf [Accessed September 2nd, 2008]. 10. Seward J, Marin M, Vazquez M. Varicella vaccine effectiveness in the US vaccination program: A review. J Infect Dis 2008; 197: S82-87. 11. Kuter B, Matthews H, Shineeld H, et al. Ten year follow-up of healthy children who received one or two injections of varicella vaccine. Pediatr. Infect. Dis. J. 2004; 23: 132-137.

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Misconceptions about vaccinations

References
1. Fenner F, Henderson DA, Arita I, et al. 1988. Smallpox and Its Eradication: The Pathogenesis, Immunology, and Pathology of Smallpox and Vaccinia. World Health Organization, Geneva. 2. Centers for Disease Control and Prevention. Impact of vaccines universally recommended for childrenUnited States, 19901998. MMWR 1999; 48: 243-248. 3. World Health Organisation. Six common misconceptions about immunization. Available at: http://www.who.int/immunization_safety/ae/immunization_misconceptions/en/ (Accessed on October 3th, 2010). 4. U.S. Census Bureau, Statistical Abstracts of the United States: 1999. Section 31. 20th Century Statistics. p. 875. 5. Stewart GT. Vaccination against whooping-cough, Lancet 1977; 1: 234-237. 6. Gangarosa EJ, Galazka AM, Wolfe CR, et al. Impact of anti-vaccine movements on pertussis control: the untold story. Lancet 1998; 351: 356-361. 7. Andr FE. Vaccinology past achievements, present roadblocks and future promises. Vaccine 2003; 21: 593-595.

Summary For many families, mass vaccination programs have turned several childhood diseases such as measles, mumps, rubella, and polio, into distant memories. However, in the absence of recurrent outbreaks, public attention has begun to focus on the risks of vaccination, either real or perceived. Without balanced evidence, anti-vaccine trends can gain momentum, and vaccine coverage may fall leading to outbreaks of vaccine-preventable diseases where the disease has been previously contained.

Vaccination campaigns to control infectious disease represent one of the greatest public health achievements in human history. The smallpox vaccine, rst developed in 1798 by Edward Jenner, resulted in the eventual eliminaton in 1977 of this highly lethal human pathogen from nature.1 Through effective vaccination programs, the U.S. has seen disease incidence reduced by 95100% for many infectious agents including polio, measles, mumps, rubella, diphtheria, pertussis (whooping cough), and tetanus.2 However, the success with vaccination in the U.S. and other countries have also had an unexpected, self-limiting effect with regard to public perception of disease risk. In this modern age of communication, health-care workers will encounter patients who have reservations about getting vaccinations for themselves or their children. There can be many reasons for fear or opposition to vaccination. Some people have religious or philosophical objections. Some people see mandatory vaccination as interference by the government into what they believe should be a personal choice. Others are concerned about the safety or efcacy of vaccines, or believe that vaccine-preventable diseases do not pose a serious health risk.3 All health-care workers giving vaccines have a responsibility to listen to and try to understand a patient's concerns, fears, and beliefs about vaccination and to take them into consideration when offering vaccines. These efforts will not only help to strengthen the bond of trust between staff and patient but will also help determine what information may be appropriate to discuss with the patient in understanding the benets of vaccination.

Statements like this are very common in anti-vaccine literature, the intent apparently being to suggest that vaccines are not needed. Improved socioeconomic conditions have undoubtedly had an indirect impact on disease. Better nutrition, not to mention the development of antibiotics and other treatments, have increased survival rates among the sick; less crowded living conditions have reduced disease transmission; and lower birth rates have decreased the number of susceptible household contacts. However, looking at the actual incidence of disease over the years can leave little doubt of the signicant direct impact vaccines have had, even in modern times (Figure 1).4 What are the experiences of several developed countries after they let their immunization levels drop? Two countries Great Britain and Japan cut back the use of pertussis vaccine because of fear about the vaccine. The effect was dramatic and immediate. In the UK in 1974 a prominent public-health academic, Dr Gordon Stewart (Glasgow University), became convinced, erroneously as it was subsequently established, that pertussis vaccine was responsible for permanent neurological damage in infants. Professor Stewart claimed that the protective effect of the vaccine was marginal and did not outweigh its danger.5 His campaigning for his belief, including television appearances, caused a dramatic fall from 81% to 31% in uptake of the vaccine in the UK. This, predictably, led to a resurgence of the disease, with an epidemic of more than 100,000 cases of pertussis and 36 deaths by 1978.6

MISCONCEPTIONS
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Misconception 1: Diseases had already begun to disappear before vaccines were introduced, because of better hygiene and sanitation.

Misconceptions about vaccinations

750

600 480.5 450

584.6

incidence per 100,000

340.8 300 194.3 150 220.7

337.9 245.4 210.1 185.1

Figure 1. The reported measles incidence per 100,000 population from 1920 to 1997.4

110.2 23.2 11.3 5.9 1.2 11.2 3.8 0.9 0.1 0.4 0.1 0.2 0.1

20

In Japan, around the same time, a drop in vaccination rates from 70% to 20%-40% led to a jump in pertussis from 393 cases and no deaths in 1974 to 13,000 cases and 41 deaths in 1979. Fortunately, in all these countries, universal vaccination has returned and pertussis has again been brought under control.

Misconception 2: Vaccines cause many harmful side effects, illnesses, and even death.
Currently available vaccines have a positive benet/ risk prole, despite implications to the contrary in many anti-vaccine publications. However, it must be recognized that vaccines can indeed cause adverse effects or adverse reactions. The most frequent adverse reactions typically are benign such as transient pain, redness and swelling at the site of injection. Systemic reactions such as fever (sometimes leading to febrile

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Year

25

30

19

19

19

19

19

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convulsions), malaise or headache can also occur after vaccination. Generally, serious reactions are rare.7 Prior to vaccination, patients should discuss the safety prole for the specic vaccines they will receive with their healthcare professional. Since the beginning of the 20th century, the wide use of vaccination has produced substantial achievements in the control of vaccine-preventable diseases. Major victories against the spread of disease have been won by vaccination, eradicating a disease or reducing its incidence to rare case reports.

Congress Calendar

ISRVI 2011 XIIIth International Symposium on Respiratory Viral Infections

Cairo, Egypt, March 12th March 15th, 2011 http://www.themacraegroup.com/xiii-internationalsymposium-on-respiratory-viral-infections

Immunology 2011 98th Annual Meeting of the American Association of Immunologists

San Francisco, US, May 13th May 17th, 2011 http://www.aai.org/

ISAAR 2011 8th International Symposium on Antimicrobial Agents and Resistance

Seoul, Korea, April 6th April 8th, 2011 http://www.isaar.org/

ESPID 2011 29th Annual Meeting of the European Society for Paediatric Infectious Diseases
The Hague, The Netherlands, June 7th June 11th, 2011 http://www2.kenes.com/espid2011/Pages/Home.aspx

ECCMID 2011 21st Annual Meeting of the European Society of Clinical Microbiology and Infectious Diseases
Milan, Italy, May 7th May 10th, 2011 http://www.escmid.org/

ESWI 2011 The fourth ESWI Inuenza Conference

Malta, September 11th September 14th, 2011 http://www.eswiconference.org/

IPvC 2011 27th International Papillomavirus Conference and Clinical Workshop

Berlin, Germany, September 16th September 22nd, 2011 http://www.hpv2011.org/

WSPID 2011 7th World congress of the World Society for Pediatric Infectious Diseases
Melbourne, Australia, November 16th November 19th, 2011 http://www2.kenes.com/wspid/Pages/Home.aspx

CONGRESS CALENDAR
35

Advances in Vaccinology e-mail: publisher@advances-in-vaccinology.com

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