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Hepatitis E vaccine: not a moment too soon - Commentary
  The Lancet, Early Online Publication, 23 August 2010
Scott D Holmberg a
a Division of Viral Hepatitis, National Center for HIV, Hepatitis, TB and STD Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA
".......financing, and immunisation policies, public health and industry leaders should immediately begin work to define the public health roles for an HEV vaccine."
Hepatitis E virus (HEV) remains one of the least understood and perplexing viruses pathogenic to human beings. From 5% to 20% of people in developed countries show a steady increase in the titre of anti-HEV IgG with increasing age,1 but infection with the prevalent genotype in Europe and the USA, genotype 3, rarely results in symptoms. Although this genotype has been recovered from feral and domestic pigs-and sometimes from people who have eaten raw pork or offal-convincing epidemiological evidence that this zoonotic reservoir is the source of most human exposures or infections remains elusive.2
Unlike the situation in developed countries, HEV infection with genotypes 1, 2, and 4, which predominate in developing countries, is not merely an academic quandary but a major cause of disease and death. Some areas of east and south Asia are highly endemic for the virus. Large outbreaks (tens of thousands of cases) have occurred in India3, 4 and China5, 6 since 1955; these were deemed to have been waterborne. More recently there have been very large outbreaks in southern Sudan7 and nearby northern Uganda,8 in what seem to be susceptible African populations in which HEV outbreaks had not previously been recorded. In these outbreaks, the testing of drinking water from wells did not reveal the virus or coliforms, and continued provision of clean water did not prevent additional infections. Several other lines of evidence suggest that some of these outbreaks are attributable to person-to-person transmission.9
Whatever the source, these outbreaks have typically extended over many months with especially high mortality in pregnant women and infants younger than 2 years, often with case-fatality rates of 10-25%. In view of the protracted nature of the epidemics and the associated substantial morbidity and mortality, the need for public health interventions to interrupt transmission has been urgent. Unfortunately, interventions focused on basic sanitation-eg, latrine-digging, education on hand-washing and provision of soap, and guarding unprotected surface water from use-have not noticeably reduced these outbreaks. Thus it is natural to wonder whether vaccination would be effective in these epidemic or highly endemic situations.
The approach to vaccine-antigen production has been to focus on the ORF 2 capsid protein-producing section of the HEV genome, the same capsid antigen as used for enzyme immunoassays for detection of the virus. A recombinant vaccine produced in insect cells by the US Army with GlaxoSmithKline Biologicals (Rixensart, Belgium) was safe and effective when given to almost 900 young Nepalese Army recruits,10 but there are neither plans for further studies nor, apparently, for eventual commercial production of this vaccine. An earlier phase 2 trial11 of the bacterial recombinant vaccine described by Zhu and colleagues12 in the The Lancet today was used in 457 healthy Chinese adults and 155 high-school students and seemed to confer protection, although infection was deduced from asymptomatic seroconversion or rise in antibody titres and not by virological testing.
Thus the report by Zhu and colleagues12 of a successful phase 3 study of this vaccine is an important event in the prevention and control of hepatitis E. The numbers of recipients of the vaccine (48 693) and placebo (hepatitis B vaccine, 48 663) in the primary analysis of this study were sufficiently large, and the number of people (15) infected with HEV in the placebo group, confirmed by testing for HEV-RNA, is convincing and credible about the vaccine's efficacy (100%, 95% CI 72·1-100·0) and safety. To assess vaccine safety and efficacy in populations most at risk of serious HEV-associated disease and death, future researchers will need to include pregnant women and young infants. Also, the duration of protection afforded by this vaccine remains unknown. Still, the recorded 100% vaccine efficacy in recipients of two vaccinations a month apart suggests that HEV vaccine can be an important component in outbreak control. In highly endemic regions, a safe and effective vaccine (if affordable) raises the prospect of routine HEV vaccination to reduce both sporadic and epidemic HEV. Because these considerations are crucial to decisions on vaccine production, financing, and immunisation policies, public health and industry leaders should immediately begin work to define the public health roles for an HEV vaccine.
Vaccines should never be a substitute for, or reason to delay, basic improvements in overall sanitation. However, in view of the slow rate of improvement of sanitary conditions in many areas of Asia and Africa, this vaccine might be our best new stopgap in the effort to control the scourge of HEV in many parts of the world.
I declare that I have no conflicts of interest.
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12 Zhu F-C, Zhang J, Zhang X-F, et al. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet 201010.1016/S0140-6736(10)61030-6. published online Aug 23.
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