Vaccine 21 (2003) 2607–2615 Pre-clinical immunogenicity and efficacy trial of a recombinant hepatitis E vaccine Robert H. Purcell a,∗ , Hanh Nguyen a , Max Shapiro b , Ronald E. Engle a , Sugantha Govindarajan c , William C. Blackwelder d , Doris C. Wong a , Jean-Paul Prieels e , Suzanne U. Emerson a a Hepatitis Viruses and Molecular Hepatitis Sections, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 50 South Drive MSC-8009, Bethesda, MD, 20892-8009, USA b Bioqual, Inc., 2501 Research Blvd., Rockville, MD 20850, USA c Liver Research & Education Foundation, Inc., Rancho Los Amigos Hospital, Downey, CA 90242, USA d 8613 Hempstead Avenue, Bethesda, MD 20817-6711, USA e Glaxo SmithKline, Rixensart, Belgium Received 18 October 2002; received in revised form 30 December 2002; accepted 3 January 2003 Abstract We have demonstrated that recombinant hepatitis E vaccine suitable for clinical evaluation was highly immunogenic and efficacious in preventing hepatitis E and even infection in rhesus macaques following intravenous challenge with three different genotypes of hepatitis E virus (HEV). Two doses of vaccine were essential for optimal protection; the two-dose regimen was more important than the formulation of the vaccine for achieving efficacy. The titers of anti-HEV that were protective in this study were quantified against a World Health Organization (WHO) standard. This permits direct comparison of the results with other studies. The results of this pre-clinical trial of a candidate hepatitis E vaccine strongly suggest that it will be highly efficacious for preventing hepatitis E in the field trial of this vaccine that is currently in progress in Nepal. © 2003 Elsevier Science Ltd. All rights reserved. Keywords: Hepatitis E; Vaccine; Monkey 1. Introduction Hepatitis E is the most important cause of acute hepati- tis in adults throughout much of Asia and it is the second most important cause of such hepatitis in the Middle East and Northern Africa [1]. Hepatitis E virus (HEV) is an unclassified, small, non-enveloped RNA virus that is trans- mitted principally by the fecal–oral route. It can cause large water-borne epidemics of disease but most infections are sporadic. Infection can occur at all ages but the peak rate of infection and the peak clinical attack rate occur in young adults. The disease is of moderate severity ex- cept in pregnant women, where the mortality may exceed 20%. Only one serotype of HEV is recognized but at least four major genotypes have been identified [2]. These comprise strains found in Asia and Northern Africa (genotype 1), ∗ Corresponding author. Tel.: +1-301-496-5090; fax: +1-301-402-0524. E-mail address: rpurcell@niaid.nih.gov (R.H. Purcell). a single strain recovered from an epidemic of hepatitis E in Mexico and related strains recovered from patients in Nigeria (genotype 2), isolates recovered from swine as well as from human cases of hepatitis E in the United States, Europe and South America (genotype 3) and a recently described fourth genotype recovered from humans in China and from humans and swine in Taiwan. There is considerable interest in developing a hepatitis E vaccine. A potentially difficult problem will be testing the protective efficacy of such a vaccine because the clinical attack rate in any one community at any one time may be low or associated with unpredictable epidemics. Assurance that a protective efficacy study will yield interpretable results may require a very large denominator of vaccinated and control individuals. Since there are no suitable cell culture systems for replication of HEV, tests of neutralizing antibody are very difficult to perform [3,4]. In an attempt to correlate levels of anti-HEV, as measured by ELISA assays, with protection in humans, we wished to compare levels of anti-HEV as measured by ELISA with protection in non-human primates. 0264-410X/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0264-410X(03)00100-2