Efficient recombinant hepatitis E virus vaccine: Mission accomplished?


  • Potential conflict of interest: Nothing to report.

Shrestha MP, Scott RM, Joshi DM, Mammen MP, Thapa GB, Thapa N, et al. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med 2007;356:895–903. (Reprinted with permission.)


Background: Hepatitis E virus (HEV) is an important cause of viral hepatitis. We evaluated the safety and efficacy of an HEV recombinant protein (rHEV) vaccine in a phase 2, randomized, double-blind, placebo-controlled trial. Methods: In Nepal, we studied 2000 healthy adults susceptible to HEV infection who were randomly assigned to receive three doses of either the rHEV vaccine or placebo at months 0, 1, and 6. Active (including hospital) surveillance was used to identify acute hepatitis and adverse events. The primary end point was the development of hepatitis E after three vaccine doses. Results: A total of 1794 subjects (898 in the vaccine group and 896 in the placebo group) received three vaccine doses; the total vaccinated cohort was followed for a median of 804 days. After three vaccine doses, hepatitis E developed in 69 subjects, of whom 66 were in the placebo group. The vaccine efficacy was 95.5% (95% confidence interval [CI], 85.6 to 98.6). In an intention-to-treat analysis that included all 87 subjects in whom hepatitis E developed after the first vaccine dose, 9 subjects were in the vaccine group, with a vaccine efficacy of 88.5% (95% CI, 77.1 to 94.2). Among subjects in a subgroup randomly selected for analysis of injection-site findings and general symptoms (reactogenicity subgroup) during the 8-day period after the administration of any dose, the proportion of subjects with adverse events was similar in the two study groups, except that injection-site pain was increased in the vaccine group (P=0.03). Conclusions: In a high-risk population, the rHEV vaccine was effective in the prevention of hepatitis E. (ClinicalTrials.gov number, NCT00287469 [www.ClinicalTrials.gov].) Copyright © 2007 Massachusetts Medical Society. All rights reserved.


The hepatitis E virus (HEV) is endemic in many developing countries. Outbreaks have been reported in Southeast and Central Asia, northern and western parts of Africa, the Middle East, and Mexico (Fig. 1A), mostly related to the consumption of fecally contaminated drinking water because HEV is transmitted fecal-orally. HEV infection can cause acute hepatitis, usually self-limiting within 1–4 weeks, and does not progress to chronic disease. However, some patients (estimated at 1%–3%) may develop severe disease, and especially pregnant women within their third trimester are at increased risk (15%–25%) to develop a rapidly progressive disease with cerebral edema and disseminated intravascular coagulation. At present, no specific treatment options exist for HEV infection.1

Figure 1.

Hepatitis E virus (HEV) vaccine trial. (A) Geographic distribution of regions endemic for HEV (dark gray) with >25% HEV infection in cases with acute hepatitis and/or sporadic outbreaks (according to surveillance data from the Centers for Disease Control and Prevention, Atlanta, GA; www.cdc.gov/hepatitis). The vaccine trial was performed in Nepal (black). (B) Schematic organization of the HEV genome, consisting of a single-stranded ≈7.2 kilobase (kb) RNA with 3 open reading frames (ORFs) coding for different proteins. The recombinant vaccine contains capsid antigen (arrow). (C,D) Efficacy of the rHEV vaccine as reported by Shrestha et al.3 (C) Subjects with symptomatic HEV infection in the vaccine and placebo group from dose 1 until end of study (per 1000 cases, intention-to-treat analysis). (D) Subjects with HEV antibody titer >20 U/mL at the end of study (about 1.5 years after the third dose of vaccine).

HEV is a small, nonenveloped virus with a 7.2-kilobase single-positive-stranded RNA comprising 3 open reading frames (Fig. 1B). Although 4 HEV genotypes and significant geographic genome variability have been described, all HEV subtypes share major cross-reactive epitopes, prompting the development of a recombinant HEV (rHEV) vaccine based on the capsid protein.2 (Fig. 1B) Shrestha et al. now report a phase 2 trial of rHEV vaccine administered to young male soldiers in Nepal, who had not been exposed to HEV before but were at risk of infection.3 In the trial, 896 subjects received 3 doses of vaccine (at 0, 1, and 6 months) and 898 received placebo. Vaccination efficiently protected from overt HEV infection (the primary study end-point, Fig. 1C), with a calculated vaccine efficacy of 95.5% after 3 doses and 85.7% after 2 doses of vaccine during a median follow-up of 804 days. Administration of the vaccine was safe; the only significant side effect was injection-site pain.3

Yet, some questions about the “true” efficacy remain unanswered. Studies from rhesus monkeys revealed that rHEV may protect from clinical disease, but not from HEV infection.4 As in the study by Shrestha et al., only symptomatic subjects were screened for HEV infection, the potential number of asymptomatic cases, who could potentially carry and spread the virus, is unknown.5 The duration of protection by the rHEV vaccine is also unclear; whereas 100% of screened rHEV-vaccinated subjects had high antibody titer 1 month after the third vaccination (81% after the second vaccination), only about 56% had HEV antibodies at the end of the study, about 1.5 years after the third dose (Fig. 1D).

Meanwhile, the study has also provoked intensive ethical discussions. The rHEV trial was conducted by the U.S. Army and GlaxoSmithKline with soldiers in Nepal, a decision that has been criticized.6, 7 Original plans for a test within the Nepalese community were opposed by local authorities, because residents would not have access to the vaccine after the trial ended.8 Indeed, GlaxoSmithKline is now seeking public-sector partners for phase 3 trials before continuation of the program, due to the anticipated low profit value of the vaccine.3, 6, 7

It is generally encouraging that rHEV was effective in preventing hepatitis E disease in a high-risk population. But where shall we go from here? Who could and who should benefit from this vaccine? The contribution of HEV to overall morbidity is still a matter of debate, because the vast majority of HEV-related diseases are benign.5 However, HEV superinfection in patients with chronic liver disease can cause severe hepatic decompensation. Therefore, vaccination of these patients would be desirable.9 Also, international travelers to endemic regions and especially development aid volunteers would likely benefit from the vaccine. Other groups at risk of HEV infection include residents of areas with extended community outbreaks, refugees residing in overcrowded temporary camps following catastrophies in endemic areas, or pregnant women without prior infection in these regions. The cost of rHEV, whenever available, will be a crucial determinant for the use of rHEV in endemic countries. Medical ethics demand that the population who tested the vaccine also benefits from the results of the study.10 The work by Shrestha et al. should therefore prompt research aimed at preventing and controlling infection and disease in areas endemic for HEV. The mission of an unorthodox alliance of “antiviral warriors”—Nepalese soldiers, the U.S. Army's money, and GlaxoSmithKline's recombinant vaccine—is not accomplished yet.