Elsevier

The Lancet

Volume 376, Issue 9744, 11–17 September 2010, Pages 895-902
The Lancet

Articles
Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(10)61030-6Get rights and content

Summary

Background

Seroprevalence data suggest that a third of the world's population has been infected with the hepatitis E virus. Our aim was to assess efficacy and safety of a recombinant hepatitis E vaccine, HEV 239 (Hecolin; Xiamen Innovax Biotech, Xiamen, China) in a randomised, double-blind, placebo-controlled, phase 3 trial.

Methods

Healthy adults aged 16–65 years in, Jiangsu Province, China were randomly assigned in a 1:1 ratio to receive three doses of HEV 239 (30 μg of purified recombinant hepatitis E antigen adsorbed to 0·8 mg aluminium hydroxide suspended in 0·5 mL buffered saline) or placebo (hepatitis B vaccine) given intramuscularly at 0, 1, and 6 months. Randomisation was done by computer-generated permuted blocks and stratified by age and sex. Participants were followed up for 19 months. The primary endpoint was prevention of hepatitis E during 12 months from the 31st day after the third dose. Analysis was based on participants who received all three doses per protocol. Study participants, care givers, and investigators were all masked to group and vaccine assignments. This trial is registered with ClinicalTrials.gov, number NCT01014845.

Findings

11 165 of the trial participants were tested for hepatitis E virus IgG, of which 5285 (47%) were seropositive for hepatitis E virus. Participants were randomly assigned to vaccine (n=56 302) or placebo (n=56 302). 48 693 (86%) participants in the vaccine group and 48 663 participants (86%) in the placebo group received three vaccine doses and were included in the primary efficacy analysis. During the 12 months after 30 days from receipt of the third dose 15 per-protocol participants in the placebo group developed hepatitis E compared with none in the vaccine group. Vaccine efficacy after three doses was 100·0% (95% CI 72·1–100·0). Adverse effects attributable to the vaccine were few and mild. No vaccination-related serious adverse event was noted.

Interpretation

HEV 239 is well tolerated and effective in the prevention of hepatitis E in the general population in China, including both men and women age 16–65 years.

Funding

Chinese National High-tech R&D Programme (863 programme), Chinese National Key Technologies R&D Programme, Chinese National Science Fund for Distinguished Young Scholars, Fujian Provincial Department of Sciences and Technology, Xiamen Science and Technology Bureau, and Fujian Provincial Science Fund for Distinguished Young Scholars.

Introduction

Hepatitis E virus is a major cause of sporadic and epidemic hepatitis.1 Seroprevalence data suggest that a third of the world's population has been infected with the virus.2 Although most cases are in developing countries, hepatitis E is no longer rare and it might be the most common type of acute viral hepatitis in industrialised countries.3

Clinically indistinguishable from other types of acute viral hepatitis, hepatitis E tends to be self-limited and usually does not become chronic.4 The severity of illness increases with age; the overall case fatality ratio is estimated to be 1–3%.5 Hepatitis E has a poor prognosis in pregnant women: mortality is 5–25%, and survivors have high rates of spontaneous abortion and stillbirth.6, 7 In patients with chronic liver disease, superinfection with hepatitis E virus often leads to a poor outcome.8, 9 Every year, 13 000–26 000 deaths are estimated in patients with chronic liver disease in industrialised countries.10 In a continuing hepatitis E epidemic in Uganda that has caused illness in more than 10 196 people and 160 deaths, mortality was 13% in children.11

At least four genotypes of hepatitis E viruses have been identified.12 Genotypes 1 and 2 were isolated from human beings and are mainly seen in developing countries. Genotypes 3 and 4 are zoonotic, with pigs being the principal reservoir; they have been identified in many sporadic cases and limited foodborne outbreaks mainly affecting middle-aged and elderly men.13, 14, 15 Nevertheless, all hepatitis E virus associated with human diseases can be considered as belonging to one serotype.16

Two recombinant vaccines have undergone phase 2 clinical trials. One of the vaccines was produced in insect cells and was safe and immunogenic in young men (mean age 25·2 years; SD 6·25), providing 95% protection against hepatitis E in Nepal, where only genotype 1 hepatitis E virus had been isolated.17 The results were encouraging but two questions remained to be answered. The first related to the safety and efficacy of the vaccine in the general population, especially in women and elderly people. The second related to the efficacy of a vaccine originally derived from hepatitis E virus genotype 1 against disease caused by heterogenic hepatitis E virus. The other candidate vaccine, HEV 239 (Hecolin; Xiamen Innovax Biotech, Xiamen, China), was produced in bacterial cells and was safe and efficacious against infection with hepatitis E virus in seronegative participants in a phase 2 trial.18

We undertook a randomised, double-blind, placebo-controlled, phase 3 trial to assess the efficacy and safety of HEV 239 in the general population. The trial included men and women from age 16 to 65 years, with or without antibodies against hepatitis E, from a region where both genotypes 1 and 4 cocirculate with the zoonotic genotype 4 predominating.

Section snippets

Study design and participants

This double-blind, randomised, placebo-controlled trial was done between August, 2007, and June, 2009, in Dongtai County, Jiangsu Province, China. On October, 2007, after enrolment in one township (Quindong), and before enrolment in ten other townships, the protocol was modified so that each of the 10 000 participants in one of the ten townships (Anfeng) had serum samples collected on day 0 and month 7 to assess the level of antibody protection through long-term follow-up. Independent ethics

Results

122 179 people from 11 townships attended the enrolment visit between August and October, 2007. 112 604 participants fulfilled the eligibility requirements, were randomly assigned to the study group, and received at least one dose of vaccine or placebo. 97 356 participants received all three doses of vaccine or placebo and were included in the analysis of the primary endpoint (figure 1). Table 1 shows the baseline characteristics of study participants.

The DSMB confirmed 23 cases of hepatitis E

Discussion

In our trial, efficacy of recombinant hepatitis E vaccine during the 12 months from the 31st day after the receipt of the third dose was 100·0% (95% CI 72·1–100·0), and protection was noted across all age and sex subgroups. Vaccination was also beneficial under less than perfect circumstances—ie, when participants did not receive all three doses. Vaccine efficacy after two doses was 100·0% (95% CI 9·1–100·0). Therefore, during a hepatitis E outbreak, or for travellers to an endemic area,

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