Long-term efficacy of a recombinant hepatitis E vaccine in adults: 10-year results from a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Hepatitis E virus (HEV) is a frequently overlooked causative agent of acute hepatitis. Evaluating the long-term durability of hepatitis E vaccine efficacy holds crucial importance.

Methods: This study was an extension to a randomised, double-blind, placebo-controlled, phase-3 clinical trial of the hepatitis E vaccine conducted in Dontai County, Jiangsu, China. Participants were recruited from 11 townships in Dongtai County. In the initial trial, a total of 112 604 healthy adults aged 16-65 years were enrolled, stratified according to age and sex, and randomly assigned in a 1:1 ratio to receive three doses of hepatitis E vaccine or placebo intramuscularly at month 0, month 1, and month 6. A sensitive hepatitis E surveillance system including 205 clinical sentinels, covering the entire study region, was established and maintained for 10 years after vaccination. The primary outcome was the per-protocol efficacy of hepatitis E virus vaccine to prevent confirmed hepatitis E occurring at least 30 days after administration of the third dose. Throughout the study, the participants, site investigators, and laboratory staff remained blinded to the treatment assignments. This study is registered with ClinicalTrials.gov (NCT01014845).

Findings: During the 10-year study period from Aug 22, 2007, to Oct 31, 2017, 90 people with hepatitis E were identified; 13 in the vaccine group (0·2 per 10 000 person-years) and 77 in the placebo group (1·4 per 10 000 person-years), corresponding to a vaccine efficacy of 83·1% (95% CI 69·4-91·4) in the modified intention-to-treat analysis and 86·6% (73·0 to 94·1) in the per-protocol analysis. In the subsets of participants assessed for immunogenicity persistence, of those who were seronegative at baseline and received three doses of hepatitis E vaccine, 254 (87·3%) of 291 vaccinees in Qindong at the 8·5-year mark and 1270 (73·0%) of 1740 vaccinees in Anfeng at the 7·5-year mark maintained detectable concentrations of antibodies.

Interpretation: Immunisation with this hepatitis E vaccine offers durable protection against hepatitis E for up to 10 years, with vaccine-induced antibodies against HEV persisting for at least 8·5 years.

Funding: National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and the Fundamental Research Funds for the Central Universities.