Elsevier

The Lancet

Volume 399, Issue 10336, 30 April–6 May 2022, Pages 1708-1717
The Lancet

Articles
Efficacy, safety, and immunogenicity of an inactivated, adjuvanted enterovirus 71 vaccine in infants and children: a multiregion, double-blind, randomised, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(22)00313-0Get rights and content

Summary

Background

Children are susceptible to severe or fatal enterovirus 71 (EV71) infections. We aimed to evaluate the efficacy, safety, and immunogenicity of EV71vac, an aluminium phosphate-adjuvanted inactivated EV71 vaccine in children aged 2–71 months.

Methods

We did a randomised, double-blinded, placebo-controlled, phase 3 trial at five hospitals in Taiwan and two in Vietnam. Children aged 2–71 months were stratified by country and age, and randomly assigned (1:1) to receive two doses of EV71vac or placebo via intramuscular injection 56 days apart. Children aged 2–23 months received a third booster dose on day 366. The primary endpoint was the clinical efficacy of the total vaccinated cohort against EV71-associated diseases during the follow-up period, from 14 days after the second dose to when 15 cases of EV71 infections were confirmed in the per-protocol population. Our safety analysis included all participants who received at least one dose of EV71vac. This trial is registered with ClinicalTrials.gov, NCT03865238, and is complete.

Findings

Between April 23 and Dec 25, 2019, of 3663 children assessed, 3061 were randomly assigned, of whom 3049 were vaccinated: 1521 children in the EV71vac group and 1528 in the placebo group. By May 20, 2021, our primary efficacy analysis included 2959 children, with 1476 children in the EV71vac group and 1483 children in the placebo group. The vaccine efficacy of EV71vac was 96·8% (95% CI 85·5–100) against EV71 associated diseases (p<0·0001). The percentage of participants who reported solicited adverse events were similar in both groups: 865 (56·9%) in the EV71vac group and 852 (55·8%) in the placebo group. Almost all reported solicited adverse events were mild and self-limited.

Interpretation

EV71vac is safe, well-tolerated, and highly effective in preventing EV71 associated diseases in children aged 2–71 months.

Funding

Medigen Vaccine Biologics and A+ Industrial Innovative R&D Program of the Ministry of Economic Affairs, Taiwan.

Introduction

Enterovirus 71 (EV71) is a single-stranded RNA virus of the genus Enterovirus within the large Picornaviridae family, which includes the rhinovirus, poliovirus, and hepatovirus.1 Most EV71 infections manifest as hand, foot, and mouth disease (HFMD) and are generally self-limiting. However, EV71 infections can lead to serious or even fatal neurological and cardiopulmonary complications, including acute flaccid myelitis, paralysis, aseptic meningitis, pulmonary oedema, and myocarditis.2

In the past 25 years, the Asia-Pacific region has had cyclical EV71 outbreaks, namely in Malaysia (1997),3 Taiwan (1998),4 China (2008),5 and Vietnam (2011).6 These outbreaks resulted in deaths ranging from hundreds to thousands, predominantly in infants and children. Thus far, the scope of vaccine protection has been insubstantial. The three EV71 vaccines on the market are manufactured by Beijing Vigoo Biological (Beijing, China), Chinese Academy of Medical Sciences (Beijing, China), and Sinovac Biotech in China (Beijing, China),7, 8, 9, 10 and they have been approved by China's regulatory authority for use in China. All three are inactivated whole virus vaccines derived from the C4 genotype, have proven efficacy against EV71-associated HFMD in children aged 6–35 months, and have shown cross-reaction against other genotypes.11 However, these studies neither targeted infants in the 2–5 months age group, which has the highest relative case severity and fatality rate,12 nor provided efficacy data beyond the C4 strain.

For comparison, our EV71 vaccine (EV71vac) is an inactivated EV71 B4 genotype-based whole virus vaccine adjuvanted with aluminium phosphate.13 For our phase 2 trial, we enrolled 366 participants in Taiwan and broadened the age range of the participants from 2-month-old infants to 71-month-old children.14 The results from our phase 2 clinical trial showed that EV71vac elicits a potent immune response in children, with a seroconversion rate of 100% against the B4 genotype. Furthermore, this vaccine showed promising in vitro cross-reaction among B5, C4, and C5 genotypes, which are prevalent in the Asia-Pacific region.14 For this phase 3 trial done in Taiwan and Vietnam, we enrolled over 3000 participants aged 2–71 months to assess the safety, tolerability, and efficacy of EV71vac against EV71 associated diseases.

Research in context

Evidence before this study

In the Asia-Pacific region, enterovirus 71 (EV71) poses prevalent and recurring threats that affect children the most. Serious EV71 infections in children lead to neurological complications or death. Currently, however, only three formalin-inactivated, C4 genotype-based EV71 vaccines have been approved for use in China, leaving children from other regions vulnerable. On Nov 19, 2021, we searched PubMed for published clinical trials that assessed the safety and efficacy of EV71 vaccines with no language restrictions. Using key terms such as “enterovirus 71”, “clinical trials”, “efficacy”, and “vaccine”, we found 14 publications, eight of which reported results for clinical or randomised controlled trials. All eight publications pertained to the three aforementioned vaccines, and the trials were all done in China. Even though these three vaccines are highly effective against EV71 infections of the C4 genotype, they have only been approved for children older than 6 months. Introducing a vaccine that casts a wider net of protection to include younger infants from other countries against different genotypes is, therefore, imperative.

Added value of this study

EV71vac is a formalin-inactivated, B4 genotype-based EV71 vaccine. We enrolled over 3000 young children aged 2 months to 5 years from Taiwan and Vietnam. Participants received two doses of EV71vac 57 days apart, and those aged 2 months to 1 year received a third booster shot a year after their first dose. By December, 2019, all participants had received their second dose, and by April, 2021, we had 22 confirmed cases of EV71-associated diseases, which formed the basis of our efficacy analysis. All 22 confirmed cases occurred in the placebo group and were caused by B5 and C4 genotypes. The lack of confirmed cases in the vaccine group gives EV71vac the calculated efficacy of 100%, and shows EV71vac's capacity to cross-protect against B5 and C4 genotypes.

Implications of all the available evidence

In our phase 2 trial, EV71vac was shown to be safe and immunogenic. In this phase 3 trial, EV71vac proves it is safe and highly effective against EV71 associated diseases in children as young as 2 months to 5 years of age, and offers cross-protection against B4 and C4 genotypes. EV71vac is manufactured in compliance with the Pharmaceutical Inspection Co-operation Scheme, and if approved by regulatory authority, will be the first EV71 vaccine ready for distribution worldwide.

Section snippets

Study design

This prospective, randomised, stratified, multicentre, phase 3 trial was done in Taiwan and Vietnam, and comprised a main study for clinical efficacy and a substudy for immunogenicity. Even though an immunogenicity study cannot replace a vaccine efficacy study, we planned the immunogenicity substudy to accelerate conditional regulatory approval in Taiwan, should the main study take years to reach its primary endpoint. The substudy assessed the immunogenicity of the first 2200 participants

Results

From April 23 to Dec 25, 2019, of 3663 participants assessed for eligibility, 3061 aged 2–71 months were enrolled, randomly assigned, and assigned 1:1 to the EV71vac group (n=1529) or the placebo group (n=1532). The trial population included 3049 participants who received EV71vac (n=1521) or placebo (n=1528), of which 2959 participants received at least two doses and were categorised as the total vaccinated cohort for efficacy analysis (figure 1).

The gender distribution for the trial population

Discussion

In this phase 3, multi-region, prospective, stratified, randomised, double-blinded, placebo-controlled trial, we evaluated the efficacy, safety, and immunogenicity of EV71vac in children aged as young as 2–71 months old. Beginning on April 23, 2019 and concluding on May 20, 2021, this trial met the efficacy, safety, and immunogenicity endpoints of the protocol. The calculated clinical efficacy is 100%, and the adjusted efficacy after Poisson regression is 96·8% with a p value of <0·0001. The

Data sharing

The individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices), the study protocol, and the statistical analysis plan, can be shared with researchers who provide a methodologically sound proposal on request, beginning at 3 months and ending 2 years following article publication. Proposals should be directed to [email protected].

Declaration of interests

CC, Y-JW, E-FH, and I-CT are employees of Medigen Vaccine Biologics Corporation and report grants from A+ Industrial Innovative R&D Program of the Ministry of Economic Affairs, Taiwan, during the conduct of the study. TTN, C-HC, C-YL, N-CC, P-YC, TTVL, DNL, AHD, VLN, TNH, HKT, S-RS, C-GH, SC, and L-MH declare no other competing interests.

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