Immunogenicity and Safety of Inactivated Enterovirus A71 Vaccines in Children Aged 6-35 Months in China: A Non-Inferiority, Randomised Controlled Trial

Abstract

Background: China’s three inactivated enterovirus A71 (EV-A71) vaccines are the first and currently world’s only EV-A71 vaccines approved by a national regulatory authority and used to prevent EV-A71 associated diseases. The three vaccines vary by vaccine strain, manufacturing cell substrate, and antigen dose, but no head-to-head comparisons of these vaccines have been done. We compared immunogenicity of the vaccines in children 6-35 months old. Methods: We recruited healthy children aged 6-35 months who resided in a study site county into a multicentre, open-label, non-inferiority, three-group, randomised controlled trial that was conducted in five counties in China. Enrolled children were randomly assigned (1:1:1) to receive two doses of one of the three EV-A71 vaccines. The primary outcome was the proportion of children with EV-A71 neutralizing antibody seroconversion 4 weeks after the second dose; a secondary outcome was adverse events in the 4 weeks after each dose. Analyses of immunogenicity included all children who completed the study (per-protocol analysis). Safety analysis included all children completed safety follow-up after one or two doses. We used a 10% margin to establish non-inferiority. This trial was registered on a World Health Organization platform: Chinese Clinical Trial Registry (ChiCTR1900026663). Findings: 1631 children were assessed for eligibility between Nov 4 and Nov 20, 2019. Of 1500 (92%) enrolled children, 500 were assigned to vaccine A, B, or C group; 483 in group A,484 in group B and 487 in group C completed the study. Before dose one, the seropositive rates in group A, B, and C were 9.7%, 7.2%, and 7.0%. Four weeks after the 2 nd dose, seroconversion rates of group A, B, and C were 98.8%, 99.4% and 99.8%, which were mutually non-inferior in all two-group comparisons. There were no serious adverse events in any group and no evidence of a difference among the three groups in the incidence of local adverse event or systemic adverse event. Fever was the most common adverse event. All children with reported adverse events recovered. Interpretation: Non-inferior and high seroconversion rates and equivalent safety of three EV-A71 vaccines supports selection any of the vaccines to prevent EV-A71-associated diseases. These results may be useful for regulators, vaccine policy makers, and immunization programs in China and in countries where EV-A71 is endemic. Trial Registration: Chinese Clinical Trial Registry (ChiCTR1900026663). Funding: National Science and Technology Major Project (No:2016ZX09101120-004) Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Ethical Review Committee of the Chinese Center for Disease Control and Prevention (approval number 201934). This study is registered on a World Health Organization platform: Chinese Clinical Trial Registry (ChiCTR), number ChiCTR1900026663.