肠病毒71疫苗在健康中国儿童与婴儿中的免疫原性与安全性：随机、双盲、安慰剂对照2期临床试验

Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu Province, China

Background Enterovirus 71 (EV71) outbreaks are a socioeconomic burden, especially in the western Pacific region. Results of phase 1 clinical trials suggest an EV71 vaccine has a clinically acceptable safety profile and immunogenicity. We aimed to assess the best possible dose and formulation, immunogenicity, and safety profile of this EV71 vaccine in healthy Chinese children. Methods This randomised, double-blind, placebo-controlled, phase 2 trial was undertaken at one site in Donghai County, Jiangsu Province, China. Eligible participants were healthy boys or girls aged 6-36 months. Participants were randomly assigned (1:1:1:1:1) to receive either 160 U, 320 U, or 640 U alum-adjuvant EV71 vaccine, 640 U adjuvantfree EV71 vaccine, or a placebo (containing alum adjuvant only), according to a blocked randomisation list generated by SAS 9.1. Participants and investigators were masked to the assignment. The primary endpoint was anti-EV71 neutralising antibody geometric mean titres (GMTs) at day 56, analysed according to protocol. The study is registered with ClinicalTrials.gov, number NCT01399853. Findings We randomly assigned 1200 participants, 240 (120 aged 6-11 months [infants] and 120 aged 12-36 months [children]) of whom were assigned to each dose. 1106 participants completed the study and were included in the according-to-protocol analysis. The main reasons for dropout were withdrawal of consent and refusal to donate a blood sample. Infants who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (742•2 [95% CI 577•3-954•3]), followed by those who received the 320 U formulation (497•9 [383•1-647•0]). For children, those who received the 320 U formulation had the highest GMTs on day 56 (1383•2 [1037•3-1844•5]). Participants who received the vaccine had significantly higher GMTs than did who received placebo (p<0•0001). For the subgroup of participants who were seronegative at baseline, both infants and children who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (522•8 [403•9-676•6] in infants and 708•4 [524•1-957•6] in children), followed by those who received the 320 U adjuvant vaccine (358•2 [280•5-457•5] in infants and 498•0 [383•4-646•9] in children). 549 (45•8%) of 1200 participants (95 CI 42•9-48•6%) reported at least one injection-site or systemic adverse reaction, but the incidence of adverse reactions did not differ significantly between groups (p=0•36). The 640 U alum-adjuvant vaccine group had a significantly higher incidence of induration than did the 640 U adjuvant-free group (p=0•001). Interpretation Taking immunogenicity, safety, and production capacity into account, the 320 U alum-adjuvant formulation of the EV71 vaccine is probably the best possible formulation for phase 3 trials. Funding The National Science and Technology Major Project (2011ZX10004-902) of the Chinese Ministry of Science and Technology, China's 12-5 National Major Infectious Disease Program (2012ZX10002-001), and Beijing Vigoo Biological.

Shen, X.-L.; Beijing Vigoo Biological, No 4, Sanjianfangnanli, ChaoYang District, Beijing 100024, China; email:hen54@x263.net