Background The enterovirus 71 (EV71) vaccine produced by Wuhan Institute of Biological Products Co., Ltd. (WIBP) (B-EV71) has been given to children aged 6-35 months, and it has shown good safety, immunogenicity and efficacy. However, the administration of EV71 vaccine in children aged 36-71 months, which is another target population, needs further exploration. Methods We conducted a double-blind, randomised, controlled, non-inferiority phase III clinical trial in children aged 36-71 months, with a further comparison group of children aged 6-35 months in China. Children aged 6-71 months with no history of hand, foot and mouth disease or prior-vaccination of EV71 vaccine were eligible and recruited. Eligible participants aged 36-71 months were randomly assigned (1:1) to receive two doses of the B-EV71 vaccine (Older-B group) or the control EV71 vaccine (C-EV71 vaccine, produced by Institute of Medical Biology, Chinese Academy of Medical Sciences) (Older-C group), administered at a 30-day interval. Eligible participants aged 6-35 months were enrolled consecutively to receive two doses of the B-EV71 vaccine (Younger-B group) at a 30-day interval. Participants, investigators and those assessing outcomes were masked to the vaccine received. Non-inferiority analyses were conducted to compare the immunogenicity of EV71 vaccine in the Older-B group with that in the Older-C and Younger-B groups. Non-inferiority margins were 10% for seroconversion rate differences and 0.5 for geometric mean titre (GMT) ratios. The primary endpoints were the GMT level and seroconversion rate of anti-EV71 neutralising antibody 30 days after the second dose of vaccination. The primary analysis was performed in the per-protocol population. Safety analyses were conducted amongst participants receiving at least one dose of vaccine. This trial was registered at Chinadrugtrials.org.cn (#CTR20192345). Findings Between June 3 and June 30, 2020, 1600 participants were enrolled and assigned, including 625 participants in the Older-B group, 625 participants in the Older-C group and 350 participants in the Younger-B group. The seroconversion rate of anti-EV71 neutralising antibody in the Older-B group (99.66%; 95% CI: 99.18%-100.00%) was non-inferior to that of the Older-C (99.32%; 95% CI: 98.65%-99.98%) and Younger-B groups (100.00%; 95% CI: 100.00%-100.00%). The differences in seroconversion rates in the Older-B group to those in the Older-C and Younger-B groups were 0.34% (95%CI:-2.17%-2.86%) and-0.34% (95%CI:-2.78%-2.09%). The GMT of the anti-EV71 neutralising antibody in the Older-B group (693.87) was also non-inferior to that in the Older-C (289.37) and Younger-B groups (634.80). The ratios of GMTs in the Older-B group to those in the Older-C and Younger-B groups were 2.67 (95%CI: 2.00-3.00) and 1.00 (95%CI: 0.75-1.00), respectively. The incidence of any adverse event (AE) related to vaccination was similar amongst the three groups (34/625 [5.44%1 in the Older-B group, 32/ 623 [5.14%1 in the Older-C group, and 26/349 [7.45%1 in the Younger-B group), with only 2 (0.57%) participants hav-ing grade 3 AEs in the Younger-B group. Fifteen (0.94%) participants from these three groups had reported serious AEs (SAEs), all of which were unrelated to vaccines. Interpretation EV71 vaccine produced by WIBP could extend to be administered to children aged 36-71 months against EV71 infection. However, the persistence of vaccine-induced immunities needs to be further investigated. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

目的 观察肠道病毒71型(entervirus type 71,EV71)灭活疫苗(人二倍体细胞)适龄接种儿童柯萨奇病毒A组6型(Coxsackievirus A6,CVA6)血清中和抗体变化情况.方法 收集EV71灭活疫苗接种儿童的免疫前及免疫后血清,采用微量中和试验检测抗EV71和CVA6中和抗体滴度.结果 无手足口病(hand,foot and mouth disease,HFMD)疾病史及EV71灭活疫苗接种史的6～71月龄儿童的血清抗EV71及抗CVA6中和抗体阳性率分别为27.93％和33.91％,共同阳性率为15.32％;两种抗体阳性率总体呈随月龄增加而逐渐升高的趋势(EV71 :x2=4.436,P＜0.001;CVA6:x2=2.083,P=0.037).完成EV71灭活疫苗2剂免疫后,抗EV71及抗CVA6中和抗体共同阳性率由15.32％升至32.74％,4个年龄组的抗体共同阳性率也分别由0.00％、8.33％、8.33％和31.11％上升至23.81％、28.00％、13.04％和50.00％;抗EV71中和抗体阳性率(27.93％ vs.98.23％;x2=119.257,P＜0.001)和几何平均滴度(geometric mean titer,GMT)(7.01 vs.46.52;x2=78.730,P＜0.001)均较免疫前明显上升;而抗CVA6中和抗体阳性率在免疫前后均为33.91％ (x2=0.000,P＞0.05),GMT在免疫前后差异也无统计学意义(3.09 vs.4.10;x2=0.883,P=0.348).结论 EV71灭活疫苗适龄接种人群EV71及CVA6的隐性感染率和共同隐性感染率较高.接种EV71灭活疫苗对适龄儿童的抗CVA6中和抗体水平无影响,表明EV71和CVA6之间无中和交叉反应.

Background. Evaluation of a licensed inactivated enterovirus type 71 (EV71) vaccine is needed in a phase IV study with a large population to identify its effectiveness and safety for further application. Methods. An open-label, controlled trial involving a large population of 155 995 children aged 6-71 months was performed; 40 724 were enrolled in the vaccine group and received 2 doses of inactivated EV71 vaccine at an interval of 1 month, and the remaining children were used as the control group. The EV71-infected cases with hand, foot, and mouth disease were monitored in the vaccine and control groups during a follow-up period of 14 months since the 28th day postinoculation through the local database of the Notifiable Infectious Diseases Network. The effectiveness of the vaccine was estimated by comparing the incidence density in the vaccine group versus that in the control group based upon EV71-infected patients identified via laboratory testing. In parallel, the active and passive surveillance for safety of the vaccine was conducted by home or telephone visits and by using the Adverse Event Following Immunization (AEFI) system, respectively. Results. An overall level of 89.7% (95% confidence interval, 24.0-98.6%) vaccine effectiveness against EV71 infection and a 4.58% rate of reported adverse events were observed. Passive surveillance demonstrated a 0.31% rate of reported common minor reactions. Conclusions. The clinical protection and safety of the EV71 vaccine were demonstrated in the immunization of a large population.