Evaluation Of Inactivated Enterovirus 71 Vaccine Effectiveness Based On Test-negative Design

Background:Diseases caused by EV71 infection,especially hand,foot and mouth disease,pose a major threat to the health of children and infants in China.In order to prevent and control EV71 infection-related diseases,inactivated EV71 vaccines developed by three manufacturers in China(Vigoo,Sinovac and CAMS)have been marketed after the end of 2015.In order to better formulate the immunization strategy related to EV71 vaccine,it is necessary to evaluate the protective effectiveness of EV71 vaccine on the market.Test negative design(TND)is a popular observational epidemiological method in recent years,which is used to evaluate the effectiveness of vaccines on the market,especially in influenza vaccine effectiveness evaluation studies.However,there are few studies on the use of test-negative design to evaluate EV71 vaccine,and the protective effectiveness of EV71 vaccine in Jiangsu Province has not been evaluated.Objective:1 To explore whether the test negative design is feasible and accurate in the effectiveness evaluation of EV71 vaccine.2 The test negative design was used to evaluate the actual effectiveness of EV71 vaccine against hand-foot-mouth disease in Jiangsu Province.Methods:Part 1: The data were collected from the phase III clinical trial of Beijing Vigoo EV71 vaccine.The target population of the trial was 6-35-month-old children and infants,who were immunized twice in 0 and 28 days.There were 10245 subjects in the trial,5120 in the vaccine group and 5125 in the placebo group.The surveillance was from56 days to 14 months after the first immunization.Any suspicious cases were collected,sampled and tested in the laboratory with the combination of active monitoring and passive monitoring.The positive EV71 group was the case group and the EV71 negative group was the control group.The protective effectiveness of EV71 vaccine was calculated by using TND,and compared with the efficacy results of phase III clinical trials to explore whether TND is accurate and reliable in the evaluation of EV71 vaccine effectiveness.The method of stratified analysis was used to evaluate whether age,sex and calendar would affect the results.Part 2: In Jiangsu Province,taking counties and districts as units,we selected the areas where the EV71 vaccination rate was between 10% and 50% from 2017 to the end of January 2020,and the EV71 vaccination information system was fully registered.The baseline information,laboratory test results and EV71 vaccination information of reported HFMD cases were retrospectively investigated and collected.The age range of the cases included in the study was limited to 6-71 months old.The retrospective survey was conducted from May to July 2020.According to the laboratory test results,the collected cases were divided into EV71 positive group and EV71 negative group.The proportion of indirect EV71 vaccine in the two groups was compared,and the protective effect of the vaccine against hand,foot and mouth disease caused by EV71 was calculated.Results:Part 1: During the surveillance,we included a total of 7325 clinically suspected subjects with EV71 infection,of whom 52 were positive and 7273 were negative.The baseline characteristics between the two groups were balanced.The protective effectiveness of the vaccine against EV71 infection-related diseases calculated by TND was 81.7%(95%CI: 61.1%-91.4%),the effectiveness against EV71 HFMD-like disease was 91.2%(95%CI: 71.2%-97.3%),and the effectiveness against other diseases infected by EV71 was53.9%(95% CI: 32.8%-84.0%),which was similar to the efficacy of the previous phase III clinical results.According to the analysis of gender stratification,the protective effectiveness of the vaccine against male EV71 infection-related diseases was 70.1%(95% CI: 30.2%-87.2%),while the effectiveness on female EV71 infection-related diseases was 95.1%(95% CI: 63.3%-99.3%).Analyzed by age stratification,the protective effectiveness of the vaccine against <=12-month-old EV71 infection-related diseases was 91.1%(95% CI: 30.7%-98.8%),while for >12-month-old EV71 infectionrelated diseases,the effectiveness was 78.5%(95% CI: 51.3%-90.5%).According to the stratification of disease incidence in the epidemic season,the protective effectiveness of the vaccine against EV71 infection-related diseases in the epidemic season is 85.5%(95% CI: 58.7%-94.9%),while for EV71 infection-related diseases that are not in the epidemic season,it is 75.1%(95% CI: 25.3%-91.7%).Part 2: A total of 475 cases were collected and 448 cases were included in the analysis.The collected cases were mainly concentrated in 2018 and 2019,and most of the cases were CA16 and CA6 infection,and the onset time was mainly in April-June and October-December.Among the 448 patients,50 cases were EV71 positive,that is,the case group,and 398 cases were EV71 negative,that is,the control group.The proportion of severe and hospitalized cases in the case group was higher than that in the control group.48 cases in the case group had not received EV71 vaccine,2 cases had received at least one dose of EV71 vaccine,332 cases in the control group had not received EV71 vaccine,and 66 cases had received at least one dose of EV71 vaccine.The protective effectiveness of EV71 vaccine against hand-foot-mouth disease was about 80.0%.However,it has no protective effectiveness on hand,foot and mouth disease caused by CA16 infection,CA6 infection and EV-G infection.Conclusions:It is accurate and feasible for TND to evaluate the effectiveness of EV71 vaccine,but it is necessary to pay attention to various confounding factors.EV71 vaccine has protective effectiveness against hand-foot-mouth disease caused by EV71 infection in Jiangsu Province,but larger studies are needed to further evaluate the effectiveness of EV71 vaccine.