A Post-marketing Study On Effectiveness And Safety Of Inactivated Enterovirus 71 Vaccine(Human Diploid Cell)

BackgroundHand,foot and mouth disease(HFMD)is a common infectious disease in children under 5 years old.It is caused by a variety of enteroviruses,and a few casees can rapidly develop into severe cases,which can be fatal.EV71(Enterovirus 71)is one of the main pathogens of common HFMD cases,and caused 80-90% of severe cases.There is no specific treatment for HFMD,and vaccination is the most effective and economical means of prevention.At present,the EV71 vaccine has been on the market in China,and pre-marketing clinical trials have exhibited high protective efficiency and safety.However,the lack of post-marketing study data makes it difficult to evaluate the effectiveness and efficiency and safety of EV71 vaccine in the general population.This study is the first phase IV trials of EV71vaccine(human diploid cell)worldwide.ObjectivesThe aim of this study was to assess the population-scale effectiveness and safety of EV71 vaccine(human diploid cell)and influence factors among children of 6-71 months in area with high incidence of HFMD.Methods(1)Vaccination: The open label community trial was conducted at three districts with high incidence of HFMD(Xiangzhou,Xiangcheng and Fancheng)of Xiangyang city,Hubei Province,China.From September 10 th,2016 to October 31 st,2016,40,000 eligible children of 6-71 months were vaccinated.After obtaining informed consent from the guardians of each participant,children were given 2 intramuscular injections of EV71 vaccine at intervals of a month.(2)Efficiency of vaccine: During the study period(from September 10 th,2016to December 31 st,2017),all children between 6 and 71 months during mass vaccination period(target population)were monitored for HFMD.The throat swabs stool and blood specimens from the all reported HFMD cases were collected immediately for enteroviruses pathogen test.The primary observation endpoint was hand-foot-mouth disease(HFMD)caused by EV71,while the secondary observation endpoint was all the hospitalized cases of HFMD and severe HFMD.Target children who were not vaccinated with any manufacturer’s EV71 vaccine during the study period in the study area were enrolled as the whole control group.Individuals from the whole control group who were 1:1 matched with vaccine group by sex and age(±15 days)formed the 1:1 control group,and then HFMD incidence in vaccine group and control group was monitored.(3)Safety of vaccine: Each vaccinated child was asked to stay at the inoculating unit for at least 30 minutes to observe immediate reaction after vaccination.The staffs made home or telephone visits to the vaccinated child at day 1st,3rd,7th and 30 th after each injection to learn solicited adverse events within 0-7 days and unsolicited adverse events within 0-30 days.Guardians for vaccinated children were asked to report any serious adverse events to study staff after onset as promptly as possible during duration of the entire study period.Serious adverse events were also collected according Immunization information management system and disease surveillance system.(4)Statistical analysis: The protection rate of EV71 vaccine and 95% confidence interval were calculated according to the incidence density.Mantel-Haenszel chi-square test was used to compare the differences in vaccine effectiveness between different subgroups.The efficiency was assessed in full analysis set(FAS)and Per protocol set(PPS),respectively.Sensitivity analysis was performed to evaluate the efficiency of EV71 vaccine by Cox proportional-hazards regression model and test-negative case-control study design.We graded all adverse events according to severity and evaluated their association with vaccination.Unsolicited adverse events and serious adverse events were coded by using Medical Dictionary for Regulatory Activities(Med DRA,version 21.0)and tabulated by the preferred term.Chi-square test and the possion regression model were used for univariate and multivariate analysis for safety,respectively.Results(1)Effectiveness of EV71 vaccine.For the effectiveness of EV71 vaccine against EV71-associated HFMD,results of comparison of incidence of HFMD in vaccinated subjects and 1:1 control group showed that the effectiveness was 94.74%(95%CI,60.69 to 99.30)in FAS and 92.31%(95%CI,41.20 to 98.99)in PPS.Results of comparison of incidence of HFMD in vaccinated subjects and whole control group showed that the effectiveness was 90.99%(95%CI,33.82 to 98.77)in FAS and 89.65%(95%CI,24.03 to 98.59)in PPS.No protective effect of EV71 against all HFMD and other enterovirus-associated HFMD was observed.Subgroup analysis of effectiveness.For the effectiveness of EV71 vaccine against EV71-associated HFMD,results of comparison of incidence of HFMD in vaccinated subjects and 1:1 control group in FAS were as follows.In the 6-35 months subgroup,the effectiveness was 93.75%(95%CI: 52.87,99.17),and in the 36-71 months subgroup,the effectiveness was 100.00%(P=0.248).In males,the effectiveness was 90.91(95%CI: 29.59,98.83),and in females,the effectiveness was100.00%(P=0.013).During the six-month effectiveness observation period,the effectiveness was 93.75%(95%CI: 52.87,99.17).The above results were consistent with those obtained in PPS and the whole control group.No differences were detected by the Mantel-Haenszel chi-square test between different gender and age groups on the effectiveness of EV71 vaccine against EV71-associated HFMD.Cox proportional-hazards regression analysis showed that the effectiveness of EV71 vaccine for EV71 associated HFMD was 94.73%(95%CI: 60.63,99.29).No protective effect of EV71 against all HFMD and other enterovirus-associated HFMD was observed.Sensitivity analysis by test negative design.The effectiveness of EV71 vaccine against EV71-associated HFMD was 96.93%(95%CI: 77.74,99.58).EV71 vaccine has no protective effect against all HFMD and other enterovirus-associated HFMD.Both FAS and PPS analysis results showed that vaccination could significantly reduce the risk of HFMD caused by EV71 infection when the age and gender were controlled.Younger(6-35 months)was a risk factor of HFMD caused by EV71 infection.(2)Safety of EV71 vaccine.During active safety monitoring,947(2.33%)participants reported 971 serious adverse events,of which 35(0.09%)participants reported 35 serious vaccine-associated adverse events.A total of 1865(4.58%)participant reported 2688 adverse events,of which 1307(3.21%)participants reported1921 vaccine-associated adverse events.The incidence of solicited adverse events was 2.92%,including local reaction(0.72%)and systemic reaction(2.30%).Redness was the most common local reaction,followed by pain and swelling.The highest incidence of systemic reaction was fever.The severity of solicited adverse events was mainly 1-2 level.The incidence of unsolicited adverse events was 1.99%,with the highest incidence of cough and upper respiratory infection(URI).The severity of unsolicited adverse events was mainly 1-2 level.Conclusions(1)EV71 vaccine protects the majority of children inoculated against EV71 infection,and provides good protection against EV71-related HFMD.Age and sex were not influencing factors for effectiveness of EV71 vaccine.(2)After EV71 mass vaccination,the overall incidence of adverse events was low and the severity was low.No unexpected serious adverse event was found.The EV71 vaccine showed satisfactory safety.Incidence rate of adverse events decreased with the increase of age.