2-Year Efficacy,Immunogenicity,and Safety Of Enterovirus 71 Inactivated Vaccine

[Backgroud]Hand foot mouth disease(HFMD)is a common infectious disease caused by multiple enteroviruses,and is China's statutory report on category C infectious disease.Enterovirus 71(EV71)is dominant pathogen,which leading to HFMD of severe cases and deaths.In recent years,the epidemic of EV71-associated severe HFMD and EV71-associated diseases,which is seriously endanger to children's life and health in our country.At present,EV71 vaccine developed by a number of countries and regions,of which three Inactivated EV71 vaccines developed by mainland China have been completed Phase III clinical trials and have been registered.However,the protective efficacy and serum antibody levels observed in the clinical trial of the EV71 vaccine are limited to the first year.Thus,the long-term efficacy and the persistence of protective antibodies of this EV71 vaccine is required to be studied.[Objective]1.To determine the efficacy of the Beijing EV71 inactivated vaccine for EV71-induced HFMD/disease during the 2-year follow-up period.2.To evaluate the persistence of protective antibodies induced by Beijing EV71 inactivated vaccine.3.To evaluate the incidence of serious adverse events of the Beijing EV71 inactivated vaccine during the 2-year follow-up period.[Materials and methods]In 2012,we recruited 10,245 healthy children aged 6-35 months(at enrollment)into a randomized,double-blinded,placebo-controlled,phase 3 clinical trial to evaluate the 1-year efficacy of the inactivated EV71 vaccine.In this trial,participants were randomly assigned in a ratio of 1:1 to administered the EV71 vaccine(n=5,120)or placebo(n=5,125)according to a 2-dose schedule(on day 0 and day 28).After the completion of the first-year follow-up study to determine the efficacy of the EV71 vaccine,we performed an extra follow-up study lasting up to 2 years.Because masking in the initial study was partially removed at month 14,at the end of the first year of follow-up,surveillance for EV71-associated HFMD during the extended second year of follow-up was open labeled;the investigators who measured antibody levels and tested for the presence of pathogen remained masked with respect to vaccine or placebo allocation.Based on the pre-established enterovirus surveillance system,we determined HFMD/disease caused by EV71 during the second year follow-up period(from 13 months to 26 months).In addition,we collected blood sample and measured EV71 neutralization antibody level at the 26th month.Combined the initial study and the extended follow-up study,we can evaluate the efficacy,immunity and safety of EV71 vaccine during the whole 2 years period and the second year period,respectively.Blood samples were collected from a subset of participants in the immunogenicity cohort,described previously,on days 0 and 56 in the initial study and during months 8,14,and 26 in the extended follow-up period and the anti-EV71 neutralizing antibodies were detected.Meanwhile,we also calculated the neutralizing antibody GMT and the positive rate to assess the persistence of vaccine-induced antibody levels during 2 years period.From day 0 to months 26,any serious adverse event(SAE)reported by the guardians of participants was recorded.All SAEs were classified using the terminology specified in the Medical Dictionary for Drug Regulatory Activities(MedDRA).The overall and classification incidence of SAE in the vaccine group and the control group were calculated.A ?2 or Fisher exact test was used to compare categorical data,while the Student t test was used to compare log-transformed neutralizing antibody values.All reported p values were 2 sided,and values of<.05 were regarded as statistically significant.Statistical analyses were done by an independent,external statistician,using SAS software,version 9.2(SAS Institute).[Results]1.Results of the efficacy of EV71 vaccine1.1 The efficacy of EV71 vaccine during the 2 yearsThe vaccine efficacy was 94.84%(95%confidence interval[CI],83.53%-98.38%)against EV71-associated HFMD during 2-year follow-up period(p<0.0001).The vaccine efficacy was 95.84%(95%CI,86.81%-98.69%)against EV71-associated diseases during 2-year follow-up period(p<0.0001).The vaccine efficacy was-1.53%(95%CI,-18.07-12.70)against Coxsackievirus A16(CA16)associated HFMD during 2-year follow-up period(p=0.8442).Meanwhile,the vaccine efficacy was 2.91%(95%CI,-11.58-15.51)against other enteroviruses associated diseases during 2-year follow-up period(p=0.6775).1.2 The efficacy of the vaccine during the second yearThe vaccine efficacy was 100.00%(95%CI,84.15%-100.00%)against EV71-associated HFMD during the second year(p<0.0001).The vaccine efficacy was 100.00%(95%CI,90.11%-100.00%)against EV71-associated diseases during the second year(p<0.0001).The vaccine efficacy was-67.33%(95%CI,-600.2-60.01)against CA16-associated HFMD the second year(p=0.4760).Meanwhile,the vaccine efficacy was-0.30%(95%CI,-53.84-34.60)against other enteroviruses associated diseases during 2-year follow-up period(p=0.9890).2.Results of the immunogenicity of the EV71 vaccineDuring the 2-year follow-up study,the GMTs(Geometric mean titers,GMTs)of EV71 neutralizing antibody in vaccine recipients increased from 325.3(95%CI,284.8-371.7)at day 56 to 685.7(95%CI,591.4-795.1)at month 26.Similarly,the GMTs of EV71 neutralizing antibody in the placebo group also gradually increased during this period,from 13.0(95%CI,11.1-15.2)at day 56 to 39.1(95%CI,31.0-49.2)at month 26.The results show that the GMTs of neutralizing antibody in participants remained high during the 2-year follow-up period.3.Results of the safety of the EV71 vaccineDuring the 2-year follow-up period,180 of 10 245 participants(1.76%)reported SAEs(78 of 5120[1.52%]in the vaccine group and 102 of 5125[1.99%]in the placebo group),with a similar incidence of occurrence between the groups(p=0.0834),whereas in the second-year follow-up study,40 of 10 245(0.39%)reported SAEs(14[0.27%]in the vaccine group and 26[0.51%]in the placebo group;p=0.0801).[Conclusions]The EV71 inactivated vaccine provided sustained high protection against EV71-associated HFMD/disease and persistent immunity in children aged 6-35 months for up to 2 years after the 2-dose vaccination.No safety concerns about the EV71 vaccine were identified during the 2-year follow-up study.[Significance]These findings of 2-Year Efficacy,Immunogenicity,and Safety of the enterovirus 71 inactivated Vaccine,which might play an important role in its clinical application of post-licensing,decisions about mass administration of EV71 vaccine for controlling EV71-associated HFMD epidemics and the decision of the need for booster injections.