| Since Enterovirus type 71(EV71) was first isolated in the United States from the stool sample fro m an infant with encephalitis in 1969, more than 40 countries or regions have reported outbreaks or prevalence caused by EV71, especially in the Southeast Asia. Previous studies showed that EV71 was a major cause of hand, foot and mouth disease(HFMD) especially for the severe HFM D cases and fatal cases. In the past few years, the prevalence of HFMD has become one of the most important public health issues in the mainland China, Taiwan, and some other countries in the Southe ast Asia, causing larg e economic losses and burden on society. Since there is no specific treatment for HFMD, it is a n urgent need to develop an efficient vaccine and immunization strategies to control the prevalence of HF MD. We aimed to study on the key issues of the immunization strategy of a novel EV71 inactivated vaccine developed b y Beijing Vigoo Biologicals Co., Ltd.【Objectives】1.To determine the optimum dosage, formulation, and immunization schedule for the EV71 vaccine.2.To evaluate the persistence of the vaccine induced immunity and the need of boosting.3.To determine the efficacy of the EV71 vaccine against EV71 associated HFMD /disease.4.To explore the serological surrogate endpoint for the EV71 vaccine efficacy5.To analyze the cross-immu nity or cross-protection of EV71 vaccine against other enterovirus.6.To evaluate the consistency between different batches of EV71 vaccines.【Methods】1.Dosage, formulation, and immunization schedule study for the EV71 vaccine.It was a double-blind, randomized, placebo-controlled study with 600 children aged between 12~60 months, and 600 infants aged between 6~11 months to investigate the immunogenicity and safety profile of EV71 vaccine s with different dosage and formulations, including alum-adjuvant 160 U, alum-adjuvant 320 U, alum-adjuvant 640 U, and adjuvant-free 640 U EV71 vaccines. The post-vaccination neutrali zing antibody levels induced by EV71 vaccine and the adverse incidences were compared between groups, to determine the optimu m dosage, formulation and i mmunization schedule.2.Antibody persistence and booster injection studyBased on the same cohort of the optimum dosage, formulation an d immunization schedule, we followed the participants and took blood samples at month 8 and 14 post-vaccination, to measure the neutralizing antibody against EV71. Participants who had completed two-dose primary vaccinations were re-recruited, and randomized at a ratio of 2:1 to receive a booster dose of the same EV71 vaccine at month 14 to evaluate the boost vaccination approach.3.EV71 vaccine efficacy studyWe conducted a multicenter, double-blind, randomized, placebo-controlled study, by recruiting healthy infants and children aged between 6-35 months and allocating randomly to receive EV71 vaccine or placebo in a ratio of 1:1. The efficacy and safety after vaccinations were observed. Through the surveillance system for enterovirus disease, we followed the participants from day 56 to month 14 and collected all the EV71-associated disease/HFMD during the surveillance period.4.Serological surrogate endpoint for the EV71 vaccine efficacyBased on the efficacy study cohort, a nested case-control study was carried out for the serological surrogate endpoint for the EV71 vaccine efficacy. We matched each confirmed EV71 cases with four EV71-free participants to make a subgroup. Sensitivity, specificity, and Youden index were calculated using the antibody titer of the subgroup at day 56 to explore the surrogate endpoint for the EV71 vaccine efficacy.5.The cross-immunity or cross-protection of EV71 vaccineThe cross-immunity between EV71 and polio was also studied on the basis of the 600 cohort for the optimu m dosage, formulation and immunization schedule. The blood samples collected at day 0 pre-vaccination and at day 28, 56 post-vaccination were used for the detection of neutralizing antibody type I, II and III against polio. The efficacy of cross-protection of EV71 vaccine agains t Coxsackievirus A16(CA16) or other EV71 vaccine was observed from day 56 to month 14, by collecting all the CA16 or other enterovirus-associated disease/ HFMD.6.Batch-consistence of EV71 vaccinesWe designed a nested, double-blind, randomized study for batchconsistence study in the participants who received alu m-adjuvant 320 U EV71 vaccine in the efficacy cohort. Participants were randomly allocated to receive three different batches of EV71 vaccine in a 1:1:1 ratio. If the 95% confidence interval of GMT ratio of any two of the batches fall between 0.67 and 1.5, then the EV71 vaccine could be considered with an acceptable batch-to-batch consistency.【 Results】1.The results from vaccine dosage, formu lation an d immunization schedule study showed that at day 28 after the first dose, the GMTs of the group receiving alum-adjuvant 160 U, 320 U, 640 U EV71 vaccine, adjuvant-free 640 U EV71 vaccine, and placebo were 36.91, 63.14, 82.39, 70.79, and 18.00, respectively. And at day 28 after the second dose, the GMTs of the group receiving alum-adjuvant 160 U, 320 U, 640 U EV71 vaccine, adjuvant-free 640 U EV71 vaccine, and placebo were 517.65, 831.75, 1003.01, 330.34, and 21.61, respectively. Significant higher post-vaccination antibody re sponse was elicite d by two-dose vaccination than the placebo(P<0.05). No significant difference i n terms of GMTs was found between 640 U and 320 U EV71 vaccine group. Safety observation data indicated that no significant difference was noticed among the EV71 vaccine and placebo groups.2. The antibody persistence showed that: At the end of month 8, the GMTs of the group receiving alum-adjuvant 160 U, 320 U, 640 U EV71 vaccine, and adjuvant-free 640 U EV71 vaccine were 95.58, 130.06, 146.74 and 65.25, which were significant lower than those at day 56; At the end of month 14, the GMTs of the group receiving alum-adjuvant 160 U, 320 U, 640 U EV71 vaccine, and adjuvant-free 640 U EV71 vaccine were 199.38, 246.79, 261.09 and 144.78. The highest antibody level was observed in the alum-adjuvant 640 U EV71 vaccine group, followed by alum-adjuvant 320 U and 160 U va ccine group, but with no statistical difference. A booster dose at month 14 could elicit a strong immun e me mory response with an antibody titer increase fold of 6-10.3.The first year vaccine efficacy against EV71-associated HFMD was 90.93%(95%CI:70.42%-97.22%), while the efficacy against EV71-associated disease was 81.85%(95%CI:61.46%-91.46%). Th e efficacy against EV71-associated hospitalization cases was 100.00%(95%CI:41.56%-100.00%).4.In the serological surrogate endpoint analysis, a maximu m Youden index was obtained at the titer of 1:16, with a sensitivity of 84.6% and a specificity of 70.8%. The second maximu m Youden index wa s observed at a titer of 1:32, wit h a sensitivity of 88.5% and a specificity of 66.0%.5.EV71 vaccination showed no interference with the pre-existing antibodies against polio in infants. Besides, the protection rates of EV71 vaccine against CA16-associated diseases, other enterovirus-associated disease, and all the clinical HFMD were-0.10%(95%CI:-11.45-10.09), 3.98%(95%CI:-2.98-10.48), and 3.16%(95%CI:-6.01-11.53).6.The GMT ratios of the antibody level at day 56 post-vaccination of eac h paired batches of EV71 vaccine were all between 0.67~1.50.【Conclusion】1.The alum-adjuvant EV71 vaccines showed a better immunogenicity tha n the adjuvant-free EV71 vaccines did. Two-dose va ccination was more efficient than one-dose vaccination. A dose-response relationship was observed among alum-adjuvant EV71 vaccines with antigen of 160 U, 320 U and 640 U. The opti mum dosage and formulation for EV71 vaccine was alum-adjuvant 320 U with a two-dose immune schedule on day 0 and 28.2.There’s no need to have a booster dose currently, since the prevalence of EV71 may have a natural boosting effect on the antibody persistence.3. High vaccine efficacy against EV71-associated disease or HFMD was observed.4.The titer of 1:16 or 1: 32 was considered as the possible surrogate endpoint for the protection of EV71 vaccine and no cross-protection against the disease or HFMD caused by CA16 or other enterovirus.5.The solid evidence of the study confirmed that no cross-immune response between EV71 and polio and no interference with the pre-existing antibodies against polio.6.Good in batch consistency of EV71 vaccine was determined.【Significance】These clinical studies on novel EV71 vaccines provided solid scientific evidences and solved a series of key pr oblems associated with the EV71 vaccine such as the optimu m dosa ge and formulation, immune schedule, antibody persistence, vaccine efficacy, serological surrogate endpoint, cross-immunity and batch consistence. The clinical evaluation of the EV71 vaccine in this stud y provides valuable information for the vaccine development in the future. |
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