The Persistence Of Neutralizing Antibodies Induced By Enterovirus 71 Vaccine And Predicted By Model

Objectives:(1) To understand the dynamic change and distribution characteristics of enterovirus 71 neutralizing antibodies, estimating the persistence of neutralizing antibodies induced by natural infection with enterovirus 71. (2) To understand the short-time persistence of neutralizing antibodies induced by inactivated enterovirus 71 vaccine, for the selection, validation and prediction of the prediction model. (3) Through the establishment of mathematical model based on monitoring data, the long-term persistence of neutralizing antibodies induced by inactivated enterovirus 71 vaccine was evaluated, thereby to provide basis for post market surveillance and booster immunization of inactivated enterovirus 71 vaccine.Methods:This study was based on phase 3 clinical trial of enterovirus 71 vaccine developed by Sinovac Biotech Co.Ltd, Beijing, and the extended follow-up, and subjects aged 6-35 months were recruited from Ganyu, Sheyang and Taixing in Jiangsu province. The subjects were assigned randomly to receive 400U vaccine and placebo. Their blood were collected on month 0,2,8,14 and 26 after first vaccination. All serum samples were assessed for EV71 neutralizing antibodies using a modified cytopathogenic effect assay, to understand the dynamic change distribution characteristic of neutralizing antibodies induced by natural infection and vaccine. The long-term persistence of neutralizing antibodies induced by enterovirus 71 vaccine was evaluated using a conventional power law model and a modified power-law model.Results:A total of 1150 patients in the antibodies persistence subgroup were followed up in the phase 3 clinical trial of enterovirus 71 vaccine, including 579 in vaccine group and 571 in placebo group. In 2 years of follow-up, the completion rates on month 2, month 8, month 14 and month 26 were 100%、95.48%、91.30% and 83.56%, respectively. The positive rates of enterovirus 71 neutralizing antibodies in general population (placebo group) were the highest in subjects aged 24-35 months, and the lowest in subjects aged 6-11 months. The positive rates of enterovirus 71 neutralizing antibodies in placebo group were increased with age, with the positive rates and geometric mean titers of antibodies remained at 40.54% and 1:14.6 by 26 months after first injection. In the two years follow-up, the annually new infection rates were 12.64%(66/522) and 17.29%(78/451), and the annually decay rates of enterovirus 71 neutralizing antibodies were 20.83%(20/96) and 55.00% (66/120).After injection with inactivated enterovirus 71 vaccine on 0,28 days, the geometric mean titer reached peak level (1:165.8) on 2 months after first immunization, and the positive rate was 98.79%, and remained at 89.38% on 26 months. The antibodies level decreased during 2 months to 8 months after first vaccination, and reached 1:56.3 by 26 months. The positive rate and geometric mean titer of antibodies induced by vaccine were still above 86.10% and 1:27.8 on 26 months.The enterovirus 71 neutralizing antibodies level induced by vaccine could maintain above 1:16 for 10 years, which was predicted by the power law model. The antibodies level induced by vaccine could maintain above 1:16 for 9 years was predicted by the modified power-law model.Conclusions:(1) In two years, the positive rates of antibodies were increased with age in general population (placebo group), with the positive rate and the geometric mean titer remaining at 40.54% and 1:14.6 by 26 months, respectively. (2) On 2 months after first vaccination, the antibodies reached the peak level, with the positive rate and the geometric mean titer remaining at 86% and 1:27.8 by 26 months, respectively. The persistence of antibodies induced by vaccine maintained well within two years. (3) Based on the results of this study, regarding 1:16 as the estimated value of vaccine protection level, protection induced by vaccine sustained for 10 years, predicted by model.