Long-term immune persistence induced by two-dose BBIBP-CorV vaccine with different intervals, and immunogenicity and safety of a homologous booster dose in high-risk occupational population. Secondary Study Based on a Randomized Clinical Trial
Authors: Yao Tian , Zhang Xiaohong , Mu Shengcai , Guo Yana , Xu Xiuyang , Huo Junfeng , Wei Zhiyun , Liu Ling , Li Xiaoqing , Li Hong , Xing Rongqin , Feng Yongliang , Chen Jing , Feng Lizhong , Wang Suping 
Published: June 2022

Background
BBIBP-CorV vaccine with two doses and an interval of 3-4 weeks had been proved to have good immunogenicity and efficacy as well as an acceptable safety profile according to our initial research and other similar studies. Maintaining adequate neutralizing antibody levels is also necessary for long-term protection, especially in the midst of the COVID-19 pandemic. Our aim was to evaluate the immune persistence of neutralizing antibody elicited by BBIBP-CorV vaccines with day 0-14, 0-21 and 0-28 schedule, and assess the immunogenicity and safety of a homologous booster dose in the high-risk occupational population aged 18-59 years.
Methods
A total of 809 eligible participants, aged 18-59 years, were recruited and randomly allocated to receive BBIBP-CorV vaccine with day 0-14, 0-21 or 0-28 schedule respectively between January and May 2021 in Taiyuan City, Shanxi Province, China among the public security officers and the airport ground staff in initial study. In this secondary study, the responders (GMT ≥ 16) at day 28 after priming two-dose vaccine were followed up at months 3, 6 and 10 to evaluate the immune persistence of three two-dose schedules. At month 10, eligible participants of three two-dose schedules were received a homologous booster dose respectively (hereafter abbreviated as 0-14d-10m group, 0-21d-10m group and 0-28d-10m group), and followed up at day 28 post-booster to assess the safety and immunogenicity of the booster dose. The contents of follow-up included the blood samples, oropharyngeal/nasal swabs, and adverse reactions collection. The main outcomes of the study included geometric mean titers (GMT) of neutralizing antibody to live SARS-CoV-2, the positive rates of different criteria and the constituent ratio of GMT of neutralizing antibodies at different follow-up point. Meanwhile, we explored the kinetics of antibody levels of different vaccination regimens by generalized estimating equations (GEE) and used exponent curve model to predict the duration of maintaining protected antibody after the booster dose. We also determined predictors of maintaining protected antibody level within 10 months after the second dose by Cox proportional hazards regression model and nomogram. The trial was registered with ChiCTR.org.cn (ChiCTR2100041705, ChiCTR2100041706).
Results
The number of 241, 247 and 256 responders (GMT ≥ 16) at day 28 after two-dose BBIBP-CorV vaccine in 0-14d, 0-21d and 0-28d schedule were followed-up at months 3, 6, and 10 for immune persistence evaluation. At month 10, a total of 390 participants were eligible and received a booster dose with 130 participants in the 0-14d-10m, 0-21d-10m and 0-28d-10m group respectively, of whom 74.1% (289/390) were male, with a mean age of 37.1±10.3 years. The GMT of neutralizing antibody in 0-28d-10m and 0-21d-10m group were significantly higher than 0-14d-10m group at month 3 (GMT: 71.6 & 64.2 vs 46.4, P＜0.0001 ), month 6 (GMT: 47.1 & 42.8 vs 30.5, P＜0.0001) and month 10 (GMT: 32.4 vs 20.3, P＜0.0001; 28.8 vs 20.3, P=0.0004) after the second dose. A sharply decrease by 4.85-fold (GMT: 94.4-20.3), 4.67-fold (GMT: 134.4-28.8) and 4.49-fold (GMT: 145.5-32.4) was observed from day 28 to month 10 after the second dose in 0-14d-10m, 0-21d-10m and 0-28d-10m group, respectively, and they had similar decline kinetics (P=0.67). At 28 days after booster dose, a remarkable rebound in neutralizing antibody (GMT: 246.2, 277.5 and 288.6) were observed in three groups, respectively. Notably, the GMT after booster dose was not affected by priming two-dose schedule. The predictive duration of neutralizing antibody declining to the cutoff level of positive antibody response may be 18.08 months, 18.83 months and 19.08 months after booster dose in three groups, respectively. Long-term immune persistence within 10 months after the second dose was associated with age<40, female, and history of influenza vaccination. All adverse reactions were mild after the booster injection. None of the participants were infected SARS-CoV-2 during the trial period.
Conclusions
The priming two-dose BBIBP-CorV vaccine with 0-28 days and 0-21 days schedule could lead a longer persistence of neutralizing antibody than 0-14 days schedule. Maintaining long-term immune persistence was also associated with age<40, female, and history of influenza vaccination. Regardless of priming two-doses vaccination regimens, a homologous booster dose led to a strong rebound in neutralizing antibody and might elicit satisfactory persistent immunity.