Vaccine and Infectious Disease and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center and Department of Biostatistics, University of Washington, USA.
World Health Organization, Geneva, Switzerland.
Vaccine. 2022 Jul 30;40(32):4283-4291. doi: 10.1016/j.vaccine.2022.05.016. Epub 2022 Jun 29.
Worldwide, childhood mortality has declined significantly, with improvements in hygiene and vaccinations against common childhood illnesses, yet newborn mortality remains high. Group B Streptococcus (GBS) disease significantly contributes to newborn mortality and is the leading cause of meningitis in infants. Many years of research have demonstrated the potential for maternal vaccination against GBS to confer protection to the infant, and at least three vaccine candidates are currently undergoing clinical trials. Given the relatively low disease incidence, any clinical vaccine efficacy study would need to include at least 40,000 to 60,000 participants. Therefore, a path to vaccine licensure based on a correlate of protection (CoP) would be the preferred route, with post-approval effectiveness studies demonstrating vaccine impact on reduction of disease burden likely to be required as part of conditional marketing approval. This workshop, hosted by the Bill & Melinda Gates Foundation on 10 and 11 February 2021, discussed considerations and potential statistical methodologies for establishing a CoP for GBS disease. Consensus was reached that an antibody marker with global threshold predictive of a high level of vaccine protection would be most beneficial for licensure assessments. IgG binding antibody in cord blood would likely serve as the CoP, with additional studies needed to confirm a high correlation with functional antibody and to demonstrate comparable kinetics of natural versus vaccine-induced antibody. Common analyses of ongoing seroepidemiological studies include estimation of absolute and relative disease risk as a function of infant antibody concentration, with adjustment for confounders of the impact of antibody concentration on infant GBS disease including gestational age and maternal age. Estimation of an antibody concentration threshold indicative of high protection should build in margin for uncertainties from sources including unmeasured confounders, imperfect causal mediation, and variability in point and confidence interval estimates across regions and/or serotypes.
全球范围内，儿童死亡率显著下降，这得益于卫生条件的改善和针对常见儿童疾病的疫苗接种，但新生儿死亡率仍然很高。B 型链球菌（GBS）疾病显著增加了新生儿的死亡率，是导致婴儿脑膜炎的主要原因。多年的研究表明，对母亲进行 GBS 疫苗接种可以为婴儿提供保护，目前至少有三种疫苗候选物正在进行临床试验。鉴于疾病发病率相对较低，任何临床疫苗功效研究都需要至少纳入 4 万至 6 万名参与者。因此，基于保护相关物（CoP）的疫苗许可途径将是首选，在获得批准后，还需要进行疫苗对疾病负担减少的影响的有效性研究，这可能是有条件批准上市的要求。此次研讨会由比尔及梅琳达·盖茨基金会于 2021 年 2 月 10 日和 11 日主办，讨论了为 GBS 疾病建立 CoP 的考虑因素和潜在统计方法。会上达成共识，具有全球预测高疫苗保护水平的抗体标志物将最有利于许可评估。脐带血中的 IgG 结合抗体可能作为 CoP，还需要进一步研究以确认其与功能性抗体的高度相关性，并证明天然抗体与疫苗诱导的抗体具有可比的动力学。正在进行的血清流行病学研究的常见分析包括估计婴儿抗体浓度与绝对和相对疾病风险的函数关系，同时调整影响婴儿 GBS 疾病的抗体浓度的混杂因素，包括胎龄和产妇年龄。用于确定高保护作用的抗体浓度阈值的估计值应考虑到来自未测量混杂因素、因果中介不完全以及区域和/或血清型之间点估计和置信区间估计的变异性等来源的不确定性。
