Abstract

Accurate estimates of malaria vaccine efficacy require a reliable definition of a malaria case. However, the symptoms of clinical malaria are unspecific, overlapping with other childhood illnesses. Additionally, children in endemic areas tolerate varying levels of parasitemia without symptoms. Together, this makes finding a gold-standard case definition challenging. We present a method to identify and estimate malaria vaccine efficacy that does not require an observable gold-standard case definition. Instead, we leverage genetic traits that are protective against malaria but not against other illnesses, for example, the sickle cell trait, to identify vaccine efficacy in a randomized trial. Inspired by Mendelian randomization, we introduce Mendelian factorial design, a method that augments a randomized trial with genetic variation to produce a natural factorial experiment, which identifies vaccine efficacy under realistic assumptions. A robust, covariance adjusted estimation procedure is developed for estimating vaccine efficacy on the risk ratio and incidence rate ratio scales. Simulations suggest that our estimator has good performance whereas standard methods are systematically biased. We demonstrate that a combined estimator using both our proposed estimator and the standard approach yields significant improvements when the Mendelian factor is only weakly protective. Our method can be applied in vaccine and prevention trials of other childhood diseases that have no gold-standard case definition and known genetic risk factors. Supplementary materials for this article are available online.

摘要

准确估计疟疾疫苗功效需要对疟疾病例进行可靠定义。然而，临床疟疾的症状是非特异性的，与其他儿童疾病重叠。此外，流行地区的儿童可以忍受不同程度的寄生虫血症而没有症状。总之，这使得寻找黄金标准案例定义具有挑战性。我们提出了一种识别和估计疟疾疫苗功效的方法，该方法不需要可观察的金标准病例定义。相反，我们利用对疟疾有保护作用但对其他疾病没有保护作用的遗传特征，例如镰状细胞特征，在随机试验中确定疫苗的功效。受孟德尔随机化的启发，我们引入孟德尔因子设计，一种通过遗传变异增强随机试验以产生自然因子实验的方法，该实验在现实假设下确定疫苗功效。开发了一种稳健的协方差调整估计程序，用于在风险比和发病率比量表上估计疫苗功效。模拟表明，我们的估计器具有良好的性能，而标准方法存在系统偏差。我们证明，当孟德尔因子仅具有弱保护性时，使用我们提出的估计器和标准方法的组合估计器会产生显着的改进。我们的方法可应用于其他没有金标准病例定义和已知遗传风险因素的儿童疾病的疫苗和预防试验。本文的补充材料可在线获取。