A systems immunology approach to evaluate malaria vaccine performance in endemic regions of Kenya

高效疟疾疫苗仍然是控制和消除疟疾的终极工具。领跑者 是恶性疟原虫环子孢子部分重组蛋白S/AS01RTS 蛋白质(CSP)。然而，在疟疾流行的儿童中观察到疫苗对临床疟疾的疗效 设置仅为36%。为了了解如何改进这种疫苗，对 阻碍疟疾疫苗效果的基线和累积因素，与这些因素形成直接对比 与预防疟疾相关的，是必要的。我们最近定义了更强的保护相关性 基于使用系统血清学方法的功能性抗体活性。到目前为止，这些系统血清学 研究仅针对来自非流行地区的成年人。在这里，我们的目标是测试总体 假设生活在疟疾流行地区的儿童免疫细胞不太成熟或异常 无法开发RTS引发的功能性抗体和T细胞的广度，S为了成为 预防疟疾。在世界卫生组织疟疾疫苗实施方案的帮助下 在肯尼亚的传播地区，我们将采用密集的纵向队列研究设计来跟踪儿童 在4剂RTS期间，S制定了疫苗接种计划，对PF感染进行了主动和被动的随访和 临床疟疾发作，直到他们达到4岁。我们的总体假设将由 以下具体目标：SA1：全面描述基线和疫苗接种期间的因素， 与疫苗的低反应性有关。使用集成的系统免疫学和机器 学习方法，我们将确定持续暴露于疟疾、全身炎症、前 既有抗疟疾免疫，又有不成熟的细胞免疫标志的RTS，S疫苗次之。 反应性，定义为不能产生一组功能性的抗CSP抗体。SA2：TO 全面描述儿童接种疫苗后的免疫特征，这些特征与 预防疟疾。使用系统免疫学方法，我们将确定疫苗的功能- 诱导的抗CSP抗体及其与年龄、细胞免疫特征和免疫保护的相关性 疟疾。体外功能研究将评估子孢子的抗体调理和抗体依赖 有无天然免疫细胞的细胞毒性；评估疫苗的表型和功能- 诱导CSP特异性T细胞；探索单核细胞表观遗传修饰的可能性(经训练 免疫力)来影响疫苗的性能。使用计算建模/机器学习方法，我们 将整合深入的免疫图谱特征，以预测与预防疟疾的相关性。总而言之，这 这项研究旨在为下一代疟疾疫苗和疫苗接种计划提供信息，可能包括 结合抗疟疾预防/治疗的免疫调节成分或建议 疫苗接种时间表。

A highly effective malaria vaccine remains the ultimate tool for malaria control and elimination. The front runner is RTS,S/AS01, a recombinant protein comprising portions of Plasmodium falciparum (Pf) circumsporozoite protein (CSP). However, the observed vaccine efficacy to clinical malaria in children living in malaria endemic settings is only 36%. In order to understand how to improve upon this vaccine, a comprehensive evaluation of baseline and cumulative factors that impede malaria vaccine performance, in direct contrast to factors associated with protection from malaria, is needed. We have recently defined stronger correlates of protection based on functional antibody activity using a systems serology approach. To date, these system serology studies have been conducted only for adults from non-endemic regions. Here, we aim to test the overall hypothesis that children living in malaria endemic areas who have less mature or aberrant immune cells are unable to develop the breadth of functional antibodies and T cells elicited by RTS,S in order to become protected against malaria. Drawing on the WHO Malaria Vaccine Implementation Program in a high- transmission region in Kenya, we will employ an intensive longitudinal cohort study design to follow children during their 4-dose RTS,S vaccination schedule, with active and passive follow-up for Pf infections and episodes of clinical malaria until they reach 4 years of age. Our overall hypothesis will be tested by the following specific aims: SA1: To comprehensively characterize baseline and peri-vaccination factors that correlate with vaccine hyporesponsiveness. Using an integrated systems immunology and machine learning approach, we will determine the effects of ongoing exposures to malaria, systemic inflammation, pre- existing anti-malarial immunity, and immaturity of cellular immune signatures on RTS,S vaccine hypo- responsiveness, defined as the inability to develop a core group of functional anti-CSP antibodies. SA2: To comprehensively characterize the post-vaccination immune signatures in children that correlate with protection from malaria. Using a systems immunology approach, we will determine the function of vaccine- elicited anti-CSP antibodies and their correlation with age, cellular immune signatures, and protection from malaria. Functional in vitro studies will assess antibody opsonization of sporozoites and antibody-dependent cellular cytotoxicity with and without innate immune cells; assess the phenotype and function of vaccine- elicited CSP-specific T cells; and explore the potential for epigenetic modifications of monocytes (trained immunity) to influence vaccine performance. Using a computational modeling/machine learning approach, we will integrate deep immunoprofiling features to predict correlates with protection from malaria. Together, this study aims to inform the next generation of malaria vaccines and vaccination programs that could include immune-modulatory components or recommendations to combine antimalarial prophylaxis/treatment within the vaccine schedule.