Mechanisms of naturally-acquired immunity to malaria

由恶性疟原虫引起的疟疾仍然是一个主要的公共卫生威胁。每年在世界最贫穷人口中发生2.25亿多例疟疾病例，仅在非洲每年就夺去大约50万儿童的生命。由于许多疟疾流行国家的保健基础设施有限，广泛实施以青蒿素为基础的综合疗法和驱虫蚊帐等疟疾控制干预措施受到了阻碍。此外，恶性疟原虫已被证明善于获得并迅速传播对抗疟药物的耐药性，而且不可避免地出现的抗杀虫剂蚊子不断威胁着病媒控制。最终，控制、消除甚至根除疟疾的一个关键工具是有效的疫苗。由于对恶性疟原虫与人类免疫系统之间的相互作用了解不足，在一定程度上阻碍了高效疟疾疫苗的开发。重要的是，在反复感染恶性疟原虫后可获得对疟疾的保护性免疫，但在没有持续接触的情况下会迅速减弱。最终提供这种保护的先天和适应性免疫反应的质量，以及它们获得效率低下和迅速丧失的机制，目前尚不清楚。我们的目标是通过解决这些关键的知识空白，为发现和开发预防和治疗疟疾的新工具提供信息。为此，我们应用免疫学和基因组学技术的最新进展，在疟疾流行地区进行了严格的纵向队列研究，以加深我们对恶性疟原虫与人类免疫系统之间相互作用的理解，定义疟疾免疫的分子和细胞特征，并确定潜在的疟疾疫苗靶点。在2022财年，我们继续追求五个主要目标：1)从马里正在进行的纵向队列研究中获得高质量的临床数据和生物标本，这些研究可靠地评估了恶性疟原虫感染暴露和对疟疾的保护作用；2)确定恶性疟原虫抗体反应的抗原特异性、功能、动力学和细胞基础，包括分离针对恶性疟原虫生命周期各个阶段的单克隆抗体；3)明确恶性疟原虫诱导炎症的调控机制，4)通过系统生物学方法确定疟疾免疫的分子特征，5)确定持续无症状恶性疟原虫感染与疟疾风险之间的关系，并阐明这一现象背后的宿主和寄生虫因素。我们与巴马科科技大学（USTTB）经验丰富的临床医生和科学家团队密切合作，在马里开展了大规模队列研究。为了扩大我们的工作范围并最大限度地利用我们在马里进行的队列研究所获得的知识，我们与寄生虫生物学、昆虫学、基础免疫学、基因组学和计算生物学方面的专家合作。这些正在进行的项目有助于更全面地了解获得和维持对疟疾的免疫力，也有助于深入了解人类对传染病的免疫反应中起作用的机制。通过几年的仔细观察研究，马里研究地点的疟疾流行病学已经得到了很好的描述，现在可以有效地进行候选疟疾干预措施的临床试验。2022年2月，我们在马里完成了一项剂量递增试验和一项成人随机双盲试验，以测试CIS43LS（一种抗恶性疟原虫的人单克隆抗体）的安全性和有效性。2022年3月，我们在马里启动了一项剂量递增试验和一项针对6-10岁儿童的随机双盲试验，以测试L9LS（第二代人抗恶性疟原虫单克隆抗体）的安全性和有效性。这些临床试验是与Kassoum Kayentao博士（巴马科科学、技术和技术大学）和Robert Seder博士（VRC/NIAID）合作进行的。

Malaria caused by Plasmodium falciparum remains a major public health threat. Over 225 million cases of malaria occur annually among the world's poorest populations, claiming the lives of approximately 500,000 children each year in Africa alone. The widespread implementation of malaria control interventions such as artemisinin-based combination therapy and insecticide-treated bed nets is hampered by the limited health-care infrastructure of many malaria-endemic countries. Moreover, P. falciparum has proven adept at acquiring and rapidly spreading resistance to antimalarial drugs, and vector control is constantly threatened by the inevitability of the emergence of insecticide-resistant mosquitoes. Ultimately, a key tool for the control, elimination, or even eradication of malaria is an effective vaccine. The development of a highly effective malaria vaccine has been hindered in part by a poor understanding of the interaction between P. falciparum and the human immune system. Importantly, protective immunity to malaria can be acquired after repeated P. falciparum infections but wanes rapidly in the absence of ongoing exposure. The quality of the innate and adaptive immune responses that ultimately confers this protection and the mechanisms that underlie their inefficient acquisition and rapid loss are poorly understood. Our objective is to inform the discovery and development of new tools to prevent and treat malaria by addressing these critical knowledge gaps. To this end, we apply recent advances in immunology and genomics-based technology to rigorously conducted longitudinal cohort studies in malaria-endemic areas to deepen our understanding of the interaction between P. falciparum and the human immune system, to define molecular and cellular signatures of malaria immunity and to identify potential malaria vaccine targets. In FY 2022 we continued to pursue five main objectives: 1) obtain high quality clinical data and biospecimens from ongoing longitudinal cohort studies in Mali in which exposure to P. falciparum infection and protection against malaria are reliably assessed, 2) determine the antigen specificity, function, kinetics and cellular basis of the antibody response to P. falciparum, including the isolation of monoclonal antibodies against various stages of the P. falciparum life cycle, 3) define the mechanisms by which P. falciparum-induced inflammation is regulated, 4) identify a molecular signature of immunity to malaria through systems biology approaches, and 5) determine the relationship between persistent asymptomatic P. falciparum infection and malaria risk, and elucidate the host and parasite factors that underlie this phenomenon. The large cohort studies we conduct in Mali are made possible through a close collaboration with an experienced team of clinicians and scientists at the University of Sciences, Techniques & Technologies of Bamako (USTTB). To expand the scope of our work and to maximize the knowledge gained from our cohort studies in Mali, we collaborate with experts in parasite biology, entomology, basic immunology, genomics and computational biology. These ongoing projects are contributing to a more comprehensive understanding of the acquisition and maintenance of immunity to malaria, and also providing insights into the mechanisms at play in human immune responses to infectious diseases more generally. The malaria epidemiology at the study site in Mali has been well characterized through several years of careful observational studies, which now allows for clinical trials of candidate malaria interventions to be efficiently conducted. In February 2022 we completed a a dose-escalation trial and a randomized, double-blind trial of adults in Mali to test the safety and efficacy of CIS43LS, a human monoclonal antibody against Plasmodium falciparum. In March 2022 we initiated a a dose-escalation trial and a randomized, double-blind trial of children aged 6-10 years in Mali to test the safety and efficacy of L9LS, a second-generation human monoclonal antibody against Plasmodium falciparum. These clinical trials are being conducted in collaboration with Dr. Kassoum Kayentao (University of Sciences, Techniques, & Technologies of Bamako), and Dr. Robert Seder (VRC/NIAID).