Mechanisms of naturally-acquired immunity to malaria

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

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).