Mechanisms of naturally-acquired immunity to malaria and clinical trials of anti-malaria monoclonal antibodies

National Institute Of Allergy And Infectious Diseases

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Abstract

Malaria caused by Plasmodium falciparum remains a major public health threat. Over 200 million cases of malaria occur annually among the world's poorest populations, claiming the lives of over 500,000 children each year in Africa alone. In addition, malaria remains a life-threatening threat to travelers to malaria endemic areas. In the US alone there are approximately 2000 cases of malaria among travelers each year. Recently there has also been a return of locally transmitted malaria in the US, with a small number of locally acquired cases of malaria reported in Florida and Texas in 2023. 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 a highly effective vaccine that provides durable protection. 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. One of our objectives 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 targets for malaria vaccines and monoclonal antibodies. The malaria epidemiology at the study sites in Mali has been well characterized through several years of careful observational studies, which has allowed for our more recent focus on conducting clinical trials of malaria interventions. We are conducting several clinical trials at the sites in Mali to test the safety and efficacy of anti-malarial monoclonal antibodies in the context of intense, seasonal malaria transmission. In FY 2025 we continued to pursue six 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, 5) determine the relationship between persistent asymptomatic P. falciparum infection and malaria risk, and elucidate the host and parasite factors that underlie this phenomenon, and 6) evaluate the safety and efficacy of anti-malarial monoclonal antibodies in clinical trials. 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. As noted, the malaria epidemiology at the study sites in Mali has been well characterized through several years of careful observational studies, which has allowed us to conduct the first clinical trials of antimalarial monoclonal antibodies in Africa. During FY 2025 we continued the analysis of several completed and ongoing randomized, double-blind, placebo-controlled trials in Mali to test the safety, efficacy and pharmacokinetics of anti-malaria monoclonal antibodies in adults, children and infants. 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).