An antigen-agnostic approach to understanding antibody responses against blood-stage Plasmodium falciparum 2309989

Abstract Introduction Malaria is a deadly disease that has been managed using approaches that target the mosquito vector or the parasite within the host. However, the emergence of resistance in both the mosquito and parasite has highlighted the need for novel interventions. The discovery of potent monoclonal antibodies (mAbs) against blood-stage Plasmodium falciparum merozoite antigens has elucidated mechanisms of red blood cell invasion and facilitated new clinical developments such as the development of the RH5 vaccine. More, however, remains to be uncovered regarding the merozoite membrane antigenic landscape and its interactions with the human humoral immune system. Methods Here, we use an antigen-agnostic approach to study the human antibody response to merozoite membrane antigens after natural malaria infection. We evaluated circulating antibody reactivity in a Malian cohort to P. falciparum merozoites. To exclude donors that had high reactivity to MSP1, an immunodominant polymorphic antigen on the merozoite surface, we included a pre-blocking step with this antigen. We identified individuals that retained high antibody reactivity to merozoites despite MSP1 blocking. These individuals have been selected for isolation of mAbs targeting merozoites in an antigen-agnostic manner using the Beacon optofluidic system. Results We have started screening B cells for merozoite reactivity from these donors of interest. From a single donor, we have isolated four unique mAbs. These mAbs bound merozoites to varying degrees and will be tested for neutralization using a growth inhibition assay. Conclusion Future work includes screening more donors, identifying target antigens from strong neutralizing mAbs, and performing structural studies to identify key antibody-antigen contact residues. Funding Source This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)