Human monoclonal antibodies targeting infectious pathogens

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

The overarching goal of this project is to study the immune response to pathogens at the monoclonal level to increase our understanding of basic biology and develop new tools to combat disease. We are currently focusing our efforts on human monoclonal antibodies against two pathogens, Plasmodium falciparum and SARS-CoV-2. The SARS-CoV-2 work is described in the accompanying report. For P. falciparum, we are in the process of setting up high-throughput assays to screen for antibodies against various stages of the life cycle, including sporozoites, blood stages and sexual stages. In FY21, we developed a novel pipeline to study the IgA antibody response to P. falciparum sporozoites. IgA antibodies play a critical role in protection against mucosal pathogens, but their role in immunity to nonmucosal pathogens, such as Plasmodium falciparum, is poorly understood. We investigated the human IgA response to P. falciparum sporozoites and found that circulating IgA was induced in three independent sporozoite-exposed cohorts: Malian individuals living in an endemic region, malaria-nave individuals immunized with three doses of radiation-attenuated sporozoites, and malaria-naive individuals exposed to a single controlled mosquito bite infection. We found in a mouse model that IgA responses were triggered by sporozoites at dermal inoculation sites. From two malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the N-terminus of the P. falciparum circumsporozoite protein (CSP), the dominant protein on the sporozoite surface. This work revealed a role for circulating IgA in malaria and identified the N-terminus of the circumsporozoite protein as a target of functional antibodies, supporting further exploration of this region as a vaccine candidate. We have also started studies to look at the antibody response to blood-stage P. falciparum, as well as to non-CSP antigens on the sporozoite surface, to explore alternative targets to CSP, which is the leading antigen in subunit vaccine development thus far.