Mechanisms of effective antibody neutralization

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Malaria causes hundreds of thousands of deaths per year, but many adults in endemic regions are protected from the clinical manifestation of disease by naturally acquired immunity (NAI). Passive transfer of malaria immunity confers protection, suggesting that a vaccine inducing immune responses similar to NAI could effectively stop malaria pathogenesis. While both T-cell and B-cell responses play a role in NAI to malaria, focusing the B-cell responses on conserved broadly-neutralizing functional epitopes significantly improves protection and may lead to sterile immunity. However, three aspects of parasite biology confound malaria vaccine development: (1) antigenic variability, (2) the presence of immunodominant but non-neutralizing epitopes in antigens, and (3) the diverse and numerous parasite antigens required for the three independent stages of the life cycle. These hurdles can now be overcome due to major advances in technology enabling structural definition of neutralizing epitopes in key malaria antigens. This work will ultimately inform structure-guided design of immunogens for malaria vaccine development. We propose to reliably identify epitopes targeted by neutralizing antibodies and define the components required to elicit a strong broadly-neutralizing immune response to malaria. These studies would form the basis for creating novel engineered immunogens that will harness the immune system more effectively to protect against both Plasmodium falciparum and Plasmodium vivax, the two species causing the majority of malaria cases. In recent years, research has identified parasite surface proteins that are required for parasite viability and can potentially elicit a neutralizing antibody response. While antibodies targeting these surface proteins can reduce viability, only a subset of antibodies that bind to these vaccine candidates are neutralizing, and an even smaller subset are broadly-neutralizing against diverse parasite strains. In addition, a complete halt of disease progression will require targeting of multiple parasite proteins simultaneously, due to the functional redundancy within and across protein families available to the parasite. There is a significant gap in our understanding of the neutralizing potential of epitopes. In the absence of this knowledge, efficient vaccine design to prevent the pathogenesis of malaria will be severely hampered. In FY2023, we published a study in Nature Communications describing human monoclonal antibodies derived by LIG from individuals with naturally acquired immunity against the malaria vaccine antigen MSP1. At least two classes of monoclonal antibodies were identified: neutralizing antibodies that prevent parasite growth and interfering non-neutralizing antibodies that hindered the neutralizing antibody from functioning. These studies defined the structural and mechanistic basis for an immune evasion mechanism termed antigenic diversion created by these diverse human antibodies. We also published the human antibody epitope maps of the key transmission blocking vaccine antigens Pfs230D1 and Pfs25 in the journals Immunity and NPJ Vaccines respectively. These studies integrated structural and functional data for human monoclonal antibodies derived from clinical trials conducted by LMIV where adults were immunized with two distinct transmission-blocking vaccine candidates. The Pfs230D1 human antibody epitope map established binary antibody combinations that synergized for highly effect transmission blocking activity and formed a clear map for the structure-based design of Pfs230D1 for highly effective and durable transmission blocking vaccines. Similarly, the Pfs25 human antibody epitope map identified novel epitopes and surfaces on Pfs25 that could be targeted for transmission blocking vaccine design. Lastly, we contributed to two collaborative studies published in Frontiers in Cellular and Infection Microbiology and PLoS Neglected Tropical Diseases examining the immune response to key P. vivax antigens. Identifying strongly neutralizing epitopes and eliminating weakly- or non-neutralizing epitopes is fundamental to the design of effective malaria vaccines. New immunogens are being designed to eliminate or shield weakly- or non-neutralizing epitopes, while preserving or promoting strongly-neutralizing epitopes; this effort will leverage our existing data, studies, and publications.