Mechanisms of effective antibody neutralization

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

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 FY2022, we prioritized human monoclonal antibodies derived by LIG from individuals with naturally acquired immunity against two key blood-stage malaria antigens. 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. As described in Scientific Advances below, we published a study in Nature Communications defining the structural and mechanistic basis for an immune evasion mechanism termed antigenic diversion created by these diverse human antibodies. We also continue to examine human monoclonal antibodies derived from clinical trials conducted by LMIV, where adults were immunized with two distinct transmission-blocking vaccine candidates. We evaluated the functional activity of these monoclonal antibodies and characterized their binding to antigens by epitope binning. Furthermore, we revealed the binding epitopes of these monoclonal antibodies at the atomic level. By integrating these new findings, we were able to generate a functional activity map that covers most of the surface of each antigen, revealing surface regions on which the antigen is functional. 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.