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). The passive transfer of malaria immunity confers protection, suggesting that a vaccine that induces immune responses similar to those induced by NAI could effectively stop malaria pathogenesis. While both T-cell and B-cell responses play a role in NAI against malaria, focusing 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 provide the basis for creating novel engineered immunogens that can 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 FY25, we published a study in Cell Reports Medicine examining Plasmodium falciparum apical membrane antigen 1 (AMA1) that is crucial for malaria parasite invasion of red blood cells and a major target for vaccine and antibody development. This study provided new structural and immunological insight into naturally acquired human antibody response to malaria, enhanced our understanding of AMA1 immunity and identified new broadly neutralizing epitopes. Synergistic enhancement of parasite neutralization was observed when two of these newly identified antibodies were combined. The discovery of strain-transcending epitopes in AMA1 and synergistic antibody combinations provides new mechanisms to develop potent and durable vaccines and antibody therapeutics for malaria. We also published a review of the recent advancements in the structure and immunological understanding of the P. falciparum PTRAMP, CSS, RH5, CyRPA, and RIPR (PCRCR) multiprotein complex. The Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) binds to basigin on host red cells and RH5 is a crucial target for malaria vaccines and neutralizing antibodies. The review highlights the importance of targeting conserved epitopes on RH5 to enhance vaccine efficacy and outlines how antibody interactions can modulate parasite neutralization, either enhancing or hampering it. The publication underscores the complexity of antibody-mediated neutralization and emphasizes the potential for developing next-generation vaccines and prophylactic antibodies to combat malaria effectively.