Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies

Sean Yanik, Varsha Venkatesh, Michelle L. Parker, Raghavendran Ramaswamy, Ababacar Diouf, Deepti Sarkar, Kazutoyo Miura, Carole A. Long, Martin J. Boulanger and Prakash Srinivasan ()
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Sean Yanik: Johns Hopkins School of Public Health
Varsha Venkatesh: Johns Hopkins School of Public Health
Michelle L. Parker: University of Victoria
Raghavendran Ramaswamy: University of Victoria
Ababacar Diouf: Laboratory of Malaria and Vector Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health
Deepti Sarkar: Johns Hopkins School of Public Health
Kazutoyo Miura: Laboratory of Malaria and Vector Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health
Carole A. Long: Laboratory of Malaria and Vector Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health
Martin J. Boulanger: University of Victoria
Prakash Srinivasan: Johns Hopkins School of Public Health

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Invasion of human erythrocytes by Plasmodium falciparum (Pf) merozoites relies on the interaction between two parasite proteins: apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2). While antibodies to AMA1 provide limited protection against Pf in non-human primate malaria models, clinical trials using recombinant AMA1 alone (apoAMA1) yielded no protection due to insufficient functional antibodies. Immunization with AMA1 bound to RON2L, a 49-amino acid peptide from its ligand RON2, has shown superior protection by increasing the proportion of neutralizing antibodies. However, this approach relies on the formation of a complex in solution between the two vaccine components. To advance vaccine development, here we engineered chimeric antigens by replacing the AMA1 DII loop, displaced upon ligand binding, with RON2L. Structural analysis confirmed that the fusion chimera (Fusion-FD12) closely mimics the binary AMA1-RON2L complex. Immunization studies in female rats demonstrated that Fusion-FD12 immune sera, but not purified IgG, neutralized vaccine-type parasites more efficiently compared to apoAMA1, despite lower overall anti-AMA1 titers. Interestingly, Fusion-FD12 immunization enhanced antibodies targeting conserved epitopes on AMA1, leading to increased neutralization of non-vaccine type parasites. Identifying these cross-neutralizing antibody epitopes holds promise for developing an effective, strain-transcending malaria vaccine.

Date: 2023
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DOI: 10.1038/s41467-023-41636-5

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