Hierarchy of immunogenicity of Plasmodium falciparum merozoite antigens and vaccine candidates in first human infection

Background: Merozoite antigens are targets of acquired immunity and are promising targets for next-generation malaria vaccines and serosurveillance tools. However, the immunogenicity of each antigen and their induction of antibodies following infection remains unclear, impacting vaccine design, antigen selection in serosurveillance, and our understanding of naturally-acquired immunity. Methods: To address this, we assessed IgG and IgM responses to whole merozoites and individual merozoite antigens in 81 malaria-naive adults who experienced a blood-stage P. falciparum Controlled Human Malaria Infection (CHMI). Results: Significant acquisition of IgG and IgM against whole merozoites could be detected as early as two weeks after infection. For IgG responses, a strong hierarchy of immunogenicity among merozoite antigens was observed, with several prominent antigen targets. In contrast, IgM was acquired to most antigens and was less hierarchical with a broader and less antigen-dominant acquisition profile. Participants clustered into distinct immune-acquisition groups according to the breadth and magnitude of their antibody responses, suggesting that individual variation in the development of malaria immunity begins as early as first exposure. Conclusions: Our findings provide important insights into the immunogenicity of merozoite antigens under consideration for vaccine development and identify antigens that could be used in the development of malaria sero-surveillance tools