Evaluating a Potential Dose-Sparing Self-Amplifying RNA Vaccine for Induction of Functional Antibodies to Blood-Stage Plasmodium falciparum Malaria

Introduction: Next-generation malaria vaccines are urgently needed to provide greater efficacy and longevity. Antibodies targeting blood-stage merozoites can confer protection against clinical malaria through multiple Fc-mediated functions. In particular, merozoite surface protein 2 (PfMSP2) is a known target of protective antibodies that can clear merozoites via multiple antibody Fc-mediated functions, making it a highly promising vaccine candidate. Methods: We developed PfMSP2 as a self-amplifying RNA (saRNA) vaccine, which was successfully validated for in vitro expression in mammalian cells. Subsequently, the PfMSP2-saRNA was formulated as lipid nanoparticles (LNPs) and evaluated for immunogenicity in mice following a three-dose regimen comparing 1 μg and 10 μg doses. We evaluated the induction of antibodies with functional activities relevant to protective immunity. Results: Our PfMSP2-saRNA vaccine induced antigen-specific IgG responses that recognised the surface of whole merozoites. Both 1 μg and 10 μg dosing regimens induced comparable antibodies to PfMSP2, and responses were predominantly murine cytophilic IgG subclasses. These vaccine-induced antibodies demonstrated potent Fc-mediated functions, including complement fixation and binding of human Fcγ-receptor I (FcγRI), after only two doses, which remained consistent after the third dose. Conclusions: PfMSP2 is highly immunogenic using the saRNA vaccine platform in a potential dose-sparing regimen, and induces antibodies with multiple Fc-mediated functions associated with protective immunity in humans. This saRNA platform is a promising strategy to develop highly efficacious vaccines requiring lower and fewer doses.