Dose-sparing self-amplifying RNA vaccine induces high functional antibodies to blood-stage Plasmodium falciparum malaria

IntroductionNext-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 is a highly promising vaccine candidate. MethodsWe 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 (LNP) and evaluated for immunogenicity in mice in a 3-dose regimen comparing 1 g and 10 g doses. We evaluated the induction of antibodies with functional activities relevant to protective immunity. ResultsOur PfMSP2-saRNA vaccine induced antigen-specific IgG responses that recognised the surface of whole merozoites. Both 1 g and 10 g dosing 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 Fc{gamma}-receptor I (Fc{gamma}RI), after only two doses, which remained consistent after the third dose. ConclusionsPfMSP2 is highly immunogenic using the saRNA vaccine platform in a 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.