Targeting a malaria merozoite surface protein with mRNA vaccine generates multifunctional antibodies

Abstract Introduction Malaria is a leading health problem with high disease burden and mortality rates worldwide. Currently approved vaccines target the sporozoite form of Plasmodium falciparum that initially infects the liver, but only provide modest protection against malaria in young children. There is an urgent need to develop next-generation malaria vaccines that target multiple parasite developmental stages for greater efficacy. Antibodies to merozoites, which are involved in blood-stage replication, and are associated with clinical illness, have multiple functional activities and can protect against malaria. A promising merozoite vaccine candidate is Merozoite Surface Protein 2 ( Pf MSP2). Antibodies to Pf MSP2 can promote multiple antibody Fc-mediated functional activities to clear merozoites. Methods We developed and evaluated monovalent and bivalent (3D7 and FC27 variants) Pf MSP2-based mRNA vaccines. We designed and codon-optimised mRNA, which was validated for in vitro expression in mammalian cells, and subsequently formulated as lipid nanoparticles for vaccination of mice in a 3-dose regimen. Vaccination with recombinant Pf MSP2 protein with adjuvant was performed for comparison. We evaluated the induction of antibodies and functional activities relevant to protective immunity. Results mRNA vaccines induced prominent IgG responses using monovalent (3D7 allele) and bivalent (3D7 and FC27 alleles) vaccines encoding near full-length Pf MSP2, and antibodies recognised the surface of whole merozoites. Vaccine responses were equivalent to, or superior than, a recombinant protein-based Pf MSP2 vaccine. The bivalent vaccine induced equivalent antibodies to the two Pf MSP2 alleles. Vaccination induced cytophilic IgG subclasses with multiple functional activities, including complement fixation, binding of human Fcγ-receptors I and IIa, and opsonic phagocytosis. Conclusions Pf MSP2 is highly immunogenic using the mRNA vaccine platform and induces antibodies with multiple functional activities associated with protective immunity in humans. Combining Pf MSP2 with other merozoite and sporozoite antigens is a promising strategy to develop highly efficacious vaccines to achieve malaria control and elimination goals.