Distinct immunogenicity outcomes of DNA vaccines encoding malaria transmission-blocking vaccine target antigens Pfs230D1M and Pvs230D1

Transmission-blocking vaccines (TBVs) targeting sexual-stage antigens represent a critical tool for malaria control and elimination through inhibiting parasite development within mosquitoes. P230, displayed on the surface of gametocytes and gametes, plays a crucial role in gamete fertilization and is one of the leading TBV candidates for both Plasmodium falciparum and P. vivax. Antibodies induced by immunization with a recombinant P. falciparum protein encompassing a portion of N-terminal prodomain and domain 1 (Pfs230D1M) have revealed strong transmission-reducing activity (TRA) in preclinical studies. While a recombinant Pvs230D1, the P. vivax homolog of Pfs230D1M, has not been evaluated in preclinical immunogenicity studies, both Pfs230D1M and Pvs230D1 are currently scheduled for evaluation in clinical trials. In this study, we developed DNA vaccines encoding Pfs230D1M and Pvs230D1 for a side-by-side comparison of their immunogenicity. Potent antibody responses were induced in mice immunized with each DNA vaccine delivered by in vivo electroporation (EP). Anti-Pfs230D1M IgG exhibited potent dose-dependent TRA in a complement-dependent manner in standard membrane feeding assays (SMFA). In contrast, anti-Pvs230D1 IgG exhibited only moderate TRA in direct membrane feeding assay (DMFA) using blood from multiple P. vivax-infected donors. Antibodies induced by the Pfs230D1M DNA vaccine revealed a strong IgG1 bias and higher avidity as compared to a balanced IgG1/IgG2 response and lower antibody avidity by the Pvs230D1 DNA vaccine. Our results demonstrate the potential of both Pfs230D1M and Pvs230D1 DNA vaccines as TBV candidates against P. falciparum and P. vivax, and provide a rationale for future optimization to enhance the efficacy of DNA vaccines based on Pfs230 and Pvs230.