Circular RNA vaccines encoding Pvs25 induce antibodies that block Plasmodium vivax transmission

Plasmodium vivax is a major malaria parasite that causes acute illness in millions of people each year. Transmission-blocking vaccines (TBVs) could contribute substantially to malaria elimination, although none has yet been approved. We previously demonstrated that a nucleoside-modified mRNA-lipid nanoparticle (mRNA-LNP) vaccine targeting Pvs25, a leading P. vivax TBV antigen, elicited potent and durable transmission-blocking immunity in mice. Emerging evidence suggests that circular RNA (circRNA) may enhance RNA stability, prolong antigen expression, and potentially reduce manufacturing costs compared with conventional linear mRNA. We therefore developed and evaluated two circular Pvs25 RNA-LNP vaccines: one encoding wild-type Pvs25 and another encoding Pvs25 fused to the MHC class I trafficking domain (MITD). Their immunogenicity and functional activity were compared with those of a linear nucleoside-modified Pvs25 mRNA-LNP vaccine. In mice, a single immunization with either the circular RNA or linear mRNA Pvs25 vaccine induced detectable Pvs25-specific antibodies, while booster immunization substantially increased antibody titers and resulted in complete inhibition of P. vivax development in mosquitoes. Both vaccines also elicited robust Pvs25-specific antibody-secreting cell response and cytokine-producing cellular responses. Together, these findings demonstrate the potential of circRNA as a platform for malaria vaccine development and support further evaluation in non-human primates.