An mRNA Vaccine Expressing Blood-Stage Malaria Antigens Induces Complete Protection Against Lethal .

BACKGROUND AND OBJECTIVES

To evaluate the mRNA vaccine platform for blood-stage parasites, we completed a proof-of-concept study using the mouse model of malaria and two mRNA-based vaccines. Both encoded MSP1 fused to MSP8 (MSP1/8). One was designed for secretion of the encoded protein (MSP1/8-sec); the other encoded membrane-bound antigen (MSP1/8-mem).

METHODS

Secretion of MSP1/8-sec and membrane localization of MSP1/8-mem were verified in mRNA-transfected cells. As recombinant MSP1/8 (rMSP1/8) is known to protect mice against lethal 17XL infection, we first compared immunogenicity and efficacy of the MSP1/8-sec mRNA vaccine versus the recombinant formulation in outbred mice. Animals were immunized three times followed by challenge with a lethal dose of 17XL-parasitized RBCs (pRBCs). Similar immunization and challenge experiments were conducted to compare MSP1/8-sec versus MSP1/8-mem mRNA vaccines.

RESULTS

Immunogenicity of the MSP1/8-sec mRNA vaccine was superior to the recombinant formulation, inducing higher antibody titers against both vaccine components. Following challenge with 17XL pRBCs, all MSP1/8-sec-immunized animals survived, with 50% of these showing no detectible pRBCs in circulation (<0.01%). In addition, mean peak parasitemia in MSP1/8-sec mRNA-immunized mice was significantly lower than that in the rMSP1/8 vaccine group. Both MSP1/8-sec and MSP1/8-mem were protective against 17XL challenge, with MSP1/8-mem immunization providing a significantly higher level of protection than MSP1/8-sec immunization considering the number of animals with no detectable pRBCs in circulation and the mean peak parasitemia in animals with detectable parasitemia.

CONCLUSIONS

mRNA vaccines were highly immunogenic and potently protective against blood-stage malaria, outperforming a similar recombinant-based vaccine. The membrane-bound antigen was more effective at inducing protective antibody responses, highlighting the need to consider antigen localization for mRNA vaccine design.