Malaria remains a significant health problem in many tropical and sub-tropical regions. The development of
vaccines against the clinically active blood-stage of
infection needs to consider variability and polymorphism in target
antigens, and an adjuvant system able to induce broad spectrum immunity comprising both
antibodies and helper T cells. Moreover, recent studies have shown some conventional pro-inflammatory adjuvants can also promote expansion of immunosuppressive regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC), both of which could negatively impact
malaria disease progression. Herein, we explore the ability of a model nanoparticle delivery system (
polystyrene nanoparticles; PSNPs), previously proven to not induce conventional
inflammation, Treg or MDSC, to induce immunity to MSP4/5 from Plasmodium yoelii, a member of the MSP4 and MSP5 family of
proteins which are highly conserved across diverse
malaria species including P. falciparum. The results show PSNPs-MSP4/5 conjugates are highly immunogenic, inducing immune responses comprising both T helper 1 (Th1) and Th2 cellular immunity, and a spectrum of antibody subclasses including
IgG1,
IgG2a, and
IgG2b. Benchmarked against
Alum and Complete
Freund's Adjuvant (CFA), the immune responses that were induced were of comparable or higher magnitude, for both T cell frequencies by ELISpot and antibody responses in terms of ELISA end titer. Importantly, immunization with PSNPs-MSP4/5 induced partial protection against
malaria blood-stage
infection (50-80%) shown to be mechanistically dependent on
interferon gamma (IFN-γ) production. These results expand the scope of adjuvants considered for
malaria blood-stage
vaccine development to those that do not use conventional adjuvant pathways and emphasizes the critical role of cellular immunity and specifically IFN-γ producing cells in providing moderate protection against blood-stage
malaria comparable to
Freunds adjuvant.