Plasmodium falciparum Cysteine-Rich Protective Antigen (CyRPA) Elicits Detectable Levels of Invasion-Inhibitory Antibodies during Natural Infection in Humans.

Plasmodium falciparum Cysteine-Rich Protective Antigen (CyRPA) is a conserved component of an essential erythrocyte invasion complex (RH5/Ripr/CyRPA) and a target of potent cross-strain parasite-neutralizing antibodies. While, naturally acquired human RH5 antibodies have been functionally characterized, there are no similar reports on CyRPA. Thus, we analyzed the parasite neutralizing activity of naturally acquired human CyRPA antibodies. In this regard, CyRPA human antibodies were measured and purified from malaria infected sera obtained from central India and analyzed for their parasite neutralizing activity in in vitro growth inhibition assays (GIA). We report that despite being susceptible to antibody, CyRPA being a highly conserved antigen does not appear to be under substantial immune selection pressure as a very low acquisition of anti-CyRPA antibodies was reported in malaria-exposed Indians. We demonstrate for the first time that the low amounts of natural CyRPA antibodies exhibited functional parasite-neutralizing activity and that a CyRPA based vaccine formulation induces highly potent antibodies in rabbits. Importantly, the vaccine induced CyRPA antibodies exhibited a robust IC50 of 21.96 μg/ml that is comparable to IC50 of antibodies against the leading blood stage vaccine candidate, RH5. Our data support CyRPA as a unique vaccine target that is highly susceptible to immune attack but highly conserved compared to other leading candidates such as MSP-1, AMA-1, further substantiating its promise as a leading blood-stage vaccine candidate.