New antigens for a multicomponent blood-stage malaria vaccine

Uncharacterized proteins from the merozoite stage of Plasmodium falciparum provide new antigens for malaria blood-stage vaccine development. Combine and Conquer Malaria vaccine development has been hampered by the inability to produce high-quality recombinant proteins for immunological studies. In a new study by Osier and colleagues, this constraint was overcome by systematically testing a library of biochemically active malaria parasite proteins in Kenyan children naturally exposed to malaria. The authors identified new proteins with superior or equivalent potential protective efficacy compared to established vaccine candidates. Moreover, cumulative responses to combinations of 5 of the top 10 ranked antigens correlated with 100% protection against malaria. These data suggest that there are potentially many more vaccine targets and that effective vaccination may be achieved through combinations of the best of these. An effective blood-stage vaccine against Plasmodium falciparum remains a research priority, but the number of antigens that have been translated into multicomponent vaccines for testing in clinical trials remains limited. Investigating the large number of potential targets found in the parasite proteome has been constrained by an inability to produce natively folded recombinant antigens for immunological studies. We overcame these constraints by generating a large library of biochemically active merozoite surface and secreted full-length ectodomain proteins. We then systematically examined the antibody reactivity against these proteins in a cohort of Kenyan children (n = 286) who were sampled at the start of a malaria transmission season and prospectively monitored for clinical episodes of malaria over the ensuing 6 months. We found that antibodies to previously untested or little-studied proteins had superior or equivalent potential protective efficacy to the handful of current leading malaria vaccine candidates. Moreover, cumulative responses to combinations comprising 5 of the 10 top-ranked antigens, including PF3D7_1136200, MSP2, RhopH3, P41, MSP11, MSP3, PF3D7_0606800, AMA1, Pf113, and MSRP1, were associated with 100% protection against clinical episodes of malaria. These data suggest not only that there are many more potential antigen candidates for the malaria vaccine development pipeline but also that effective vaccination may be achieved by combining a selection of these antigens.