Systematic Serological Diversity of a Putative Malaria Vaccine Candidate and Broad Protection

Abstract Comprehensive approaches to determine the most appropriate antigen variants to provide broad protection from malaria are challenging and consequently rarely undertaken. Here we prioritized 27 variants of the novel vaccine candidate PF3D7_1136200 from 1,333 African isolates. We designed a custom protein microarray and systematically profiled IgG and IgM antibodies against these proteins in cohort studies in Burkina Faso, Mali and Kenya. We found only four pairwise amino acid differences between variants, but the proportion seropositive varied widely between 20 and 80%. Hierarchical clustering of the correlation coefficients between all pairs of antigens revealed just three serogroups. An antibody dissimilarity analysis between samples identified six response profiles that largely reflected geographical origin. Combinations of IgG and IgM against two variants from distinct serogroups predicted up to 100% protection against clinical malaria, but the effect varied by geographical location and age. Our novel systematic strategy exploits contemporary sequence data to deduce the handful of antigen variants that have the strongest potential to induce broad protective immunity. This analytical approach is applicable to a wide variety of infectious diseases and can provide a strong evidence base for the design of next-generation vaccines.