Protective targets of PfSPZ vaccines identified from whole-genome sieve analysis of isolates from malaria vaccine efficacy trials in West Africa.

Identification of antigens targeted by a protective response is a central quest in malaria vaccinology. Whole-genome sieve analysis (SAWG) in samples collected from placebo-controlled field trials of Plasmodium falciparum (Pf) sporozoite (SPZ) vaccines may enable identification of Pf pre-erythrocytic antigens. We applied SAWG to genomic data generated from Pf isolates collected during two field trials measuring the efficacy, in malaria-exposed African adults, of two PfSPZ vaccines. These randomized, double-blind, placebo-controlled trials were conducted in regions of Mali and Burkina Faso characterized by high seasonal transmission, where parasite genetic diversity is high. Genomic sites in which the vaccine allelic state was significantly underrepresented among breakthrough infections in vaccinees relative to placebo recipients were termed "target sites". Protein-coding loci containing target sites that changed amino acids were termed "target loci". The SAWG conducted on clinical trial samples from the Burkina Faso and Mali trials identified 138 and 80 single-copy protein-coding target loci in the Burkinabe and Malian data sets, respectively, with twelve common to both, a number significantly higher than expected (E = 3.9; 99%CI = [0, 9]). Among these was the thrombospondin-related anonymous protein locus, which encodes PfSSP2|TRAP, one of the most abundant and well-characterized pre-erythrocytic stage antigen as well as other genes encoding membrane-associated proteins of unknown function. These results identify SAWG as a potentially powerful tool for identifying protective vaccine antigens in recombining pathogens with large genome size and reveals potential new protective Pf antigens.