Whole-genome sieve analysis: Identification of protective malaria antigens by leveraging allele-specific vaccine efficacy.

Discovery of new protective malaria antigens will enable the development of novel vaccine formulations with potentially higher efficacy. While several high-throughput experimental approaches enable the identification of novel immunogens, none so far has been designed to selectively identify protective antigens. Here, we propose that sieve analysis conducted on the whole genome (SAWG) can be used specifically for this purpose. We review available medium- to high-throughput methods for antigen identification and contextualize the need for the identification of protective antigens. We then provide the rationale for why SAWG is ideally suited for the identification of protective antigens in recombining pathogens with large genome size, describe conditions for optimal use, and discuss potential pitfalls. Most importantly, this approach can be applied to the discovery of new protective targets in any recombining organism for which there is a whole organism-based vaccine that can be safely deployed in a disease-endemic region.