Novel antigen discovery by proteome-wide screening of CD4 and CD8 T cell epitopes using P. falciparum as a model (53.14)

Abstract

Abstract For many complex pathogens, the targets of cellular immunity are largely unknown and correlates of protection after exposure or immunization are unclear. A major challenge for rational vaccine development is to identify the key antigens and epitopes targeted by protective immune responses. Using malaria as a model, we are addressing this problem using an integrated approach that incorporates bioinformatic predictions, HLA supertype considerations, high-throughput MHC peptide binding assays, and cellular assays. Antigens and epitopes can be prioritized on the basis of frequency and magnitude of immune responses, and responses to novel proteins ranked against characterized antigens already in clinical development. This strategy has allowed us to identify a number of novel immunoprevalent target antigens from P. falciparum that are recognized frequently and in the context of multiple genetic restrictions. Many of these antigens are more immunogenic than antigens identified historically, and at least one has been confirmed as a target of cross-species protection. These antigens and their epitopes represent promising candidates for next generation vaccine development. Additionally, data provide important information on the patterns of immunodominance following exposure to a complex pathogen.