Malaria remains a major global health challenge despite the deployment of RTS,S and R21 vaccines targeting the sporozoite surface protein, circumsporozoite protein (CSP). These vaccines provide limited, strain-specific protection, highlighting the need for broader, more robust and durable immunity across diverse Plasmodium species. Although the Plasmodium falciparum proteome encodes over 5,000 proteins, the most effective vaccine targets remain poorly defined. Robust T cell-mediated responses against conserved liver-stage proteins offer strong potential for cross-species protection, but optimal targets are not well established.
To address this, we are conducting a systematic, genome-guided, human-informed approach to rational malaria vaccine design. We profiled immune responses to the full P. falciparum proteome, capturing both T cell and antibody reactivity in individuals with lifelong natural immunity. Antigens were prioritized based on their capacity to elicit T cell or antibody responses. Notably, T cell and antibody targets showed minimal overlap, revealing distinct repertoires for cellular and humoral immunity. We identified physicochemical features that differentiate T cell from antibody targets and used machine learning to build predictive models of immunogenicity from genomic features alone. This analysis yielded a prioritized list of novel T cell antigen candidates, representing the first rationally selected T cell-only malaria vaccine targets.
Antigens with strong T cell but minimal antibody immunogenicity are being evaluated in a murine malaria model using mRNA, plasmid DNA, and a liver-targeted “Prime-Trap” recombinant adenoviral platform. Lead candidates induced robust T cell responses, including liver-resident memory T cells, with immune profiles varying by antigen and vaccine delivery platform. In other studies, the most immunogenic T cell-exclusive antigen conferred significant protection against Plasmodium yoelii sporozoite challenge, with a substantial reduction in liver- and blood-stage burden. These findings validate genome-guided vaccine design and establish a new paradigm for T cell-focused vaccines against challenging pathogens.