353 Harnessing computational tools to rank vaccine targets in <i>Plasmodium falciparum</i> candidate antigens

Objectives/Goals: We aim to predict and rank conserved, immunogenic targets within key malaria proteins using computational tools. These tools incorporate parasite protein diversity and regional HLA allele frequencies to prioritize antigens for further validation and inclusion in a malaria vaccine targeting circulating strains. Methods/Study Population: We identified 42 conserved malaria proteins with nonredundant functions for P. falciparum invasion and transmission as vaccine targets. Protein sequence datasets were constructed from samples collected in highly endemic areas. We predicted targets most likely to be presented to CD4+ and CD8+ T cells. We designed and used heuristic-based and AI-weighting models that integrated predicted binding affinities to HLA alleles, HLA allele frequency data, and sequence conservation to score and rank targets. We validated our model by comparing predicted epitope distributions with published in vitro and in vivo immunogenicity data available in the Immune Epitope Database and Tools repository. Results/Anticipated Results: We successfully predicted and ranked targets within the vaccine candidate proteins, identifying conserved and HLA-nonspecific targets that correspond to positive immunogenicity data, validating our approach. We are currently analyzing model performance by comparing predictions to over 5,800 experimentally validated P. falciparum targets from clinical trials and immune assays. We will evaluate each models’ accuracy and ability to prioritize targets and compare their performances as measured quantitatively by precision and area under the curve metrics. We expect the AI-based model to significantly outperform the heuristic approach, improving the identification of effective vaccine targets. Discussion/Significance of Impact: By incorporating parasite diversity and regional HLA allele frequencies, our approach addresses the challenge of directing the human immune response against genetically diverse P. falciparum strains in highly endemic areas. This strategy could significantly enhance malaria vaccine efficacy and can be adapted for use against other pathogens.