Population HLA coverage of experimentally characterized P. falciparum CD8 ⁺ T cell epitopes as potential components of a multi-epitope malaria vaccine construct: an in silico insight

Objective: Malaria remains a significant global health challenge, with Plasmodium falciparum causing the most severe cases and deaths, particularly in sub-Saharan Africa. An effective universal or pan vaccine is needed to augment current concerted control efforts. This in silico study investigated the global population coverage of human leukocyte antigen (HLA) that recognize experimentally validated CD8⁺ T cell epitopes derived from three P. falciparum antigens (CSP, AMA1 and TRAP), focusing on their potential for inclusion in a globally effective multi-epitope malaria vaccine. Methodology: Sixteen experimentally validated CD8⁺ T cell epitopes, together with the HLA typing data of study participants were curated from our previously published work. Using the Immune Epitope Database and Analysis conservancy and population coverage tool, the epitopes were analyzed for their conservancy and ability to bind HLA alleles from fourteen geographic subregions and seventy-eight countries. Result: CSPep1, CSPep2, CSPep4, CSPep6, CSPep9, CSPep10, CSPep11, and TRAPep1 were 100% conserved across the sixteen strains of P. falciparum while the other epitopes had conservancy of 55% or more. The CSP-derived epitope IQNSLSTEW (CSPep5) demonstrated the highest epitope coverage globally (>85%) and in West Africa (93.35%). In contrast, ILSVSSFLF (CSPep4) showed minimal coverage (<5% in Africa, <2% in other populations), and these highlight the impact of HLA diversity on epitope recognition. LLACAGLAYK (TRAPep1) and STEWSPCSV (CSPep10) had >50% population coverage but were highly conserved across diverse P. falciparum strains. Spearman’s correlation clustering shows three distinct clusters of epitopes with similar HLA coverage across the subregions. Conclusion: These findings highlight the importance of integrating host HLA binding promiscuity and parasite epitope conservation in developing universal or pan multi-epitope malaria vaccines. By combining conserved epitopes with broad HLA coverage, this approach promotes wide immune recognition while limiting strain-specific immune evasion. Incorporating relevant HLA class II and antibody epitopes could further enhance immune responses, providing effective protection for both children in malaria-endemic regions and malaria-naïve travelers.