T cell responses against liver stage Plasmodium help protect against reinfection, but the antigens and epitopes targeted by these T cells are largely unknown. This knowledge gap has impeded mechanistic studies to identify the effector functions most critical for protection. We performed a bioinformatic analysis of gene expression datasets to identify plasmodial genes that are highly and selectively expressed during liver stage infection and predict epitopes within them likely to bind MHC-II molecules prevalent in Uganda. We then tested their recognition by malaria-exposed Ugandan children. In over two-thirds of the children, we detected a peripheral blood CD4+ T cell response to one or more antigens. The most highly targeted antigen, LISP1, contained several epitopes, including one that was promiscuously presented and recognized by most participants. These novel liver stage P. falciparum epitopes should be explored as potential vaccine targets and will facilitate the development of tools to interrogate antimalarial immunity at the single-cell level and inform future vaccine development efforts.
Copyright: © 2025 Acevedo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.