Enhancing T and B cell responses to Plasmodium infection and vaccination via IL-15

Malaria, which results from infection with Plasmodium parasites, is a significant global health problem with nearly 250 million clinical cases and over 600,000 deaths annually worldwide. With growing anti-malarial drug and insecticide resistance, new therapeutic strategies and highly effective vaccines are urgently needed. Protection against symptomatic disease develops after years of repeated exposures to Plasmodium parasites. However, there is no definitive evidence of long-lived, sterilizing immunity in humans following repeated exposure to Plasmodium parasites, and clinical immunity to malaria rapidly wanes in the absence of re- infection. Similarly, the limited protection offered by the most advanced malaria vaccines lose efficacy quickly in malaria endemic areas. Dysregulated inflammation is thought to contribute to the short-lived response to Plasmodium. The cellular processes impairing the acquisition and maintenance of cellular and humoral immunity to Plasmodium are not known. Therapies that boost the robustness and durability of the immune response could be transformative in vaccine development.

This project centers on investigating an IL-15 cytokine-based therapy that enhances the immune response to Plasmodium infection and vaccination. The proposed studies will utilize novel peptide:MHC class II and B cell tetramers in experimental Plasmodium infection and vaccination mouse models. It was found out that in the context of Plasmodium infection in mice, IL-15 therapy promotes the differentiation of T follicular helper (Tfh) cells, which are critical for promoting long-lived and high-quality antibody responses. In the context of whole sporozoite Plasmodium vaccination, IL- 15 therapy increases the number of liver-resident CD8 T memory (Trm) cells and antibody levels, suggesting that IL-15 could be harnessed as an adjuvant to enhance Plasmodium vaccine immunogenicity. These studies will define the mechanistic pathways induced by IL-15 treatment that enhance Plasmodium control to both understand the disease more completely and develop therapies that exploit these pathways. Overall, these studies will deliver foundational knowledge of the naturally-acquired and vaccine-elicited immune response to Plasmodium. This information will be leveraged for the rational design of vaccination strategies to improve anti-Plasmodium immunity.

NIH Project details

Vaccines (Immune Correlates)

Jun 2024 — Apr 2029

$556,832

United States