mRNA vaccination overcomes hemozoin-mediated impairment of whole parasite vaccine efficacy for malaria
Year: 2025
Type: preprint
Abstract: ABSTRACT Malaria is a persistent global public health threat. Immunization with Radiation Attenuated Sporozoites (RAS) drives efficient CD8+ T cell dependent sterilizing immunity to malaria in humans. However, this protection is compromised in individuals living in malaria endemic regions and the mechanism(s) of the vaccine failure remain incompletely understood. In this study, we develop a murine model of Plasmodium infection where prior blood-stage exposure compromises RAS-induced CD8+ T cell responses and subsequent protection. We further identify the persisting malarial pigment hemozoin as a mediator of impaired CD8+ T cell responses. Mechanistically, we link this defect to impaired antigen uptake by dendritic cells, leading to reduced T cell activation. Importantly, we designed a lipid nanoparticle-encapsulated mRNA vaccine that encodes a string of Plasmodium CD8+ T cell epitopes and found that this vaccine overcomes the T cell defect and restores protection in Plasmodium exposed mice. Moreover, a combined RAS+mRNA vaccine regimen enhances liver resident memory T cells and protection even in malaria experienced hosts. These findings support the identification of hemozoin as a long-lived obstacle to vaccine efficacy in malaria endemic areas and provide a rational framework for designing malaria vaccines that are effective in endemic settings.
Institution: University of Iowa
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Environmental Health Sciences, National Institute of Dental and Craniofacial Research, Common Fund
Awards: G1296717744, G2210366145, RII Track-1: Building Capacity across Iowa to Meet Human Needs from Things that Grow, G3274227067, Cationic CAMKIIN nanoparticles that reduce chlorine-induced airway oxidative stress, G3372094017, Dissecting compromised efficacy of liver-stage malaria immunizations in hosts with a history of blood-stage malaria, G420307924, G4363928965, Antiviral lung resident memory T cell maintenance and reinvigoration, G4914594042, Memory CD8 T cell localization and protection from influenza, Mechanisms of compromised CD8 T cell responses to vaccination in malaria experienced hosts, G6075351268, CD8+ T Cell effector mechanisms against L. monocytogenes, CST6-mRNA activated matrices for efficient bone regeneration, Understanding immune regulation in blood-stage malaria, Interdisciplinary Immunology Postdoctoral Training Program, T resident memory in the lung, G8200119549, G8217142628, Regulation of primary and secondary CD4 and CD8 T cell memory, G8506014587, G9000104028, G9000325626, Environmental Health Sciences Research Center, Immunity to Liver-stage malaria, Cancer Center Support Grant, Medical Scientist Training Program, Hemozoin and liver stage malaria vaccine efficacy
OpenAlex ID: W4415682801