Research on how prior malaria infection compromises subsequent vaccine responses and development of strategies to overcome this dysfunction by Mariah Hassert, PhD; Lisa Drewry, PhD, Lecia Epping, BS; Lisa Hancox, BA; and Sahaana Arumugam, BA, BS from the Harty lab was recently published in Nature Microbiology.
mRNA vaccination overcomes haemozoin-mediated impairment of whole-parasite malaria vaccines in mice
Mariah Hassert*, Lisa. L. Drewry*, Lecia L. Pewe, Lisa S. Hancox, Rui He, Sahaana Arumugam, Madison R. Mix, Aliasger K. Salem, and John T. Harty
*Co-first authors
Abstract. Immunization with radiation-attenuated sporozoites (RAS) drives effective sterilizing immunity against liver-stage Plasmodium infection. However, protection is compromised in individuals living in malaria endemic regions and the mechanisms of vaccine failure are unclear. Here we show that previous blood-stage exposure in a mouse model of Plasmodium yoelii infection compromises Plasmodium berghei RAS-induced essential CD8+ T cell responses and subsequent protection. The persisting malarial pigment haemozoin mediates impaired CD8+ T cell responses owing to impaired antigen uptake by dendritic cells, leading to reduced T cell activation. We designed a lipid nanoparticle-encapsulated mRNA vaccine that encodes a string of Plasmodium CD8+ T cell epitopes, which overcomes the defective T cell response and restores protection in Plasmodium-exposed mice. A combined RAS-plus-mRNA vaccine regimen enhances liver-resident memory T cells and protection in murine malaria-experienced hosts. The identification of haemozoin as a potential obstacle to vaccine efficacy in malaria endemic areas can inform the design of more effective malaria vaccines.
Drs. Hassert and Drewry were lead authors of the study. Co-authors include Epping, Hancox, Arumugam and Madison Mix, BA from the Harty lab in the Department of Pathology and Rui He from the Aliasger Salem lab in the College of Pharmacy. The study was funded by grants from the NIH to JTH, AKS, MH, and LLD.