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<p>Immunization with radiation-attenuated sporozoites (RAS) drives effective sterilizing immunity against liver-stage <i>Plasmodium</i> 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 <i>Plasmodium yoelii</i> infection compromises <i>Plasmodium berghei</i> RAS-induced essential CD8<sup>+</sup> T cell responses and subsequent protection. The persisting malarial pigment haemozoin mediates impaired CD8<sup>+</sup> 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 <i>Plasmodium</i> CD8<sup>+</sup> T cell epitopes, which overcomes the defective T cell response and restores protection in <i>Plasmodium-</i>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.</p>

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mRNA vaccination overcomes haemozoin-mediated impairment of whole-parasite malaria vaccines in mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月2日

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  • Mariah Hassert,
  • Lisa L. Drewry,
  • Lecia L. Pewe,
  • Lisa S. Hancox,
  • Rui He,
  • Sahaana Arumugam,
  • Madison R. Mix,
  • Aliasger K. Salem,
  • John T. Harty

摘要

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.