iDC-targeting PfCSP mRNA vaccine confers superior protection against Plasmodium compared to conventional mRNA

  • NPJ Vaccines. 2025 Feb 19;10(1):34. doi: 10.1038/s41541-025-01089-x.
Sean Yanik  #  1  2 ,  Varsha Venkatesh  #  1  2 ,  James T Gordy  1 ,  Mohamad-Gabriel Alameh  3 ,  Jacob Meza  1 ,  Yangchen Li  1 ,  Elizabeth Glass  1 ,  Yevel Flores-Garcia  1  2 ,  Ying Tam  4 ,  Nattawat Chaiyawong  1  2 ,  Deepti Sarkar  1  2 ,  Drew Weissman  3 ,  Richard Markham  1 ,  Prakash Srinivasan  5  6
Affiliations
  • 1. Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA.
  • 2. The Johns Hopkins Malaria Research Institute, Baltimore, MD, USA.
  • 3. Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA.
  • 4. Acuitas Therapeutics, Vancouver, BC, Canada.
  • 5. Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA. [email protected].
  • 6. The Johns Hopkins Malaria Research Institute, Baltimore, MD, USA. [email protected].
  • # Contributed equally.
PMID: 39971939 DOI: 10.1038/s41541-025-01089-x
Abstract

Malaria resurgence in 2022 saw 249 million clinical cases and 608,000 deaths, mostly in children under five. The WHO-approved circumsporozoite protein (CSP)-targeting vaccines, RTS,S and R21, remain limited in availability. Strong humoral responses are crucial for sporozoite neutralization before hepatocyte Infection, yet first-generation vaccines provide suboptimal protection, necessitating improved strategies. With the success of mRNA-LNP vaccines against COVID-19, there is interest in leveraging this approach to malaria. Here, we developed a novel chemokine fusion mRNA vaccine targeting immature dendritic cells (iDC) to enhance immunity against P. falciparum CSP (PfCSP). Mice immunized with MIP3α-CSP mRNA-LNP exhibited stronger CD4 + T cell responses and higher anti-NANP6 antibody titers than conventional CSP mRNA-LNP. Importantly, upon P. berghei PfCSP transgenic sporozoite challenge, MIP3α-CSP mRNA provided significantly greater protection from liver Infection, strongly associated with multifunctional CD4 + T cells and anti-NANP6 titers. This study underscores iDC targeting as a promising strategy to enhance malaria vaccine efficacy.

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