2. Academic Validation
  3. iDC-targeting PfCSP mRNA vaccine confers superior protection against Plasmodium compared to conventional mRNA

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

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. psriniv3@jhu.edu.
  • 6 The Johns Hopkins Malaria Research Institute, Baltimore, MD, USA. psriniv3@jhu.edu.
  • # 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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