2. Academic Validation
  3. Impact of pre-existing anti-replicase immunity on the efficacy of self-amplifying mRNA vaccines

Impact of pre-existing anti-replicase immunity on the efficacy of self-amplifying mRNA vaccines

  • Nat Commun. 2025 Dec 6;17(1):278. doi: 10.1038/s41467-025-66993-1.
Xiaole Cui 1,  Laura Amelinck 2 3,  Oriane Gillon 1,  João Paulo Portela Catani 2 3,  Ya Gao 4,  Qing Sun 1,  Elisabeth De Sutter 1,  Pieter Vervaeke 1,  Janne Snoeck 1,  Stefan Lienenklaus 5,  Xavier Saelens 2 3,  Zifu Zhong 6 7,  Niek N Sanders 8 9
Affiliations

Affiliations

  • 1 Laboratory of Gene Therapy, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
  • 2 Center for Medical Biotechnology, VIB, Ghent, Belgium.
  • 3 Department of Biochemistry and Biotechnology, Ghent University, Ghent, Belgium.
  • 4 Department of Translational Physiology, Infectiology and Public Health, Ghent University, Merelbeke, Belgium.
  • 5 Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.
  • 6 Department of Pharmaceutics, Ghent University, Ghent, Belgium. [email protected].
  • 7 Cancer Research Institute (CRIG), Ghent University, Ghent, Belgium. [email protected].
  • 8 Laboratory of Gene Therapy, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium. [email protected].
  • 9 Cancer Research Institute (CRIG), Ghent University, Ghent, Belgium. [email protected].
PMID: 41353442 DOI: 10.1038/s41467-025-66993-1
Abstract

Self-amplifying mRNA vaccines use a viral replicase for self-amplification. It is currently unclear whether anti-replicase immunity occurs after saRNA vaccination, and whether such pre-existing anti-replicase immunity impacts the efficacy of subsequent saRNA vaccines. Using female mice, this study demonstrates that an initial saRNA vaccination schedule elicits replicase-specific immunity, which reduces the in vivo expression and impairs the Th1 cell responses of subsequent saRNA vaccines. Passive transfer experiments demonstrate that the suppression of T cell responses is driven by a synergistic effect of both anti-replicase antibodies and anti-replicase T cells. Interestingly, pre-existing anti-replicase immunity does not affect the ability of an influenza saRNA vaccine to provide full protection against an H5N1 challenge in female mice. Taken together, these results provide crucial insights on the effects of anti-replicase immunity induced by a first saRNA vaccination schedule on the expression, immunogenicity and protection efficacy of a subsequent saRNA vaccine.

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