The activation of pattern recognition receptors (PRRs) orchestrates inflammation and regulates adaptive immunity. To test whether tuning inflammation through PRR stimulation enhanced the efficacy of mRNA vaccines, we combined an mRNA-based vaccine generated against the ancestral spike protein of SARS-CoV-2 with mannadjuvant, a formulation of fungal mannan and aluminum hydroxide targeting the PRR dectin-2. In mice and non-human primates, mannadjuvant increased the magnitude and durability of the response elicited by the mRNA-based vaccine, and it also led to the induction of neutralizing antibodies directed against variants of concern with a high escape capacity, overcoming antigenic imprinting. Mechanistically, prolonged type I interferon (IFN) production and potentiated interleukin-1 (IL-1) signaling locally within the draining lymph node in mice or in human cells were necessary and sufficient to exert the effect of mannadjuvant. Our data indicate that antifungal PRRs can be harnessed to create more potent and durable mRNA-based vaccines.
https://doi.org/10.1038/s41590-026-02517-3
