A glycan-based adjuvant expands the breadth and duration of protection of mRNA-based vaccines.

Inflammation initiated in response to a microbial encounter, or deliberately induced upon vaccination, is central for the activation of adaptive lymphocytes. The stimulation of pattern recognition receptors (PRRs) orchestrates the inflammatory programs that regulate adaptive immunity. Here, we took advantage of an mRNA-based vaccine generated against the ancestral spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to test whether tuning inflammation via PRR stimulation enhances the efficacy of mRNA vaccines. We combined mRNA-based vaccine with mannadjuvant, a formulation of fungal mannan and aluminum hydroxide that targets Dectin-2, a C-type lectin PRR. 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, we demonstrated that prolonged type I interferon production and potentiated interleukin-1 signaling are necessary and sufficient to exert the activities of mannadjuvant in mice and in human myeloid cells. Overall, our data demonstrate that an anti-fungal PRR can be harnessed to create more potent and durable mRNA-based vaccines.