Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses

SUMMARY Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against SARS-CoV-2, but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes the induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell and memory B cell responses that are associated with durable and protective antibodies in mice. Comparative experiments demonstrated that this LNP outperformed a widely used MF59-like adjuvant, AddaVax™. The adjuvant activity of the LNP relies on the ionizable lipid component and on IL-6 cytokine induction, but not on MyD88- or MAVS-dependent sensing of LNPs. Our study identified LNPs as a versatile adjuvant that enhances the efficacy of both traditional and next-generation vaccine platforms.