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

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 severe acute respiratory syndrome coronavirus 2 (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 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 formulation 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 traditional and next-generation vaccine platforms.
Competing Interests: Declaration of interests In accordance with the University of Pennsylvania policies and procedures and our ethical obligations as researchers, we report that D.W. and N.P. are named on a patent describing the use of nucleoside-modified mRNA in lipid nanoparticles as a vaccine platform. We have disclosed those interests fully to the University of Pennsylvania, and we have in place an approved plan for managing any potential conflicts arising from licensing of our patents. K.K. is an employee of BioNTech. P.J.C.L., B.L.M., and Y.K.T. are employees of Acuitas Therapeutics, a company involved in the development of mRNA-LNP therapeutics. Y.K.T., D.W., and M.G.A. are named on patents that describe lipid nanoparticles for delivery of nucleic acid therapeutics, including mRNA and the use of modified mRNA in lipid nanoparticles as a vaccine platform. The Icahn School of Medicine at Mount Sinai has filed patent applications regarding SARS-CoV-2 and influenza virus vaccines that name F.K. as co-inventor.
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