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

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 12; pp. 2877 - 2892.e7
• Main Authors: Alameh, Mohamad-Gabriel, Tombácz, István, Bettini, Emily, Lederer, Katlyn, Ndeupen, Sonia, Sittplangkoon, Chutamath, Wilmore, Joel R., Gaudette, Brian T., Soliman, Ousamah Y., Pine, Matthew, Hicks, Philip, Manzoni, Tomaz B., Knox, James J., Johnson, John L., Laczkó, Dorottya, Muramatsu, Hiromi, Davis, Benjamin, Meng, Wenzhao, Rosenfeld, Aaron M., Strohmeier, Shirin, Lin, Paulo J.C., Mui, Barbara L., Tam, Ying K., Karikó, Katalin, Jacquet, Alain, Krammer, Florian, Bates, Paul, Cancro, Michael P., Weissman, Drew, Luning Prak, Eline T., Allman, David, Igyártó, Botond Z., Locci, Michela, Pardi, Norbert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.12.2021
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; adjuvant; Adjuvants, Immunologic; Animals; B-Lymphocytes - immunology; COVID-19 - immunology; COVID-19 Vaccines - immunology; Germinal Center - immunology; germinal centers; HEK293 Cells; Humans; IL-6; Immunity, Humoral; influenza virus; Interleukin-6 - genetics; Interleukin-6 - metabolism; lipid nanoparticle; Liposomes - administration & dosage; Mice; Mice, Inbred BALB C; mRNA Vaccines - genetics; mRNA Vaccines - immunology; Nanoparticles - administration & dosage; Protein Subunits - genetics; SARS-CoV-2; SARS-CoV-2 - physiology; T-Lymphocytes, Helper-Inducer - immunology; Tfh cell; vaccine; vaccine; lipid nanoparticle; SARS-CoV-2; adjuvant; influenza virus; germinal centers; Tfh cell; IL-6
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2021.11.001

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. [Display omitted] •LNPs are immunostimulatory and act as an adjuvant component of modified mRNA vaccines•LNP-adjuvanted protein subunit vaccines foster potent Tfh cell and humoral responses•LNPs are not sensed by receptors signaling through MyD88 or MAVS•IL-6 induction and the ionizable lipid are critical for the adjuvant activity of LNPs The mechanism of action of nucleoside-modified mRNA-LNP vaccines is unknown. Alameh et al. demonstrate that LNPs can possess adjuvant activity and promote robust induction of Tfh cell, B cell, and humoral responses when utilized in mRNA and protein subunit vaccines in mice. IL-6 induction and the ionizable lipid component are critical for the adjuvant activity of LNPs.