title: Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge.
abstract: Current hemagglutinin (HA)-based seasonal influenza vaccines induce vaccine strain-specific neutralizing antibodies that usually fail to provide protection against mismatched circulating viruses. Inclusion in the vaccine of highly conserved internal proteins such as the nucleoprotein (NP) and the matrix protein 1 (M1) was shown previously to increase vaccine efficacy by eliciting cross-reactive T-cells. However, appropriate delivery systems are required for efficient priming of T-cell responses. In this study, we demonstrated that administration of novel self-amplifying mRNA (SAM®) vectors expressing influenza NP (SAM(NP)), M1 (SAM(M1)), and NP and M1 (SAM(M1-NP)) delivered with lipid nanoparticles (LNP) induced robust polyfunctional CD4 T helper 1 cells, while NP-containing SAM also induced cytotoxic CD8 T cells. Robust expansions of central memory (TCM) and effector memory (TEM) CD4 and CD8 T cells were also measured. An enhanced recruitment of NP-specific cytotoxic CD8 T cells was observed in the lungs of SAM(NP)-immunized mice after influenza infection that paralleled with reduced lung viral titers and pathology, and increased survival after homologous and heterosubtypic influenza challenge. Finally, we demonstrated for the first time that the co-administration of RNA (SAM(M1-NP)) and protein (monovalent inactivated influenza vaccine (MIIV)) was feasible, induced simultaneously NP-, M1- and HA-specific T cells and HA-specific neutralizing antibodies, and enhanced MIIV efficacy against a heterologous challenge. In conclusion, systemic administration of SAM vectors expressing conserved internal influenza antigens induced protective immune responses in mice, supporting the SAM® platform as another promising strategy for the development of broad-spectrum universal influenza vaccines.
authors.affiliation: Novartis Vaccines, S.r.l., Siena, Italy.|Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy.
authors.forename: Diletta
authors.initials: D
authors.lastname: Magini
authors.affiliation: Novartis Vaccines, S.r.l., Siena, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giovani
authors.affiliation: Novartis Vaccines, S.r.l., Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Mangiavacchi
authors.affiliation: Novartis Vaccines, S.r.l., Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maccari
authors.affiliation: Novartis Vaccines, S.r.l., Siena, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cecchi
authors.affiliation: Novartis Vaccines Inc., Cambridge, MA, United States of America.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Ulmer
authors.affiliation: Novartis Vaccines, S.r.l., Siena, Italy.
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
authors.affiliation: Novartis Vaccines Inc., Cambridge, MA, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Geall
authors.affiliation: Novartis Vaccines, S.r.l., Siena, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Brazzoli
authors.affiliation: Novartis Vaccines, S.r.l., Siena, Italy.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bertholet
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics* / Q000276:immunology*; D002460:Cell Line; D017124:Conserved Sequence; D006224:Cricetinae; D005784:Gene Amplification; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology / Q000502:physiology; D009980:Influenza A virus / Q000276:immunology* / Q000502:physiology*; D007252:Influenza Vaccines / Q000235:genetics* / Q000276:immunology*; D008168:Lung / Q000276:immunology; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015164:Vaccines, Inactivated / Q000235:genetics / Q000276:immunology; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D007252:Influenza Vaccines; C488936:M1 protein, Influenza A virus; D012333:RNA, Messenger; D015164:Vaccines, Inactivated; D014758:Viral Core Proteins; D014763:Viral Matrix Proteins