title: Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin.
abstract: Seasonal influenza is a vaccine-preventable disease that remains a major health problem worldwide, especially in immunocompromised populations. The impact of influenza disease is even greater when strains drift, and influenza pandemics can result when animal-derived influenza virus strains combine with seasonal strains. In this study, we used the SAM technology and characterized the immunogenicity and efficacy of a self-amplifying mRNA expressing influenza virus hemagglutinin (HA) antigen [SAM(HA)] formulated with a novel oil-in-water cationic nanoemulsion. We demonstrated that SAM(HA) was immunogenic in ferrets and facilitated containment of viral replication in the upper respiratory tract of influenza virus-infected animals. In mice, SAM(HA) induced potent functional neutralizing antibody and cellular immune responses, characterized by HA-specific CD4 T helper 1 and CD8 cytotoxic T cells. Furthermore, mice immunized with SAM(HA) derived from the influenza A virus A/California/7/2009 (H1N1) strain (Cal) were protected from a lethal challenge with the heterologous mouse-adapted A/PR/8/1934 (H1N1) virus strain (PR8). Sera derived from SAM(H1-Cal)-immunized animals were not cross-reactive with the PR8 virus, whereas cross-reactivity was observed for HA-specific CD4 and CD8 T cells. Finally, depletion of T cells demonstrated that T-cell responses were essential in mediating heterologous protection. If the SAM vaccine platform proves safe, well tolerated, and effective in humans, the fully synthetic SAM vaccine technology could provide a rapid response platform to control pandemic influenza.
  
  
  OBJECTIVE
  In this study, we describe protective immune responses in mice and ferrets after vaccination with a novel HA-based influenza vaccine. This novel type of vaccine elicits both humoral and cellular immune responses. Although vaccine-specific antibodies are the key players in mediating protection from homologous influenza virus infections, vaccine-specific T cells contribute to the control of heterologous infections. The rapid production capacity and the synthetic origin of the vaccine antigen make the SAM platform particularly exploitable in case of influenza pandemic.
authors.affiliation: Novartis Vaccines and Diagnostics S.r.l., Siena, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Brazzoli
authors.affiliation: Novartis Vaccines and Diagnostics 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 and Diagnostics S.r.l., Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bonci
authors.affiliation: Novartis Vaccines and Diagnostics S.r.l., Siena, Italy.
authors.forename: Scilla
authors.initials: S
authors.lastname: Buccato
authors.affiliation: Novartis Vaccines and Diagnostics S.r.l., Siena, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giovani
authors.affiliation: Novartis Vaccines and Diagnostics S.r.l., Siena, Italy.
authors.forename: Roland
authors.initials: R
authors.lastname: Kratzer
authors.affiliation: Novartis Vaccines and Diagnostics S.r.l., Siena, Italy Dipartimento di Biologia, Università degli Studi di Padova, Padua, Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zurli
authors.affiliation: Novartis Vaccines and Diagnostics S.r.l., Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Mangiavacchi
authors.affiliation: Novartis Vaccines and Diagnostics S.r.l., Siena, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Casini
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, USA.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Brito
authors.affiliation: Novartis Vaccines and Diagnostics S.r.l., Siena, Italy.
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mason
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Ulmer
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Geall
authors.affiliation: Novartis Vaccines and Diagnostics S.r.l., Siena, Italy sylvie.c.bertholet-girardin@gsk.com.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bertholet
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D056738:Cross Protection; D004195:Disease Models, Animal; D005260:Female; D005289:Ferrets; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics* / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D047589:Leukocyte Reduction Procedures; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D012137:Respiratory System / Q000821:virology; D016019:Survival Analysis; D016896:Treatment Outcome; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D019562:Viral Load
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D012333:RNA, Messenger; D019444:Vaccines, DNA