Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin

Brazzoli, Michela; Magini, Diletta; Bonci, Alessandra; Buccato, Scilla; Giovani, Cinzia; Kratzer, Roland; Zurli, Vanessa; Mangiavacchi, Simona; Casini, Daniele; Brito, Luis M.; De Gregorio, Ennio; Mason, Peter W.; Ulmer, Jeffrey B.; Geall, Andrew J.; Bertholet, Sylvie

doi:10.1128/jvi.01786-15

Cited by 154Influenza Virus Research StudiesImmunotherapy and Immune ResponsesVirology and Viral Diseases

Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin

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Brazzoli, Michela, Magini, Diletta, Bonci, Alessandra, Buccato, Scilla, Giovani, Cinzia, Kratzer, Roland, Zurli, Vanessa, Mangiavacchi, Simona +7 more·2016·Journal of Virology

DOI 10.1128/jvi.01786-15PMC PMC4702536

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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. IMPORTANCE 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.

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Lipid nanoparticle-mRNA vaccines are being investigated as influenza vaccines, with some formulations in clinical trials.
“Lipid nanoparticle–mRNA vaccines are also being investigated as influenza vaccines29,41,156,157,159,184,189–191, with some formulations in clinical trials (Table 1).”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [29]

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Authors: Brazzoli, M., Magini, D., Bonci, A., Buccato, S., Giovani, C., Kratzer, R., Zurli, V., Mangiavacchi, S., Casini, D., Brito, L. M., De Gregorio, E., Mason, P. W., Ulmer, J. B., Geall, A. J., & Bertholet, S.
Affiliations: Novartis Vaccines and Diagnostics S.r.l., Siena, Italy
University of Siena (IT)
University of Padua (IT)
Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, USA
ORCID: Brazzoli, Michela
Magini, Diletta
Zurli, Vanessa
Geall, Andrew J.
Bertholet, Sylvie
Venue: Journal of Virology
Publisher: American Society for Microbiology
Published: 2016-01
Volume: 90
Issue: 1
Pages: 332-344
ISSN: 0022-538X (ISSN-L)
1098-5514
DOI: 10.1128/jvi.01786-15
PMC: PMC4702536
OpenAlex: W2186068577
Cited by: 154
References: 84
Citations by year: 2026: 2 · 2025: 13 · 2024: 10 · 2023: 15 · 2022: 26 · 2021: 29 · 2020: 18 · 2019: 15 · 2018: 12 · 2017: 6 · 2016: 8
FWCI: 6.79
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Virology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: DOD Defense Advanced Research Projects Agency (HR0011-12-3-0001)
Topics: Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
Keywords: self-amplifying mRNA vaccine, influenza virus hemagglutinin, seasonal influenza vaccine, heterologous protection, cross-reactive T cells, neutralizing antibodies, CD4+ T helper cells, CD8+ cytotoxic T lymphocytes, pandemic influenza preparedness, T cell depletion
MeSH terms: Animals, Antibodies, Viral, Disease Models, Animal, Female, Ferrets, Influenza Vaccines, Mice, Inbred BALB C, Orthomyxoviridae Infections, Respiratory System, RNA, Messenger, CD4-Positive T-Lymphocytes, Survival Analysis, Treatment Outcome, CD8-Positive T-Lymphocytes, Hemagglutinin Glycoproteins, Influenza Virus, Vaccines, DNA, Viral Load, Leukocyte Reduction Procedures, Cross Protection, Antibodies, Neutralizing

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Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin

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