Enhanced Influenza Virus-Like Particle Vaccination with a Structurally Optimized RIG-I Agonist as Adjuvant
| Autor: | Terianne Wong, Greg A. Kirchenbaum, Ted M. Ross, Vladimir Beljanski, Elias K. Haddad, Cindy Chiang, David Olagnier, Chalise E. Bloom, Lydie Trautmann, John Hiscott |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
viruses
medicine.medical_treatment Primary Cell Culture Immunology Hemagglutinins Viral Neuraminidase Antibodies Viral medicine.disease_cause complex mixtures Microbiology Virus DEAD-box RNA Helicases Mice Adjuvants Immunologic Orthomyxoviridae Infections Virus-like particle Virology Vaccines and Antiviral Agents medicine Influenza A virus Animals Humans Vaccines Virus-Like Particle Receptors Immunologic Th1-Th2 Balance Immunity Cellular Mice Inbred BALB C Oligoribonucleotides Influenza A Virus H5N1 Subtype biology virus diseases Dendritic Cells Vaccine efficacy Survival Analysis Influenza A virus subtype H5N1 Immunity Humoral Vaccination HEK293 Cells Influenza Vaccines Insect Science biology.protein DEAD Box Protein 58 Female Immunization Adjuvant |
| Zdroj: | Journal of Virology. 89:10612-10624 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.01526-15 |
| Popis: | The molecular interaction between viral RNA and the cytosolic sensor RIG-I represents the initial trigger in the development of an effective immune response against infection with RNA viruses, resulting in innate immune activation and subsequent induction of adaptive responses. In the present study, the adjuvant properties of a sequence-optimized 5′-triphosphate-containing RNA (5′pppRNA) RIG-I agonist (termed M8) were examined in combination with influenza virus-like particles (VLP) (M8-VLP) expressing H5N1 influenza virus hemagglutinin (HA) and neuraminidase (NA) as immunogens. In combination with VLP, M8 increased the antibody response to VLP immunization, provided VLP antigen sparing, and protected mice from a lethal challenge with H5N1 influenza virus. M8-VLP immunization also led to long-term protective responses against influenza virus infection in mice. M8 adjuvantation of VLP increased endpoint and antibody titers and inhibited influenza virus replication in lungs compared with approved or experimental adjuvants alum, AddaVax, and poly(I·C). Uniquely, immunization with M8-VLP stimulated a T H 1-biased CD4 T cell response, as determined by increased T H 1 cytokine levels in CD4 T cells and increased IgG2 levels in sera. Collectively, these data demonstrate that a sequence-optimized, RIG-I-specific agonist is a potent adjuvant that can be utilized to increase the efficacy of influenza VLP vaccination and dramatically improve humoral and cellular mediated protective responses against influenza virus challenge. IMPORTANCE The development of novel adjuvants to increase vaccine immunogenicity is an important goal that seeks to improve vaccine efficacy and ultimately prevent infections that endanger human health. This proof-of-principle study investigated the adjuvant properties of a sequence-optimized 5′pppRNA agonist (M8) with enhanced capacity to stimulate antiviral and inflammatory gene networks using influenza virus-like particles (VLP) expressing HA and NA as immunogens. Vaccination with VLP in combination with M8 increased anti-influenza virus antibody titers and protected animals from lethal influenza virus challenge, highlighting the potential clinical use of M8 as an adjuvant in vaccine development. Altogether, the results describe a novel immunostimulatory agonist targeted to the cytosolic RIG-I sensor as an attractive vaccine adjuvant candidate that can be used to increase vaccine efficacy, a pressing issue in children and the elderly population. |
| Databáze: | OpenAIRE |
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