scholarly journals Enhanced Influenza Virus-Like Particle Vaccination with a Structurally Optimized RIG-I Agonist as Adjuvant

2015 ◽  
Vol 89 (20) ◽  
pp. 10612-10624 ◽  
Author(s):  
Vladimir Beljanski ◽  
Cindy Chiang ◽  
Greg A. Kirchenbaum ◽  
David Olagnier ◽  
Chalise E. Bloom ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Vaccine Efficacy ◽  
Gene Networks ◽  
Influenza Virus Infection ◽  
T Cell Response ◽  
H5n1 Influenza Virus ◽  
Virus Like Particles ◽  
Virus Challenge ◽  
H5n1 Influenza ◽  
Antibody Titers

ABSTRACTThe 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 TH1-biased CD4 T cell response, as determined by increased TH1 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.IMPORTANCEThe 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.

scholarly journals Cross-Reactive, Cell-Mediated Immunity and Protection of Chickens from Lethal H5N1 Influenza Virus Infection in Hong Kong Poultry Markets

2001 ◽  
Vol 75 (6) ◽  
pp. 2516-2525 ◽  
Author(s):  
Sang Heui Seo ◽  
Robert G. Webster
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Hong Kong ◽  
Virus Infection ◽  
Cellular Immunity ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
H5n1 Influenza Virus ◽  
H9n2 Influenza Virus ◽  
H5n1 Influenza

ABSTRACT In 1997, avian H5N1 influenza virus transmitted from chickens to humans resulted in 18 confirmed infections. Despite harboring lethal H5N1 influenza viruses, most chickens in the Hong Kong poultry markets showed no disease signs. At this time, H9N2 influenza viruses were cocirculating in the markets. We investigated the role of H9N2 influenza viruses in protecting chickens from lethal H5N1 influenza virus infections. Sera from chickens infected with an H9N2 influenza virus did not cross-react with an H5N1 influenza virus in neutralization or hemagglutination inhibition assays. Most chickens primed with an H9N2 influenza virus 3 to 70 days earlier survived the lethal challenge of an H5N1 influenza virus, but infected birds shed H5N1 influenza virus in their feces. Adoptive transfer of T lymphocytes or CD8+ T cells from inbred chickens (B2/B2) infected with an H9N2 influenza virus to naive inbred chickens (B2/B2) protected them from lethal H5N1 influenza virus. In vitro cytotoxicity assays showed that T lymphocytes or CD8+ T cells from chickens infected with an H9N2 influenza virus recognized target cells infected with either an H5N1 or H9N2 influenza virus in a dose-dependent manner. Our findings indicate that cross-reactive cellular immunity induced by H9N2 influenza viruses protected chickens from lethal infection with H5N1 influenza viruses in the Hong Kong markets in 1997 but permitted virus shedding in the feces. Our findings are the first to suggest that cross-reactive cellular immunity can change the outcome of avian influenza virus infection in birds in live markets and create a situation for the perpetuation of H5N1 influenza viruses.

scholarly journals Kinetic Characterization of PB1-F2-Mediated Immunopathology during Highly Pathogenic Avian H5N1 Influenza Virus Infection

PLoS ONE ◽  
2013 ◽  
Vol 8 (3) ◽  
pp. e57894 ◽  
Author(s):  
Olivier Leymarie ◽  
Grégory Jouvion ◽  
Pierre-Louis Hervé ◽  
Christophe Chevalier ◽  
Valérie Lorin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Kinetic Characterization ◽  
H5n1 Influenza Virus ◽  
Highly Pathogenic ◽  
H5n1 Influenza ◽  
Avian H5n1 Influenza Virus

scholarly journals Intranasal Vaccination with 1918 Influenza Virus-Like Particles Protects Mice and Ferrets from Lethal 1918 and H5N1 Influenza Virus Challenge

2009 ◽  
Vol 83 (11) ◽  
pp. 5726-5734 ◽  
Author(s):  
Lucy A. Perrone ◽  
Attiya Ahmad ◽  
Vic Veguilla ◽  
Xiuhua Lu ◽  
Gale Smith ◽  
...  
Keyword(s):  
Influenza Virus ◽  
H5n1 Virus ◽  
Influenza Pandemic ◽  
Human Case ◽  
Lethal Challenge ◽  
Virus Like Particles ◽  
Virus Challenge ◽  
H5n1 Influenza ◽  
Pandemic Virus ◽  
Homologous Virus

ABSTRACT Influenza vaccines capable of inducing cross-reactive or heterotypic immunity could be an important first line of prevention against a novel subtype virus. Influenza virus-like particles (VLPs) displaying functional viral proteins are effective vaccines against replication-competent homologous virus, but their ability to induce heterotypic immunity has not been adequately tested. To measure VLP vaccine efficacy against a known influenza pandemic virus, recombinant VLPs were generated from structural proteins of the 1918 H1N1 virus. Mucosal and traditional parenteral administrations of H1N1 VLPs were compared for the ability to protect against the reconstructed 1918 virus and a highly pathogenic avian H5N1 virus isolated from a fatal human case. Mice that received two intranasal immunizations of H1N1 VLPs were largely protected against a lethal challenge with both the 1918 virus and the H5N1 virus. In contrast, mice that received two intramuscular immunizations of 1918 VLPs were only protected against a homologous virus challenge. Mucosal vaccination of mice with 1918 VLPs induced higher levels of cross-reactive immunoglobulin G (IgG) and IgA antibodies than did parenteral vaccination. Similarly, ferrets mucosally vaccinated with 1918 VLPs completely survived a lethal challenge with the H5N1 virus, while only a 50% survival rate was observed in parenterally vaccinated animals. These results suggest a strategy of VLP vaccination against a pandemic virus and one that stimulates heterotypic immunity against an influenza virus strain with threatening pandemic potential.

scholarly journals Nanobodies With In Vitro Neutralizing Activity Protect Mice Against H5N1 Influenza Virus Infection

2011 ◽  
Vol 203 (8) ◽  
pp. 1063-1072 ◽  
Author(s):  
Lorena Itatí Ibañez ◽  
Marina De Filette ◽  
Anna Hultberg ◽  
Theo Verrips ◽  
Nigel Temperton ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
H5n1 Influenza Virus ◽  
Neutralizing Activity ◽  
H5n1 Influenza

scholarly journals Viral Replication Rate Regulates Clinical Outcome and CD8 T Cell Responses during Highly Pathogenic H5N1 Influenza Virus Infection in Mice

2010 ◽  
Vol 6 (10) ◽  
pp. e1001139 ◽  
Author(s):  
Yasuko Hatta ◽  
Karen Hershberger ◽  
Kyoko Shinya ◽  
Sean C. Proll ◽  
Richard R. Dubielzig ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Cd8 T Cell ◽  
H5n1 Influenza Virus ◽  
Replication Rate ◽  
Highly Pathogenic ◽  
Cell Responses ◽  
H5n1 Influenza ◽  
Pathogenic H5n1

scholarly journals Spatial and Temporal Association of Outbreaks of H5N1 Influenza Virus Infection in Wild Birds with the 0°C Isotherm

2010 ◽  
Vol 6 (4) ◽  
pp. e1000854 ◽  
Author(s):  
Leslie A. Reperant ◽  
Neven S. Fučkar ◽  
Albert D. M. E. Osterhaus ◽  
Andrew P. Dobson ◽  
Thijs Kuiken
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Wild Birds ◽  
Temporal Association ◽  
H5n1 Influenza Virus ◽  
H5n1 Influenza

scholarly journals Host DNA released by NETosis in neutrophils exposed to seasonal H1N1 and highly pathogenic H5N1 influenza viruses

2020 ◽  
Author(s):  
Louisa L.Y. Chan ◽  
John M. Nicholls ◽  
J.S. Malik Peiris ◽  
Yu Lung Lau ◽  
Michael C.W. Chan ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
H1n1 Virus ◽  
Influenza Virus Infection ◽  
Alveolar Epithelium ◽  
Influenza Viruses ◽  
H5n1 Influenza Virus ◽  
H5n1 Influenza ◽  
Influenza H1n1

Abstract Background Neutrophil (Nϕ) is of the most abundant number in human immune system. During acute influenza virus infection, Nϕs are already active in the early phase of inflammation-a time in which clinical biopsy or autopsy material is not readily available. However, the role of Nϕ in virus infection is not well understood. Here, we studied the role of Nϕ in host defense during influenza A virus infection, specifically assessing if it contributes to the differential pathogenesis in H5N1 disease. Methods Nϕs were freshly isolated from healthy volunteers and subjected to direct influenza H1N1 and H5N1 virus infection in vitro . The ability of the naïve Nϕs to infiltrate from the basolateral to the apical phase of the influenza virus infected alveolar epithelium was assessed. The viral replication, innate immune responses and Neutrophil extracellular trap (NET) formation of Nϕs upon influenza virus infection were evaluated. Results Our results demonstrated that influenza virus infected alveolar epithelium allowed more Nϕs transmigration. Significantly more Nϕs migrated across the H5N1 influenza virus infected the epithelium than the counterpart infected by the seasonal influenza H1N1 virus infected. Nϕs were equally susceptible to H5N1 and H1N1 virus infection with similar viral gene transcription. Productive replication was observed in H5N1 infected Nϕs. Both H5N1 and H1N1 infected Nϕs induced cytokines and chemokines including TNF-α, IFN-β, CXCL10, MIP-1α and IL-8. This inferred a more intense inflammatory response posed by H5N1 than H1N1 virus. Strikingly, NADPH oxidase-independent NET formation was observed in H1N1 infected Nϕs at 6 hpi while no NET formation was observed upon H5N1 infection. Conclusion Our data is the first to demonstrate that NET formation is abrogated in H5N1 influenza virus infection. Its contribution to the differential severity of H5N1 disease requires further investigation.

scholarly journals Single-Domain Antibodies Targeting Neuraminidase Protect against an H5N1 Influenza Virus Challenge

2014 ◽  
Vol 88 (15) ◽  
pp. 8278-8296 ◽  
Author(s):  
F. M. Cardoso ◽  
L. I. Ibanez ◽  
S. Van den Hoecke ◽  
S. De Baets ◽  
A. Smet ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Single Domain ◽  
H5n1 Influenza Virus ◽  
Virus Challenge ◽  
H5n1 Influenza ◽  
Single Domain Antibodies

H5N1 influenza virus-like particles produced by transient expression in mammalian cells induce humoral and cellular immune responses in mice

2012 ◽  
Vol 58 (4) ◽  
pp. 391-401 ◽  
Author(s):  
Ling Tao ◽  
Jianjun Chen ◽  
Zhenhua Zheng ◽  
Jin Meng ◽  
Zhenfeng Zhang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Cleavage Site ◽  
Mammalian Cells ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Virus Like Particles ◽  
Cellular Immune Responses ◽  
H5n1 Influenza ◽  
Cellular Immune

Vaccination is an effective way to protect from influenza virus infection. Among the new candidates of influenza vaccines, influenza virus-like particles (VLPs) seem to be promising. Here, we generated 2 types of H5N1 influenza VLPs by co-expressing influenza virus Env (envelope protein) and murine leukemia virus (MLV) Gag–Pol. VLPs generated by co-transfection of pHCMV-wtH5 or pHCMV-mtH5 with pSV-Mo-MLVgagpol and pHCMV-N1 were named as wtH5N1 VLPs or mtH5N1 VLPs. The plasmid of pHCMV-wtH5 encoded the wild-type hemagglutinin (HA) (wtH5) from A/swine/Anhui/ca/2004 (H5N1) with a multibasic cleavage site, while pHCMV-mtH5 encoded the modified mutant-type (mtH5) with a monobasic cleavage site. Influenza virus HA VLPs were characterized and equal amounts of them were used to immunize mice subcutaneously, intraperitoneally, or intramuscularly. The levels of HA-specific IgG1, IFN-γ, and neutralization antibodies were significantly induced in mice immunized with wtH5N1 VLPs or mtH5N1 VLPs via all 3 routes, while HA-specific IgG2a was barely detectable. IL-4 secretion was detected in mice subcutaneously immunized with wtH5N1 VLPs or mtH5N1 VLPs, or intramuscularly immunized with mtH5N1 VLPs. Our results indicated that both H5N1 influenza VLPs could induce specific humoral and cellular immune responses in immunized mice. In conclusion, our study provides helpful information for designing new candidate vaccines against H5N1 influenza viruses.

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