Preclinical Evaluation of a Replication-Deficient Intranasal ΔNS1 H5N1 Influenza Vaccine
| Autor: | Thomas Muster, Martin Slais, Monika Sachet, Julia Romanova, Ekaterina Romanovskaja-Romanko, Sabine Nakowitsch, Markus Wolschek, Anna-Polina Shurygina, Bettina Kiefmann, Oleg I. Kiselev, Alex Mann, Shobana Balasingam, Andrej Egorov, Tanja Ruthsatz, Alexander Morokutti, Brigitte M. Krenn, John S. Oxford, Boris Ferko, Ulrich König, Michael Bergmann |
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| Rok vydání: | 2009 |
| Předmět: |
H5N1 vaccine
Influenza vaccine Drug Evaluation Preclinical lcsh:Medicine Bronchi Hemagglutinin Glycoproteins Influenza Virus Biology Virus Replication medicine.disease_cause Cell Line Microbiology Mice Dogs Immunology/Immunity to Infections Chlorocebus aethiops Infectious Diseases/Viral Infections Influenza A virus medicine Animals Humans lcsh:Science Vero Cells Administration Intranasal Virology/Vaccines Duck embryo vaccine Multidisciplinary Attenuated vaccine Influenza A Virus H5N1 Subtype Macrophages Infectious Diseases/Respiratory Infections Viral Vaccine lcsh:R Ferrets virus diseases Epithelial Cells Virology Influenza A virus subtype H5N1 Microbiology/Immunity to Infections Viral replication Influenza Vaccines lcsh:Q Chickens Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 4, Iss 6, p e5984 (2009) |
| ISSN: | 1932-6203 |
| Popis: | BACKGROUND:We developed a novel intranasal influenza vaccine approach that is based on the construction of replication-deficient vaccine viruses that lack the entire NS1 gene (DeltaNS1 virus). We previously showed that these viruses undergo abortive replication in the respiratory tract of animals. The local release of type I interferons and other cytokines and chemokines in the upper respiratory tract may have a "self-adjuvant effect", in turn increasing vaccine immunogenicity. As a result, DeltaNS1 viruses elicit strong B- and T- cell mediated immune responses. METHODOLOGY/PRINCIPAL FINDINGS:We applied this technology to the development of a pandemic H5N1 vaccine candidate. The vaccine virus was constructed by reverse genetics in Vero cells, as a 5:3 reassortant, encoding four proteins HA, NA, M1, and M2 of the A/Vietnam/1203/04 virus while the remaining genes were derived from IVR-116. The HA cleavage site was modified in a trypsin dependent manner, serving as the second attenuation factor in addition to the deleted NS1 gene. The vaccine candidate was able to grow in the Vero cells that were cultivated in a serum free medium to titers exceeding 8 log(10) TCID(50)/ml. The vaccine virus was replication deficient in interferon competent cells and did not lead to viral shedding in the vaccinated animals. The studies performed in three animal models confirmed the safety and immunogenicity of the vaccine. Intranasal immunization protected ferrets and mice from being infected with influenza H5 viruses of different clades. In a primate model (Macaca mulatta), one dose of vaccine delivered intranasally was sufficient for the induction of antibodies against homologous A/Vietnam/1203/04 and heterologous A/Indonesia/5/05 H5N1 strains. CONCLUSION/SIGNIFICANCE:Our findings show that intranasal immunization with the replication deficient H5N1 DeltaNS1 vaccine candidate is sufficient to induce a protective immune response against H5N1 viruses. This approach might be attractive as an alternative to conventional influenza vaccines. Clinical evaluation of DeltaNS1 pandemic and seasonal influenza vaccine candidates are currently in progress. |
| Databáze: | OpenAIRE |
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