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A novel type of influenza vaccine: safety and immunogenicity of replication-deficient influenza virus created by deletion of the interferon antagonist NS1.

Abstract

BACKGROUND

. The nonstructural protein NS1 of influenza virus counteracts the interferon-mediated immune response of the host. By deleting the open reading frame of NS1, we have generated a novel type of influenza vaccine. We studied the safety and immunogenicity of an influenza strain lacking the NS1 gene (DeltaNS1-H1N1) in healthy volunteers.

METHODS.

Healthy seronegative adult volunteers were randomized to receive either a single intranasal dose of the DeltaNS1-H1N1 A/New Caledonia vaccine at 1 of 5 dose levels (6.4, 6.7, 7.0, 7.4, and 7.7 log(10) median tissue culture infective dose) (n = 36 recipients) or placebo (n = 12 recipients).

RESULTS.

Intranasal vaccination with the replication-deficient DeltaNS1-H1N1 vaccine was well tolerated. Rhinitis-like symptoms and headache were the most common adverse events identified during the 28-day observation period. Adverse events were similarly distributed between the treatment and placebo groups. Vaccine-specific local and serum antibodies were induced in a dose-dependent manner. In the highest dose group, vaccine-specific antibodies were detected in 10 of 12 volunteers. Importantly, the vaccine also induced neutralizing antibodies against heterologous drift variants.

CONCLUSIONS.

We show that vaccination with an influenza virus strain lacking the viral interferon antagonist NS1 induces statistically significant levels of strain-specific and cross-neutralizing antibodies despite the highly attenuated replication-deficient phenotype. Further studies are warranted to determine whether these results translate into protection from influenza virus infection. TRIAL REGISTRATION. ClinicalTrials.gov identifier: NCT00724997 .

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  • Authors+Show Affiliations

    ,

    Departments of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

    , , , , , , , , , , , , , , , , , , , ,

    Source

    The Journal of infectious diseases 201:3 2010 Feb 01 pg 354-62

    MeSH

    Adult
    Antibodies, Viral
    Dose-Response Relationship, Immunologic
    Double-Blind Method
    Gene Deletion
    Humans
    Influenza A Virus, H1N1 Subtype
    Influenza Vaccines
    Influenza, Human
    Nasal Lavage Fluid
    Vaccines, Attenuated
    Viral Nonstructural Proteins
    Virus Shedding

    Pub Type(s)

    Journal Article
    Randomized Controlled Trial
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    20039806

    Citation

    Wacheck, Volker, et al. "A Novel Type of Influenza Vaccine: Safety and Immunogenicity of Replication-deficient Influenza Virus Created By Deletion of the Interferon Antagonist NS1." The Journal of Infectious Diseases, vol. 201, no. 3, 2010, pp. 354-62.
    Wacheck V, Egorov A, Groiss F, et al. A novel type of influenza vaccine: safety and immunogenicity of replication-deficient influenza virus created by deletion of the interferon antagonist NS1. J Infect Dis. 2010;201(3):354-62.
    Wacheck, V., Egorov, A., Groiss, F., Pfeiffer, A., Fuereder, T., Hoeflmayer, D., ... Muster, T. (2010). A novel type of influenza vaccine: safety and immunogenicity of replication-deficient influenza virus created by deletion of the interferon antagonist NS1. The Journal of Infectious Diseases, 201(3), pp. 354-62. doi:10.1086/649428.
    Wacheck V, et al. A Novel Type of Influenza Vaccine: Safety and Immunogenicity of Replication-deficient Influenza Virus Created By Deletion of the Interferon Antagonist NS1. J Infect Dis. 2010 Feb 1;201(3):354-62. PubMed PMID: 20039806.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A novel type of influenza vaccine: safety and immunogenicity of replication-deficient influenza virus created by deletion of the interferon antagonist NS1. AU - Wacheck,Volker, AU - Egorov,Andrej, AU - Groiss,Franz, AU - Pfeiffer,Andrea, AU - Fuereder,Thorsten, AU - Hoeflmayer,Doris, AU - Kundi,Michael, AU - Popow-Kraupp,Therese, AU - Redlberger-Fritz,Monika, AU - Mueller,Christian A, AU - Cinatl,Jindrich, AU - Michaelis,Martin, AU - Geiler,Janina, AU - Bergmann,Michael, AU - Romanova,Julia, AU - Roethl,Elisabeth, AU - Morokutti,Alexander, AU - Wolschek,Markus, AU - Ferko,Boris, AU - Seipelt,Joachim, AU - Dick-Gudenus,Rosmarie, AU - Muster,Thomas, PY - 2009/12/31/entrez PY - 2009/12/31/pubmed PY - 2010/1/28/medline SP - 354 EP - 62 JF - The Journal of infectious diseases JO - J. Infect. Dis. VL - 201 IS - 3 N2 - BACKGROUND. The nonstructural protein NS1 of influenza virus counteracts the interferon-mediated immune response of the host. By deleting the open reading frame of NS1, we have generated a novel type of influenza vaccine. We studied the safety and immunogenicity of an influenza strain lacking the NS1 gene (DeltaNS1-H1N1) in healthy volunteers. METHODS. Healthy seronegative adult volunteers were randomized to receive either a single intranasal dose of the DeltaNS1-H1N1 A/New Caledonia vaccine at 1 of 5 dose levels (6.4, 6.7, 7.0, 7.4, and 7.7 log(10) median tissue culture infective dose) (n = 36 recipients) or placebo (n = 12 recipients). RESULTS. Intranasal vaccination with the replication-deficient DeltaNS1-H1N1 vaccine was well tolerated. Rhinitis-like symptoms and headache were the most common adverse events identified during the 28-day observation period. Adverse events were similarly distributed between the treatment and placebo groups. Vaccine-specific local and serum antibodies were induced in a dose-dependent manner. In the highest dose group, vaccine-specific antibodies were detected in 10 of 12 volunteers. Importantly, the vaccine also induced neutralizing antibodies against heterologous drift variants. CONCLUSIONS. We show that vaccination with an influenza virus strain lacking the viral interferon antagonist NS1 induces statistically significant levels of strain-specific and cross-neutralizing antibodies despite the highly attenuated replication-deficient phenotype. Further studies are warranted to determine whether these results translate into protection from influenza virus infection. TRIAL REGISTRATION. ClinicalTrials.gov identifier: NCT00724997 . SN - 1537-6613 UR - https://www.unboundmedicine.com/medline/citation/20039806/A_novel_type_of_influenza_vaccine:_safety_and_immunogenicity_of_replication_deficient_influenza_virus_created_by_deletion_of_the_interferon_antagonist_NS1_ L2 - https://academic.oup.com/jid/article-lookup/doi/10.1086/649428 DB - PRIME DP - Unbound Medicine ER -