title: 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 .
authors.affiliation: Departments of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Volker
authors.initials: V
authors.lastname: Wacheck
authors.forename: Andrej
authors.initials: A
authors.lastname: Egorov
authors.forename: Franz
authors.initials: F
authors.lastname: Groiss
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfeiffer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Fuereder
authors.forename: Doris
authors.initials: D
authors.lastname: Hoeflmayer
authors.forename: Michael
authors.initials: M
authors.lastname: Kundi
authors.forename: Therese
authors.initials: T
authors.lastname: Popow-Kraupp
authors.forename: Monika
authors.initials: M
authors.lastname: Redlberger-Fritz
authors.forename: Christian A
authors.initials: CA
authors.lastname: Mueller
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.forename: Janina
authors.initials: J
authors.lastname: Geiler
authors.forename: Michael
authors.initials: M
authors.lastname: Bergmann
authors.forename: Julia
authors.initials: J
authors.lastname: Romanova
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Roethl
authors.forename: Alexander
authors.initials: A
authors.lastname: Morokutti
authors.forename: Markus
authors.initials: M
authors.lastname: Wolschek
authors.forename: Boris
authors.initials: B
authors.lastname: Ferko
authors.forename: Joachim
authors.initials: J
authors.lastname: Seipelt
authors.forename: Rosmarie
authors.initials: R
authors.lastname: Dick-Gudenus
authors.forename: Thomas
authors.initials: T
authors.lastname: Muster
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000097:blood / Q000302:isolation & purification; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D017353:Gene Deletion; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control*; D017817:Nasal Lavage Fluid / Q000276:immunology / Q000821:virology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D017201:Virus Shedding
chemical_list: D000914:Antibodies, Viral; C085820:INS1 protein, influenza virus; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated; D017361:Viral Nonstructural Proteins