Journal Article

A Novel Type of Influenza Vaccine: Safety and Immunogenicity of Replication-Deficient Influenza Virus Created by Deletion of the Interferon Antagonist NS1

Wacheck, Volker, Cinatl, Jindrich, Michaelis, Martin, Roethl, Elisabeth, Egorov, Andrej, Dick-Gudenus, Rosmarie, Ferko, Boris, Bergmann, Michael, Geiler, Janina, Hoeflmayer, Doris, Pfeiffer, Andrea, Popow-Kraupp, Therese, Romanova, Julia, Groiss, Franz, Kundi, Michael, Morokutti, Alexander, Mueller, Christian A., Muster, Thomas, Wolschek, Markus, Seipelt, Joachim, Redlberger-Fritz, Monika, Fuereder, Thorsten

2010

Overview

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 (ΔNS1-H1N1) in healthy volunteers. Methods. Healthy seronegative adult volunteers were randomized to receive either a single intranasal dose of the ΔNS1-H1N1 A/New Caledonia vaccine at 1 of 5 dose levels (6.4, 6.7, 7.0, 7.4, and 7.7 log10 median tissue culture infective dose) (n= 36 recipients) or placebo (n= 12 recipients). Results. Intranasal vaccination with the replication-deficient ΔNS1-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.

• Publisher: The University of Chicago Press,University of Chicago Press,Oxford University Press
• Subject: Adult / Antibodies / Antibodies, Viral - blood / Antibodies, Viral - isolation & purification / Applied microbiology / Biological and medical sciences / Dosage / Dose-Response Relationship, Immunologic / Double-Blind Method / Fundamental and applied biological sciences. Psychology / Gene Deletion / Humans / Immune response / Infectious diseases / Influenza A Virus, H1N1 Subtype - genetics / Influenza A Virus, H1N1 Subtype - immunology / Influenza vaccines / Influenza Vaccines - administration & dosage / Influenza Vaccines - adverse effects / Influenza Vaccines - immunology / Influenza virus / Influenza, Human - prevention & control / Medical sciences / Microbiology / Miscellaneous / Nasal Lavage Fluid - immunology / Nasal Lavage Fluid - virology / Orthomyxoviridae / Placebos / Transponders / Vaccination / Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects) / Vaccines, Attenuated - administration & dosage / Vaccines, Attenuated - adverse effects / Vaccines, Attenuated - immunology / Viral Nonstructural Proteins - genetics / Virology / Virus Shedding / Viruses / Volunteerism