A novel type of influenza vaccine: safety and immunogenicity of replication-deficient influenza virus created by deletion of the interferon antagonist NS1.
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 .
Wacheck
Volker
V
Departments of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Egorov
Andrej
A
Groiss
Franz
F
Pfeiffer
Andrea
A
Fuereder
Thorsten
T
Hoeflmayer
Doris
D
Kundi
Michael
M
Popow-Kraupp
Therese
T
Redlberger-Fritz
Monika
M
Mueller
Christian A
CA
Cinatl
Jindrich
J
Michaelis
Martin
M
Geiler
Janina
J
Bergmann
Michael
M
Romanova
Julia
J
Roethl
Elisabeth
E
Morokutti
Alexander
A
Wolschek
Markus
M
Ferko
Boris
B
Seipelt
Joachim
J
Dick-Gudenus
Rosmarie
R
Muster
Thomas
T
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
D000914:Antibodies, Viral; C085820:INS1 protein, influenza virus; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated; D017361:Viral Nonstructural Proteins