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Functional Genomic and Serological Analysis of the Protective Immune Response Resulting from Vaccination of Macaques with an NS1-Truncated Influenza Virus

Department of Comparative Medicine, University of Washington, Seattle, Washington 98195,¹ Washington National Primate Research Center, University of Washington, Seattle, Washington 98195,² College of Veterinary Medicine & Biomedical Sciences, Department of Microbiology, Immunology & Pathology, Colorado State University, Fort Collins, Colorado,³ Department of Microbiology,⁴ Department of Medicine, Division of Infectious Diseases,⁵ Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York 10029,⁶ Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333,⁷ Department of Microbiology, University of Washington, Seattle, Washington 98195,⁸ Department of Immunology, University of Washington, Seattle, Washington 98195⁹

Received 20 March 2007/ Accepted 13 August 2007

We are still inadequately prepared for an influenza pandemic due to the lack of a vaccine effective for subtypes to which the majority of the human population has no prior immunity and which could be produced rapidly in sufficient quantities. There is therefore an urgent need to investigate novel vaccination approaches. Using a combination of genomic and traditional tools, this study compares the protective efficacy in macaques of an intrarespiratory live influenza virus vaccine produced by truncating NS1 in the human influenza A/Texas/36/91 (H1N1) virus with that of a conventional vaccine based on formalin-killed whole virus. After homologous challenge, animals in the live-vaccine group had greatly reduced viral replication and pathology in lungs and reduced upper respiratory inflammation. They also had lesser induction of innate immune pathways in lungs and of interferon-sensitive genes in bronchial epithelium. This postchallenge response contrasted with that shortly after vaccination, when more expression of interferon-sensitive genes was observed in bronchial cells from the live-vaccine group. This suggested induction of a strong innate immune response shortly after vaccination with the NS1-truncated virus, followed by greater maturity of the postchallenge immune response, as demonstrated with robust influenza virus-specific CD4⁺ T-cell proliferation, immunoglobulin G production, and transcriptional induction of T- and B-cell pathways in lung tissue. In conclusion, a single respiratory tract inoculation with an NS1-truncated influenza virus was effective in protecting nonhuman primates from homologous challenge. This protection was achieved in the absence of significant or long-lasting adverse effects and through induction of a robust adaptive immune response.

Published ahead of print on 22 August 2007.

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