Pre-clinical evaluation of a replication-competent recombinant adenovirus serotype 4 vaccine expressing influenza H5 hemagglutinin

• Published in: PloS one Vol. 7; no. 2; p. e31177
• Main Authors: Alexander, Jeff, Ward, Simone, Mendy, Jason, Manayani, Darly J, Farness, Peggy, Avanzini, Jenny B, Guenther, Ben, Garduno, Fermin, Jow, Lily, Snarsky, Victoria, Ishioka, Glenn, Dong, Xin, Vang, Lo, Newman, Mark J, Mayall, Tim
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.02.2012; Public Library of Science (PLoS)
• Subjects: Adenoviridae - classification; Adenoviridae - growth & development; Adenoviridae - physiology; Adenoviruses; Amino Acid Sequence; Animals; Avian influenza; Base Sequence; Biology; Cell Line; Cell lines; Cell-mediated immunity; Cells (Biology); Clinical trials; Clonal deletion; Cytometry; Evaluation; Flow cytometry; Genetic Vectors - genetics; Growth kinetics; Hemagglutinin Glycoproteins, Influenza Virus - chemistry; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Hemagglutinins; Humans; Humoral immunity; Immune response; Immunity; Immunity, Cellular - immunology; Immunity, Humoral - immunology; Immunization; Infection; Influenza; Influenza A Virus, H5N1 Subtype - immunology; Influenza vaccines; Influenza Vaccines - immunology; Influenza viruses; Kinetics; Lectins; Lung - pathology; Lung - virology; Medicine; Mice; Molecular Sequence Data; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - virology; Pandemics; Pathogenesis; Reassortant Viruses; Recombination, Genetic - genetics; Replication; Serotyping; Species Specificity; Survival Analysis; Vaccines; Viral Load - immunology; Virus replication; Virus Replication - physiology; Viruses; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0031177

Influenza virus remains a significant health and social concern in part because of newly emerging strains, such as avian H5N1 virus. We have developed a prototype H5N1 vaccine using a recombinant, replication-competent Adenovirus serotype 4 (Ad4) vector, derived from the U.S. military Ad4 vaccine strain, to express the hemagglutinin (HA) gene from A/Vietnam/1194/2004 influenza virus (Ad4-H5-Vtn). Our hypothesis is that a mucosally-delivered replicating Ad4-H5-Vtn recombinant vector will be safe and induce protective immunity against H5N1 influenza virus infection and disease pathogenesis. The Ad4-H5-Vtn vaccine was designed with a partial deletion of the E3 region of Ad4 to accommodate the influenza HA gene. Replication and growth kinetics of the vaccine virus in multiple human cell lines indicated that the vaccine virus is attenuated relative to the wild type virus. Expression of the HA transgene in infected cells was documented by flow cytometry, western blot analysis and induction of HA-specific antibody and cellular immune responses in mice. Of particular note, mice immunized intranasally with the Ad4-H5-Vtn vaccine were protected against lethal H5N1 reassortant viral challenge even in the presence of pre-existing immunity to the Ad4 wild type virus. Several non-clinical attributes of this vaccine including safety, induction of HA-specific humoral and cellular immunity, and efficacy were demonstrated using an animal model to support Phase 1 clinical trial evaluation of this new vaccine.