Abstract
BackgroundInfluenza 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.Methodology/Principal FindingsThe 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.Conclusions/SignificanceSeveral 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.
Highlights
Since 1996, it has been reported that several novel avian subtypes, H5N1, H7N1, H7N2, H7N3, H7N7 and H9N2 have crossed the species barrier from domestic poultry to humans and caused a spectrum in severity of human disease, including fatalities [1,2,3,4]
The immune responses of vaccinated mice challenged with the H5N1/ PR8 reassortant virus five days post influenza virus challenge were characterized by rapid increases of both H5HA-specific antibody and cellular immune responses
A study by Hoelscher and colleagues using a similar vaccine approach demonstrated that mice immunized with a recombinant adenovirus H5 HA vaccine induced an HA-518epitope-specific IFN-c-secreting CD8+ T cell response [30]
Summary
Since 1996, it has been reported that several novel avian subtypes, H5N1, H7N1, H7N2, H7N3, H7N7 and H9N2 have crossed the species barrier from domestic poultry to humans and caused a spectrum in severity of human disease, including fatalities [1,2,3,4]. H5N1 influenza virus is of special concern due to several factors including its endemic hold in poultry populations in Southeast Asia, a spread to at least 60 countries, and a case fatality rate of more than 50% upon transmission to humans [5]. The recent outbreak and subsequent pandemic caused by a swine-origin H1N1 influenza virus highlights the real danger regarding emergence of novel influenza strains. The only U.S approved stockpiled H5N1 influenza vaccine is based on virus propagated in embryonated chicken eggs. Several issues limit the effective use of inactivated H5N1 influenza vaccines generated using this strategy: 1) reliance on embryonated chicken eggs; 2) safety concerns of the H5N1 influenza virus grown in bulk before inactivation [7]; 3) delivery of the vaccine by needle; and 4) requirement for two doses to generate significant immune responses in naıve individuals. 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
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