Abstract
BackgroundRecent outbreaks of highly pathogenic influenza A H5N1 viruses in humans and avian species that began in Asia and have spread to other continents underscore an urgent need to develop vaccines that would protect the human population in the event of a pandemic.Methods and FindingsLive, attenuated candidate vaccines possessing genes encoding a modified H5 hemagglutinin (HA) and a wild-type (wt) N1 neuraminidase from influenza A H5N1 viruses isolated in Hong Kong and Vietnam in 1997, 2003, and 2004, and remaining gene segments derived from the cold-adapted (ca) influenza A vaccine donor strain, influenza A/Ann Arbor/6/60 ca (H2N2), were generated by reverse genetics. The H5N1 ca vaccine viruses required trypsin for efficient growth in vitro, as predicted by the modification engineered in the gene encoding the HA, and possessed the temperature-sensitive and attenuation phenotypes specified by the internal protein genes of the ca vaccine donor strain. More importantly, the candidate vaccines were immunogenic in mice. Four weeks after receiving a single dose of 106 50% tissue culture infectious doses of intranasally administered vaccines, mice were fully protected from lethality following challenge with homologous and antigenically distinct heterologous wt H5N1 viruses from different genetic sublineages (clades 1, 2, and 3) that were isolated in Asia between 1997 and 2005. Four weeks after receiving two doses of the vaccines, mice and ferrets were fully protected against pulmonary replication of homologous and heterologous wt H5N1 viruses.ConclusionsThe promising findings in these preclinical studies of safety, immunogenicity, and efficacy of the H5N1 ca vaccines against antigenically diverse H5N1 vaccines provide support for their careful evaluation in Phase 1 clinical trials in humans.
Highlights
On several occasions since 1997, outbreaks of highly pathogenic avian influenza (HPAI) H5N1 infections have occurred in poultry and in humans, fueling public health concerns over their potential to ignite a pandemic that would cause significant morbidity and loss of life
Four weeks after receiving a single dose of 106 50% tissue culture infectious doses of intranasally administered vaccines, mice were fully protected from lethality following challenge with homologous and antigenically distinct heterologous wt H5N1 viruses from different genetic sublineages that were isolated in Asia between 1997 and 2005
Infections with H5N1 influenza viruses in avian species and in humans have been occurring sporadically since 1997 and phylogenetic and antigenic analyses of H5N1 viruses collected over this period indicate that they have evolved into different sublineages or clades: 2004 viruses are designated clade 1, 2003 viruses clade 19, some 2005 isolates clade 2, and the 1997 viruses clade 3 [4,5]
Summary
On several occasions since 1997, outbreaks of highly pathogenic avian influenza (HPAI) H5N1 infections have occurred in poultry and in humans, fueling public health concerns over their potential to ignite a pandemic that would cause significant morbidity and loss of life. Infections with H5N1 influenza viruses in avian species and in humans have been occurring sporadically since 1997 and phylogenetic and antigenic analyses of H5N1 viruses collected over this period indicate that they have evolved into different sublineages or clades: 2004 viruses are designated clade 1, 2003 viruses clade 19, some 2005 isolates clade 2, and the 1997 viruses clade 3 [4,5]. Recent outbreaks of highly pathogenic influenza A H5N1 viruses in humans and avian species that began in Asia and have spread to other continents underscore an urgent need to develop vaccines that would protect the human population in the event of a pandemic. This study was done to develop a new H5N1 vaccine and to test it in animals
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