Submitted to: PLoS Medicine
Publication Type: Peer reviewed journal
Publication Acceptance Date: 8/1/2006
Publication Date: 9/12/2006
Citation: Suguitan, A.L., Mcauliffe, J., Mills, K.L., Jin, H., Duke, G., Lu, B., Luke, C.J., Murphy, B., Swayne, D.E., Kemble, G., Subbarao, K. 2006. Live attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets. PLoS Medicine. 3(9):e360. Interpretive Summary: Vaccines against the H5N1 highly pathogenic avian influenza are needed to protect the human population. Three influenza vaccines were developed using reverse genetics and cold-adapted human influenza vaccine strain. The vaccines protected mice and ferrets from H5N1 high pathogenicity avian influenza. The vaccines were environmentally safe as evident by failure of the vaccines to infect chickens.
Technical Abstract: 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. Live attenuated candidate vaccines possessing a modified H5 hemagglutinin (HA) and N1 neuraminidase (NA) genes from influenza A H5N1 viruses A/HK/491/1997, A/HK/213/2003, and A/VietNam/1203/2004 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 HA gene 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 (106 TCID50) of intranasally administered vaccines, mice were fully protected from lethal challenge with homologous and antigenically distinct heterologous wildtype (wt) H5N1 viruses from different genetic sublineages (clades 1, 2 and 3) that were isolated in Asia between 1997 and 2005. Four weeks after two doses of the vaccines, complete protection was observed against pulmonary replication of homologous and heterologous wt H5N1 viruses in mice. The 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.