Submitted to: Keystone Symposia
Publication Type: Abstract Only
Publication Acceptance Date: 1/2/2006
Publication Date: 3/28/2006
Citation: Mills, K., Suguitan, A., Mcauliffe, J.M., Duke, G., Wang, Z., Dixon, M., Lu, B., Jin, H., Beck, J.R., Swayne, D.E., Kemble, G., Subbarao, K. 2006. A live attenuated H5N1 vaccine candidate is efficacious against homologous and heterologous H5N1 virus challenge [abstract]. Abstracts of Advances in Influenza Research: From Birds to Bench to Bedside, Keystone Symposium, March 28-April 2, 2006, Steamboat Springs, Colorado. p. 158.
Technical Abstract: Since 1997, H5N1 influenza viruses of avian origin have infected humans in Southeast Asia and China, raising concerns that a pandemic strain could emerge. Using reverse genetics, we have generated a live, attenuated vaccine containing a modified hemagglutinin and neuraminidase from the A/Vietnam/1203/2004 (H5N1) and the six internal gene segments from the A/Ann Arbor/6/60 ca (AA ca) vaccine donor strain. As a consequence of the modification of the hemagglutinin gene to remove the multibasic amino acid cleavage site and the contribution of attenuating genes from the AA ca virus, the H5N1 ca vaccine virus was no longer highly pathogenic in chickens. After confirming that the vaccine had retained the temperature sensitive and attenuation phenotype of the A/Ann Arbor/6/60 strain, we evaluated its immunogenicity and efficacy against homologous and heterologous H5N1virus challenge in mice. Neutralizing antibodies (Nt Ab) were not detectable in mice 28 days after a single dose of the vaccine, but a significant rise was seen by day 56. Two doses of the vaccine elicited a higher and more cross-protective Nt Ab response. A single dose of the vaccine administered intranasally conferred complete protection from lethal challenge with homologous and heterologous H5N1 viruses. A single dose of vaccine was also able to significantly reduce pulmonary virus replication of both homologous and heterologous H5N1 viruses, while two doses provided complete protection from pulmonary virus replication. In summary, the live attenuated 2004 H5N1 candidate vaccine shows promise in preclinical testing. Clinical evaluation of the safety and immunogenicity of the vaccine is planned.