Abstract
Live attenuated influenza vaccine (LAIV) candidates of the H7 subtype, A/Netherlands/219/03 (H7N7, NL03 ca) and A/chicken/British Columbia/CN-6/2004 (H7N3, BC04 ca), were evaluated for their receptor binding specificity and immunogenicity in ferrets. The BC04 ca virus exhibited α2,3-SA and α2,6-SA dual receptor binding preference while the NL03 ca virus preferentially bound to α2,3-SA. Substitution of the Q226 and G228 (Q-G) by the L226 and S228 (L-S) residues in the HA improved binding to α2,6-SA for NL03 ca. The vaccine viruses with L-S retained the attenuation phenotype. NL03 L-S ca replicated more efficiently than the original NL03 ca virus in the upper respiratory tract of ferrets, and induced higher levels of humoral and cellular immune responses. Prior vaccination with seasonal LAIV reduced H7-specific antibody responses, but did not reduce the H7N7 vaccine mediated protection against a heterologous H7N3 BC04 wt virus infection in ferrets. In addition, the H7N3 and H7N7 vaccine immunized ferret sera cross reacted with the newly emerged H7N9 virus. These data, in combination with the safety data from previously conducted Phase 1 studies, suggest that these vaccines may have a role in responding to the threat posed by the H7N9 virus.
Highlights
Influenza A viruses cause yearly seasonal influenza epidemics and occasional influenza pandemics when a novel influenza virus with an antigenically shifted hemagglutinin (HA) emerges in humans resulting in widespread infection, high morbidity and high mortality [1]
Live attenuated influenza vaccines that can bind to both α2,3-SA and α2,6-SA are more likely to grow to the high titers in embryonated chicken eggs required for commercial manufacturing and to replicate efficiently in the human respiratory tract resulting in induction of protective immune responses
The H7N7 NL03 virus predominantly bound to α2,3-SA and replicated at a lower level in the respiratory tract of ferrets; this may explain why it appeared to be less immunogenic than the H7N3 BC04 ca vaccine in preclinical and clinical studies [13,14,15]
Summary
Influenza A viruses cause yearly seasonal influenza epidemics and occasional influenza pandemics when a novel influenza virus with an antigenically shifted hemagglutinin (HA) emerges in humans resulting in widespread infection, high morbidity and high mortality [1]. Avian influenza H7 subtype viruses have caused occasional human infections and have raised pandemic concerns. The highly pathogenic avian influenza (HPAI) H7N7 virus with multibasic amino acids at the HA cleavage site infected more than 30 million birds in poultry farms. Among the viruses isolated from the outbreak, A/chicken/British Columbia/ CN-7/2004 was identified as an HPAI virus due to the presence of the multibasic amino acids at the HA cleavage site, while A/chicken/British Columbia/CN-6/2004 was confirmed to be a low pathogenic avian influenza (LPAI) virus due to the monobasic amino acid at the HA cleavage site [6]. The discovery of human infections caused by the viruses in China is a major public health concern as it is unlikely that there will be pre-existing immunity to this subtype in the population [8]. As of August 2013, there were 132 reported human infections including 43 fatal cases since February 2013
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