PIV5 as a novel vaccine vector for pandemic influenza
Mooney, Alaina Jones
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Highly pathogenic avian influenza virus (HPAI) and the H5N1 subtype in particular, poses a formidable pandemic threat. Current HPAI vaccine candidates suffer from poor immunogenicity, and there are challenges associated with sufficient production and distribution. Parainfluenza virus 5 (PIV5) provides an appealing approach for live virus vectored vaccines. It can be produced quickly and safely in cell culture which is especially important in the event of a pandemic. Here, we have inserted the HA gene of A/Vietnam/1203/04 (H5N1) into the PIV5 genome with the goal of testing the efficacy and mechanism of protection of recombinant PIV5-H5 vaccine vectors. The natural gradient of mRNA translated in PIV5 is dictated by the proximity of the gene to the 3’ UTR. Thus, we tested expression and immunogenicity of H5 vaccine vectors where the HA gene is inserted in distinct locations in the PIV5 genome. We show here that vaccination with rPIV5-H5 is safe and effective as a vaccine vector and that it provides protection against highly pathogenic H5N1 challenge. Neuraminidase (NA) is a glycoprotein on the surface of the virus as well as virus-infected cells and is responsible for cleavage of sialic acid residues as the virus buds from the cell at the end of the replication cycle. NA is more conserved than HA, the current influenza vaccine target, which increases the likelihood of achieving broader protection if used as a vaccine antigen. In this study, we extend the work with rPIV5-H5 to show that vaccination with rPIV5-N1 primes an NA-specific antibody response and T cell response and confers complete protection against homologous influenza virus challenge and significant cross-protection against heterologous influenza virus within the same subtype. There is also evidence of limited cross-protection against virus of a different subtype (H3N2). Because PIV5 is not sialic acid-restricted for replication, it is possible to utilize alternate routes of administration. We continue this work by showing that rPIV5-H5 is effective at providing protection against HPAIV H5N1 when administered intramuscularly as well as intranasally.