SAFE AND EFFECTIVE NEWCASTLE DISEASE VIRUS VECTORED LIVE ATTENUATED SWINE INFLUENZA VACCINES

Swine influenza viruses (SIVs) are a major cause of respiratory disease in pigs, resulting in significant economic losses for the U.S. swine industry. Controlling swine influenza has been extremely challenging as the current inactivated swine influenza vaccines do not provide long-lasting cross-protective immunity, and also occasionally induce vaccine associated enhanced respiratory disease (VAERD) when the vaccine strains do not match the circulating viruses. Swine live attenuated influenza vaccines provide cross-protection against heterovariant and heterosubtypic viruses and do not induce VAERD. However, these vaccines are likely no longer used by the pig industry since the discovery that virulent viruses can be produced through reassortment between the vaccine strain and circulating viruses, which is a major safety concern for swine and public health. It is urgent to develop effective and safe influenza vaccines for swine industry. We have demonstrated that Newcastle disease virus (NDV) vectored live attenuated avian and swine influenza vaccines, which express the optimized HA of influenza A viruses (IAVs), are safe and able to protect birds and pigs against homologous influenza virus challenges. Antibodies against influenza neuraminidase (NA) have been shown to correlate with protection of virus infection. NP is a conserved internal protein in all H1-H16 subtype of IAVs and plays the critical role in eliciting CD8 T cell immune responses responsible for cross-protection among different genotypes and subtypes. To develop safe and effective swine influenza vaccines, we will produce recombinant NDVs that express optimized H1, H3, N1, N2 or NP from prototype H1N1 and H3N2 SIVs, use them as a cocktail vaccine and determine the efficacy and mechanisms of protection through two specific aims: Aim 1 will develop NDV-based swine influenza vaccine and determine immunogenicity of developed vaccine candidates. Aim 2 will determine the efficacy of NDV-based swine influenza vaccine and understand the mechanisms of the vaccine protection. Completing these objectives will have the potential to develop a safe and effective swine influenza vaccine that is expected to prevent and reduce the spread of SIVs within swine herds, which would lower the economic burden of swine influenza for the U.S. swine industry.