Performing Department
(N/A)
Non Technical Summary
Swine influenza caused by influenza A viruses (IAVs) is an important respiratory disease that causes significant economic losses for the US swine industry. Although swine influenza vaccines have been widely used in the USA, swine influenza remains ineffectively controlled and outbreaks remain a major and growing problem for the swine industry. The main issue is that current swine vaccines cannot keep up with the rapid changes of circulating virus strains. This often leads to vaccines providing ineffective cross-protection against different IAV strains such as antigenically heterologous and heterosubtypic virus strains. Commercially available swine live attenuated vaccines (LAIVs) from Boehringer Ingelheim Animal Health overcomes the disadvantages of traditional killed vaccines, but reassorts with circulating swine influenza viruses. This has the potential to generate virulent viruses that could pose a significant threat to animal and human health. Because of the issues with the currently available killed and live swine influenza vaccine, there is a critical need for safer and effective swine influenza vaccines.The goal of this project is to develop safe and effective live attenuated swine influenza vaccines using Newcastle disease virus (NDV) as the vector. This approach has potential to develop safer and more effective swine influenza vaccine. Recently, we showed that NDV-based swine influenza vaccine can provide complete protection in pigs against a homologous swine influenza virus challenge, indicating the NDV-based vaccine can be used in pigs. Therefore, we hypothesize that NDV-based swine influenza vaccine can be developed and has potential to provide cross-protection against different genotype and subtype SIVs. Accordingly, our application offers a novel strategy to produce safe and effective swine influenza vaccine using the NDV as the vector. If successful, our strategy has the potential to reduce both animal and human influenza infections, and block potential zoonotic transmission from swine to humans.Development of universal human and swine influenza vaccines is ideal to protect public and animal health. However, no universal influenza vaccine approach has been demonstrated to be feasible so far. Successful completion of the tasks in this application will offer an alternative strategy to develop safe and effective live swine influenza vaccine. Furthermore, it will provide important insight into how to develop universal influenza vaccines. Specifically, pigs have been described as an excellent model for human influenza infections because swine have clinical manifestations and pathogenesis that is highly similar to that of human infections. Therefore, results of this study could provide invaluable insights into future vaccination strategies for human influenza vaccines.
Animal Health Component
100%
Research Effort Categories
Basic
50%
Applied
50%
Developmental
(N/A)
Goals / Objectives
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.
Project Methods
We will generate Newcastle disease virus (NDV)-vectored swine influenza vaccines that express antigens of influenza viruses and are expected to be safe and effective to provide homologous and heterologous influenza virus challenges. Then we will characterize these vaccine candidates in cells by Western blotting and determine their immunogenicity in pigs and investigate cross-protective antibodies induced by the vaccines against a comprehensive panel of swine influenza viruses detected in the US swine populations. We will determine the efficacy of NDV-based swine influenza vaccine against heterovariant and heterologous virus challenge in pigs and understand the mechanisms of the vaccine protection.