Location: Virus and Prion Research
Project Number: 5030-32000-120-00-D
Project Type: In-House Appropriated
Start Date: Oct 19, 2016
End Date: Oct 18, 2021
Objective 1. Identify mechanisms of influenza A virus (IAV) pathogenesis and host adaptation to swine. This includes investigating host-pathogen interactions at cellular or molecular levels, identifying determinants of swine IAV infection and shedding from respiratory mucosa, and investigating host range restriction to identify mechanisms by which non-swine adapted viruses infect and adapt to swine. Objective 2. Evaluate emerging IAV at the genetic and antigenic levels as a risk to swine or other host species. This includes identifying emerging IAV and monitoring genetic and antigenic evolution in swine, and identifying genetic changes important for antigenic drift or pathogenicity in swine or other hosts. Objective 3. Identify novel influenza vaccine platforms and improve vaccination strategies. This includes characterizing humoral and cellular immune responses to wild-type and attenuated viruses compared to inactivated vaccines to identify correlates of protection, investigating adjuvants or immune-modulatory agents that result in robust immune responses (mucosal delivered, long lived, broadly cross-protective and/or reduce the number of vaccine boosters), and investigating technologies to override IAV vaccine interference from passively acquired immunity.
Influenza A virus (IAV) will be investigated in swine or relevant in vitro models to 1) understand the genetic predictors of host range and virulence in swine; 2) understand the genetic and antigenic variability of endemic viruses and how this affects vaccine strain selection and efficacy; and 3) develop new vaccines that can override maternally-derived antibody interference and provide broader cross-protection. Disease pathogenesis, transmission, and vaccine efficacy studies will be conducted in the natural swine host. Knowledge obtained will be applied to break the cycle of transmission through development of better vaccines or other novel intervention strategies. Computational biology methods will be used to evaluate virus evolution in the natural host to enable predictions to be made on virulence and/or antigenic factors. These predictions will be tested in the lab and in animal studies with wild type viruses and through the use of reverse engineering and mutational studies to identify virulence components of IAV. Experimentally mutated viruses will be evaluated by test parameters that measure both virus and host properties. Development of vaccines that provide better cross-protective immunity than what is currently available with today's vaccines will be approached through understanding correlates of protection, the impact of prior exposure or passive immunity, and through vaccine vector platform development, attenuated strains for vaccines, and other novel vaccine technologies.