Models of H9N2 avian influenza virus infection and vaccination in chickens

Abstract

This thesis presents within-host compartment models to describe the chicken immune responses to H9N2 avian influenza virus (AIV) vaccination and infection and examined the effects of vaccination on outbreak dynamics in a flock-level compartment model. Within-host models of the gastrointestinal and respiratory systems were used to identify type-I interferon (IFN) pathways and an eclipse phase which contribute to localized virus shedding patterns based on virus shedding data from chickens experimentally infected with H9N2 AIV. The hemagglutinin inhibition (HI) antibody response to vaccination was assessed at the host level to determine the duration at which seroprotective HI antibody titres are maintained post-vaccination. The contributions of both the HI antibody response and the cytotoxic T lymphocyte (CTL) response on virus clearance were assessed in a model of a vaccinated host. The effect of vaccination using four candidate vaccines at the flock-level was compared to outbreak dynamics in an unvaccinated flock. The studies demonstrated in several key findings. First, the inclusion of an eclipse phase and the type-I IFN pathways involved in gastrointestinal and respiratory H9N2 AIV infection in chickens differ in the model, which may in part explain the differences in virus shedding patterns. Second, prime-and-boost vaccination strategies provide seroprotective HI antibody titres for the duration of a broiler chicken lifespan, but a third vaccination should be considered for layers considering antibody clearance over time. Third, a delayed CTL response to virus infection allows for virus clearance within the expected timeframe in vaccination chickens, resulting in reduced shedding overall. Finally, vaccination of chicken flocks dramatically reduces outbreak size compared to unvaccinated flocks, however further research is required to examine the transmission rate of H9N2 AIV between vaccinated birds, which would ultimately serve to obtain more accurate simulations of disease spread within flocks. This research represents an important first step in developing compartment models as a tool to examine the host response to H9N2 AIV vaccination and infection, and in identifying key gaps in empirical data which would serve to improve our understanding of the impact of vaccination at both the host and flock levels.