Identification of clinical and virological correlates associated with influenza A candidate vaccine virus (CVV) attenuation in a ferret model.

Influenza A viruses continuously circulate among avian and swine species, posing a persistent threat to public health. The development of influenza candidate vaccine viruses (CVVs) plays a pivotal role in the global strategy for influenza pandemic preparedness. Safety-testing of CVVs for attenuation in ferrets represents a critical step that takes place prior to making these viruses available to vaccine manufacturers. Development of pathogenicity standards is needed to establish acceptable thresholds of disease so that CVV safety can be assessed without the need for comparison to the parental virus. To assess the capacity of diverse CVVs to cause pathogenesis in mammalian hosts, clinical and virological parameters were compiled from CVV assessments in ferrets conducted using consistent methods over approximately 20 years to identify disease parameters most reflective of attenuation compared to wild-type strains. These analyses revealed an overall reduction in ferret weight loss and fever relative to wild-type controls. Viral titers in nasal washes were reduced with limited spread to tissues beyond the respiratory tract. Regression models further support the significance of clinical signs in distinguishing the virulence of wild-type viruses and CVVs. These findings provide support for the development of standardized parameters for assessing pathogenicity of CVVs and their suitability for manufacturers. IMPORTANCE: The development and safety testing of candidate vaccine viruses (CVVs) against emerging zoonotic influenza strains prior to sharing with vaccine manufacturers is a critical component of influenza pandemic preparedness. The extensive data set reported here provides critical information that will drastically streamline the safety testing process, thereby enabling more efficient CVV assessments and improving public health in the event of an influenza pandemic.