Utility of Human In Vitro Data in Risk Assessments of Influenza A Virus Using the Ferret Model

As influenza A viruses (IAV) continue to cross species barriers and cause human infection, the establishment of risk assessment rubrics has improved pandemic preparedness efforts. pathogenicity and transmissibility evaluations in the ferret model represent a critical component of this work. As the relative contribution of experimentation to these rubrics has not been closely examined, we sought to evaluate to what extent viral titer measurements over the course of infections are predictive or correlates of nasal wash and tissue measurements for IAV infections . We compiled data from ferrets inoculated with an extensive panel of over 50 human and zoonotic IAV (inclusive of swine-origin and high- and low-pathogenicity avian influenza viruses associated with human infection) under a consistent protocol, with all viruses concurrently tested in a human bronchial epithelial cell line (Calu-3). Viral titers in ferret nasal wash specimens and nasal turbinate tissue correlated positively with peak titer in Calu-3 cells, whereas additional phenotypic and molecular determinants of influenza virus virulence and transmissibility in ferrets varied in their association with viral titer measurements. Mathematical modeling was used to estimate more generalizable key replication kinetic parameters from raw viral titers, revealing commonalities between viral infection progression and . Meta-analyses inclusive of IAV that display a diverse range of phenotypes in ferrets, interpreted with mathematical modeling of viral kinetic parameters, can provide critical information supporting a more rigorous and appropriate contextualization of experiments toward pandemic preparedness. Both and models are employed for assessing the pandemic potential of novel and emerging influenza A viruses in laboratory settings, but systematic examinations of how well viral titer measurements obtained align with results from experimentation are not frequently performed. We show that certain viral titer measurements following infection of a human bronchial epithelial cell line are positively correlated with viral titers in specimens collected from virus-inoculated ferrets and employ mathematical modeling to identify commonalities between viral infection progression between both models. These analyses provide a necessary first step in enhanced interpretation and incorporation of -derived data in risk assessment activities and highlight the utility of employing mathematical modeling approaches to more cl