Use of Highly Pathogenic Avian Influenza A(H5N1) Gain-Of-Function Studies for Molecular-Based Surveillance and Pandemic Preparedness

Davis, C. Todd; Chen, Li-Mei; Pappas, Claudia; Stevens, James; Tumpey, Terrence M.; Gubareva, Larisa V.; Katz, Jacqueline M.; Villanueva, Julie M.; Donis, Ruben O.; Cox, Nancy J.

In recent years, both the range and speed of molecular surveillance for H5N1 and other avian influenza viruses have continued to improve. Notwithstanding, GOF studies are needed to inform our interpretation of genetic data obtained from naturally occurring viruses. Despite recent gains in our understanding of the molecular basis for phenotypic properties of HPAI H5N1 and LPAI H7N9 viruses, more data are required to fully elucidate the mechanisms by which influenza viruses with pandemic potential cause severe disease and how they evolve during replication in mammalian hosts. This is especially true for studies that offer insight into the virologic and molecular changes associated with increased capacity for mammalian transmission, a hallmark of pandemic influenza viruses. As outlined above, GOF studies have provided critical information for molecularly based surveillance, as well as for research groups sequencing, characterizing, or experimentally testing these viruses. Besides answering fundamental questions about the molecular basis for key phenotypic characteristics of H5N1 and other avian influenza viruses, GOF data have been used to launch outbreak investigations and allocate resources (e.g., H5N1 in Cambodia), to develop criteria for the Influenza Risk Assessment Tool, and to make difficult and sometimes costly pandemic planning policy decisions, such as preparing CVVs and purchasing prepandemic vaccine stockpiles (e.g., H7N9 in China). The detection of GOF mutations in HPAI H5N1 and LPAI H7N9 viruses prompted immediate public health responses that differed from the actions that would have occurred with a rise in case numbers alone because concurrent detection of GOF mutations with an increase in human cases could be a signal that human-to-human transmission had begun, a situation where rapid response is paramount. By coupling results obtained from GOF studies with enhanced surveillance and preparedness, we as a community of scientists, veterinary and public health experts, regulators, and policy advisers have an opportunity to use the most advanced methodologies available to address the continuing threat posed by influenza viruses with pandemic potential.