Understanding the Molecular Features of Novel Emergent (H9Nx and H7Nx) Avian Influenza Viruses Posing Zoonotic and Pandemic Threats

A diverse range of avian influenza viruses (AIV), currently circulates among domestic poultry and wild bird populations. These viruses are continually evolving and acquiring genetic changes that facilitate infection and transmission between different avian and mammalian species, including humans. In recent years, we have observed an exceptionally high rate of genetic evolution in some AIVs, specifically in the H9 and H7 subtypes. This has led to the emergence of diversified H9Nx and H7Nx variants (H9N2, H9N9, H7N1, H7N3, H7N7, H7N9), which have gained the potential to infect humans from infected birds. For instance, over the last three years, more than 60 human infections with the H9N2 virus have been reported. Similarly, H7N9 has caused over 1500 human infections, with a 50% mortality rate. Most of these human infection cases have been reported in China, where these viruses are endemic in bird populations. However, these viruses pose a global threat as they can spread around the world through migratory birds, including the UK. The lack of scientific evidence requires the understanding to anticipate the impact and risk associated with the global dissemination of influenza viruses, especially those with core genotypic evolution, and the potential consequences for transmission from domestic poultry to humans. Over a period of more than 15 years, Asia, Europe, and Africa have been exposed to multiple waves of infection with the evolving group of viruses that this study intends to investigate. Despite substantial improvements in the rapid generation of surveillance data due to reduced cost and higher output of genomic sequencing, this rich data pipeline cannot definitively inform risk. This project aims to provide fundamental knowledge of the correlates required for the successful evolution, maintenance, and dissemination of such viruses from avian species to humans, along with markers identified for successful zoonotic transmission resulting in severe outcomes. Our findings will generate a roadmap for in-vitro analyses to assess the pandemic potential of virus variants. There is now a much greater international focus on monitoring virus evolution and understanding their correlation with risk, as well as enhancing national preparedness for early detection and response to such threats to human health. These insights may help develop the appropriate use of available vaccines and antivirals. Such assessments are currently hindered by the lack of credible, robust understanding of the genetic markers of viruses with significant selective advantages, and therefore a higher threat level. To overcome this hindrance, we must first unravel the complex inter-relationships that underpin the frequent emergence of viruses with the necessary adaptations to cross species barriers and develop resistance to available pre-pandemic vaccines and drugs. This project, through a combination of in vitro and in vivo analyses, aims to provide insights that can serve as a baseline for assessing new and emerging strains that have zoonotic and pandemic potential. The research outcomes will enable national and international health agencies to design and implement contingency plans as part of risk mitigation and pandemic preparedness, reducing the ever-increasing threat from these viruses to human health, food security, and the economy.