Establishing a Rapid and Safe Genotype-to-Phenotype Platform to Characterize Circulating Highly Pathogenic Avian Influenza Strains

Highly Pathogenic Avian Influenza (HPAI) poses a significant threat to wild and domestic animals, with increasing risks to human health. Since its initial detection in humans in 1997, HPAI has evolved into diverse subtypes, collectively termed H5Nx, which have caused severe outbreaks across species. To date, H5N1 has infected over 900 humans, with a fatality rate exceeding 50%. In March 2024, a notable spillover event led to an outbreak of HPAI in Texas dairy cattle. Although symptoms in cattle remained mild, the zoonotic potential raises concerns about genetic adaptations in H5N1 that would favor mammalian infection. Alarmingly, the first documented mammal-to-mammal transmission of HPAI to humans occurred in individuals exposed to H5N1-positive cattle. While human-to-human transmission has not been observed, the ongoing risk underscores the need for proactive research. To address this, we are developing a virus-like particle (VLP) platform to characterize H5Nx viruses at critical stages of infection. These VLPs would lack genetic material, making them safe tools to study, but would carry surface protein Hemagglutinin (HA) and Neuraminidase (NA) to mimic behavioral traits of circulating H5Nx strains. Leveraging surveillance data from national and international collaborators, this VLP system provides a rapid, safe, and scalable approach to studying emerging HPAI variants. It provides a tool to detect mutations that enhance human transmissibility and evaluate the efficacy of current antiviral therapeutics. Furthermore, this platform can aid in selecting vaccine candidates, enhancing preparedness for potential outbreaks and mitigating pandemic risks. The adaptability and impact of this project underscore its importance in global public health efforts to prevent pandemics.