Potential epidemic or even pandemic of H3Ny avian influenza A virus: Public health concern and preparedness

In the early years of the 21st century, humans have experienced the 2009 H1N1 influenza pandemic and the COVID-19 pandemic, which had a significant impact on human public health, social stability and the global economy. Historically, animal influenza viruses have caused at least five pandemics. In recent years, the disconcerting trend of animal influenza viruses frequently crossing species barriers to infect humans has raised concerns regarding the potential emergence of another devastating human influenza pandemic. In 2022, a novel H3N8 subtype avian influenza viruses (AIVs) caused two confirmed human infections in China, followed by a fatal case reported in Guangdong Province in 2023. All three human cases had a history of exposure to live poultry, indicating poultry as a source of H3N8 AIVs transmission. Epidemiological investigations of AIVs have revealed that since the appearance of the novel H3N8 AIVs among poultry in South China in 2021, the virus has disseminated to regions in Eastern and Northern China. Furthermore, the H3N8 AIVs have undergone genetic reassortment with multiple subtypes of AIVs, such as H9N2 and H10N3, leading to the generation of novel reassortant viruses including H3N2 and H3N3. Multiple scientific teams have systematically studied the biological characteristics of the H3N8 AIVs and explored the public health risks associated with its ability to cross-species barriers to infect humans. These studies have shown that the novel H3N8 AIVs possess a dual receptor binding capability for both human and avian receptors. It could efficiently infect and replicate in human respiratory epithelial cells, mouse and ferret models. Most worrisome is the potential of avian H3N8 to rapidly acquire human-adaptive mutations following infection in humans, such as HA G228S and PB2 E627K/V, which enable the virus to acquire airborne transmissibility among ferrets. Human populations, even when vaccinated against human H3N2 virus, appear immunologically naive to emerging mammalian-adapted H3N8 AIVs, underscoring its potential for human-to-human transmission and thus its capacity to spark a pandemic. Historically, influenza pandemics have been caused exclusively by influenza A viruses of H1, H2 and H3 subtypes, and H1N1 and H3N2 viruses have become established in humans as annual seasonal flu. Thus, the emergence of novel H1 or H3 subtype viruses in humans is a potential public health concern. Once the novel H3Ny AIVs reassort with human seasonal H1N1 or H3N2 virus, produce a novel reassortant virus carrying H3Ny AIVs-derived surface genes. This novel virus could potentially evade antibody protection conferred by the existing H3N2 seasonal influenza vaccine, effectively replicate and spread in the human population, posing a significant public health threat. Therefore, to prevent the emergence of pandemic influenza virus, we recommend implementing the following measures: (1) Conduct active epidemiological investigations of novel H3Ny AIVs in poultry farms and live poultry markets, while promptly implementing close monitoring of poultry working populations. Swift diagnosis and notification of individuals with suspected avian H3Ny virus infection are essential to facilitate contact tracing. (2) Administration of the H3N8 vaccine in poultry could effectively reduce the prevalence of H3Ny in chickens, leading to a significant reduction in human H3N8 virus infection. (3) We advocate for either the closure of live poultry markets or regular, comprehensive disinfection of these markets. (4) We recommend research into novel H3Ny subtype influenza vaccines and drugs for human use.