Highly pathogenic avian influenza (HPAI) viruses have potential to cross species barriers and cause pandemics. Since 2022, HPAI A(H5N1) belonging to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade have infected poultry, wild birds, and mammals across North America. Continued circulation in birds and infection of multiple mammalian species with strains possessing adaptation mutations increase the risk for infection and subsequent reassortment with influenza A viruses endemic in swine. We assessed the susceptibility of swine to avian and mammalian HPAI H5N1 clade 2.3.4.4b strains using a pathogenesis and transmission model. All strains replicated in the lung of pigs and caused lesions consistent with influenza A infection. However, viral replication in the nasal cavity and transmission was only observed with mammalian isolates. Mammalian adaptation and reassortment may increase the risk for incursion and transmission of HPAI viruses in feral, backyard, or commercial swine.

We report full-genome characterization of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus from an outbreak among sea lions (August 2023) in Argentina and possible spillover to fur seals and terns. Mammalian adaptation mutations in virus isolated from marine mammals and a human in Chile were detected in mammalian and avian hosts.

Between 24 June and 1 September 2023, highly pathogenic avian influenza (HPAI) A(H5) outbreaks were reported in domestic (25) and wild (482) birds across 21 countries in Europe. Most of these outbreaks appeared to be clustered along coastlines with only few HPAI virus detections inland. In poultry, all HPAI outbreaks were primary and sporadic with most of them occurring in the United Kingdom. In wild birds, colony-breeding seabirds continued to be most heavily affected, but an increasing number of HPAI virus detections in waterfowl is expected in the coming weeks. The current epidemic in wild birds has already surpassed the one of the previous epidemiological year in terms of total number of HPAI virus detections. As regards mammals, A(H5N1) virus was identified in 26 fur animal farms in Finland. Affected species included American mink, red and Arctic fox, and common raccoon dog. The most likely source of introduction was contact with gulls. Wild mammals continued to be affected worldwide, mostly red foxes and different seal species. Since the last report and as of 28 September 2023, two A(H5N1) clade 2.3.4.4b virus detections in humans have been reported by the United Kingdom, and three human infections with A(H5N6) and two with A(H9N2) were reported from China, respectively. No human infection related to the avian influenza detections in animals on fur farms in Finland or in cats in Poland have been reported, and human infections with avian influenza remain a rare event. The risk of infection with currently circulating avian H5 influenza viruses of clade 2.3.4.4b in Europe remains low for the general population in the EU/EEA. The risk of infection remains low to moderate for occupationally or otherwise exposed people to infected birds or mammals (wild or domesticated); this assessment covers different situations that depend on the level of exposure.

Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans and cause severe respiratory disease and fatalities. Currently, these viruses are not efficiently transmitted from person to person, although limited human-to-human transmission may have occurred. Nevertheless, further adaptation of avian H5N1 influenza A viruses to humans and/or reassortment with human influenza A viruses may result in aerosol transmissible viruses with pandemic potential. Although the full range of factors that modulate the transmission and replication of influenza A viruses in humans are not yet known, we are beginning to understand some of the molecular changes that may allow H5N1 influenza A viruses to transmit via aerosols or respiratory droplets among mammals. A better understanding of the biological basis and genetic determinants that confer transmissibility to H5N1 influenza A viruses in mammals is important to enhance our pandemic preparedness.

Avian A/H5N1 influenza viruses pose a pandemic threat. As few as five amino acid substitutions, or four with reassortment, might be sufficient for mammal-to-mammal transmission through respiratory droplets. From surveillance data, we found that two of these substitutions are common in A/H5N1 viruses, and thus, some viruses might require only three additional substitutions to become transmissible via respiratory droplets between mammals. We used a mathematical model of within-host virus evolution to study factors that could increase and decrease the probability of the remaining substitutions evolving after the virus has infected a mammalian host. These factors, combined with the presence of some of these substitutions in circulating strains, make a virus evolving in nature a potentially serious threat. These results highlight critical areas in which more data are needed for assessing, and potentially averting, this threat.

Avian influenza A H5N1 viruses continue to spread globally among birds, resulting in occasional transmission of virus from infected poultry to humans. Probable human-to-human transmission has been documented rarely, but H5N1 viruses have not yet acquired the ability to transmit efficiently among humans, an essential property of a pandemic virus. The pandemics of 1957 and 1968 were caused by avian-human reassortant influenza viruses that had acquired human virus-like receptor binding properties. However, the relative contribution of human internal protein genes or other molecular changes to the efficient transmission of influenza viruses among humans remains poorly understood. Here, we report on a comparative ferret model that parallels the efficient transmission of H3N2 human viruses and the poor transmission of H5N1 avian viruses in humans. In this model, an H3N2 reassortant virus with avian virus internal protein genes exhibited efficient replication but inefficient transmission, whereas H5N1 reassortant viruses with four or six human virus internal protein genes exhibited reduced replication and no transmission. These findings indicate that the human virus H3N2 surface protein genes alone did not confer efficient transmissibility and that acquisition of human virus internal protein genes alone was insufficient for this 1997 H5N1 virus to develop pandemic capabilities, even after serial passages in a mammalian host. These results highlight the complexity of the genetic basis of influenza virus transmissibility and suggest that H5N1 viruses may require further adaptation to acquire this essential pandemic trait.

Clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses have caused large outbreaks within avian populations on five continents, with concurrent spillover into a variety of mammalian species. Mutations associated with mammalian adaptation have been sporadically identified in avian isolates, and more frequently among mammalian isolates following infection. Reports of human infection with A(H5N1) viruses following contact with infected wildlife have been reported on multiple continents, highlighting the need for pandemic risk assessment of these viruses. In this study, the pathogenicity and transmissibility of A/Chile/25945/2023 HPAI A(H5N1) virus, a novel reassortment with four gene segments (PB1, PB2, NP, MP) from North America lineage, isolated from a severe human case in Chile, was evaluated in vitro and using the ferret model. This virus possessed a high capacity to cause fatal disease, characterized by high morbidity and extrapulmonary spread in virus-inoculated ferrets. The virus was capable of transmission to naïve contacts in a direct contact setting, with contact animals similarly exhibiting severe disease, but did not exhibit productive transmission in respiratory droplet or fomite transmission models. Our results indicate that the virus would need to acquire an airborne transmissible phenotype in mammals to potentially cause a pandemic. Nonetheless, this work warrants continuous monitoring of mammalian adaptations in avian viruses, especially in strains isolated from humans, to aid pandemic preparedness efforts.

Strains of avian influenza A, believed to have originated in poultry with transmission to wild birds, have been associated with epidemics and four major pandemics in humans in the past century. The 1918 influenza pandemic was caused by an avian strain of the influenza A(H1N1) virus that initially adapted to infect humans and then rapidly spread between humans. Since 2021, highly pathogenic avian influenza (HPAI) virus subtypes have been identified in poultry and wild birds. In October 2022, the HPAI virus variant A(H5N1) was isolated from intensively farmed American mink. The World Health Organization (WHO), the US Centers for Disease Control and Prevention (CDC), and the European Union Reference Laboratory for Avian Influenza (EURL) have stated that the risk of human infection from birds and mammals and human-to-human transmission from known HPAI viruses is currently low. However, they recommend increased infection surveillance and preparedness. This editorial aims to present the status of HPAI virus transmission in poultry, wild birds, and mammals to highlight the importance of international infection surveillance, control, and preparedness to prevent the next human influenza pandemic.