HPAI A(H5N1) viruses in wild birds and poultry
Since 2005, HPAI A(H5N1) viruses have undergone extensive genetic diversification including the formation of hundreds of genotypes following reassortment with other avian influenza A viruses. Clade 2.3.4.4b HPAI A(H5N1) viruses emerged in 2020 and were introduced into North America in late 2021 [1,2]and spread to Central and South America, resulting in wild bird infections (in terrestrial, seabird, shorebird, and migratory species) and poultry outbreaks in many countries [3-8]. In Fall 2023, the first detections of HPAI A(H5N1) viruses in birds in the Antarctica region were reported [9]. Globally, this 2.3.4.4b clade of HPAI A(H5N1) viruses has become widespread causing record numbers of bird outbreaks in wild, backyard, village, and farm birds.
In the United States,USDA APHIS monitors for avian influenza A viruses in wild, commercial, and backyard birds. From January 2022 through June 4, 2024, APHIS reported HPAI A(H5)/A(H5N1) virus detections in more than 9,300 wild birds in 50 states or territories and more than 1,140 commercial and backyard flocks affecting more than 96.5 million birds in 48 states.
HPAI A(H5N1) virus infections among mammals
Sporadic HPAI A(H5N1) virus infections of mammals have been reported since 2003-2004 during HPAI A(H5N1) virus outbreaks in poultry or wild birds [10-12]. HPAI A(H5) viruses are known to occasionally infect mammals that eat (presumably infected) birds or poultry and mammals that are exposed to environments with a high concentration of virus.
Globally, sporadic HPAI A(H5N1) virus infections and outbreaks in a wide range of mammal species were reported by countries in different regions of the world to theWorld Organisation for Animal Healthsince January 2022. HPAI A(H5N1) virus infections of mammals have included a polar bear in the United States, farmed mink inSpainandfarmed foxes and other mammals in Finland,harbor and gray seals in the United States,sea lions in Peru, Argentina, andChile, elephant seals in Argentina, baby goats in the United States, alpacas in the United States, and domesticated pets suchas cats in Poland,France, South Korea, and theUnited States, and dogs inItaly. During March through June 4, 2024, the United States reported HPAI A(H5N1) virus infections of dairy cows at more than 80 farms in nine states.Spread from dairy farm-to-dairy farm was reported, and routes of transmission are under investigation. In the United States, from May 2022 through June 4, 2024, USDA APHIS reported HPAI A(H5N1) virus detections in wild mammals comprising a wide range of different species in 31 states.
Experimental studies have used the ferret model to assess transmissibility and disease severity of HPAI A(H5N1) clade 2.3.4.4b viruses. One study used a recombinant virus that was based upon a virus isolated from a mink during a mink farm outbreak in Spain in 2022. When ferrets were experimentally infected with the recombinant HPAI A(H5N1) clade 2.3.4.4b virus, transmission to co-housed susceptible ferrets through direct contact was observed, but transmission through respiratory droplets to separated ferrets was less efficient [13]. In another study, ferrets experimentally infected with a HPAI A(H5N1) clade 2.3.4.4b virus isolated from a human case in Chile in 2023 transmitted to susceptible ferrets by direct contact but not through respiratory droplets or fomites[14]. Importantly, in this study, all experimentallyinfected ferrets experienced fatal disease [14].
Human cases of A(H5N1)
While HPAI A(H5N1) viruses are currently circulating widely in wild birds and poultry in many geographic regions, relatively few human cases of HPAI A(H5N1) have been reported in recent years [Figure 1]. From January 2022 through June 4, 2024, 29 sporadic human cases of A(H5N1) were reported from nine countries, including 15 cases of severe or critical illness, and seven deaths, six cases of mild illness, and eight asymptomatic cases [Table 1].
One human case of HPAI A(H5N1) was reported in the United States in April 2022 while exposed to poultry. The individual reported fatigue without other symptoms during poultry culling activities at a farm with confirmed HPAI A(H5N1) virus infection of poultry, and a low level of A(H5N1) viral RNA was detected in a single upper respiratory tract specimen. It is possible that detection of A(H5N1) viral RNA resulted from deposition of non-infectious viral material in the upper respiratory tract of the individual and did not represent true infection, similar to the environmental contamination that was attributed to two asymptomatic cases in poultry workers reported in Spain [15]. Transient environmental deposition may also explain the detection of A(H5N1) viral RNA in cases of A(H5N1) reported in asymptomatic poultry workers in the U.K. that were investigated as part of a surveillance study [16-18].
One human case of A(H5N1) was reported in the United States in April 2024 in an adult dairy farm worker. The individual worked at a farm with sick cows presumed to be infected with HPAI A(H5N1) virus in an area in which cows at other dairy farms were confirmed with HPAI A(H5N1) virus infection in Texas [19]. The worker only experienced conjunctivitis without any other signs or symptoms of illness. HPAI A(H5N1) virus was detected in conjunctival and nasopharyngeal swab specimens, and sequence data confirmed clade 2.3.4.4b, genotype B3.13, and close genetic relatedness to viruses detected in other dairy cattle farms in Texas. Oseltamivir was provided for treatment of the individual and for post-exposure prophylaxis of household contacts. Conjunctivitis resolved without other symptoms and household contacts remained well [19]. No additional human cases related to this case were detected.
One human case of A(H5N1) was reported in the United States in May 2024 in an adult dairy farm worker. The individual worked at a farm with sick cows confirmed to be infected with HPAI A(H5N1) virus in Michigan. The worker only experienced conjunctivitis. HPAI A(H5N1) virus was detected in a conjunctival swab specimen, and sequence data confirmed clade 2.3.4.4b, genotype B3.13, closely related to genotype B3.13 viruses detected in dairy cows were sequenced and shared by USDA. Oseltamivir was offered to the worker and household contacts. No additional human cases related to this case were detected.
One human case of A(H5N1) was reported in the United States in May 2024 in an adult farm worker. The individual worked at a farm with sick cows confirmed to be infected with HPAI A(H5N1) virus in Michigan. The worker experienced upper respiratory symptoms. HPAI A(H5N1) virus was detected in a nasopharyngeal swab specimen, and partial HA and full-length NA sequence data confirmed clade 2.3.4.4b, closely related to viruses detected in dairy cows. Oseltamivir was provided for treatment of the individual and for post-exposure prophylaxis of household contacts. No additional human cases related to this case were detected.
Most human cases of HPAI A(H5N1) reported since January 2022 had recent exposure to sick or dead poultry, and no cases of human-to-human HPAI A(H5N1) virus transmission were identified. Fifteen cases (8 children, 7 adults) had severe or critical illness, and seven (3 children, 4 adults) died. Fourteen cases were associated with clade 2.3.4.4b HPAI A(H5N1) virus in 7 countries, and eleven cases were associated or assumed to be associated with clade 2.3.2.1c HPAI A(H5N1) viruses in Cambodia and Vietnam. Of the 7 cases of clade 2.3.4.4b HPAI A(H5N1) virus infections that were symptomatic (conjunctivitis or respiratory illness), 4 had severe or critical illness (57%) and one of the 4 died (25%). One case of severe illness in a child in Australia in March 2024 with recent travel history to India was associated with clade 2.3.2.1a HPAI A(H5N1) virus. None of the HPAI A(H5N1) virus genetic sequences contained any known markers of reduced susceptibility to currently recommended FDA-approved influenza antiviral medications.
Genetic data have revealed that when some mammals, including humans, are infected with HPAI A(H5N1) virus, the virus may undergo intra-host evolution resulting in genetic changes that allow more efficient replication in the lower respiratory tract or extrapulmonary tissues [20-22]. Some HPAI A(H5N1) viruses that have infected humans in 2023 and 2024 have also shown the same or similar genetic changes as those identified in wild and captive mammals. For example, sequencing of viruses from specimens collected from human cases identified in Cambodia during October and November 2023, in Vietnam in 2024 and in the dairy farm worker in Texas in April 2024 revealed the presence of the polymerase basic protein 2 (PB2) 627K marker, which is often associated with mammalian adaptation during infection [23]. The HPAI A(H5N1) virus sequenced from the human case in Chile identified in March 2023 had different genetic changes (PB2 591K and 701N) that are also associated with mammalian adaptation [24]. Sequencing of the HPAI A(H5N1) virus from the first dairy farm worker case in Michigan did not identify the PB2 627K marker but revealed the presence of PB2 M631L, that is known to be associated with viral adaptation to mammalian hosts, and which has been detected in 99% of dairy cow sequences but only sporadically in birds [25]. PB2 M631L has been identified as resulting in enhancement of virus replication and disease severity in mice during studies with avian influenza A(H10N7) viruses [26]. The remainder of the genome of A/Michigan/90/2024 was closely related to sequences detected in infected dairy cows and strongly suggests cow-to-human transmission.
Although these genetic changes may impact mammalian disease outcome, they have not been associated with enhanced transmissibility of the virus to humans. HPAI A(H5N1) viruses preferentially bind to α2,3-linked sialic acid receptors that are prevalent in the respiratory and intestinal tracts of waterfowl and poultry, and in the human lower respiratory tract but do not currently have the ability to easily infect cells and bind efficiently to α2,6-linked sialic acid receptors that are predominant in the human upper respiratory tract [2]. The ability to bind efficiently to α2,6-linked sialic acid receptors would be needed to increase the risk of transmission to people [27,28]. Using recombinantly expressed hemagglutinin, analysis of receptor binding of the HPAI A(H5N1) virus identified in the dairy farm worker from Texas (A/Texas/37/2024) revealed binding only to avian-type α2,3-linked sialic acid receptors.
