Technical Report: Highly Pathogenic Avian Influenza A(H5N1) Viruses

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 viruses in wild, commercial, and backyard birds. From January 2022 through April 23, 2024, APHIS reported HPAI A(H5)/A(H5N1) virus detections in more than 9,200 wild birds in 50 states or territories and more than 1,100 commercial and backyard flocks affecting more than 90 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 the World Organisation for Animal Health since January 2022. HPAI A(H5N1) virus infections of mammals have included a polar bear in the United States, farmed mink in Spain and farmed foxes and other mammals in Finland, harbor and gray seals in the United States, sea lions in Peru, Argentina, and Chile, elephant seals in Argentina, baby goats in the United States, and domesticated pets such as cats in Poland, France, South Korea, and the United States, and dogs in Italy. In March and April 2024, the United States reported HPAI A(H5N1) virus infections of dairy cattle at farms in multiple states. Spread from dairy farm-to-dairy farm was reported [292KB, 6 pages], and routes of transmission are under investigation. In the United States, from May 2022 through April 23, 2024, USDA APHIS reported HPAI A(H5N1) virus detections in wild mammals comprising a wide range of different species in 28 states.

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 April 23, 2024, 26 sporadic human cases of A(H5N1) were reported from eight countries, including 14 cases of severe or critical illness, and seven deaths, four 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. The individual reported fatigue without other symptoms 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 [13]. 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 [14-16].

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. 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.

Nearly all 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. Fourteen cases (7 children, 7 adults) had severe or critical illness, and seven (3 children, 4 adults) died. Thirteen 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. 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 [17-19]. 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 revealed the presence of the polymerase basic protein 2 (PB2) 627K marker, which is often associated with mammalian adaptation during infection [20]. 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 [21].

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 do not currently have the ability to easily infect and bind to α2,6-linked sialic acid receptors that are predominant in the human upper respiratory tract [2], which would be needed to increase the risk of transmission to people [22,23].