Mammalian infections with highly pathogenic avian influenza viruses renew concerns of pandemic potential

Abstract

There is unprecedented spread of highly pathogenic avian influenza A H5N1 viruses in bird species on five continents, and many reports of infections in mammals most likely resulting from consumption of infected birds. As H5N1 viruses infect more species, their geographical range increases and more viral variants are produced that could have new biological properties including adaptation to mammals and potentially to humans. This highlights the need to continually monitor and assess mammalian-origin H5N1 clade 2.3.4.4b viruses for the presence of mutations that could potentially increase their pandemic risk for humans. Fortunately, to date there have been a limited number of human cases, but infection of mammals increases the opportunity for the virus to acquire mutations that enhance efficient infection, replication, and spread in mammals, properties that have not been seen in these viruses in the past.

Evolution of HPAI H5N1 viruses. All circulating HPAI H5N1 viruses trace back to influenza A/goose/Guangdong/1/96. Over time, H5 viruses have diversified into different genetic clades. Clade 2.3.4.4 viruses originated from clade 2.3.4, and while both primarily only infect birds, clade 2.3.4.4 viruses have an increased capacity to reassort, giving rise to H5Nx viruses with novel NA pairings. Evolution of this lineage gave rise to clade 2.3.4.4b viruses where the H5 re-acquired an N1 NA pairing. Apart from birds, these viruses can now infect various small mammals, although these are largely dead-end infections acquired by direct contact with infected birds, without further spread between mammals. Two recent outbreaks in seals and minks mark the first reports of possible mammal-to-mammal transmission by these viruses. The mink viruses showed between eight and nine amino acid differences in comparison to closely related H5N1 viruses. Notably, all of the viruses from minks contained an alanine at position 271 of PB2 (T271A) and a methionine at position 396 located in the 2SBS of the NA (I396M; Agüero et al., 2023). A number of mammalian-origin clade 2.3.4.4b H5N1 viruses have also been found to contain mammalian adaptive mutations (E627K, E627V, and D701N) in the PB2 subunit of the RNA polymerase complex (Alkie et al., 2023) as well as mutations in other internal protein genes. Of concern, the rapid acquisition of adaptive mutations in mammalian-origin H5N1 2.3.4.4b viruses potentially increases their pandemic risk for humans.