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Review
. 2025 Apr 15;99(4):e0220924.
doi: 10.1128/jvi.02209-24. Epub 2025 Mar 27.

Highly pathogenic avian influenza H5N1: history, current situation, and outlook

Florian Krammer  1   2   3   4 , Enikö Hermann  4 , Angela L Rasmussen  5   6   7
Affiliations
Review

Highly pathogenic avian influenza H5N1: history, current situation, and outlook

Florian Krammer et al. J Virol. .

Abstract

The H5N1 avian panzootic has resulted in cross-species transmission to birds and mammals, causing outbreaks in wildlife, poultry, and US dairy cattle with a range of host-dependent pathogenic outcomes. Although no human-to-human transmission has been observed, the rising number of zoonotic human cases creates opportunities for adaptive mutation or reassortment. This Gem explores the history, evolution, virology, and epidemiology of clade 2.3.4.4b H5N1 relative to its pandemic potential. Pandemic risk reduction measures are urgently required.

Keywords: H5N1; avian viruses; evolution; influenza vaccines; influenza virus; pandemic risk; reassortment; viral pathogenesis; virus-host interactions; zoonotic infections.

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Conflict of interest statement

The Icahn School of Medicine at Mount Sinai has filed patent applications regarding influenza virus vaccines on which F.K. is listed as inventor. The Icahn School of Medicine at Mount Sinai has also filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines influenza virus vaccines, and influenza virus therapeutics which list F.K. as co-inventor, and F.K. has received royalty payments from some of these patents. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, Castlevax, to develop SARS-CoV-2 vaccines. F.K. is co-founder and scientific advisory board member of Castlevax. F.K. has consulted for Merck, GSK, Sanofi, Curevac, Seqirus, and Pfizer and is currently consulting for 3rd Rock Ventures, Gritstone, and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development and with VIR on influenza virus therapeutics. A.L.R. has consulted for Guidepoint, Edelman, W2O Group, MJH Life Sciences, and Siemens, as well as served as an expert witness in pandemic- and infectious disease-related litigation.

Figures

Fig 1
Fig 1
Animal species infected with H5N1. Wildlife species are encircled in green, agricultural species are encircled in blue, and peridomestic and domestic species are circled in red. Orange arrows depict transmission from an avian host. Purple arrows depict transmission from a bovine host. Viruses indicate influenza A strains known to circulate in species that present a high risk for reassortment.
Fig 2
Fig 2
HA and NA of clade 2.3.4.4b H5N1 viruses. (a–d) Comparison of the HA and NA of a human pandemic H1N1 virus (A/California/04/2009) to genotypes B3.13 (a and c) and D1.1 (b and d) (86) of clade 2.3.4.4b H5N1. The differences in the amino acid sequence are marked in orange (B3.13) or purple (D1.1) onto H1 (a and b, PDB: 5GJS [87]) or N1 (c and d, PDB: 3NSS [88]) structures. The proteins are represented as surfaces. (e, f) Comparison of the reference genotype D1.1 (86) H5 hemagglutinin with two severe human cases from clade D1.1 (A/Louisiana/12/2024 and A/British Columbia/PHL_2032/2024). Fixed mutations are marked as blue sticks, while positions with reported mixed mutations are shown as yellow sticks (77, 89). The receptor binding site is enlarged, and mutations possibly influencing receptor binding and specificity are labeled. Models of the reference D1.1 genotype HA were created with Chai-1 (90, 91). Figures were created using PyMol version 3.0.
See this image and copyright information in PMC

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