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The episodic resurgence of highly pathogenic avian influenza H5 virus

Nature volume 622, pages 810–817 (2023)Cite this article

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Abstract

Highly pathogenic avian influenza (HPAI) H5N1 activity has intensified globally since 2021, increasingly causing mass mortality in wild birds and poultry and incidental infections in mammals1,2,3. However, the ecological and virological properties that underscore future mitigation strategies still remain unclear. Using epidemiological, spatial and genomic approaches, we demonstrate changes in the origins of resurgent HPAI H5 and reveal significant shifts in virus ecology and evolution. Outbreak data show key resurgent events in 2016–2017 and 2020–2021, contributing to the emergence and panzootic spread of H5N1 in 2021–2022. Genomic analysis reveals that the 2016–2017 epizootics originated in Asia, where HPAI H5 reservoirs are endemic. In 2020–2021, 2.3.4.4b H5N8 viruses emerged in African poultry, featuring mutations altering HA structure and receptor binding. In 2021–2022, a new H5N1 virus evolved through reassortment in wild birds in Europe, undergoing further reassortment with low-pathogenic avian influenza in wild and domestic birds during global dissemination. These results highlight a shift in the HPAI H5 epicentre beyond Asia and indicate that increasing persistence of HPAI H5 in wild birds is facilitating geographic and host range expansion, accelerating dispersion velocity and increasing reassortment potential. As earlier outbreaks of H5N1 and H5N8 were caused by more stable genomic constellations, these recent changes reflect adaptation across the domestic-bird–wild-bird interface. Elimination strategies in domestic birds therefore remain a high priority to limit future epizootics.

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Fig. 1: HPAI H5 outbreak reports, subtypes and clades.
Fig. 2: Evolution of clade 2.3.4.4b HA genes and early migration patterns of resurgent HPAI.
Fig. 3: Geographic and host transmission patterns of principal HPAI H5 clades.
Fig. 4: The contrasting spatial epidemiology among HPAI H5 clades 2.3.4.4b, 2.3.4.4x, 2.3.2.1 and 2.2.
Fig. 5: Circulation of HPAI gene segments in resurgent 2020–2021 and 2021–2022 viruses.
Fig. 6: Graphical summary of the episodic resurgence of HPAI H5N1 in wild birds.

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Data availability

The avian influenza virus sequences and associated metadata used in this study were downloaded from GISAID and NCBI GenBank. Accession numbers and acknowledgements are provided in Supplementary Data 3. Details of confirmed detections/outbreaks in domestic and wild birds globally are available from World Animal Health Information System, WOAH (https://wahis.woah.org/) and EMPRES-i+ Global Animal Disease Information System, Food and Agriculture Organization (https://empres-i.apps.fao.org/).

Code availability

Data, code and analysis files are available at https://doi.org/10.5281/zenodo.8251324.

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Acknowledgements

The computations were performed using research facilities offered by Information Technology Services, the University of Hong Kong. We gratefully acknowledge the staff from the originating laboratories responsible for obtaining the specimens and the submitting laboratories where the genome data were generated and shared by means of GISAID (Supplementary Data 3). We thank J.L.-H. Tsui for valuable discussions about phylogeographic analysis. The funding bodies had no role in the design of the study and collection, analysis and interpretation of data or the writing of the manuscript. Support came from National Institutes of Health contract number 75N93021C00016 and US National Science Foundation awards 1911955 and 2200310.

Author information

Authors and Affiliations

  1. School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Ruopeng Xie, Kimberly M. Edwards, Xiaoman Wei, Sook-San Wong, Mark Zanin, Leo L. M. Poon & Vijaykrishna Dhanasekaran

  2. HKU-Pasteur Research Pole, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Ruopeng Xie, Kimberly M. Edwards, Xiaoman Wei, Sook-San Wong, Leo L. M. Poon & Vijaykrishna Dhanasekaran

  3. Sydney Institute for Infectious Diseases, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia

    Michelle Wille

  4. Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia

    Michelle Wille

  5. Centre for Immunology & Infection, Hong Kong Science and Technology Park, Hong Kong SAR, China

    Mark Zanin & Leo L. M. Poon

  6. Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza, Egypt

    Rabeh El-Shesheny

  7. IHAP, Université de Toulouse, Institut national de recherche pour l’agriculture, l’alimentation et l’environnement, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France

    Mariette Ducatez

  8. Human Link, DMCC, Dubai, United Arab Emirates

    Ghazi Kayali

  9. Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, TN, USA

    Richard J. Webby

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Contributions

V.D. conceived and designed the research. R.X. and X.W. curated the genome datasets. K.M.E. curated the outbreak reports. R.X., K.M.E., X.W. and V.D. performed analysis and designed the figures. R.X., K.M.E., M.W. and V.D. wrote the manuscript with input from S-S.W., M.Z., R.E-S., M.D., L.L.M.P., G.K. and R.J.W. All authors discussed and approved the manuscript.

Corresponding author

Correspondence to Vijaykrishna Dhanasekaran.

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Extended data figures and tables

Extended Data Fig. 1 Number and proportion of HPAI H5 outbreaks.

Data according to the EMPRESS-i+ Global Animal Disease Information System, Food and Agriculture Organization of the United Nations (FAO) (https://empres-i.apps.fao.org/) from January 2004 to May 2022 coloured by subtype.

Extended Data Fig. 2 Comparison of affected wild bird species by taxonomic order.

Data reported to the EMPRESS-i+ Global Animal Disease Information System, Food and Agriculture Organization of the United Nations (FAO) (https://empres-i.apps.fao.org/) in HPAI H5Nx outbreaks between 2016/17, 2020/21, and 2021/22. Avian orders with fewer than ten outbreaks are not shown.

Extended Data Fig. 3 Spatial distribution of HPAI H5 outbreaks in Europe during 2020–2022.

EMPRESS-i+ Global Animal Disease Information System, Food and Agriculture Organization of the United Nations (FAO) (https://empres-i.apps.fao.org/). Outbreaks are coloured by subtype, and maps were generated using the R package “rnaturalearth”.

Extended Data Fig. 4 Temporal changes in HPAI H5 lineage predominance.

(a) The number of HA sequences coloured by lineage since 2020. (b) Proportional lineage distribution by month inferred from (a).

Extended Data Fig. 5 Evolutionary relationships of Panzootic-2020 (including 2020/21 and 2021/22 resurgence) and JKE-2019 lineage.

Maximum-likelihood tree of Panzootic-2020 (a) and JKE-2019 (b) for each of the eight gene segments. Samples collected in Africa are highlighted in red.

Extended Data Fig. 6 Maximum clade credibility tree of panzootic-2020 clade with branches coloured by geographic region.

The posterior probabilities of regions over 0.8 are annotated in the nodes.

Extended Data Fig. 7 Dynamics of HPAI H5 transmission lineages in clades 2.3.4.4b, 2.3.4.4x, 2.3.2.1 and 2.2.

Virus lineage movements were inferred by continuous phylogeographic analysis for each clade.

Extended Data Fig. 8 The contrasting geographic and host transmission patterns among HPAI H5 2.3.4.4b, 2.3.4.4x, 2.3.2.1, and 2.2 clades inferred from discrete phylogeography.

From left to right, the figures represent regional Markov jumps, regional Markov rewards, host Markov jumps, and host Markov rewards.

Extended Data Fig. 9 Tanglegram of HPAI H5 virus reassortment.

Coloured lines connect each virus across all eight genes, showing incongruence between and within major clades.

Extended Data Fig. 10 Genomic surveillance of HPAI H5 viruses by geographic region from 2005 to 2022.

(a) Temporal changes of all HPAI H5 sequences available on the Global Initiative for Sharing All Influenza Data (GISAID) and NCBI Influenza Virus Resource databases from January 2005 to June 2022 using collection dates. (b) Temporal changes of HPAI H5 sequences per outbreak reported to the Food and Agriculture Organization of the United Nations (FAO). (c) Temporal changes of HPAI H5 sequences per case reported to the World Organization for Animal Health (WOAH).

Supplementary information

Supplementary Information

This file contains a table of contents and Supplementary Tables 1–8.

Reporting Summary

Peer Review File

Supplementary Data 1

Summary of HPAI H5 monophyletic clades for each of the eight gene segments.

Supplementary Data 2

Summary of the proportion of HPAI H5 cases and outbreaks sequenced from 2004 to 2022.

Supplementary Data 3

Acknowledgements for sequences obtained from GISAID and NCBI (accessed on 11 July 2022).

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Xie, R., Edwards, K.M., Wille, M. et al. The episodic resurgence of highly pathogenic avian influenza H5 virus. Nature 622, 810–817 (2023). https://doi.org/10.1038/s41586-023-06631-2

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