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Transmission of a human isolate of clade 2.3.4.4b A(H5N1) virus in ferrets

Nature volume 636, pages 705–710 (2024)Cite this article

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Abstract

Since 2020, there has been unprecedented global spread of highly pathogenic avian influenza A(H5N1) in wild bird populations with spillover into a variety of mammalian species and sporadically humans1. In March 2024, clade 2.3.4.4b A(H5N1) virus was first detected in dairy cattle in the USA, with subsequent detection in numerous states2, leading to more than a dozen confirmed human cases3,4. In this study, we used the ferret, a well-characterized animal model that permits concurrent investigation of viral pathogenicity and transmissibility5, in the evaluation of A/Texas/37/2024 (TX/37) A(H5N1) virus isolated from a dairy farm worker in Texas6. Here we show that the virus has a remarkable ability for robust systemic infection in ferrets, leading to high levels of virus shedding and spread to naive contacts. Ferrets inoculated with TX/37 rapidly exhibited a severe and fatal infection, characterized by viraemia and extrapulmonary spread. The virus efficiently transmitted in a direct contact setting and was capable of indirect transmission through fomites. Airborne transmission was corroborated by the detection of infectious virus shed into the air by infected animals, albeit at lower levels compared to those of the highly transmissible human seasonal and swine-origin H1 subtype strains. Our results show that despite maintaining an avian-like receptor-binding specificity, TX/37 exhibits heightened virulence, transmissibility and airborne shedding relative to other clade 2.3.4.4b virus isolated before the 2024 cattle outbreaks7, underscoring the need for continued public health vigilance.

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Fig. 1: Glycan microarray analyses of recent clade 2.3.4.4b H5 recombinant HAs.
Fig. 2: Transmission and pathogenesis of TX/37 A(H5N1) in the ferret model.
Fig. 3: Detection of airborne influenza virus released from inoculated ferrets.

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Data availability

Next-generation sequencing data have been deposited in the Sequence Read Archive of the National Center for Biotechnology Information under the BioProject accession number PRJNA1128668. Genome sequences of TX/37 are publicly available from GenBank (under the accession numbers PP577940–PP577947) and GISAID (under the accession number EPI_ISL_19027114). Source data are provided with this paper.

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Acknowledgements

We thank the Comparative Medicine Branch at the Centers for Disease Control and Prevention for care of the animals used in this study; Public Health Region 1 of the Texas Department of State Health Services, the Texas Tech University Bioterrorism Response Laboratory in Lubbock, TX and the Texas Department of State Health Services for access to the human sample from which TX/37 was isolated; and the research institutes that have provided sequence data used in this study and for making this information publicly available in GISAID and GenBank. Glycan microarrays were produced under contract by J. Paulson. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry.

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Authors and Affiliations

  1. Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA

    Joanna A. Pulit-Penaloza, Jessica A. Belser, Nicole Brock, Troy J. Kieran, Xiangjie Sun, Claudia Pappas, Hui Zeng, Paul Carney, Jessie Chang, Brandon Bradley-Ferrell, James Stevens, Juan A. De La Cruz, Yasuko Hatta, Han Di, C. Todd Davis, Terrence M. Tumpey & Taronna R. Maines

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Contributions

J.A.P.-P. designed and optimized aerosol collection procedures, performed ferret experiments, processed samples and analysed data. J.A.B., N.B., C.P., X.S. and T.R.M. performed ferret experiments and processed ferret samples. T.J.K. and X.S. performed sequence analysis. T.J.K. performed statistical analysis. H.Z. assisted with plaque assays. P.C., J.C. and B.B.-F. produced the recombinant HA and performed receptor binding experiments. J.S. performed receptor binding data analysis. J.A.D.L.C. and Y.H. isolated and characterized the virus under the supervision of H.D. and C.T.D., J.A.P.-P. and J.A.B. wrote the initial draft of the manuscript with input from T.R.M., T.M.T. and J.S. who also supervised the work. All authors reviewed and approved the manuscript.

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Correspondence to Joanna A. Pulit-Penaloza.

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Extended data figures and tables

Extended Data Fig. 1 Comparison of receptor binding site residues in diverse H5 HAs.

(A) Sequence residues that comprise the TX/37 HA receptor binding site (RBS) aligned with HA sequences from this and a previous study44, as well as with a recent bovine A(H5N1) virus sequence that reported both human and avian receptor binding18. Alignments with amino acid positions (H3 and H5 numbering) are indicated above the alignment. Conserved residues are indicated as dots. The position of the RBS on the HA is illustrated on the TX/37 structural model. The HA is illustrated as a cartoon, while the receptor binding site residues listed in the alignment are shown as a surface representation. Figure was generated using PyMol 2.5.5. *Current data. †HAs with published glycan array binding results. #Isolates associated with dairy farm outbreaks including dairy cow isolate consensus sequence. (B) Full alignment of the HA for all viruses associated with dairy farm outbreaks included in A.

Source Data

Extended Data Fig. 2 Glycan microarray analysis of the TX/37 recHA.

A second glycan array containing only a limited set of linear and biantennary (A) α2-6 and (B) α2-3 linked sialosides of different lengths (from 1 to 4 LacNAc repeats), printed onto the array at different concentrations, were used to assess both HA binding specificity and avidity of the TX/37 recHA. Error bars are standard deviations from six independent replicates on the array. Each of the glycans’ structures are listed in Supplemental Table 2.

Extended Data Fig. 3 Changes in body weight, temperature, and lethargy in ferrets inoculated intranasally with 6 log10[PFUs] of TX/37.

(A) Percent weight loss from pre-inoculation baseline body weight. (B) Body temperature change from pre-inoculation baseline temperature. Time courses for individual ferrets are shown up to the day of euthanasia (days 2-3), n = 12. (C) Lethargy was evaluated based on a scoring system of 0 to 3.

Source Data

Extended Data Fig. 4 Viral titers in rectal swabs collected from inoculated and contact ferrets.

Twelve ferrets were inoculated intranasally with 6 log10 [PFUs] of TX/37 virus. Transmission to naive contacts in (A) direct contact transmission (DC), (B) fomite transmission (FC), and (C) respiratory droplet transmission (RD) settings were established, and rectal swabs were collected every other day post-inoculation or contact, or on the day of euthanasia (day 2 or day 4 indicated on top of the bar). Rectal swab titers for the inoculated animals are shown on the left side of each graph, and rectal swab titers for contact animals are shown on the right side of each graph. Red asterisks denote animals that succumbed to infection prior to sample collection. The limit of detection is 10 PFU/ml, dashed line. Each bar represents an individual ferret.

Source Data

Extended Data Fig. 5 Viral titers in conjunctival wash samples from ferrets inoculated with 6 log10 [PFUs] of TX/37 A(H5N1) virus.

Conjunctival washes collected from inoculated ferrets (n = 6). The samples were titered in MDCK cells. The limit of detection is 10 PFU/ml, dashed line. Each symbol represents an individual ferret.

Source Data

Extended Data Fig. 6 Transmission of H1 subtype viruses in the ferret fomite model.

Three ferrets per group were inoculated with 6 log10 [PFUs] of (A, B) human seasonal NE/14 A(H1N1), (C, D) swine-origin MN/45 A(H1N2)v, (E, F) swine-origin OH/09 A(H1N1)v, (G, H) or swine-origin OH/02 A(H1N1)v viruses. The transmission experiment was conducted for 5 days (5 cage swaps). (A, C, E, G). Titers in nasal washes collected from inoculated animals (left graph side), and contact (right graph side) are expressed as log10 [PFU/ml]. The limit of detection is 10 PFU (dashed line). (B, D, F, H) Each cage was swabbed prior to cage swap. Infectious virus titers and RNA copy number titers in cage swabs are expressed as log10 [PFU or RNA/swab]. Limit of detection is 1 PFU (dashed line), and 2.9 log10 [RNA copies]. Each bar and symbol represent an individual ferret.

Source Data

Extended Data Fig. 7 Detection of infectious TX/37 A(H5N1) on fomites.

(A) Experimental design (n = 3). A ferret inoculated with 6 log10 of TX/37 A(H5N1) was placed in cage 1 (grey), and a naive ferret was placed in cage 2 (blue). Twenty-four hours post inoculation a cage swab was collected from the cage housing each of the inoculated ferrets (cage 1). An air sample was collected (1 h using BC 251 samplers) from each cage housing the naive ferret [cage 2, air sample 1 (AS1)]. Following cage swap, air sample was collected from cage 1 which now housed the respective contact ferret [air sample 2 (AS2)]. The process was repeated the next day [cage swab 2, air sample 3 (AS3), and air sample 4 (AS4)]. (B) Infectious virus titers and RNA copy number titers in cage swabs are expressed as log10 [PFU or RNA copies/swab]. Limit of detection is 1 PFU, and 2.9 log10 [RNA copies]. (C) Infectious virus titers in air samples are expressed as log10 [PFU/hour] (red symbols; limit of detection 1 PFU/hour; the data represents infectious virus recovered in the >4 µm fraction of the BC 251 sampler, no infectious virus was recovered from the fractions containing particles of 1–4 µm, or <1 µm). Viral RNA copy titers in air samples are expressed as log10 RNA copies/ hour (bars; limit of detection 2.5 log10 RNA copies/hour; data represents the sum from the three sampler fractions). Each ferret is represented by a different symbol and the order of ferrets corresponds to the order of ferrets in Figure 2b.

Source Data

Extended Data Fig. 8 Tissue distribution of TX/37 H5N1 in infected contact ferrets.

Virus dissemination to tissues collected from contacts in the (A) direct contact (DC) and fomite (FC), and (B) respiratory droplet transmission (RDC) set-ups. Viral titers were obtained using standard plaque assay and are reported at log10 [PFU/ml] [blood, soft palate (soft pal), nasal turbinates (nasal tur), ethmoid turbinates (ethmoid tur), eye, conjunctiva(conj)] or log10 [PFU/gram of tissue] [kidney, spleen, liver, intestines, olfactory bulb (olfact bulb), brain, lungs, trachea]. The red asterisk indicate a sample that was not collected. Days post contact on which the samples were collected are shown in parentheses. The limit of detection is 10 PFU/ml or g, dashed line. Colors correspond to the contact ferrets in Figure 2a–c. Each bar represents an individual ferret.

Source Data

Supplementary information

Supplementary Information

Supplementary Tables 1–5. Supplementary Table 1: Glycan microarray binding for recombinant HAs. Supplementary Table 2: Glycans present on alternative microarray assessing glycan length preference. Supplementary Table 3: Next-generation sequencing data. Supplementary Table 4: Summary statistics of the differences in viral RNA copy and PFU titres for each sampling day. Supplementary Table 5: Amino acid differences between TX/37 A(H5N1) and other clade 2.3.4.4b viruses.

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Pulit-Penaloza, J.A., Belser, J.A., Brock, N. et al. Transmission of a human isolate of clade 2.3.4.4b A(H5N1) virus in ferrets. Nature 636, 705–710 (2024). https://doi.org/10.1038/s41586-024-08246-7

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