---
title: "Risk assessment of A(H5N5) from the first human case using the ferret model"
id: "pubmed-42578664"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42578664"
content_type: "clinical_feed_article"
specialty: "Critical Care"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42578664/"
doi: "10.1128/jvi.00856-26"
published_at: "2026-09-22T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Risk assessment of A(H5N5) from the first human case using the ferret model
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42578664
- **Specialty:** [Critical Care](https://medichelpline.com/clinical-feed/critical-care.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42578664/)
- **DOI:** [10.1128/jvi.00856-26](https://doi.org/10.1128%2Fjvi.00856-26)
- **Published At:** 2026-09-22T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The study evaluated the zoonotic and pandemic risk of Eurasian-origin genotype **A6 A(H5N5)** virus following the first reported human infection (A/Washington/2148/2025). - In vitro, the virus replicated robustly in polarized human bronchial epithelial **Calu-3** cells at both 33°C and 37°C, with kinetics and peak titers comparable to contemporary genotype B3.13 and D1.1 **A(H5N1)** viruses. - In the ferret model, A(H5N5) replicated efficiently throughout the respiratory tract, disseminated to extrapulmonary tissues, and caused fatal disease in all inoculated animals. - Airborne transmission between ferrets was not observed; detection of virus in air samples was infrequent and low level and paralleled patterns seen with A(H5) viruses that do not transmit via air in ferrets. - In a direct-contact transmission model, limited transmission occurred within 4 days of exposure; contacts showed evidence of lower respiratory tract replication. - Overall, the virus demonstrates capacity for robust replication in mammalian airway cells and severe systemic disease in ferrets but lacks adaptations for efficient airborne spread. - Authors emphasize heterogeneity among clade **2.3.4.4b A(H5Nx)** viruses in North America and recommend genotype-by-genotype evaluation of newly emerged viruses to inform public health risk assessments. - The study used the ferret model and polarized human bronchial epithelial cells to assess replication kinetics, pathogenesis, transmissibility (direct contact and respiratory droplet models), and airborne virus shedding. - Keywords reported: A(H5N5); **ferret model**; influenza; pathogenesis; transmission.
## Clinical Analysis & Structured Key Points
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Epub 2026 Aug 11. # Risk assessment of avian influenza A(H5N5) virus from the first human case using the ferret model [Joanna Pulit-Penaloza](https://pubmed.ncbi.nlm.nih.gov/?term=Pulit-Penaloza+J&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Jessica A Belser](https://pubmed.ncbi.nlm.nih.gov/?term=Belser+JA&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Nicole Brock](https://pubmed.ncbi.nlm.nih.gov/?term=Brock+N&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Troy J Kieran](https://pubmed.ncbi.nlm.nih.gov/?term=Kieran+TJ&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Claudia Pappas](https://pubmed.ncbi.nlm.nih.gov/?term=Pappas+C&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Hui Zeng](https://pubmed.ncbi.nlm.nih.gov/?term=Zeng+H&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Xiangjie Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+X&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Juan A De La Cruz](https://pubmed.ncbi.nlm.nih.gov/?term=De+La+Cruz+JA&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Yasuko Hatta](https://pubmed.ncbi.nlm.nih.gov/?term=Hatta+Y&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Han Di](https://pubmed.ncbi.nlm.nih.gov/?term=Di+H&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [C Todd Davis](https://pubmed.ncbi.nlm.nih.gov/?term=Davis+CT&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Taronna R Maines](https://pubmed.ncbi.nlm.nih.gov/?term=Maines+TR&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#full-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.") Affiliations Expand ### Affiliation * 1 Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. * PMID: **42578664** * DOI: [ 10.1128/jvi.00856-26 ](https://doi.org/10.1128/jvi.00856-26) Item in Clipboard # Risk assessment of avian influenza A(H5N5) virus from the first human case using the ferret model Joanna Pulit-Penaloza et al. J Virol. 2026. Show details Display options Display options Format Abstract PubMed PMID J Virol Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22J+Virol%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22J+Virol%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42578664/) . 2026 Sep 22;100(9):e0085626. doi: 10.1128/jvi.00856-26. Epub 2026 Aug 11. ### Authors [Joanna Pulit-Penaloza](https://pubmed.ncbi.nlm.nih.gov/?term=Pulit-Penaloza+J&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Jessica A Belser](https://pubmed.ncbi.nlm.nih.gov/?term=Belser+JA&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Nicole Brock](https://pubmed.ncbi.nlm.nih.gov/?term=Brock+N&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Troy J Kieran](https://pubmed.ncbi.nlm.nih.gov/?term=Kieran+TJ&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Claudia Pappas](https://pubmed.ncbi.nlm.nih.gov/?term=Pappas+C&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Hui Zeng](https://pubmed.ncbi.nlm.nih.gov/?term=Zeng+H&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Xiangjie Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+X&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Juan A De La Cruz](https://pubmed.ncbi.nlm.nih.gov/?term=De+La+Cruz+JA&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Yasuko Hatta](https://pubmed.ncbi.nlm.nih.gov/?term=Hatta+Y&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Han Di](https://pubmed.ncbi.nlm.nih.gov/?term=Di+H&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [C Todd Davis](https://pubmed.ncbi.nlm.nih.gov/?term=Davis+CT&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA."), [Taronna R Maines](https://pubmed.ncbi.nlm.nih.gov/?term=Maines+TR&cauthor_id=42578664)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42578664/#short-view-affiliation-1 "Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.") ### Affiliation * 1 Influenza Division, NCIRD, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. * PMID: **42578664** * DOI: [ 10.1128/jvi.00856-26 ](https://doi.org/10.1128/jvi.00856-26) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract The incursion of Eurasian-origin genotype A6 A(H5N5) virus into North America expanded the genetic diversity among North American highly pathogenic avian influenza viruses and heightened concern about zoonotic risk. Following a fatal human infection with the A(H5N5) virus A/Washington/2148/2025, viral replication was assessed in polarized human bronchial epithelial cells, and pathogenicity, transmissibility in direct contact and respiratory droplet models, and airborne virus shedding were evaluated in ferrets to inform pandemic risk assessment. A(H5N5) displayed robust replication in Calu-3 cells at 33°C and 37°C, showing kinetics and peak titers comparable to those of contemporary genotype B3.13 and D1.1 A(H5N1) viruses. In ferrets, A(H5N5) replicated efficiently in the respiratory tract, disseminated to extrapulmonary tissues, and caused fatal disease in all inoculated animals. Airborne transmission was not observed, and infrequent, low-level detection of virus in air samples paralleled that of A(H5) viruses that are not transmissible via air in ferrets. In a direct contact model, limited transmission was detected within 4 days of exposure, with evidence of lower respiratory tract replication in contact animals. These findings indicate that the A(H5N5) virus has the capacity for robust replication in an airway epithelial cell line and can cause severe systemic infection and mortality in ferrets but has not acquired adaptations for airborne spread in mammals. Collectively, these results underscore heterogeneity among clade 2.3.4.4b A(H5Nx) viruses in North America and the need for genotype-by-genotype evaluation of newly emerged viruses to understand public health risk.IMPORTANCEThe emergence of Eurasian-origin genotype A6 highly pathogenic avian influenza A(H5N5) virus in North America has increased viral diversity and raised concerns about zoonotic and pandemic risk. In this study, we evaluated the replication kinetics, pathogenesis, and transmission of A/Washington/2148/2025 A(H5N5) virus, which was isolated from the first reported human infection with this influenza virus subtype, using polarized human bronchial epithelial cells and the ferret model. The A(H5N5) virus replicated efficiently _in vitro_ at temperatures representative of the upper and lower respiratory tracts and caused fatal systemic disease in inoculated ferrets. Limited transmission was observed during 4 days of direct contact. Airborne virus detection was infrequent and did not result in airborne transmission. These findings show that A(H5N5) virus can replicate robustly in mammalian cells and cause severe disease but lacks adaptations supporting efficient airborne spread, informing assessment of the pandemic risk posed by genotype A6 influenza viruses. **Keywords:** A(H5N5); ferret model; influenza; pathogenesis; transmission. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement The authors declare no conflict of interest. ## Similar articles * [ Pathogenesis and Transmission of Novel Highly Pathogenic Avian Influenza H5N2 and H5N8 Viruses in Ferrets and Mice. ](https://pubmed.ncbi.nlm.nih.gov/26223637/) Pulit-Penaloza JA, Sun X, Creager HM, Zeng H, Belser JA, Maines TR, Tumpey TM.Pulit-Penaloza JA, et al.J Virol. 2015 Oct;89(20):10286-93. doi: 10.1128/JVI.01438-15. Epub 2015 Jul 29.J Virol. 2015.PMID: 26223637Free PMC article. * [ Human Clade 2.3.4.4 A/H5N6 Influenza Virus Lacks Mammalian Adaptation Markers and Does Not Transmit via the Airborne Route between Ferrets. ](https://pubmed.ncbi.nlm.nih.gov/29299528/) Herfst S, Mok CKP, van den Brand JMA, van der Vliet S, Rosu ME, Spronken MI, Yang Z, de Meulder D, Lexmond P, Bestebroer TM, Peiris JSM, Fouchier RAM, Richard M.Herfst S, et al.mSphere. 2018 Jan 3;3(1):e00405-17. doi: 10.1128/mSphere.00405-17. eCollection 2018 Jan-Feb.mSphere. 2018.PMID: 29299528Free PMC article. * [ A Dutch highly pathogenic H5N6 avian influenza virus showed remarkable tropism for extra-respiratory organs and caused severe disease but was not transmissible via air in the ferret model. ](https://pubmed.ncbi.nlm.nih.gov/37428085/) Herfst S, Begeman L, Spronken MI, Poen MJ, Eggink D, de Meulder D, Lexmond P, Bestebroer TM, Koopmans MPG, Kuiken T, Richard M, Fouchier RAM.Herfst S, et al.mSphere. 2023 Aug 24;8(4):e0020023. doi: 10.1128/msphere.00200-23. Epub 2023 Jul 10.mSphere. 2023.PMID: 37428085Free PMC article. * [ Highly pathogenic avian influenza A(H5N1) virus of clade 2.3.4.4b isolated from a human case in Chile causes fatal disease and transmits between co-housed ferrets. ](https://pubmed.ncbi.nlm.nih.gov/38494746/) Pulit-Penaloza JA, Brock N, Belser JA, Sun X, Pappas C, Kieran TJ, Basu Thakur P, Zeng H, Cui D, Frederick J, Fasce R, Tumpey TM, Maines TR.Pulit-Penaloza JA, et al.Emerg Microbes Infect. 2024 Dec;13(1):2332667. doi: 10.1080/22221751.2024.2332667. Epub 2024 Jun 13.Emerg Microbes Infect. 2024.PMID: 38494746Free PMC article. * [ Cellular tropism of highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b viruses in human respiratory and bovine mammary epithelial cells. ](https://pubmed.ncbi.nlm.nih.gov/42466872/) Brock N, Zeng H, Pappas C, Kieran TJ, Sun X, Pulit-Penaloza JA, Tumpey TM, Maines TR, Belser JA.Brock N, et al.Microbiol Spectr. 2026 Aug 4;14(8):e0137726. doi: 10.1128/spectrum.01377-26. Epub 2026 Jul 17.Microbiol Spectr. 2026.PMID: 42466872Free PMC article. [ See all similar articles ](https://pubmed.ncbi.nlm.nih.gov/?linkname=pubmed_pubmed&from_uid=42578664) ## MeSH terms * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42
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