The emergence of a Eurasian-origin genotype A6 A(H5N5) virus in North America expanded the genetic diversity of highly pathogenic avian influenza viruses and raised concerns about zoonotic and pandemic potential. Following the first reported human infection with A/Washington/2148/2025, investigators assessed replication, pathogenesis, and transmissibility using polarized human bronchial epithelial cells and the ferret model to inform public health risk assessment.
The study focused on several key outcomes: replication kinetics in a mammalian airway cell line, disease severity and tissue dissemination in ferrets, transmission between animals in both direct-contact and respiratory droplet (airborne) models, and detection of airborne virus shedding.
A/Washington/2148/2025 A(H5N5) was evaluated in polarized Calu-3 cells at temperatures representative of the mammalian upper and lower respiratory tracts (33°C and 37°C). The virus displayed robust replication at both temperatures. Kinetics and peak titers were reported as comparable to those of contemporary genotype B3.13 and D1.1 A(H5N1) viruses, indicating efficient replication capacity in airway epithelial cells.
These in vitro results suggest that the A(H5N5) virus can productively infect mammalian airway epithelium under conditions modeling the human respiratory tract. The findings support concern about zoonotic capacity but do not alone predict transmissibility between mammals.
In the ferret model, A(H5N5) replicated efficiently throughout the respiratory tract and disseminated to extrapulmonary tissues. All inoculated ferrets developed severe disease that progressed to fatal outcomes. The observations indicate substantial pathogenicity and the ability of this virus to cause systemic infection in a mammalian model widely used to approximate human influenza disease.
The study highlights that A(H5N5) can produce severe lower respiratory tract infection and extrapulmonary spread in ferrets, underscoring its virulence potential in this model. Specific tissue sites and quantitative viral loads in extrapulmonary organs were described in the source but detailed numerical values were not reported in the abstract.
Airborne transmission was specifically assessed using a respiratory droplet model and by sampling air for virus detection. Airborne transmission between ferrets was not observed. Air samples showed infrequent, low-level detection of virus; this pattern paralleled results previously seen with A(H5) viruses that fail to transmit via air in ferrets.
The lack of airborne transmission in this model indicates that the A(H5N5) virus has not acquired the adaptations required for efficient aerosol or respiratory droplet spread among mammals, at least under the experimental conditions tested.
A direct-contact transmission model was used to assess transmission following co-housing exposure. Limited transmission was detected within 4 days of exposure. Contact animals with evidence of transmission showed signs of lower respiratory tract replication.
These observations suggest that while efficient airborne spread is absent, limited transmission via direct contact is possible and may lead to deeper respiratory tract infection in exposed animals. The extent and frequency of such transmission events were characterized as limited in the study abstract.
Collectively, the data indicate that the A/Washington/2148/2025 A(H5N5) virus can replicate robustly in a mammalian airway epithelial cell line and cause severe, systemic, and fatal disease in ferrets. However, it lacks detectable adaptations for efficient airborne transmission in the ferret respiratory droplet model.
The authors emphasize the heterogeneity observed among clade 2.3.4.4b A(H5Nx) viruses in North America and argue for ongoing genotype-by-genotype evaluation of newly emerged viruses to accurately estimate public health risk. The combination of high replication competence and high pathogenicity in a mammalian model, coupled with absent airborne transmissibility, frames the virus as a serious zoonotic threat that has not demonstrated efficient mammal-to-mammal airborne spread under the conditions tested.
Surveillance efforts and risk assessments should therefore consider both virologic features (replication efficiency, tissue tropism, pathogenicity) and transmission phenotypes (airborne versus contact spread) on a per-genotype basis to guide public health responses.
Findings summarized here are drawn from the article abstract. Numerical details for viral titers, organ-specific viral loads, exact counts of transmitted animals, and statistical measures were not provided in the abstract and would require consultation of the full manuscript for complete quantitative data.