J Infect Dis . Avian influenza virus A(H5N1) genotype D1.1 is better adapted to human nasal and airway organoids than genotype B3.13

[tetano]

J Infect Dis


. 2025 Nov 24:jiaf598.
doi: 10.1093/infdis/jiaf598. Online ahead of print. Avian influenza virus A(H5N1) genotype D1.1 is better adapted to human nasal and airway organoids than genotype B3.13

Xiaojuan Zhang[SUP] 1 [/SUP], Stephanie Joy-Ann Lam[SUP] 1 2 [/SUP], Lin-Lei Chen[SUP] 1 2 [/SUP], Carol Ho-Yan Fong[SUP] 1 2 [/SUP], Wan-Mui Chan[SUP] 1 [/SUP], Jonathan Daniel Ip[SUP] 1 [/SUP], Shaofeng Deng[SUP] 1 2 [/SUP], Siwen Liu[SUP] 1 2 [/SUP], Rachel Chun-Yee Tam[SUP] 1 2 [/SUP], Pui Wang[SUP] 1 2 [/SUP], Kwok-Hung Chan[SUP] 1 2 [/SUP], King-Pui Florence Chan[SUP] 3 [/SUP], James Chung-Man Ho[SUP] 3 [/SUP], Jie Zhou[SUP] 1 2 4 [/SUP], Kwok-Yung Yuen[SUP] 1 2 4 5 6 [/SUP], Honglin Chen[SUP] 1 2 4 [/SUP], Kelvin Kai-Wang To[SUP] 1 2 4 5 6 [/SUP]



Affiliations

• PMID: 41284739
• DOI: 10.1093/infdis/jiaf598

Abstract

Three critically ill or fatal avian influenza A(H5N1) human infections have been reported in North America since November 2024. Notably, all were infected with genotype D1.1 instead of B3.13, the dominant genotype before November 2024. Here, we demonstrated that D1.1 could replicate to higher titers in human nasal and airway organoid-derived transwell monolayers from 6 donors. D1.1 exhibited a better binding to α2,3- and α2,6-linked SA than B3.13. No significant differences in most inflammatory or antiviral cytokines/chemokines was observed. These observations suggest that D1.1 is better adapted to both the upper and lower human respiratory tract epithelium than B3.13.

Keywords: Cattle H5N1; Clade 2.3.4.4b; Genotype D1.1 and B3.13; Human respiratory organoid; sialic acid receptor.

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[Commonground]

Excerpt from Post #1 above: J Infect Dis . Avian influenza virus A(H5N1) genotype D1.1 is better adapted to human nasal and airway organoids than genotype B3.13

RESULTS

Prevalence of H5N1 genotypes detected in patients from North America

First, we determined the prevalence of D1.1 in humans from the North America human outbreak.

We retrieved all available H5N1 clade 2.3.4.4b sequences from humans in North America from

January 1, 2024 to May 10, 2025 shared via GISAID [10]. A total of 53 strains were identified,

of which 6 strains had 2 sequences deposited. These 53 strains were collected from patients

between March 28, 2024 and February 12, 2025 (Supplementary Table S3). Of these 53 strains,

22 (41.5%) were assigned to genotype B3.13, 8 (15.1%) were assigned to D1.1, 1 (1.9%) was

assigned to D1.3, and 22 (41.5%) could not be assigned to any genotypes according to GenoFLU

version 1.06 (https://github.com/USDA-VS/GenoFLU).

All strains collected between March and September 2024 belonged to B3.13 (Supplementary

Figure S1C). D1.1 first emerged in October 2024 and accounted for 32% (8/25) of strains with a

successful genotype assigned and collected between September 2024 and February 2025. All

strains collected in 2025 belong to genotype D1.
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[Commonground]

Excerpt from Post #1 above: J Infect Dis . Avian influenza virus A(H5N1) genotype D1.1 is better adapted to human nasal and airway organoids than genotype B3.13​

The reverse genetically derived D1.1 strain we used in this experiment was constructed based on

the D1.1 from a critically ill patient, and contained 3 markers of human adaptation, including HA

E186D, HA Q222H, and PB2 E627K [2]. HA Q222L and PB2 E627K have been associated with

airborne transmission of H5N1 virus [15]. Further studies are required to delineate whether the

difference in replication between D1.1 and B3.13 is related to these markers.

Our observations suggest that D1.1 genotype may be better adapted to humans than B3.13.

Further studies are required to determine if there are differences in the replication of different

strains within the same clade. As D1.1 is now widespread among dairy cows in the United

States, there is an increasing risk of further adaptation of D1.1 with higher transmissibility or

virulence among mammals. Continuous phenotypic monitoring using human organoids and other

in vivo models will provide critical information for assessing the risk of D1.1 or other novel

genotypes in humans.

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