05 May 2026
A recent preprint published on the bioRxiv server has unveiled a major evolutionary shift in the highly pathogenic avian influenza (HPAI) H5N1 epizootic in North America. The comprehensive genomic analysis of over 21,000 H5N1 sequences reveals that while early strains in the Americas originated from Europe, a new reassortant genotype known as "D1.1" emerged from an Asian lineage in mid-2024 and has since dominated the region.
This latest genomic analysis complements previous research recently published in Nature Medicine, which first tracked the rapid genotypic sweep of D1.1 across North American migratory flyways during the autumn 2024 season.
Asian Origins and Novel Reassortment
According to the bioRxiv study, the D1.1 genotype traces its roots back to the introduction of an Asian virus into the North American Pacific flyway. Once introduced, it underwent a significant 4:4 genomic reassortment with local North American low pathogenicity avian influenza (LPAI) viruses. Crucially, the virus acquired a completely new North American-derived N1 segment, along with PB2, PA, and NP segments. The newly acquired N1 features 22 amino acid differences concentrated on the highly conserved underside of the neuraminidase head domain, which differentiates it from previous Eurasian strains.
As highlighted in the Nature Medicine study, this distinct NA segment likely provides an antigenic advantage due to lower existing population immunity compared to earlier strains.
Expanding Host Range and Zoonotic Risk
The bioRxiv research emphasizes that D1.1 spreads faster, possesses a higher reassortment potential, and exhibits an unprecedented host range compared to prior genotypes. It is the only genotype documented to infect seven different host types: wild birds, domestic birds, marine mammals, terrestrial mammals, domestic mammals, cattle, and humans. Furthermore, when spilling over directly from wild birds to mammals, D1.1 shows a strong selection for specific mammalian-adaptive mutations in the PB2 segment, such as E627K and D701N, which significantly improve viral replication in mammalian hosts.
These findings strongly align with the ecological and clinical observations from the Nature Medicine study. The earlier publication noted that the success of D1.1 was exacerbated by ecological stressors, such as persistent droughts, which forced higher bird densities at remaining water sources and facilitated interspecies transmission.
While the bioRxiv study notes that D1.1 has been responsible for severe human illnesses, including the first H5N1-associated fatalities in the Americas and critical illness in individuals with no known animal exposure, the Nature Medicine study provides important context regarding transmissibility. It reported 17 human cases linked to the sweep (four of which were severe and two fatal) but confirmed via receptor binding assays that the wild bird viruses maintain a strong affinity for avian-like receptors, meaning the current risk for sustained human-to-human transmission remains low.
Ultimately, both studies underscore a shifting zoonotic threat.
Crespo-Bellido A, Trovão NS, Puryear W, Maksiaev A, Pekar JE, Baele G, Dellicour S, Nelson MI. Emergence of D1.1 reassortant H5N1 avian influenza viruses in North America. bioRxiv [Preprint]. 2026 Apr 20:2025.12.19.695329.
