H5N1 Genotype D1.1: Understanding Its Evolution, Risks, and Public Health Solutions

Biosecurity and human risk mitigation strategies urgently needed for an evolving virus poised for severe, human-to-human outbreaks.

By Nicolas Hulscher, MPH and Peter A. McCullough, MD, MPH

When assessing highly mutagenic infectious diseases such as H5N1 avian influenza, it is crucial to consider all possible future scenarios. At the same time, it is essential to avoid reactionary responses to sensationalist fear-mongering headlines. In this article, we will provide a balanced analysis of the newly identified H5N1 clade 2.3.4.4b genotype D1.1.

According to a new study titled, Timing and molecular characterisation of the transmission to cattle of H5N1 influenza A virus genotype D1.1, clade 2.3.4.4b:

The second H5N1 influenza A virus (IAV) genotype detected in United States (US) cattle is a clade 2.3.4.4b, genotype D1.1 virus (IAV) that was discovered recently through the National Milk Testing Strategy’s (NMTS) testing program (1). Genotype D1.1 is a 4:4 reassortant that retained PB1, HA, MP, and NS segments from the Eurasian avian lineage and acquired PB2, PA, NP, and, most notably, N1 from low-pathogenicity avian influenza viruses (LPAIV) circulating in the Americas. The D1.1 genotype has become widespread in North American wild birds and is a major source of poultry outbreaks, along with severe zoonotic infections in Louisiana (2) and British Columbia (3). On January 6, 2025, the patient in Louisiana became the first US fatality from H5N1.

The authors report that this new strain has caused only mild illness in cattle. However, genotype D1.1 was detected in a severe human case in British Columbia and a reportedly fatal human case in Louisiana. The study identified the PB2 D701N mutation in all sequenced cattle-derived D1.1 viruses, a change that has frequently emerged following mammalian spillover in previous H5N1 outbreaks.