Alfonsi, T.; Bernasconi, A.; Chiara, M.; Ceri, S.

Spillovers of Influenza A viruses into farmed animals and humans have the potential to trigger epidemics or even global pandemics. We introduce FluWarning, a highly efficient and elegant computational method based on anomaly detection of codon bias and dinucleotide composition for early flagging of divergent viral HA segments. Applied to H1N1 specimens collected between 2008-2009, FluWarning accurately identifies the emergence of pdm09 - the virus that caused the 2009 flu pandemic; warnings precede the observed progression of the pandemic. Applied to H5N1 specimens collected between 2019 and 2025, FluWarning flagged the emergence of the B3.13 genotype, linked to a spillover event in dairy cows in the United States. In summary, FluWarning is an effective multi-scale warning system for IAVs, detecting spillovers with few available sequences.