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BACKGROUNDThe ongoing panzootic of highly pathogenic avian influenza A(H5N1) presents a risk to human health both from infections resulting from exposure to infected birds or mammals, and from potential mutations enabling human-to-human transmission of a virus to which there is little or no population immunity.AIMThis cohort study was designed with the aim of informing assessments of the risk of avian influenza to human health and the public health management of influenza A(H5N1) exposures.METHODSWe recruited 428 individuals at 34 highly pathogenic avian influenza A(H5N1) outbreak sites between April 2023 to March 2025, throughout England. Through nasopharyngeal samples and questionnaires, we investigated risk factors including exposure periods and usage of personal protective equipment (PPE), and characteristics of influenza A(H5N1) infection.RESULTSThe median participant age was 37 years (interquartile range: 28-51 years), 296 (69%) were male. Most participants (85%) reported full PPE use when exposed, and 82 (19%) were vaccinated against seasonal influenza. Six persons tested PCR-positive for influenza A(H5N1), of whom three (< 1%) met the case definition for infection (two confirmed, one unclear) attributable to exposure periods. No severe illness was reported; no secondary cases were identified. None of the six cases with positive detections were vaccinated against seasonal influenza; two of them reported not wearing full PPE when exposed.CONCLUSIONWe recommend continued conscientious PPE use and the resumption of enhanced surveillance following detection of an increased risk of animal-human transmission, with a One Health focus, to mitigate pandemic risk of influenza A(H5N1).