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bioRxiv · 10.64898/2025.12.10.693614

Vaccine-induced antigenic drift of a human-origin H3N2 Influenza A virus in swine alters glycan binding and sialic acid avidity

Cardenas, M.·Chopra, P.·Cowan, B.·Caceres, C. J.·Anderson, T. K.·Baker, A. L.·Perez, D. R.·Boons, G.-J.·Rajao, D. S.
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Abstract

Interspecies transmission of human influenza A viruses (FLUAV) to swine occurs frequently, yet the molecular factors driving adaptation remain poorly understood. Here we investigated how vaccine-induced immunity shapes the evolution of a human-origin H3N2 virus in pigs using an in vivo sustained transmission model. Pigs (seeders) were vaccinated with a commercial inactivated swine vaccine and then infected with an antigenically distinct FLUAV containing human-origin HA/NA. Contact pigs were introduced two days later. After 3 days, seeder pigs were removed, and new contacts introduced. This was repeated for a total of 4 contacts. Sequencing of nasal swab samples showed the emergence of mutations clustered near the HA receptor binding site, enabling immune escape and abolishing binding to N-glycolylneuraminic acid. Mutant viruses recognized 2,6-sialosides with 3 N-acetyllactosamine repeats, which are rare in swine lungs, while the parental virus bound structures with a minimum of 2 repeats. Adaptative HA mutations enhanced avidity for 2,6-linked sialic acid, likely compensating for the low abundance of extended glycans. Notably, residues outside the canonical HA binding pocket contribute to glycan binding, suggesting a trade-off between receptor breadth and avidity. These findings show that non-neutralizing immunity promotes viral adaptation by fine-tuning receptor engagement and immune evasion. SIGNIFICANCEUnderstanding how vaccination shapes influenza A virus (FLUAV) evolution across species barriers is critical for predicting and preventing zoonotic and reverse-zoonotic events. Our study demonstrates that vaccine-induced immune pressure can drive antigenic drift in a human-origin H3N2 virus, altering HA receptor binding properties that could inadvertently facilitate adaptation to swine. These changes shifted glycan specificity toward extended poly-LacNAc structures and enhanced 2,6-linked sialoglycans binding while abolishing Neu5Gc recognition. By revealing how non-neutralizing immunity fine-tunes HA-glycan interactions by engaging antigenically relevant residues in glycan binding, this work highlights vaccination as an underappreciated driver of host adaptation and viral evolution.

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Cardenas, M., Chopra, P., Cowan, B., Caceres, C. J., Anderson, T. K., Baker, A. L., Perez, D. R., Boons, G.-J., Rajao, D. S.. 2025-12-11. Vaccine-induced antigenic drift of a human-origin H3N2 Influenza A virus in swine alters glycan binding and sialic acid avidity. https://doi.org/10.64898/2025.12.10.693614

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