#18,984
While desperate farmers, beleaguered politicians, and shell-shocked consumers are all looking for ways to reduce the burden of avian flu - and livestock vaccination seems the obvious solution - we must always be cognizant of the law of unintended consequences,Over the years we've seen growing evidence that the use of non-neutralizing, poorly matched, or improperly applied, veterinary vaccines actually risks making matters worse (see PLoS Bio: Imperfect Poultry Vaccines, Unintended Results).In 2014's EID Journal dispatch Subclinical Highly Pathogenic Avian Influenza Virus Infection among Vaccinated Chickens, China, the authors wrote:
HPAI mass vaccination played a crucial role in HPAI control in China. However, this study demonstrated multiple disadvantages of HPAI mass vaccination, which had been suspected (13,14). For example, this study showed that H5N1 subtype HPAI virus has evolved into multiple H5N2 genotypes, which are all likely vaccine-escape variants, suggesting that this virus can easily evolve into vaccine-escape variants.More recently, in 2021's J. Virus Erad.: Ineffective Control Of LPAI H9N2 By Inactivated Poultry Vaccines - China, the authors warned that China's current inactivated vaccines were no match against this rapidly evolving pathogen.
This observation suggests that HPAI mass vaccination, which is highly effective in the beginning of an outbreak, may lose its effectiveness with time unless the vaccine strains are updated. Moreover, this study showed that vaccinated chicken flocks can be infected with vaccine-escape variants without signs of illness.
And just a little over a month ago (see MOA Announces New Guidelines to Expedite Animal Vaccine Strain Approvals) China tacitly admitted that many of their current animal vaccines (including against H9N2) are inadequate and/or suboptimal - and ordered major regulatory changes in order to accelerate updates.Last April, in NPJ Vaccines: Impact of Inactivated Vaccine on Transmission and Evolution of H9N2 Avian Influenza Virus in Chickens, we saw evidence that not only had inactivated vaccines failed to prevent - or even reduce - H9N2 in China's poultry, they may have driven viral evolution (including mammalian adaptations).
These vaccine problems extend far beyond China.
- In 2012's Egypt: A Paltry Poultry Vaccine, researchers examined the effectiveness of six commercially available H5 poultry vaccines used in Egypt and found only one actually appeared to offer protection.
- Six years later, another study (see Sci. Reports: Efficacy Of AI Vaccines Against The H5N8 Virus in Egypt) found `. . . most of the commercial poultry H5 vaccines used in the present study were ineffective. . . '
- in 2023's WUR: 2 of 4 H5 Poultry Vaccines Tested Appear Effective Against H5N1, researchers in the Netherlands found ineffective vaccines were still being marketed.
All of which brings us to a new preprint on U.S. Government research which looks at the impact of swine-influenza vaccines in pigs, and how they too can help drive viral evolution.
Although this study is on a different influenza A subtype (H3N2), affecting a different species (swine), it finds a similar pattern of vaccine-induced evolution. Due to it length, and technical nature, I've just posted some excerpts.
Follow the link to read it in its entirety. I'll have a bit more after the break.
Vaccine-induced antigenic drift of a human-origin H3N2 Influenza A virus in swine alters glycan binding and sialic acid avidity
Matias Cardenas, Pradeep Chopra, Brianna Cowan, C. Joaquin Caceres, Tavis K. Anderson, Amy L. Baker, Daniel R. Perez, Geert-Jan Boons, Daniela S Rajao
doi: https://doi.org/10.64898/2025.12.10.693614
This article is a preprint and has not been certified by peer review [what does this mean?].
Preview PDF
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 accine 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 α2,6-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 α2,6-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.
(SNIP)
SIGNIFICANCE
Understanding 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 α2,6-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.
Overall, our findings demonstrate that vaccine-induced immunity in pigs can shape the evolution of human-origin H3N2 viruses. This process seems to select mutants with restricted receptor binding but enhanced a2,6-SA avidity while maintaining an optimal HA/NA balance. The fixation of F193Y highlights how immune escape and host adaptation can converge to promote viral fitness in a new host.
These results indicate that vaccination may inadvertently accelerate viral adaptation following a spillover by favoring mutation of antigenically relevant residues that can alter glycan selectivity and enhance binding to host-specific structures.
Properly done, poultry and/or livestock vaccination against novel flu should be both a safe and effective strategy, but we are going to need better (and continually updated) vaccines, along with finding ways to ensure they are being properly and consistently applied.
Even then, we can't just `vaccinate and forget'.
None of which will be easy or cheap.
But the evidence suggests, doing anything less risks creating even greater viral challenges down the road.
