Vaccine-Associated Enhanced Respiratory Disease following Influenza Virus Infection in Ferrets Recapitulates the Model in Pigs.

Influenza A virus (IAV) causes respiratory disease in swine and humans. Vaccines are used to prevent influenza illness in both populations but must be frequently updated due to rapidly evolving strains. Mismatch between the circulating strains and the strains contained in vaccines may cause loss of efficacy. Whole inactivated virus (WIV) vaccines with adjuvant, utilized by the swine industry, are effective against antigenically similar viruses; however, vaccine-associated enhanced respiratory disease (VAERD) may happen when the WIV is antigenically mismatched with the infecting virus. VAERD is a repeatable model in pigs, but had yet to be experimentally demonstrated in other mammalian species. We recapitulated VAERD in ferrets, a standard benchmark animal model for studying human influenza infection, in a direct comparison to VAERD in pigs. Both species were vaccinated with WIV with oil-in-water adjuvant containing a δ-1 H1N2 (1B.2.2) derived from the pre-2009 human seasonal lineage, then challenged with a 2009 pandemic H1N1 (H1N1pdm09, 1A.3.3.2) 5 weeks after vaccination. Nonvaccinated and challenged groups showed typical signs of influenza disease, but the mismatched vaccinated and challenged pigs and ferrets showed elevated clinical signs, despite similar viral loads. VAERD-affected pigs exhibited a 2-fold increase in lung lesions, while VAERD-affected ferrets showed a 4-fold increase. Similar to pigs, antibodies from VAERD-affected ferrets preferentially bound to the HA2 domain of the H1N1pdm09 challenge strain. These results indicate that VAERD is not limited to pigs, as demonstrated here in ferrets, and the need to consider VAERD when evaluating new vaccine platforms and strategies.