Vaccine-associated enhanced respiratory disease following influenza virus infection in ferrets recapitulates the model in pigs

Authors: KIMBLE, BRIAN - Orise Fellow; BRAND, MEGHAN - Orise Fellow; KAPLAN, BRYAN - Orise Fellow; COYLE, ELIZABITH - Food And Drug Administration(FDA); CHILCOTE, KATRINA - Food And Drug Administration(FDA); GAUGER, PHILLIP - Iowa State University; KHURANA, SURRENDER - Food And Drug Administration(FDA); Baker, Amy

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/5/2022
Publication Date: 3/9/2022
Citation: Kimble, B.J., Brand, M.W., Kaplan, B.S., Coyle, E.M., Chilcote, K., Gauger, P., Khurana, S., Baker, A.L. 2022. Vaccine-associated enhanced respiratory disease following influenza virus infection in ferrets recapitulates the model in pigs. Journal of Virology. 96(5). https://doi.org/10.1128/jvi.01725-21.
DOI: https://doi.org/10.1128/jvi.01725-21

Interpretive Summary: Results from this study showed that a standard research model for influenza, the ferret, demonstrated the clinical disease characteristics of vaccine associated enhanced respiratory disease (VAERD) and this model provides an additional tool to study influenza vaccine safety and efficacy. Prior to this report, research described VAERD in swine, but it was not well-characterized in other influenza host species such as ferrets. Influenza A viruses in swine are highly diverse, and although vaccines are the best method to prevent influenza illness in swine, mismatched vaccines of the whole inactivated virus platform are associated with VAERD. We demonstrated the susceptibility of ferrets, a common model species of human influenza infection, to VAERD using an experimental model of VAERD previously demonstrated in pigs and showed that the clinical disease between the two host species were similar. The induction of VAERD in ferrets highlights the potential risk in humans and the need to consider VAERD when designing and evaluating vaccine strategies.

Technical Abstract: Influenza A virus (IAV) is a major contributor to swine disease in the US and places a substantial burden on the swine industry each year. Genetic diversity of IAV is high in US swine herds due to genetic drift and the numerous introductions of human seasonal influenza genes via reverse zoonosis. Whole inactivated vaccines (WIV) are a common method utilized by the swine industry to control IAV. WIV platforms are effective against antigenically similar viruses, however, enhanced morbidity can happen when the WIV is antigenically mismatched with the infecting virus. Models for vaccine-associated enhanced respiratory disease (VAERD) have been established in pigs, but questions remain about the relevance of this model in other mammalian species. Here, we aimed to recapitulate VAERD in ferrets, the gold standard animal model for studying human influenza infection, in a direct comparison to VAERD in pigs. Groups of ferrets and pigs were vaccinated with two doses of whole inactivated virus vaccine (WIV) with oil in water adjuvant containing a d-1 H1N2 (1B.2.2) with the HA derived from the pre-2009 human seasonal lineage H1N1 and challenged with a 2009 pandemic H1N1 (H1N1pdm09, 1A.3.3.2) five weeks after the final vaccination. No vaccine/challenge groups (NV/C) showed signs of disease including fever, weight loss, lethargy, and coughing. However, the vaccine/challenge (V/C) pigs and ferrets showed elevated clinical signs of disease compared to NV/C groups, despite similar viral loads in nasal swabs and lavage fluids. VAERD affected V/C pigs exhibited a 2-fold increase in macroscopic lung lesions compared to NV/C pigs, while V/C ferrets showed a 4-fold increase over NV/C ferrets. Similar to pigs, antibodies from VAERD affected ferrets preferentially bound to the HA2 domain of the H1N1pdm09 challenge strain. These results indicate the VAERD phenomenon is not limited to pigs, as demonstrated here in ferrets.