Vaccine-associated enhanced respiratory pathology in COVID-19 hamsters after T_H2-biased immunization

Vaccine-associated enhanced respiratory disease (VAERD) is a severe complication for some respiratory infections. To investigate the potential for VAERD induction in COVID-19, we evaluate two vaccine leads utilizing a severe hamster infection model: a TH1-biased measles vaccine-derived candidate and a TH2-biased alum-adjuvanted, non-stabilized Spike protein. The MeV-derived vaccine protects the animals, but the protein lead induces VAERD, which can be alleviated by dexamethasone treatment. Bulk transcriptomic analysis reveals that our protein vaccine prepares enhanced host gene dysregulation in the lung, exclusively up-regulating mRNAs encoding the eosinophil attractant CCL-11, TH2-driving IL-19, or TH2-cytokines IL-4, IL-5, and IL-13. scRNA-Seq identifies lung macrophages or lymphoid cells as sources, respectively. Our findings imply VAERD is caused by the concerted action of hyperstimulated macrophages and TH2 cytokine-secreting lymphoid cells and potentially links VAERD to antibody-dependent enhancement (ADE). In summary, we identify the cytokine drivers and cellular contributors, which mediate VAERD after TH2-biased vaccination.