Vaccine-associated enhanced respiratory pathology in COVID-19 hamsters after TH2-biased immunization.

Vaccine-associated enhanced respiratory disease (VAERD) is a severe complication for some respiratory infections. To investigate the potential for VAERD induction in coronavirus disease 2019 (COVID-19), we evaluate two vaccine leads utilizing a severe hamster infection model: a T helper type 1 (TH1)-biased measles vaccine-derived candidate and a TH2-biased alum-adjuvanted, non-stabilized spike protein. The measles virus (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 interleukin (IL)-19, or TH2 cytokines IL-4, IL-5, and IL-13. Single-cell RNA sequencing (scRNA-seq) identifies lung macrophages or lymphoid cells as sources, respectively. Our findings imply that 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 that mediate VAERD after TH2-biased vaccination.

Macrophages and Dendritic Cells Are Not the Major Source of Pro-Inflammatory Cytokines Upon SARS-CoV-2 Infection.

The exact role of innate immune cells upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their contribution to the formation of the corona virus-induced disease (COVID)-19 associated cytokine storm is not yet fully understood. We show that human in vitro differentiated myeloid dendritic cells (mDC) as well as M1 and M2 macrophages are susceptible to infection with SARS-CoV-2 but are not productively infected. Furthermore, infected mDC, M1-, and M2 macrophages show only slight changes in their activation status. Surprisingly, none of the infected innate immune cells produced the pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, or interferon (IFN)-α. Moreover, even in co-infection experiments using different stimuli, as well as non-influenza (non-flu) or influenza A (flu) viruses, only very minor IL-6 production was induced. In summary, we conclude that mDC and macrophages are unlikely the source of the first wave of cytokines upon infection with SARS-CoV-2.