Vaccines have shown remarkable protection against COVID-19, but vaccination-enhanced respiratory disease (VAERD) following breakthrough infections poses safety concerns. SARS-CoV-2 Spike (SARS-2 S) protein subunit vaccines induced VAERD in hamsters, where aluminum adjuvant primed a Th2-biased immunization, resulting in elevated type 2 pulmonary inflammation in animals with breakthrough infections. To further understand the potential risks and immunopathogenesis of VAERD, we immunized K18-hACE2 mice with SARS-2 S protein in the presence of aluminum and CpG ODN adjuvants and infected them with a lethal dose of SARS-2. The vaccine induced robust antibody and T cell responses, significantly reducing viral titers and increasing host survival. However, following breakthrough infection, vaccinated animals exhibited severe airway immunopathology, with a dramatic increase of eosinophils and CD4 +T cells, and elevated Th2/Th17 cytokines in the lungs. Intracellular flow cytometric analysis showed a systemic Th2/Th17 inflammatory response, prominently in the lungs. Our data show that the aluminum/ODN adjuvants elicit strong protection against COVID-19 but prime a robust Th2/Th17 inflammatory response that may contribute to rapid onset of T cell-mediated pulmonary immunopathology following breakthrough infection. Our results highlight the need for additional studies to elucidate COVID-19-associated VAERD and to further improve vaccine formulations for broad protection and maximal safety.

This research was supported in part by grants from the National Institutes of Health (P20 GM130555-6610 and R01 AI151139).

This content is only available via PDF.