Ad26.COV2.S prevents upregulation of SARS-CoV-2 induced pathways of inflammation and thrombosis in hamsters and rhesus macaques

Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 WA1/2020 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 WA1/2020 challenge in hamsters stimulates myeloid and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways, such that the mRNA expression profiles of vaccinated hamsters are comparable to uninfected animals. Using proteomics profiling, we validated these findings in rhesus macaques challenged with SARS-CoV-2 WA1/2020 or SARS-CoV-2 B.1.351. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses weeks following vaccination. These data provide insights into the molecular mechanisms of Ad26.COV2.S protection against severe COVID-19 in animal models. Author summaryIn this study, we show that vaccination with Ad26.COV2.S protected hamsters and rhesus macaques challenged with SARS-CoV-2 from developing excessive proinflammatory responses mediated by IL-6 and IL-1, macrophages, and neutrophil activation. Ad26 vaccination also prevented the upregulation of coagulation and clotting cascades pathways. In contrast, unvaccinated challenged animals showed a significant increase of these proinflammatory and prothrombotic pathways. These data provide insights into the molecular mechanisms of Ad26.COV2.S protection against SARS-CoV-2.

Automated summary

This study demonstrates the protective effect of Ad26.COV2.S vaccination against SARS-CoV-2 in hamsters and rhesus macaques by preventing excessive immune and coagulation responses. It provides insights into the molecular mechanisms of Ad26.COV2.S vaccine protection against SARS-CoV-2.