Although we observed differences in the innate proinflammatory programs induced by the WA1/2020 or the B.1.351 challenge, serum levels of significant proinflammatory markers associated with COVID-19 severity, such as IL6 and IL1, CCL8 NFKB, STAT3, MX1, and CSF, were significantly increased in sham unvaccinated compared with vaccinated macaques (Fig 4C). Similarly, markers of the complement cascade (C6, C2, C3, CFB), clotting, and coagulation cascades (TFPI, FBP2, TGFB, FCN1) were increased in sham unvaccinated compared to vaccinated macaques at days 2–10 following challenge (Fig 4C). Here, IL6 is linked to COVID-19.