Angiotensin-converting enzyme 2 (ACE2) is a key component of the renin–angiotensin system (RAS)

SARS-CoV-2 virus uses ACE2 for cell entry

These two facts can explain high-risk populations, symptoms, and clinical progression

High-risk groups likely to be zinc or ACE2 deficient

ACE2 and zinc deficiency leads to imbalance of the RAS, predominance of ACE adverse axis. Exacerbated by downregulation of ACE2 with viral entry leads to Ang II-mediated increase in vasoconstrictive, inflammatory, and thrombotic actions leading to severe sequelae (e.g., ARDS, cytokine storm)

Randomized clinical trials needed to confirm efficacy and safety of zinc supplementation to decrease severe sequelae and mortality of COVID-19, especially in those unable or unwilling to access vaccination or those who may be at increased risk from viral variants that are insufficiently covered by available vaccines.