Zinc

• Direct antiviral effects in vitro — zinc can inhibit replication of some RNA viruses (including coronaviruses) by impairing viral RNA-dependent RNA polymerase and other steps of viral replication in laboratory studies. Reviews summarize these molecular mechanisms and the theoretical basis for use in SARS-CoV-2. Cambridge University Press & Assessment MDPI
• Immune-supporting roles — zinc is essential for normal innate and adaptive immune function (T cell activity, cytokine regulation). Zinc deficiency is associated with worse outcomes in many infections; this supports the hypothesis that replacing low zinc might help host defense. Frontiers MDPI
• Anti-inflammatory / antioxidant effects — zinc can modulate inflammatory responses and oxidative stress, which are relevant in severe COVID-19. MDPI
• Ionophore hypothesis (context only) — some laboratory studies show zinc uptake into cells is increased by certain ionophores (molecules that help zinc cross cell membranes) — this was part of early hypotheses about combinations like zinc + chloroquine/hydroxychloroquine, but clinical evidence for benefit of such combinations is lacking and hydroxychloroquine is not recommended for COVID-19. (Mechanistic lab data ≠ proven clinical benefit.) ScienceDirect Cambridge University Press & Assessment

Summary: there’s a plausible antiviral + immune rationale (strongest as a nutrient that supports immune function). That plausibility motivated clinical trials — but lab/mechanistic plausibility alone does not prove an effective clinical therapy. Cambridge University Press & Assessment MDPI

Important: there is no universally accepted clinical “protocol” for zinc to treat COVID-19. Guidelines (see next section) generally say there’s insufficient evidence to recommend routine use beyond correcting deficiency. When researchers tested zinc they used different regimens:

• Outpatient RCT (COVID A to Z, JAMA Network Open) — ambulatory adults were randomized to 10 days of zinc gluconate 50 mg daily (given at bedtime) (or high-dose vitamin C, combination, or usual care). That trial did not show a reduction in symptom duration. Europe PMC Infectious Disease Advisor
• Hospitalized / non-critically ill RCT (VIZIR — Clinical Infectious Diseases) — a randomized, double-blind trial in Tunisia used 25 mg elemental zinc twice daily (total 50 mg/day) for 15 days (capsules) versus placebo. Investigators reported fewer ICU admissions and lower 30-day mortality in the zinc arm (see original paper for details and subgroup analyses). Oxford Academic Broome Docs
• Other trials / routes — small case reports and early series used high-dose zinc lozenges or salts; some clinical trials explored IV zinc (trial protocols exist). Doses and formulations vary between studies (elemental zinc amount and salt form — gluconate, sulfate, acetate — matter). ScienceDirect BMJ Open

1. COVID A to Z (JAMA Netw Open) — randomized outpatient trial (N≈214). High-dose zinc gluconate 50 mg/day for 10 days (or vitamin C, or both) did not shorten symptom duration versus usual care. This is a high-quality randomized trial in outpatients. Europe PMC Infectious Disease Advisor
2. VIZIR trial (Clinical Infectious Diseases, 2022/2023) — randomized, double-blind, placebo-controlled, multicenter trial in Tunisia (non-critically ill COVID-19 patients). 25 mg elemental zinc twice daily for 15 days (50 mg/day) — investigators reported reduced combined endpoint of ICU admission or death and shorter hospital/illness duration in the zinc arm. This trial suggests a possible benefit in hospitalized non-critically ill patients, but it is a single trial and needs confirmation. Oxford Academic Broome Docs
3. Meta-analyses / systematic reviews — there are meta-analyses combining observational studies and RCTs that report possible associations between zinc supplementation and lower mortality or improved outcomes, but included studies are heterogeneous (different doses, populations, often observational). The overall evidence base is mixed and not definitive. BioMed Central+1
4. Mechanistic & review literature — multiple reviews summarize antiviral, immunomodulatory, and antioxidant actions of zinc and call for more rigorous trials. Cambridge University Press & Assessment MDPI

Summary: some high-quality evidence shows no benefit in outpatients (COVID A to Z), while a well-conducted randomized inpatient trial (VIZIR) reported clinically important benefits. Evidence is therefore mixed, and clinical guidelines have generally considered the evidence insufficient or inconclusive for routine routine treatment outside trials. Europe PMC Oxford Academic