SARS-CoV-2 infection primarily begins in the upper respiratory tract and may progress to the lower respiratory tract, other tissues, and the nervous and cardiovascular systems, which may lead to cytokine storm, pneumonia, ARDS, neurological injury27-43 and cognitive deficits30,35, cardiovascular complications44-50, DNA damage51-54, organ failure, and death. Even mild untreated infections may result in persistent cognitive deficits55—the spike protein binds to fibrin leading to fibrinolysis-resistant blood clots, thromboinflammation, and neuropathology. Minimizing replication as early as possible is recommended.

SARS-CoV-2 infection and replication involves the complex interplay of 500+ host and viral proteins and other factorsA,56-63, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 12,000 compounds may reduce COVID-19 risk64, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications.

We analyze all significant controlled studies of vitamin D for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We perform random-effects meta-analysis for all treatment studies, Randomized Controlled Trials, peer-reviewed studies, studies using cholecalciferol vs. calcifediol/calcitriol and analogs, studies using large bolus doses vs. ongoing treatment, higher quality studies, and for specific outcomes: mortality, mechanical ventilation, ICU admission, hospitalization, and case results. Results are presented for prophylaxis, early treatment, and late treatment. Separately, we perform random-effects meta-analysis for studies that analyze outcomes based on vitamin D sufficiency (non-treatment studies).

Vitamin D has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function65-68. Vitamin D inhibits SARS-CoV-2 replication in vitro69,70, mitigates lung inflammation, damage, and lethality in mice with an MHV-3 model for β-CoV respiratory infections69,70, reduces SARS-CoV-2 replication in nasal epithelial cells via increased type I interferon expression71, downregulates proinflammatory cytokines IL-1β and TNF-α in SARS-CoV-2 spike protein-stimulated cells72, attenuates nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway73, may be neuroprotective by protecting the blood-brain barrier, reducing neuroinflammation, and via immunomodulatory effects74, may mitigate hyperinflammation and cytokine storm by upregulating TLR10 expression which downregulates proinflammatory cytokines75, downregulates ACE2 and TMPRSS2 in human trophoblasts and minimizes spike protein-induced inflammation76, may minimize cytokine storm by dampening excessive cytokine production77, may suppress viral entry and replication via LL-37 induction78,79, and minimizes platelet aggregation mediated by SARS-CoV-2 spike protein via inhibiting integrin αIIbβ3 outside-in signaling80. Cholecalciferol and calcifediol directly bind two allosteric pockets on the SARS-CoV-2 Spike RBD, bias the trimer toward a closed state, weaken ACE2 engagement, and reduce viral entry in cell models81. Calcitriol may destabilize the Spike protein architecture and inhibit IL-17R dimerization, blocking viral entry and mitigating hyperinflammatory cytokine storm82. Vitamin D improves regulatory immune cell levels and control of proinflammatory cytokines in severe COVID-1983. Calcifediol inhibits SARS-CoV-2 papain-like protease (PLpro), a critical enzyme for viral replication84. Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells and vitamin D has been shown to improve NK cell activity85,86.

Studies have shown efficacy with vitamin D for influenza87, RSV87, and acute respiratory tract infections88-90.

Vitamin D is a steroid hormone that helps regulate the immune system by binding to specific receptors and activating genes involved in immune defense. It increases the production of antimicrobial proteins, like cathelicidin and defensins, which fight a variety of pathogens, including bacteria, viruses, and fungi. Vitamin D supports the immune system by boosting our natural defenses and promoting healthy cell connections. It helps clear respiratory pathogens through processes like apoptosis and autophagy and regulates toll-like receptors, which play a key role in immunity. Vitamin D also aids in immune cell maturation, balances inflammation, and reduces the production of proinflammatory cytokines. Vitamin D has been shown to downregulate angiotensin-converting enzyme-2 (ACE-2) receptors, which play a role in COVID-19 infection. By suppressing the production of ACE-2 and related molecules, vitamin D increases antioxidant and anti-inflammatory effects, enhances antimicrobial defenses, reduces cytokine storms, and promotes a protective immune response, all of which help decrease the severity of the disease. Vitamin D was first identified in relation to bone health, but is now known to have multiple functions, including an important role in the immune system91,92. For example, Quraishi et al. show a strong association between pre-operative vitamin D levels and hospital-acquired infections, as shown in Fig. 3.

Vitamin D undergoes two conversion steps before reaching the biologically active form as shown in Fig. 4. The first step is conversion to calcidiol, or 25(OH)D, in the liver. The second is conversion to calcitriol, or 1,25(OH)2D, which occurs in the kidneys, the immune system, and elsewhere. Calcitriol is the active, steroid-hormone form of vitamin D, which binds with vitamin D receptors found in most cells in the body. There is a significant delay involved in the conversion from cholecalciferol, therefore calcifediol (calcidiol) or calcitriol may be preferable for treatment.

Many vitamin D studies analyze outcomes based on serum vitamin D levels which may be maintained via sun exposure, diet, or supplementation. We refer to these studies as sufficiency studies, as they typically present outcomes based on vitamin D sufficiency. These studies do not establish a causal link between vitamin D and outcomes. In general, low vitamin D levels are correlated with many other factors that may influence COVID-19 susceptibility and severity. Therefore, beneficial effects found in these studies may be due to factors other than vitamin D. On the other hand, if vitamin D is causally linked to the observed benefits, it is possible that adjustments for correlated factors could obscure this relationship. COVID-19 disease may also affect vitamin D levels94, suggesting additional caution in interpreting results for studies where the vitamin D levels are measured during the disease. For these reasons, we analyze sufficiency studies separately from treatment studies. We include all sufficiency studies that provide a comparison between two groups with low and high levels. Some studies only provide results as a function of change in vitamin D levels95-97, which may not be indicative of results for deficiency/insufficiency versus sufficiency (increasing already sufficient levels may be less useful for example). Some studies only show the average vitamin D level for patients in different groups98-140, most of which show lower D levels for worse outcomes. Other studies analyze vitamin D status and outcomes in geographic regions141-148, all finding worse outcomes to be more likely with lower D levels.

Sufficiency studies vary widely in terms of when vitamin D levels were measured, the cutoff level used, and the population analyzed (for example studies with hospitalized patients exclude the effect of vitamin D on the risk of hospitalization). We do not analyze sufficiency studies in more detail because there are many controlled treatment studies that provide better information on the use of vitamin D as a treatment for COVID-19. A more detailed analysis of sufficiency studies can be found in Chiodini et al. Mishra et al. present a systematic review and meta-analysis showing that vitamin D levels are significantly associated with COVID-19 cases.

For studies regarding treatment with vitamin D, we distinguish three stages as shown in Fig. 5. Prophylaxis refers to regularly taking vitamin D before being infected in order to minimize the severity of infection. Due to the mechanism of action, vitamin D is unlikely to completely prevent infection, although it may prevent infection from reaching a level detectable by PCR. Early treatment refers to treatment immediately or soon after symptoms appear, while late treatment refers to more delayed treatment.