Vitamin D & COVID-19
10th Feb, 2022

Vitamin D and COVID-19


Since the outbreak of the pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, a flurry of research has been conducted into the relationship between vitamin D deficiency, vitamin D supplementation and risk of infection, severity of illness and mortality, resulting in controversy and debate.

Research is trying to address two main questions:

  • Is vitamin D deficiency associated with rates of SARS-CoV-2 infection or with severity and outcomes of COVID-19, the disease caused by SARS-CoV-2 infection?
  • Is vitamin D supplementation beneficial in preventing SARS-CoV-2 infection or in favourably altering the severity and course of COVID-19?

What has become clear is that the relationship between vitamin D status and/or supplementation and infection risk and disease outcomes is complex, and many factors need to be considered when deciding whether to supplement with vitamin D for COVID-19 prevention or treatment. Vitamin D deficiency is widespread worldwide, and the prevention of COVID-19 through vitamin D supplementation is being considered as a possible cost-effective and easy to implement therapeutic strategy (1).


Biological plausibility

Although the exact mechanism by which vitamin D could prevent SARS-CoV-2 infection or improve COVID-19 prognosis is unclear, there is clear biological plausibility of the relationship between vitamin D and COVID-19. Vitamin D and its metabolites may be involved both in the viral replication process and in the binding of the virus to the host (2).

  • Vitamin D is known to exert immunomodulatory effects in innate and adaptive immune responses, plays a significant role in various bacterial and viral infections and could act as an anti-inflammatory agent (3,4,5,6,7,8,9).
  • Vitamin D receptors are expressed in many immune cells, including monocytes, macrophages, dendritic cells, neutrophils, and lymphocytes (10,11,12). Vitamin D increases the antimicrobial activity of monocytes and macrophages (13) and has anti-inflammatory effects due to the induction of T regulatory cells and reduction in the T helper-17 immune response and pro-inflammatory cytokine production (12).
  • Vitamin D regulates the renin-angiotensin system and expression of angiotensin-converting enzyme 2 (ACE2) and its receptor that mediates SARS-CoV-2 infection (6).
  • Vitamin D has the potential to affect SARS-CoV-2 gene expression and alleviate infection upon binding to the vitamin D response element (6,14).
  • Vitamin D deficiency is a documented risk factor for the development of exaggerated and persistent inflammation, which is a precursor to acute respiratory distress syndrome (ARDS) (15).


The evidence

Vitamin D deficiency

Strong observational evidence indicates that vitamin D deficiency is a leading candidate in association with COVID-19 susceptibility, severity, progression and mortality, with a higher prevalence of vitamin D deficiency in more severe COVID-19 cases (16,17,18,19,20,21,22,23). Vitamin D deficiency is also associated with comorbidities that are known to affect COVID-19 severity and outcome, such as diabetes, cardiovascular disease, hypertension, obesity, and age (24). However, further research is needed to better understand the relationship between vitamin D and COVID-19. 

A recent study found that patients with vitamin D deficiency (< 50 nmol/L) were 14 times more likely to have a severe or critical case of COVID than those with > 100 nmol/L. Mortality among patients with sufficient vitamin D levels was 2.3%, in contrast to 25.6% in the vitamin D deficient group (25).


Vitamin D supplementation

There is no strong evidence through randomised controlled trials (RCTs) on the therapeutic benefits of vitamin D supplementation in COVID-19 outcomes. The beneficial use of vitamin D supplements in COVID-19 has been reported in some non-randomised observational cohorts (26). Observational studies have been mostly preliminary, with much reporting being retrospective, descriptive, or only associative (1). Information in such studies should be interpreted with caution. Systematic reviews and meta-analyses on the clinical trials to date conclude that there is insufficient good-quality evidence to determine whether vitamin D is an effective or safe treatment for adults with COVID-19 (27).

A recent systematic review and meta-analysis of RCTs found that COVID-19 patients treated with vitamin D are more likely to demonstrate lower rates of ICU admission, mortality events and RT-PCR positivity relative to patients receiving no vitamin D, standard care or placebo (18). However, no statistical significance was achieved for individual outcomes of ICU and deaths. There was a statistically significant decrease in the rates of RT-PCR positivity in COVID-19 patients supplemented with vitamin D. More RCTs and completion of ongoing trials are needed to precisely establish the association between vitamin D supplementation and COVID-19 (18). 

Below is a summary of the main clinical trial results:

  • An RCT recommended using 5,000 IU daily vitamin D3, even for a short period, as adjuvant therapy for COVID-19 patients with suboptimal vitamin D status (< 50 nmol/L). Results indicate a decrease in time to recovery for cough and gustatory sensory loss among mild to moderate COVID-19 patients with suboptimal vitamin D status after 2 weeks of supplementation. However, almost half of the randomised patients also received vitamin C supplements (28).
  • A single dose of 200,000 IU vitamin D3 in moderate to severely ill hospitalised patients did not significantly reduce the length of hospital stay, hospital discharge, ICU admission and rates of mechanical ventilation and mortality compared to placebo (29).
  • Daily oral administration of 10,000 IU vitamin D3 in mild COVID-19 patients for 14 days resulted in significantly increased vitamin D levels post-treatment and fewer symptoms on the seventh and fourteenth day of follow-up. The vitamin D treatment group also had lower rates of seropositivity and RT-PCR positivity on the seventh and fourteenth days, respectively (30).
  • Similarly, a 3-week intervention of 60,000 IU of vitamin D3 (oral nano-liquid droplets) daily for 7 days in mildly symptomatic or symptomatic COVID-19 patients resulted in a significant increase in the proportion of SARS-CoV-2 RNA negativity compared to placebo (31).
  • A cohort of mild to moderate COVID-19 patients with suboptimal vitamin D status received 60,000 IU of oral vitamin D3 daily for 8-10 days and the outcomes were recorded until 21 days. Supplementation resulted in a significant increase in vitamin D levels with a lower rate of ICU and mortalities in the intervention arm as compared to the comparator group. Supplementation significantly improved inflammatory markers (32).
  • A pilot RCT demonstrated that administration of high-dose calcifediol or cholecalciferol in conjunction with standard care reduced the need for ICU admission among hospitalised COVID-19 patients compared to unsupplemented patients. Baseline and post-treatment vitamin D levels were not reported (33).

Current literature reports that clinical trials of vitamin D supplementation are not entirely successful and show discordant results both in COVID-19 and in non-COVID-19 subjects (1). Vitamin D could be considered effective as a preventive measure and not as a therapy for acute respiratory infections using high doses in patients already suffering from severe infection (34).



Results of meta-analyses investigating vitamin D in COVID prevention/treatment need to be treated with caution given the following limitations:

  • Clinical trials investigating vitamin D supplementation in COVID have substantial clinical and methodological heterogeneity, mainly due to different supplementation strategies, formulations, vitamin D status of participants, ethnicity, seasonal variation and reported outcomes.
  • Vitamin D absorption varies with factors such as age or excess weight, which could also affect the results of clinical trials (35).
  • Small sample sizes and the criteria for sufficient and deficient vitamin D status varied across the trials.
  • The variations in the COVID-19 severity, comorbidities proportions and standard care treatment strategies could have influenced the heterogeneity and the overall result.
  • Differences in the study settings, timings, randomisation, blinding, and data collection strategies could have influenced the outcomes.

There is an urgent need to well-designed and adequately powered RCTs with an appropropriate randomisation procedure, comparability of study arms and preferably double-blinding (27,34).



Data on vitamin D and acute respiratory infections are promising and support recommendations for a sufficient vitamin D status during this pandemic; however, it is still unclear whether this also applies to COVID-19 (34). To date, the optimal vitamin D threshold for the prevention or treatment of COVID-19 and the doses that should be used to reach this threshold remains unknown (1).

There is still a scarcity of information through RCTs on the use of vitamin D supplementation in COVID-19 patients (18,36). High doses of vitamin D could provide a benefit for COVID-19 hospitalised patients (37); however, further studies are needed to establish the optimal dose of vitamin D as well as the type, form and delivery route of supplementation to achieve beneficial effects on the infection and course of COVID-19 (38).

For now, experts recommend incorporating regular supplementation for general health and well-being during the pandemic but have stopped short of suggesting the widespread use of vitamin D therapy in the acute setting of COVID-19 (39). There are currently more than 30 relevant clinical trials registered on which will hopefully shed more light on the situation (1).

1Contreras-Bolívar V, García-Fontana B, García-Fontana C, Muñoz-Torres M. Vitamin D and COVID-19: where are we now? Postgrad Med. 2021 Dec 27;1–13.
2Qayyum S, Mohammad T, Slominski RM, Hassan MI, Tuckey RC, Raman C, et al. Vitamin D and lumisterol novel metabolites can inhibit SARS-CoV-2 replication machinery enzymes. Am J Physiol Endocrinol Metab. 2021 Aug 1;321(2):E246–51.
3Jolliffe DA, Camargo CA, Sluyter JD, Aglipay M, Aloia JF, Ganmaa D, et al. Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol. 2021 May;9(5):276–92.
4Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, et al. Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technol Assess. 2019 Jan;23(2):1–44.
5Teymoori-Rad M, Shokri F, Salimi V, Marashi SM. The interplay between vitamin D and viral infections. Rev Med Virol. 2019 Mar;29(2):e2032.
6Brito DTM, Ribeiro LHC, Daltro CH da C, Silva R de B. The possible benefits of vitamin D in COVID-19. Nutrition. 2021 Dec;91–92:111356.
7Gois PHF, Ferreira D, Olenski S, Seguro AC. Vitamin D and Infectious Diseases: Simple Bystander or Contributing Factor? Nutrients. 2017 Jun 24;9(7):E651.
8AlSafar H, Grant WB, Hijazi R, Uddin M, Alkaabi N, Tay G, et al. COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents. Nutrients. 2021 May 19;13(5):1714.
9Lips P. Vitamin D to prevent acute respiratory infections. Lancet Diabetes Endocrinol. 2021 May;9(5):249–51.
10Takahashi K, Nakayama Y, Horiuchi H, Ohta T, Komoriya K, Ohmori H, et al. Human neutrophils express messenger RNA of vitamin D receptor and respond to 1alpha,25-dihydroxyvitamin D3. Immunopharmacol Immunotoxicol. 2002 Aug;24(3):335–47.
11Lin R. Crosstalk between Vitamin D Metabolism, VDR Signalling, and Innate Immunity. Biomed Res Int. 2016;2016:1375858.
12Sassi F, Tamone C, D’Amelio P. Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients. 2018 Nov 3;10(11):E1656.
13Sly LM, Lopez M, Nauseef WM, Reiner NE. 1alpha,25-Dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase. J Biol Chem. 2001 Sep 21;276(38):35482–93.
14Glinsky GV. Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells. Biomedicines. 2020 May 21;8(5):E129.
15Dancer RCA, Parekh D, Lax S, D’Souza V, Zheng S, Bassford CR, et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax. 2015 Jul;70(7):617–24.
16Menshawey E, Menshawey R, Nabeh OA. Shedding light on vitamin D: the shared mechanistic and pathophysiological role between hypovitaminosis D and COVID-19 risk factors and complications. Inflammopharmacology. 2021 Aug;29(4):1017–31.
17Kumar R, Rathi H, Haq A, Wimalawansa SJ, Sharma A. Putative roles of vitamin D in modulating immune response and immunopathology associated with COVID-19. Virus Res. 2021 Jan 15;292:198235.
18Varikasuvu SR, Thangappazham B, Vykunta A, Duggina P, Manne M, Raj H, et al. COVID-19 and vitamin D (Co-VIVID study): a systematic review and meta-analysis of randomized controlled trials. Expert Rev Anti Infect Ther. 2022 Feb 3;1–7.
19Jude EB, Ling SF, Allcock R, Yeap BXY, Pappachan JM. Vitamin D Deficiency Is Associated With Higher Hospitalization Risk From COVID-19: A Retrospective Case-control Study. J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4708–15.
20Orchard L, Baldry M, Nasim-Mohi M, Monck C, Saeed K, Grocott MPW, et al. Vitamin-D levels and intensive care unit outcomes of a cohort of critically ill COVID-19 patients. Clin Chem Lab Med. 2021 May 26;59(6):1155–63.
21Angelidi AM, Belanger MJ, Lorinsky MK, Karamanis D, Chamorro-Pareja N, Ognibene J, et al. Vitamin D Status Is Associated With In-Hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients. Mayo Clin Proc. 2021 Apr;96(4):875–86.
22Bychinin MV, Klypa TV, Mandel IA, Andreichenko SA, Baklaushev VP, Yusubalieva GM, et al. Low Circulating Vitamin D in Intensive Care Unit-Admitted COVID-19 Patients as a Predictor of Negative Outcomes. J Nutr. 2021 Aug 7;151(8):2199–205.
23Pereira M, Dantas Damascena A, Galvão Azevedo LM, de Almeida Oliveira T, da Mota Santana J. Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2020 Nov 4;1–9.
24Alberca GGF, Alberca RW. Role of vitamin D deficiency and comorbidities in COVID-19. World J Virol. 2022 Jan 25;11(1):85–9.
25Dror AA, Morozov N, Daoud A, Namir Y, Yakir O, Shachar Y, et al. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. PLoS One. 2022 Feb 3;17(2):e0263069.
26Petrelli F, Luciani A, Perego G, Dognini G, Colombelli PL, Ghidini A. Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and meta-analysis of 43 observational studies. J Steroid Biochem Mol Biol. 2021 Jul;211:105883.
27Stroehlein JK, Wallqvist J, Iannizzi C, Mikolajewska A, Metzendorf M-I, Benstoem C, et al. Vitamin D supplementation for the treatment of COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021 May 24;5:CD015043.
28Sabico S, Enani MA, Sheshah E, Aljohani NJ, Aldisi DA, Alotaibi NH, et al. Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial. Nutrients. 2021 Jun 24;13(7):2170.
29Murai IH, Fernandes AL, Sales LP, Pinto AJ, Goessler KF, Duran CSC, et al. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial. JAMA. 2021 Mar 16;325(11):1053–60.
30Sánchez-Zuno GA, González-Estevez G, Matuz-Flores MG, Macedo-Ojeda G, Hernández-Bello J, Mora-Mora JC, et al. Vitamin D Levels in COVID-19 Outpatients from Western Mexico: Clinical Correlation and Effect of Its Supplementation. J Clin Med. 2021 May 28;10(11):2378.
31Rastogi A, Bhansali A, Khare N, Suri V, Yaddanapudi N, Sachdeva N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study). Postgrad Med J. 2020 Nov;98(1156):87–90.
32Lakkireddy M, Gadiga SG, Malathi RD, Karra ML, Raju ISSVPM, Ragini, et al. Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease. Sci Rep. 2021 May 20;11:10641.
33Castillo M, Costa L, Barrios J, Díaz J, Miranda J, Bouillon R, et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J Steroid Biochem Mol Biol. 2020 Oct;203:105751.
34Pilz S, Trummer C, Theiler-Schwetz V, Grübler MR, Verheyen ND, Odler B, et al. Critical Appraisal of Large Vitamin D Randomized Controlled Trials. Nutrients. 2022 Jan 12;14(2):303.
35Boucher BJ. Why do so many trials of vitamin D supplementation fail? Endocr Connect. 2020 Oct;9(9):R195–206.
36Niknam Z, Jafari A, Golchin A, Danesh Pouya F, Nemati M, Rezaei-Tavirani M, et al. Potential therapeutic options for COVID-19: an update on current evidence. Eur J Med Res. 2022 Jan 13;27(1):6.
37Slominski AT, Slominski RM, Goepfert PA, Kim T-K, Holick MF, Jetten AM, et al. Reply to Jakovac and to Rocha et al.: Can vitamin D prevent or manage COVID-19 illness? Am J Physiol Endocrinol Metab. 2020 Aug 1;319(2):E455–7.
38Slominski RM, Stefan J, Athar M, Holick MF, Jetten AM, Raman C, et al. COVID-19 and Vitamin D: A lesson from the skin. Exp Dermatol. 2020 Sep;29(9):885–90.
39Syrek R. Trending Clinical Topic: Vitamin D [Internet]. Medscape. 2021 [cited 2022 Feb 8]. Available from: