Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials

Research output: Contribution to journalArticlepeer-review


  • David A Jolliffe
  • Carlos A Camargo
  • John D Sluyter
  • Mary Aglipay
  • John F Aloia
  • Davaasambuu Ganmaa
  • Peter Bergman
  • Heike A. Bischoff-Ferrari
  • Arturo Borzutzky
  • Camilla T Damsgaard
  • Gal Dubnov-Raz
  • Susanna Esposito
  • Clare Gilham
  • Adit A Ginde
  • Inbal Golan-Tripto
  • Emma C Goodall
  • Cameron C Grant
  • Christopher J Griffiths
  • Anna Maria Hibbs
  • Wim Janssens
  • Anuradha Vaman Khadilkar
  • Ilkka Laaksi
  • Margaret T Lee
  • Mark Loeb
  • Jonathon L Maguire
  • Paweł Majak
  • David T Mauger
  • David R Murdoch
  • Akio Nakashima
  • Rachel E Neale
  • Hai Pham
  • Christine Rake
  • Judy R Rees
  • Jenni Rosendahl
  • Robert Scragg
  • Dheeraj Shah
  • Yoshiki Shimizu
  • Steve Simpson-Yap
  • Geeta Trilok Kumar
  • Mitsuyoshi Urashima
  • Adrian R Martineau

Colleges, School and Institutes


Background: A 2017 meta-analysis of data from 25 randomised controlled trials of vitamin D supplementation for the prevention of acute respiratory infections revealed a protective effect of the intervention. Since then, 21 new RCTs have been completed.

Methods: Systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Sub-group analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, dosing regimen or age. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the registry from inception to 1st May 2020. Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. The study was registered with PROSPERO (no. CRD42020190633).

Findings: We identified 46 eligible RCTs (total 75,541 participants). Data were obtained for 48,488 (98.1%) of 49,419 participants in 43 studies, aged 0 to 95 years. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.92, 95% CI 0.86 to 0.99; 37 studies; I2 35.6%; P for heterogeneity 0.02). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen in trials where vitamin D was given using a daily dosing regimen (OR 0.78, 95% CI 0.65 to 0.94; 19 studies; I2 53.5%; P for heterogeneity 0.003), at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89; 10 studies; I2 31.2%; P for heterogeneity 0.16), for a duration of ≤12 months (OR 0.82, 95% CI 0.72 to 0.93; 29 studies; I2 38.1%; P for heterogeneity 0.02), and among participants aged 1.00 to 15.99 years at enrolment (OR 0.71, 95% CI 0.57 to 0.90; 15 studies; I2 46.0%; P for heterogeneity 0.03). No significant interaction was seen between allocation to vitamin D vs. placebo and dose frequency, dose size, study duration or age. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.97, 95% CI 0.86 to 1.07; 36 studies; I2 0.0%; P for heterogeneity 0.99). Risk of bias within individual studies was assessed as being low for all but three trials. A funnel plot showed left-sided asymmetry (P=0.007, Egger’s test).

Interpretation: Vitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months and age at enrolment of 1.00 to 15.99 years. The relevance of these findings to COVID-19 is not known and requires investigation.

Funding: None


Original languageEnglish
JournalThe Lancet
Early online date30 Mar 2021
Publication statusE-pub ahead of print - 30 Mar 2021