Vitamin D and respiratory infections: the post-VITAL 2024-2025 update

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The proposition that vitamin D protects against acute respiratory infections has been studied for more than a decade, and the evidence has not stayed still. A widely cited 2017 individual-participant-data meta-analysis suggested a modest protective effect, strongest with daily dosing in deficient people. Subsequent large, well-conducted trials — including VITAL and ViDA — found no signal in largely vitamin-D-replete populations. The reasonable way to read the current evidence is not as a contradiction but as a story about who benefits: correcting a deficiency helps a little, while topping up the already-sufficient does not.

Where the headline numbers actually came from

The optimism traces to Martineau and colleagues, who pooled individual-participant data from 25 randomized trials and more than 11,000 participants. Vitamin D supplementation reduced the odds of experiencing at least one acute respiratory infection (adjusted OR 0.88, 95% CI 0.81–0.96). The protective effect was confined to daily or weekly dosing without large bolus doses, and was far stronger in people whose baseline 25-hydroxyvitamin D was below 25 nmol/L (OR 0.30 in that deeply deficient subgroup) than in those starting at or above 25 nmol/L (OR 0.75) [1]. A 2021 update by the same group, now spanning 46 trials and roughly 75,500 participants, softened the overall figure to OR 0.92 (95% CI 0.86–0.99), again with benefit limited to daily regimens (OR 0.78) and no benefit from bolus dosing [2]. The direction held; the magnitude shrank as more data arrived.

The negative megatrials

The two large primary-prevention trials in mostly replete adults are the ones that cooled enthusiasm. A prespecified analysis of the U.S. VITAL trial — 15,804 participants with baseline 25(OH)D measured, randomized to 2,000 IU vitamin D3 daily or placebo — found no overall reduction in self-reported upper respiratory infection (OR 0.96, 95% CI 0.86–1.06), and no significant benefit even in the small deeply deficient subgroup [3]. New Zealand's ViDA trial randomized 5,110 adults aged 50–84 to monthly 100,000 IU bolus vitamin D or placebo and likewise reported no effect on acute respiratory infection among its primary outcomes [4]. Both populations were largely vitamin-D-sufficient at baseline and ViDA used exactly the bolus schedule the meta-analyses flagged as ineffective — so their null results are consistent with, rather than contradictory to, the pooled data.

What the COVID-era trials added

The pandemic produced a large, pragmatic test. The UK CORONAVIT trial offered 6,200 adults a postal vitamin D test and, for those below 75 nmol/L, six months of 800 IU/day or 3,200 IU/day, versus no testing or supplementation. Supplementation reliably raised 25(OH)D levels, but neither dose reduced all-cause acute respiratory infection (lower-dose OR 1.26, higher-dose OR 1.09) or laboratory-confirmed COVID-19 compared with the no-offer group [5]. A nested sub-study found vitamin D also did not improve the efficacy or antibody response of SARS-CoV-2 vaccination [6]. In other words, a real-world program of finding and correcting suboptimal vitamin D status did not translate into fewer respiratory infections at the population level.

Why deficiency is the dividing line

The most consistent thread across all of this is baseline status. In the 2017 individual-participant analysis, the benefit in people with 25(OH)D below 25 nmol/L was large (OR 0.30) and shrank to a weak effect once baseline levels reached 25 nmol/L or higher [1]. The negative trials enrolled the opposite kind of population: VITAL's participants had a mean baseline 25(OH)D around 31 ng/mL (roughly 77 nmol/L) with only about 2% deeply deficient, and its deficient subgroup was too small to settle the question on its own [3]; ViDA's New Zealanders were similarly replete and received bolus dosing [4]; and CORONAVIT enrolled people below 75 nmol/L but, importantly, not necessarily deficient by stricter thresholds [5]. A nutrient that works by filling a deficit will, predictably, do little in people who have no deficit to fill. That is the simplest reconciliation of the headline-grabbing "vitamin D fails" trials with the earlier "vitamin D helps" meta-analyses.

How to read it now

Putting the strands together: the most defensible position is that vitamin D supplementation produces, at best, a small reduction in respiratory-infection risk that is concentrated in genuinely deficient people taking it daily, and that it offers no measurable respiratory benefit in adults who are already replete — which describes most people in well-nourished, food-fortified countries. Daily (not intermittent high-dose bolus) regimens are the only ones that have shown benefit in the pooled trials [1][2]. None of this argues against treating biochemically confirmed deficiency, which has its own musculoskeletal rationale; it argues against taking vitamin D as a general-purpose cold and flu preventive.

Sources

1. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. "Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data." BMJ, 2017;356:i6583. PMID 28202713. DOI: 10.1136/bmj.i6583.
2. Jolliffe 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;9(5):276-292. PMID 33798465. DOI: 10.1016/S2213-8587(21)00051-6.
3. Camargo CA, Schaumberg DA, Friedenberg G, Dushkes R, Glynn RJ, Gold DR, Mora S, Lee IM, Buring JE, Manson JE. "Effect of Daily Vitamin D Supplementation on Risk of Upper Respiratory Infection in Older Adults: A Randomized Controlled Trial." Clin Infect Dis, 2024;78(5):1162-1169. PMID 38113446. DOI: 10.1093/cid/ciad770.
4. Scragg R. "The Vitamin D Assessment (ViDA) study - Design and main findings." J Steroid Biochem Mol Biol, 2020;198:105562. PMID 31809866. DOI: 10.1016/j.jsbmb.2019.105562.
5. Jolliffe DA, Holt H, Greenig M, Talaei M, Perdek N, Pfeffer P, et al. "Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT)." BMJ, 2022;378:e071230. PMID 36215226. DOI: 10.1136/bmj-2022-071230.
6. Jolliffe DA, Vivaldi G, Chambers ES, Cai W, Li W, Faustini SE, et al. "Vitamin D Supplementation Does Not Influence SARS-CoV-2 Vaccine Efficacy or Immunogenicity: Sub-Studies Nested within the CORONAVIT Randomised Controlled Trial." Nutrients, 2022;14(18):3821. PMID 36145196. DOI: 10.3390/nu14183821.