Findings from two large clinical trials published yesterday in BMJ discount the notion that vitamin D supplements protect against COVID-19 or other respiratory-tract infections, although both had notable limitations.
No differences in vitamin, placebo results
In a phase 3 randomized, controlled trial in the United Kingdom, a team led by University of London researchers enrolled 6,200 participants aged 16 years and older, tested the vitamin D levels of 3,100, and gave a 6-month supply of two different doses of oral supplements to 2,674 with suboptimal concentrations (less than 75 nanograms per deciliter [ng/dL]). The control group consisted of 2,949 participants not offered vitamin D.
Median participant age was 60.2 years, 67.0% were female, and 1.2% had received at least one dose of a COVID-19 vaccine at enrollment, a figure that rose to 89.1% by study end. Supplement recipients knew they were taking an active drug, and nearly half of controls reported taking a vitamin D supplement at least once during the study.
Participants, who reported taking no vitamin D supplements at enrollment, were given either 800 or 3,200 international units [IU]/day for 6 months. Follow-up ran from Dec 17, 2020, to Jun 16, 2021, a period of high COVID-19 prevalence and low COVID-19 vaccine coverage in the United Kingdom. During the 6-month follow-up, participants received monthly online questionnaires about any respiratory-tract or COVID-19 infections and symptoms.
A total of 299 participants tested positive for an all-cause respiratory infection. Relative to controls, at least one acute respiratory infection was diagnosed in 5.7% of the lower-dose group (odds ratio [OR], 1.26; 95% confidence interval [CI], 0.96 to 1.66) and in 5.0% of the higher-dose group (OR, 1.09; 95% CI, 0.82 to 1.46).
Compared with the 78 of 2,949 infected controls (2.6%), 55/1,515 (3.6%) in the lower-dose group tested positive for COVID-19 (OR, 1.39; 95% CI, 0.98 to 1.97), as did 45/1,515 (3.0%) in the higher-dose group (OR, 1.13; 95% CI, 0.78 to 1.63).
A subset of participants underwent vitamin D testing at the end of the study. Relative to controls, vitamin D levels were, on average, 12.7 ng/dL higher in the lower-dose group and 36.3 ng/dL higher in higher-dose recipients. A subgroup analysis found no evidence that COVID-19 vaccination changed the effect of allocation or COVID-19 incidence.
Four control patients died, as did two in the higher-dose vitamin D group and one in the lower-dose group. Also, 143 of the higher-dose and 85 of the lower-dose group had at least one serious adverse event, but none were considered related to the vitamin.
"Among people aged 16 years and older with a high baseline prevalence of suboptimal vitamin D status, implementation of a population level test-and-treat approach to vitamin D supplementation was not associated with a reduction in risk of all cause acute respiratory tract infection or COVID-19," the authors wrote.
The researchers noted that low-cost vitamin D was a target of interest because, while vaccination is the foundation of COVID-19 mitigation, its global effectiveness has been limited by cost, availability, and vaccine hesitancy, failure, and escape. "Vitamin D metabolites have long been recognised to support innate immune responses to respiratory viruses and bacteria, and regulate immunopathological inflammation," they wrote.
Infection, serious illness not reduced
In Norway, a team led by Oslo University researchers studied whether low-dose vitamin D supplementation in the form of cod liver oil in winter would prevent COVID-19 infection, serious illness, or other respiratory infections in adults not already taking the vitamin.
The quadruple-blinded, randomized, controlled trial involved 34,601 participants aged 18 to 75 years who received either 5 milliliters (mL) of cod liver oil (10 micrograms of vitamin D) a day (17,278 participants) or 5 mL of corn oil (placebo) (17,323) for up to 6 months from Nov 10, 2020, to Jun 2, 2021.
Average participant age was relatively young (44.9 years), 64.5% were women, average body mass index was 26.1 kilograms per meter squared (overweight), and 35.6% received at least one dose of COVID-19 vaccine during the study. A strong majority of participants (86%) had adequate vitamin D levels at baseline.
Participants completed questionnaires on COVID-19 and other respiratory infections, COVID-19 vaccination, and adverse events at baseline and then monthly for 6 months. Some participants (342) submitted dried-blood samples for vitamin D testing before and during the study, and 1,333 gave whole-blood samples for SARS-CoV-2 antibody testing at baseline.
Cod liver oil was not tied to a reduced risk of COVID-19 infection, serious illness, or other respiratory infection. Over a median of 164 days, 227 supplement recipients (1.31%) tested positive for COVID-19, compared with 228 (1.32%) in the control group (relative risk [RR], 1.00; adjusted 95% CI, 0.82 to 1.22).
A total of 121 supplement recipients (0.70%) and 101 controls (0.58%) had serious COVID-19 (RR, 1.20; 95% CI, 0.87 to 1.65), and 3,964 (22.9%) supplement recipients and 3,834 (22.1%) controls reported at least one acute respiratory infection (RR, 1.04; 95% CI, 0.97 to 1.11). Of all participants, 2.1% had SARS-CoV-2 antibodies, indicating active or previous infection, at baseline.
Supplement recipients who submitted two blood samples for vitamin D testing showed only marginal increases in vitamin levels during the study. Seventeen participants (8 in the supplement group, 9 controls) were admitted to a hospital, and 4 in each group needed intensive care, but none died. No serious adverse events were reported in either group.
"Supplementation with cod liver oil, a low dose vitamin D supplement, was not associated with a reduction in the incidence of SARS-CoV-2 infection, serious COVID-19, or other acute respiratory infections compared with placebo," the authors concluded.
Vaccine rollout potential confounder
In a related editorial, Peter Bergman, PhD, of the Karolinska Institutet in Sweden, said that the findings of both trials could have been skewed by the concurrent "highly successful" COVID-19 vaccine rollout in the United Kingdom and Norway.
He also said that vaccination is the gold-standard prophylaxis for COVID-19 and that vitamin D and cod liver oil should not be offered to healthy people with adequate vitamin D levels. There may, however, still be a role for vitamin D in COVID-19, pending further research, he added.
"A pragmatic approach for the clinician could be to focus on risk groups; those who could be tested before supplementation, including people with dark skin, or skin that is rarely exposed to the sun; pregnant women; and elderly people with chronic diseases," he wrote. "For those with inadequate vitamin D levels (<50 nmol/L [ng/dL]), supplementation with 1000-2000 IU/day could be a safe, simple, and affordable way to restore vitamin D levels, improve bone health, and take advantage of any possible protective effect against respiratory tract infections."