From the early days of the COVID-19 pandemic, researchers examining the question of why some people were better protected from the infection than others began to look at a possible role for vitamin D. The nutrient, which is obtained from food and exposure to sunlight, is known to contribute to a well-functioning immune system in a variety of ways, including defending the body from invading viruses and other pathogens. “Vitamin D is cheap, easily available and relatively safe,” says genetic epidemiologist Fotios Drenos of Brunel University London. Investigating whether the vitamin could make a difference in COVID patients “was an important question to ask,” he says.
Researchers already knew that vitamin D can be helpful in staving off respiratory infections. A 2017 meta-analysis of 25 randomized controlled trials involving about 11,000 people concluded that giving daily or weekly vitamin D supplements reduced the risk of acute respiratory infections—with the strongest impact predictably falling on those who started off with a serious deficiency of the vitamin. That meta-analysis, led by Adrian Martineau of Queen Mary University of London, was updated this year with data from a total of 46 trials and 75,500 participants. Martineau’s team confirmed its earlier finding but determined that the impact of the supplements appears to be quite small.
Epidemiological data emerging early in the pandemic also suggested that the vitamin might be useful. People older than age 65 and people of color are more likely to have lower levels of vitamin D. Both groups face a higher risk of poor outcomes from COVID-19, although the reasons for their vulnerability are multifaceted. In addition, studies have shown that countries farther away from the equator—where levels of the vitamin tend to be lower because of less sunlight—have higher COVID death rates than those closer to the equator.
Taken together, such data points are far from conclusive, but they served as a spur to investigate further. Fortunately, several large, potentially relevant studies of vitamin D were already underway when the pandemic struck, and others were swiftly begun.
In Brisbane, Australia, cancer researcher Rachel Neale of the QIMR Berghofer Medical Research Institute has been leading the massive D-Health Trial, a randomized controlled trial of five years of vitamin D supplementation in 21,315 older adults. It has compared monthly high doses of the vitamin (60,000 international units) with a placebo and has looked at a wide range of outcomes, including heart disease, cancer, bone fractures and overall mortality. Acute respiratory tract infection has also been among the outcomes measured in the study, and with the COVID pandemic raging, Neale and her colleagues decided to examine those data early. Their analysis, published in the Lancet Diabetes & Endocrinology in January, showed that vitamin D did not reduce the risk of acute respiratory tract infection but may have slightly reduced the duration of symptoms. Neale points out, however, that vitamin D levels tend to be high in Australia because of the long hours of sunshine, so supplementation may have a lower impact there than in less sunny places.
Another researcher who started looking at the vitamin early in the pandemic—but in a more northerly latitude—is David Meltzer, a health economist and a professor of medicine at the University of Chicago.
“I got an e-mail in the first week of March  talking about the  Martineau paper, and I was struck by the results, particularly in people who are deficient in vitamin D,” he recalls. “We had a lot of people being tested for COVID-19 in our hospital, and we had historical data from these individuals, so we cross-referenced the positive tests and the vitamin D data on record.”
The results in a diverse population of 4,638 people were published in JAMA Network Open this past March. Meltzer and his colleagues found that the risk of a positive COVID test was 2.64 times greater for Black individuals with low levels of vitamin D than for those with higher levels. There was no significant correlation in white participants. “Chicago has long winters, and people with darker skin produce less vitamin D. Our northern location and the predominance of Black people attending the hospital allowed us to spot the link,” Meltzer observes.
In England, Drenos also took a look at D levels and the risk of COVID infection but used a different methodology. He studied a group of people of European ancestry in the UK Biobank who were genetically predisposed to high or low levels of vitamin D and looked for correlations between their levels of the vitamin and their SARS-CoV-2 infection risk and COVID-19 severity. Like Neale’s trial and in contrast with Meltzer’s study, Drenos’s analysis, published in January, showed no evidence of a preventive effect of higher vitamin levels. Still, he says, “I am keeping an open mind. I believe that large, well-controlled trials will be the gold standard, but this takes time.”
The lack of a clear answer from existing studies could reflect limitations in trial design, including populations that are already replete with vitamin D, sample sizes that are too small or inconsistencies in doses or methods of measurement. Some forthcoming trials may help fill in the gaps.
The U.K.’s CORONAVIT trial, with 6,200 participants, is looking at whether correcting vitamin D deficiency during the winter with a standard or high dose of the vitamin will reduce the risk or severity of COVID-19 and other acute respiratory infections. In France, the smaller CoVitTrial is assessing the impact of a single high dose or routine dose of vitamin D on high-risk older adults with COVID-19. Results of both trials should be available later this year.
Meanwhile Meltzer is leading three studies of vitamin D supplementation in populations with mixed ethnicity: one investigation in medically complex patients, a second in health care workers and a third that is community-based. They will assess the impact of various dosages of the vitamin on COVID-19 symptoms and antibodies, as well as on symptoms of other respiratory diseases.
Given the results of Neale’s large-scale study and the modest benefits found in Martineau’s latest meta-analysis, it seems unlikely that vitamin D will prove to be a critical ingredient in fending off COVID-19 or modulating its severity. But these and other new trials may find it is useful in certain doses for certain populations. As Neale points out, “there is data that is suggestive” and enough smoke to indicate that you don’t want to be vitamin-D-deficient in a pandemic.