Abstract: Journal of Clinical Medicine Editorial COVID-19 Prevention: Vitamin D Is Still a Valid Remedy Rachel Nicoll * and Michael Y. Henein Department of Public Health and Clinical Medicine and Heart Centre, Umea University, 901 87 Umea, Sweden * Correspondence: rachel.nicoll@umu.se Citation: Nicoll, R.; Henein, M.Y. COVID-19 Prevention: Vitamin D Is Still a Valid Remedy. J. Clin. Med. 2022, 11, 6818. https://doi.org/ 10.3390/jcm11226818 Received: 13 November 2022 Accepted: 16 November 2022 Published: 18 November 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Seven meta-analyses and systematic reviews and three later clinical trials argued that low vitamin D status increased susceptibility to COVID-19 and the risk of greater disease severity and mortality [1–10]. Furthermore, there are five meta-analyses and systematic reviews of vitamin D supplementation for the prevention of acute respiratory infection (ARI) [11,12] and COVID-19 [13–15], as well as a later clinical trial [16], all showing that supplementation can protect against COVID-19 infection, disease severity, and death. The evidence could not be much more conclusive than this. Consequently, it was surprising to learn about Joliffe et al.’s recent randomized controlled trial of vitamin D to prevent ARIs and COVID-19, which concluded that ‘Among people aged 16 years and older with 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’ [17]. Joliffe et al.’s UK study was a test-and-treat approach used to determine the effect of correcting suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) < 75 nmol/L) on the risk of contracting ARIs and COVID-19. Those with 25(OH)D < 75 nmol/L (30 ng/mL) were randomized to six months of supplementary vitamin D at 3200 IU/day, 800 IU/day, or no supplements. The outcome was the percentage of subjects with confirmed ARI/COVID-19. What was different about this trial that might have caused it to fail? Analysis of Joliffe et al’s paper gives rise to a number of observations. Of particular importance was the treatment of participants randomized to ‘No supplementation’. Instead of being given a placebo, as would be normal in a controlled study, they were given nothing and were informed that it was a vitamin D trial, thereby alerting them to the fact that vitamin D supplementation could be an important infection preventive in the middle of the COVID-19 pandemic. As a result, almost 50% reported taking their own vitamin D supplements. We do not know what level of supplementation these participants took and we can assume that if 50% reported supplementation, the actual number was probably higher. As Dr David Grimes noted in a BMJ Rapid Response, this was therefore ‘a randomised UNCONTROLLED study’ [18]; consequently, any comparison of the intervention arm with the ‘no supplementation’ arm was rendered meaningless. The authors sought to overcome this limitation by conducting sensitivity analysis, but this is no substitute for conducting a properly controlled..