{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:47:48Z","timestamp":1790711268015,"version":"4.1.0"},"reference-count":294,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Clinical trials consistently demonstrate an inverse correlation between serum 25-hydroxyvitamin D [25(OH)D; calcifediol] levels and the risk of symptomatic SARS-CoV-2 disease, complications, and mortality. This systematic review (SR), guided by Bradford Hill\u2019s causality criteria, analyzed 294 peer-reviewed manuscripts published between December 2019 and November 2024, focusing on plausibility, consistency, and biological gradient. Evidence confirms that cholecalciferol (D3) and calcifediol significantly reduce symptomatic disease, complications, hospitalizations, and mortality, with optimal effects above 50 ng\/mL. While vitamin D requires 3\u20134 days to act, calcifediol shows effects within 24 h. Among 329 trials, only 11 (3%) showed no benefit due to flawed designs. At USD 2\/patient, D3 supplementation is far cheaper than hospitalization costs and more effective than standard interventions. This SR establishes a strong inverse relationship between 25(OH)D levels and SARS-CoV-2 vulnerability, meeting Hill\u2019s criteria. Vitamin D3 and calcifediol reduce infections, complications, hospitalizations, and deaths by ~50%, outperforming all patented, FDA-approved COVID-19 therapies. With over 300 trials confirming these findings, waiting for further studies is unnecessary before incorporating them into clinical protocols. Health agencies and scientific societies must recognize the significance of these results and incorporate D3 and calcifediol for prophylaxis and early treatment protocols of SARS-CoV-2 and similar viral infections. Promoting safe sun exposure and adequate vitamin D3 supplementation within communities to maintain 25(OH)D levels above 40 ng\/mL (therapeutic range: 40\u201380 ng\/mL) strengthens immune systems, reduces hospitalizations and deaths, and significantly lowers healthcare costs. When serum 25(OH)D levels exceed 70 ng\/mL, taking vitamin K2 (100 \u00b5g\/day or 800 \u00b5g\/week) alongside vitamin D helps direct any excess calcium to bones. The recommended vitamin D dosage (approximately 70 IU\/kg of body weight for a non-obese adult) to maintain 25(OH)D levels between 50\u2013100 ng\/mL is safe and cost-effective for disease prevention, ensuring optimal health outcomes.<\/jats:p>","DOI":"10.3390\/nu17030599","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T11:32:32Z","timestamp":1738841552000},"page":"599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Vitamin D Deficiency Meets Hill\u2019s Criteria for Causation in SARS-CoV-2 Susceptibility, Complications, and Mortality: A Systematic Review"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1096-8595","authenticated-orcid":false,"given":"Sunil J.","family":"Wimalawansa","sequence":"first","affiliation":[{"name":"Endocrinology and Human Nutrition, CardioMetabolic & Endocrine Institute, North Brunswick, NJ 08902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8899931","DOI":"10.1155\/2021\/8899931","article-title":"Darker skin color measured by Von Luschan Chromatic Scale and increased sunlight exposure time are independently associated with decreased odds of vitamin D deficiency in Thai ambulatory patients","volume":"2021","author":"Charoenngam","year":"2021","journal-title":"J. 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