Vitamin D Supplementation and the Risk of Acute Respiratory Infection: A Metadata-Driven Synthesis of Randomized Evidence

Abstract

Vitamin D metabolites regulate antimicrobial peptide expression in the respiratory epithelium, providing a biological rationale for supplementation as a means of preventing Acute Respiratory Infections (ARIs). Observational data have consistently linked low circulating 25-Hydroxyvitamin D (25[OH]D) with greater infection risk, but trial results have been heterogeneous. To synthesize randomized evidence on whether Vitamin D supplementation reduces ARI risk, and to characterize the factors that modify this effect. Peer-reviewed Randomized Controlled Trials (RCTs) and meta-analyses of RCTs were retrieved from PubMed and PubMed Central. Study characteristics, pooled effect estimates, and subgroup findings were extracted into an evidence matrix and summarized narratively and quantitatively. Across successive meta-analyses the pooled Odds Ratio (OR) for experiencing at least one ARI drifted toward the null as large trials accrued: 0.88 (95% CI 0.81-0.96) in the 2017 individual-participant-data analysis, 0.92 (0.86-0.99) in 2021, and 0.94 (0.88-1.00; p=0.057) in the 2025 update. Early benefit was concentrated in profoundly deficient participants given daily or weekly (non-bolus) regimens. Several large, well-powered trials in unselected or replete populations reported null effects. Supplementation was consistently safe. Vitamin D supplementation is safe and may confer a small reduction in ARI risk that is most plausible among deficient individuals receiving regular physiological doses; it is not supported as a broad preventive measure in Vitamin-D-replete populations. A precision-prevention framing-correcting deficiency rather than universal supplementation-best fits the current evidence.