Impact of chronic cholecalciferol supplementation and vitamin D status on risk of post-vaccination SARS-CoV-2 breakthrough infection

Vitamin D has been implicated in modulating immune responses to COVID-19 and anti-SARS-CoV-2 vaccination. However, whether chronic cholecalciferol supplementation influences the risk of post-vaccination breakthrough infection remains unclear. This retrospective observational study investigated the role of chronic vitamin D supplementation and circulating 25(OH) vitamin D concentrations on SARS-CoV-2 breakthrough infection after mRNA vaccination.

Adult patients vaccinated with two doses of BNT162b2 and without prior SARS-CoV-2 infection were included. Individuals chronically supplemented with cholecalciferol were compared with non-supplemented subjects and subsequently matched 1:1 for age, sex, and comorbidities. Breakthrough infection within 12 months after vaccination was recorded.

A total of 114 patients were evaluated; 70 (61.4%) received chronic cholecalciferol supplementation and 27 (23.7%) developed breakthrough infection. Infection occurred less frequently among supplemented patients (17% vs. 34%, p = 0.044). Circulating 25(OH) vitamin D concentrations were significantly lower in patients with infection (p < 0.001) and showed a significant predictive performance (AUROC 75.6%, p < 0.001), with an optimal cut-off of 18.5 ng/mL. In multivariable analysis, 25(OH) vitamin D concentrations emerged as the only independent predictor of breakthrough infection (OR 0.86, p = 0.003). In the matched cohort (n = 78), breakthrough infection remained numerically lower among supplemented individuals (18% vs. 36%, p = 0.125); lower 25(OH) vitamin D concentrations were independently associated with infection risk (OR 0.88, p = 0.007), with similar ROC performance (AUROC 77%, p < 0.001).

Adequate vitamin D status, predominantly achieved through chronic cholecalciferol supplementation, was independently associated with reduced risk of SARS-CoV-2 breakthrough infection after vaccination. Maintaining sufficient 25(OH) vitamin D concentrations may represent a simple and potentially relevant strategy to optimize post-vaccination protection.