Adequate vitamin D status, predominantly achieved through chronic cholecalciferol supplementation, was independently associated with reduced risk of SARS-CoV-2 breakthrough infection after vaccination.
Key Findings
Results
Breakthrough infection occurred less frequently among patients receiving chronic cholecalciferol supplementation compared to non-supplemented patients.
Total cohort included 114 patients; 70 (61.4%) received chronic cholecalciferol supplementation and 44 (38.6%) did not.
27 (23.7%) of all patients developed breakthrough infection within 12 months after vaccination.
Breakthrough infection rate was 17% in supplemented vs. 34% in non-supplemented patients (p = 0.044).
All patients received two doses of BNT162b2 mRNA vaccine and had no prior SARS-CoV-2 infection.
The study was retrospective and observational in design.
Results
Circulating 25(OH) vitamin D concentrations were significantly lower in patients who developed breakthrough infection.
Patients with breakthrough infection had significantly lower 25(OH) vitamin D concentrations than those without infection (p < 0.001).
25(OH) vitamin D showed significant predictive performance for breakthrough infection with an AUROC of 75.6% (p < 0.001).
The optimal cut-off for 25(OH) vitamin D was identified as 18.5 ng/mL.
This analysis was conducted in the full cohort of 114 patients.
Results
In multivariable analysis of the full cohort, 25(OH) vitamin D concentration was the only independent predictor of breakthrough infection.
Odds ratio for 25(OH) vitamin D as predictor of breakthrough infection was 0.86 (p = 0.003), indicating that higher vitamin D levels were associated with lower infection risk.
25(OH) vitamin D emerged as the only independent predictor in the multivariable model.
Analysis was conducted in the total cohort of 114 patients.
Patients were compared after adjusting for other variables in the model.
Results
In a 1:1 matched cohort controlling for age, sex, and comorbidities, lower 25(OH) vitamin D concentrations remained independently associated with breakthrough infection risk.
The matched cohort comprised 78 patients (39 supplemented, 39 non-supplemented), matched 1:1 for age, sex, and comorbidities.
Breakthrough infection was numerically lower among supplemented individuals in the matched cohort (18% vs. 36%), but this difference did not reach statistical significance (p = 0.125).
In multivariable analysis of the matched cohort, lower 25(OH) vitamin D was independently associated with infection risk (OR 0.88, p = 0.007).
ROC performance in the matched cohort was similar to the full cohort, with AUROC of 77% (p < 0.001).
Methods
The study population consisted of adult patients vaccinated with two doses of BNT162b2 without prior SARS-CoV-2 infection, followed for 12 months post-vaccination.
This was a retrospective observational study design.
Breakthrough infection was recorded within 12 months after vaccination.
Individuals with prior SARS-CoV-2 infection were excluded.
Chronic cholecalciferol supplementation was the form of vitamin D evaluated; specific dosing details are not reported in the abstract.
What This Means
This research suggests that people who regularly take vitamin D supplements (cholecalciferol) and maintain higher blood levels of vitamin D may be less likely to contract COVID-19 after being vaccinated with the Pfizer-BioNTech (BNT162b2) mRNA vaccine. In a study of 114 adults who had received two vaccine doses and had no prior COVID-19 infection, only 17% of those taking chronic vitamin D supplements developed a 'breakthrough infection' (COVID-19 after vaccination) within one year, compared to 34% of those not taking supplements. Across multiple statistical analyses, blood vitamin D levels were consistently identified as the strongest predictor of whether someone would develop a breakthrough infection, with a threshold of 18.5 ng/mL identified as a meaningful cut-off.
Importantly, when the researchers accounted for differences in age, sex, and other health conditions by comparing matched groups, the difference in breakthrough infection rates between supplemented and non-supplemented individuals was no longer statistically significant, though vitamin D blood levels themselves remained a significant independent predictor of infection risk. This suggests it may be the actual vitamin D level in the blood — rather than supplementation per se — that is most directly linked to protection, regardless of how that level is achieved.
This research suggests that maintaining adequate vitamin D status could be a simple and potentially meaningful way to support the protection offered by COVID-19 vaccines. The findings are limited by the study's retrospective and observational nature and relatively small sample size, which means causation cannot be confirmed and other unmeasured factors could be involved. Larger prospective studies would be needed to confirm these findings.
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di Filippo L, Bolamperti S, Campaniolo M, Gifuni L, Giustina A. (2026). Impact of chronic cholecalciferol supplementation and vitamin D status on risk of post-vaccination SARS-CoV-2 breakthrough infection.. Endocrine. https://doi.org/10.1007/s12020-026-04677-6