The Role of Vitamins, Minerals, and Polytherapy in Enhancing Immune Function and Reducing COVID-19 Risk: A Systematic Review and Meta-Analysis (2025)

Abstract:

Vitamins and minerals, including vitamins A, C, D, B6, B9, B12, zinc, selenium, copper, and iron, play a critical role in optimal immune function, as recognized by the European Food Safety Authority. This systematic review of 260 clinical studies and multiple meta-analyses demonstrates that supplementation with vitamins A, C, D, and zinc significantly reduces COVID-19 risk (p<0.0000000001)*, with polytherapy yielding greater efficacy (68% [57-77%] risk reduction) compared to monotherapy (33% [30-36%]). Vitamin D deficiency, prevalent in 48% of the global population, is strongly associated with worse COVID-19 outcomes, with controlled trials confirming treatment efficacy. Despite clinical evidence, health authorities often did not recommend these treatments, though their use was prevalent among healthcare professionals and highly educated individuals. Synergistic effects of combined treatments, variability across SARS-CoV-2 variants, and the risk of escape mutants highlight the need for broader, polytherapeutic approaches.

*A p-value (a statistical test) of less than 0.05 implies statistical significance and that of less than 0.01 implies high significance. Therefore p<0.0000000001 implies very high significance or high probability.

Introduction:

Nutritional status significantly influences immune system function, with deficiencies in key vitamins and minerals linked to increased susceptibility to viral infections, including SARS-CoV-2. This review synthesizes evidence from 260 clinical studies and meta-analyses to evaluate the efficacy of vitamins A, C, D, and zinc in reducing COVID-19 risk, with a focus on vitamin D due to its extensive study. Additionally, the review examines the benefits of polytherapy, the impact of genetic and viral variability, and the adoption of these treatments among specific demographics despite regulatory challenges.

Methods:

Data were compiled from 260 clinical studies (references 12-270) and supported by meta-analyses (references 271-302), sourced from c19early.org. Studies assessing the impact of vitamins A, C, D, and zinc on COVID-19 outcomes were included, alongside 125 controlled trials specific to vitamin D (references 78, 84, 103-225). Efficacy was measured as risk reduction percentages with 95% confidence intervals, comparing monotherapy (33% [30-36%]) and polytherapy (68% [57-77%]). Vitamin D deficiency prevalence was derived from a meta-analysis of 308 studies (reference 511). Surveys on supplement use among healthcare professionals and demographic groups were analyzed (references 528-543). Web-based searches provided additional context on regulatory and social trends.

Keywords: Vitamins, minerals, vitamin D, zinc, COVID-19, polytherapy, immune function, SARS-CoV-2 variants, healthcare professionals, supplementation.

Results:

The European Food Safety Authority identifies vitamins A, C, D, B6, B9, B12, zinc, selenium, copper, and iron as essential for immune function (references 2, 3). Across 260 studies, supplementation with vitamins A, C, D, and zinc reduced COVID-19 risk, with meta-analyses confirming efficacy (references 271-302). Notably, 125 controlled trials on vitamin D demonstrated significant efficacy (p<0.0000000001), supported by meta-analyses (references 278-296). Vitamin D deficiency (<50 nmol/L) affects 48% of the global population (reference 511), with studies linking low levels to worse outcomes (references 124, 138, 142, etc.). Improved results were observed with calcifediol, calcitriol, and analogs over cholecalciferol, and with multiple doses versus single bolus administration (reference 527).

Polytherapy significantly outperformed monotherapy, reducing risk by 68% [57-77%] compared to 33% [30-36%], driven by synergistic effects (references 112, 544-559). For example, Jitobaom et al. (545) reported a >10x reduction in IC50 with ivermectin and niclosamide, while Said et al. (112) found nigella sativa and vitamin D more effective together. Efficacy varied across SARS-CoV-2 variants (references 561-567), cell types (reference 569), and genetic profiles (references 570-573), supporting the use of broader, less variant-specific treatments.

Despite clinical evidence, health authorities often did not recommend these treatments. However, surveys showed higher use among healthcare professionals (references 528-530), particularly those with more experience (reference 531), as well as among highly educated (references 529, 532-539) and higher-income individuals (references 531, 534, 537, 538). Healthcare professionals also exhibited lower-than-expected COVID-19 risk (references 540, 541), potentially due to greater treatment use.

Discussion:

Vitamins A, C, D, and zinc enhance immune function through diverse mechanisms, with vitamin D showing particularly robust evidence for COVID-19 risk reduction. The high global prevalence of vitamin D deficiency underscores its public health relevance, though observational data linking low levels to worse outcomes do not establish causality due to confounding factors. Controlled trials, however, confirm treatment efficacy, with formulations like calcifediol offering faster action. Polytherapy’s superior efficacy reflects complementary mechanisms, as seen in combinations like ivermectin with niclosamide, and addresses challenges posed by SARS-CoV-2 variants and genetic variability. The risk of escape mutants (reference 575) further supports broader, multi-target approaches over variant-specific treatments like monoclonal antibodies.

Supplement use was notably higher among healthcare professionals and educated individuals, despite regulatory resistance, suggesting a disconnect between evidence and policy. This trend may have contributed to lower risk among healthcare workers. However, supplementation requires caution—e.g., high-dose vitamin C may increase kidney stone risk (references 306, 307)—and dietary sources may be preferable due to variable supplement quality (references 303-305). Limitations include potential biases in observational data and variability in treatment regimens across studies.

Conclusion:

Vitamins A, C, D, and zinc significantly reduce COVID-19 risk, with polytherapy offering greater efficacy through synergistic effects. Vitamin D’s role is particularly well-supported, though deficiency remains a global challenge. Despite regulatory barriers, adoption among healthcare professionals and educated groups highlights the need for evidence-based policy alignment. Future research should focus on optimizing treatment regimens, addressing genetic and variant-specific variability, and promoting equitable access to nutritional interventions.