The efficacy of multivitamin, vitamin A, vitamin B, vitamin C, and vitamin D supplements in the prevention and management of COVID-19 and Long-COVID: an updated systematic review and meta-analysis of randomized clinical trials

“It was considered statistically significant at p -value < 0.05 and substantial heterogeneity was defined as I 2 > 50% [23].”

“Two independent authors performed the quality assessment of the articles included in the systematic review using the revised Cochrane Risk-of-Bias tool version 2 for randomized studies [22].”

“Analyses were performed using Review Manager (RevMan, version 5.4, The Cochrane Collaboration, Copenhagen, Denmark), R Statistical Software (version 4.2.3; R Core Team 2023, R Foundation for Statistical Computing, Vienna, Austria), and the package “meta” [24].”

“As for vitamin C, even though its role as an antioxidant agent [77,78] and necessary micronutrient for leukocyte function is well recognized [79], a few positive findings were reported in some trials but results were largely inconsistent in relation to most outcomes.”

“As for vitamin C, even though its role as an antioxidant agent [77,78] and necessary micronutrient for leukocyte function is well recognized [79], a few positive findings were reported in some trials but results were largely inconsistent in relation to most outcomes.”

“For this reason, further studies are necessary to confirm our results, especially well-conducted RCTs that would contribute to populating the funnel plot and probably mitigate any potential presence of publication bias [84].”

“Indeed, although it is well-known that vitamins are critical to making the immune system work properly [66,67], the results coming from clinical trials on the role of these substances in COVID-19 disease are inconclusive [13,68].”

“…[44], the United States (n = 2 RCTs) [45,50], Croatia (n = 1 RCT) [46], Russia (n = 2 RCTs) [47,52], Belgium (n = 1 RCT) [49], Spain (n = 1 RCT) [51], Iran (n = 1 RCT) [53], Argentina (n = 1 RCT) [54], India (n = 1 RCT) [58], Mexico (n = 2 RCTs) [59,60], Brazil (n = 1 RCT, n = 3 papers)…”

“Vitamin D was always administered orally in the form of cholecal-ciferol/vitamin D3 in 11 RCTs [44,46–49,52 ,54,55,58–60 ], calcifediol in 3”

“Despite growing evidence [61,62] that proves the role of supplement compounds in supporting the immune system, the debate about the use of natural agents in the prevention and management of viral infections is still far from solved [63–65].”

“…SARS-CoV-2 infection can cause an inflammation status leading to vitamin D deficiency [85], while, on the other hand, lower serum vitamin D levels may contribute to a dysregulation of the renin–angiotensin system and thus may increase the risk of developing a cytokine storm in COVID-19 [86,87].”

“As for vitamin C, even though its role as an antioxidant agent [77,78] and necessary micronutrient for leukocyte function is well recognized [79], a few positive findings were reported in some trials but results were largely inconsistent in relation to most outcomes.”

“…while a review has concluded that some reduction in duration and severity of common cold symptoms can be observed in regular supplementation trials [11]. characteristics of the intervention (i.e., target population, sample size, vitamin administered, vitamin status at baseline, vitamin dose,…”

“Vitamin D was always administered orally in the form of cholecal-ciferol/vitamin D3 in 11 RCTs [44,46–49,52 ,54,55,58–60 ], calcifediol in 3”

“These results also align with other similar reviews conducted on COVID-19 subjects [13,15,71] and might be explained by the fact that patients with pneumonia, sepsis, and/or multiple organ failure, as happens in critically ill COVID-19 patients, have usually high oxidative stress [13,81].”

“Clinical studies show that vitamin D deficiency is associated with a higher risk of respiratory infections, including COVID-19 [8]; some authors have reported the positive effect of vitamin A supplementation on the risk of severe diseases via an immunomodulatory and anti-inflammatory effect,…”

“…any difference in severity scores, including SOFA (sequential organ failure assessment) or GCS (Glasgow Coma Scale), while five trials [33,35–37, 43] As for length of hospitalization, four trials found no difference between the intervention and control group [33,38,41,43], one study [37] found…”

“…aligns with a large population study in which an observed inverse association between habitual use of vitamin D supplements and COVID-19 infection was observed [90] and that suggests the presence of a positive effect of this vitamin on several inflammatory mechanisms induced by SARS-CoV-2 [90–93].”

“Despite growing evidence [61,62] that proves the role of supplement compounds in supporting the immune system, the debate about the use of natural agents in the prevention and management of viral infections is still far from solved [63–65].”

“…SARS-CoV-2 infection can cause an inflammation status leading to vitamin D deficiency [85], while, on the other hand, lower serum vitamin D levels may contribute to a dysregulation of the renin–angiotensin system and thus may increase the risk of developing a cytokine storm in COVID-19 [86,87].”

“…four trials found no difference between the intervention and control group [33,38,41,43], one study [37] found it was shorter among treated individuals, whereas another study [35] found that it was longer, but with no difference after restriction to the ICU-admitted patient subgroup.”

“…and the relatively safe profile of these substances, additional data could be produced in the near future, allowing a more conclusive judgment on the potential benefits of vitamin D as a prevention therapy and vitamin co-administration as a supplemental treatment for COVID-19 patients [75,76].”

“…countries and at different times during the COVID-19 pandemic and they did not specify the SARS-CoV-2 variant responsible for the infections [97], nor did they assess the effect of supplements on the management or prevention of infections caused by different SARS-CoV-2 variants, limiting…”

“It is well-known that vitamins play a crucial role in infections [7] as they are essential for the proper functioning of the immune system.”

“Combined with vaccinations, they have mitigated the effects of the COVID-19 pandemic, during which searching for any effective supplemental treatment or preventive measure rekindled the interest in the role of micronutrients [5,6].”

“Intervention protocols included the oral supplementation of cholecalciferol/vitamin D3 with different dosages, from 800 international units (IU) [25] to 4000 IU [26], administered once daily for six months [25] or 30 days [26], with a follow-up of 6 months [25] and 45 days [26], respectively.”

“Alternatively, or in addition, they had different inclusion criteria [12,14,68], such as the investigation of vitamin administration in combination with other substances or they were not updated [14,69,71–73].”

“…(n = 2 RCTs) [45,50], Croatia (n = 1 RCT) [46], Russia (n = 2 RCTs) [47,52], Belgium (n = 1 RCT) [49], Spain (n = 1 RCT) [51], Iran (n = 1 RCT) [53], Argentina (n = 1 RCT) [54], India (n = 1 RCT) [58], Mexico (n = 2 RCTs) [59,60], Brazil (n = 1 RCT, n = 3 papers) [55–57], and one RCT in four…”

“It is not surprising that many reviews have already been published on the topic [13,15,69,70] but they mostly focused on one vitamin only [14,15,68,71] or a specific outcome in COVID-19 patients [13,69,70].”

“On the one hand, SARS-CoV-2 infection can cause an inflammation status leading to vitamin D deficiency [85], while, on the other hand, lower serum vitamin D levels may contribute to a dysregulation of the renin–angiotensin system and thus may increase the risk of developing a cytokine storm in…”

“Despite growing evidence [61,62] that proves the role of supplement compounds in supporting the immune system, the debate about the use of natural agents in the prevention and management of viral infections is still far from solved [63–65].”

“…find any difference in severity scores, including SOFA (sequential organ failure assessment) or GCS (Glasgow Coma Scale), while five trials [33,35–37, 43] As for length of hospitalization, four trials found no difference between the intervention and control group [33,38,41,43], one study [37]…”

“It is not surprising that many reviews have already been published on the topic [13,15,69,70] but they mostly focused on one vitamin only [14,15,68,71] or a specific outcome in COVID-19 patients [13,69,70].”

“…aligns with a large population study in which an observed inverse association between habitual use of vitamin D supplements and COVID-19 infection was observed [90] and that suggests the presence of a positive effect of this vitamin on several inflammatory mechanisms induced by SARS-CoV-2 [90–93].”

“Intervention protocols included the oral supplementation of cholecalciferol/vitamin D3 with different dosages, from 800 international units (IU) [25] to 4000 IU [26], administered once daily for six months [25] or 30 days [26], with a follow-up of 6 months [25] and 45 days [26], respectively.”

“Vitamin D was always administered orally in the form of cholecal-ciferol/vitamin D3 in 11 RCTs [44,46–49,52 ,54,55,58–60 ], calcifediol in 3”

“…effect of vitamin A supplementation on the risk of severe diseases via an immunomodulatory and anti-inflammatory effect, replicable for COVID-19 [9,10], while a review has concluded that some reduction in duration and severity of common cold symptoms can be observed in regular supplementation…”

“The population enrolled was relatively small, ranging from 40 [58] to 240 individuals [55–57], with a varying proportion of females, from 37% [48] to 72% [46].”

“All studies assessed the clinical outcomes: of these, five trials [34,36,38,39,43] did not find any difference in severity scores, including SOFA (sequential organ failure assessment) or GCS (Glasgow Coma Scale), while five trials [33,35–37, 43] As for length of hospitalization, four trials found…”

“Similarly, even though vitamin D seems to provide some benefits in the long-term complications of COVID-19 [74], its effects in the prevention of long-COVID symptoms were poorly studied, together with the effects of vitamin co-administration in the management of COVID-19 patients, both of which did…”

“Vitamin D was always administered orally in the form of cholecal-ciferol/vitamin D3 in 11 RCTs [44,46–49,52 ,54,55,58–60 ], calcifediol in 3”

“They were conducted in Tunisia (n = 1 RCT) [44], the United States (n = 2 RCTs) [45,50], Croatia (n = 1 RCT) [46], Russia (n = 2 RCTs) [47,52], Belgium (n = 1 RCT) [49], Spain (n = 1 RCT) [51], Iran (n = 1 RCT) [53], Argentina (n = 1 RCT) [54], India (n = 1 RCT) [58], Mexico (n = 2 RCTs) [59,60],…”

“It is not surprising that many reviews have already been published on the topic [13,15,69,70] but they mostly focused on one vitamin only [14,15,68,71] or a specific outcome in COVID-19 patients [13,69,70].”

“Vitamin D was always administered orally in the form of cholecal-ciferol/vitamin D3 in 11 RCTs [44,46–49,52 ,54,55,58–60 ], calcifediol in 3”

“It is not surprising that many reviews have already been published on the topic [13,15,69,70] but they mostly focused on one vitamin only [14,15,68,71] or a specific outcome in COVID-19 patients [13,69,70].”

“The population enrolled was relatively small, ranging from 40 [58] to 240 individuals [55–57], with a varying proportion of females, from 37% [48] to 72% [46].”

“…Croatia (n = 1 RCT) [46], Russia (n = 2 RCTs) [47,52], Belgium (n = 1 RCT) [49], Spain (n = 1 RCT) [51], Iran (n = 1 RCT) [53], Argentina (n = 1 RCT) [54], India (n = 1 RCT) [58], Mexico (n = 2 RCTs) [59,60], Brazil (n = 1 RCT, n = 3 papers) [55–57], and one RCT in four countries [48] (Table 2).”

“Combined with vaccinations, they have mitigated the effects of the COVID-19 pandemic, during which searching for any effective supplemental treatment or preventive measure rekindled the interest in the role of micronutrients [5,6].”

“Results were contrasting: a reduction in some inflammatory parameters in supplemented patients was registered in one study [9] but not in the other [27], whereas Leal-Mart í nez et al. [28] reported a significantly higher hydric balance and lower gastrointestinal distension among treated…”

“Alternatively, or in addition, they had different inclusion criteria [12,14,68], such as the investigation of vitamin administration in combination with other substances or they were not updated [14,69,71–73].”

“Vitamin D was always administered orally in the form of cholecal-ciferol/vitamin D3 in 11 RCTs [44,46–49,52 ,54,55,58–60 ], calcifediol in 3”

“Despite growing evidence [61,62] that proves the role of supplement compounds in supporting the immune system, the debate about the use of natural agents in the prevention and management of viral infections is still far from solved [63–65].”

“…and inflammation pathways against COVID-19 by regulating the growth and function of innate and adaptive immune cells, the production of antibodies, and the suppression of pro-inflammatory cytokines, potentially helping to balance the immune response and mitigate excessive inflammation [82,83].”

“Vitamin D was always administered orally in the form of cholecal-ciferol/vitamin D3 in 11 RCTs [44,46–49,52 ,54,55,58–60 ], calcifediol in 3”

“…while five trials [33,35–37, 43] As for length of hospitalization, four trials found no difference between the intervention and control group [33,38,41,43], one study [37] found it was shorter among treated individuals, whereas another study [35] found that it was longer, but with no difference…”

“They can lead to a wide range of illnesses, from the common cold to more severe and lethal diseases like influenza but also acquired immunodeficiency syndrome or COVID-19 [1,2].”

“Indeed, although it is well-known that vitamins are critical to making the immune system work properly [66,67], the results coming from clinical trials on the role of these substances in COVID-19 disease are inconclusive [13,68].”

“All studies assessed the clinical outcomes: of these, five trials [34,36,38,39,43] did not find any difference in severity scores, including SOFA (sequential organ failure assessment) or GCS (Glasgow Coma Scale), while five trials [33,35–37, 43] As for length of hospitalization, four trials found…”

“Moreover, the choice between different vitamin D forms may be relevant in this context due to their different pharmacokinetic profiles [95].”

“Additionally, it is known that treating SARS-CoV-2 infections is more effective in the early stages of the disease and therefore, by the time COVID-19 patients are hospitalized due to their critical conditions, the treatment is likely to be less effective [94].”

“Results were contrasting: a reduction in some inflammatory parameters in supplemented patients was registered in one study [9] but not in the other [27], whereas Leal-Mart í nez et al. [28] reported a significantly higher hydric balance and lower gastrointestinal distension among treated…”

“By contrast, a significant improvement in some clinical symptoms such as fever, body aches, weakness, and fatigue and also significant differences in immunological response were detected in the other trial [29].”

“…did not find any difference in severity scores, including SOFA (sequential organ failure assessment) or GCS (Glasgow Coma Scale), while five trials [33,35–37, 43] As for length of hospitalization, four trials found no difference between the intervention and control group [33,38,41,43], one study…”

“It is not surprising that many reviews have already been published on the topic [13,15,69,70] but they mostly focused on one vitamin only [14,15,68,71] or a specific outcome in COVID-19 patients [13,69,70].”

“It is not surprising that many reviews have already been published on the topic [13,15,69,70] but they mostly focused on one vitamin only [14,15,68,71] or a specific outcome in COVID-19 patients [13,69,70].”

“They were conducted in Tunisia (n = 1 RCT) [44], the United States (n = 2 RCTs) [45,50], Croatia (n = 1 RCT) [46], Russia (n = 2 RCTs) [47,52], Belgium (n = 1 RCT) [49], Spain (n = 1 RCT) [51], Iran (n = 1 RCT) [53], Argentina (n = 1 RCT) [54], India (n = 1 RCT) [58], Mexico (n = 2 RCTs) [59,60],…”

“…and inflammation pathways against COVID-19 by regulating the growth and function of innate and adaptive immune cells, the production of antibodies, and the suppression of pro-inflammatory cytokines, potentially helping to balance the immune response and mitigate excessive inflammation [82,83].”

“Participants were mainly recruited among hospitalized patients with moderate or severe COVID-19 (n = 6) [33,35,37,38,40,41], in three cases among ICU patients [36,39,43], and in the other two studies among non-hospitalized adults with mild or moderate COVID-19 [34,42].”

“It is not surprising that many reviews have already been published on the topic [13,15,69,70] but they mostly focused on one vitamin only [14,15,68,71] or a specific outcome in COVID-19 patients [13,69,70].”

“OH vitamin D levels may benefit to a different extent from the supplementation [68,88,89], we did not detect any increased effect, as already reported in the literature [68].”

“This was not unexpected, given that, as highlighted by Honarmand et al. [98], several biases affected the largest part of the RTCs on COVID-19 management and prevention, making it imperative to prioritize rigorous trial design to address the demand for effective and safe treatment and prevention…”

“All studies assessed the clinical outcomes: of these, five trials [34,36,38,39,43] did not find any difference in severity scores, including SOFA (sequential organ failure assessment) or GCS (Glasgow Coma Scale), while five trials [33,35–37, 43] As for length of hospitalization, four trials found…”

“Vitamin D was always administered orally in the form of cholecal-ciferol/vitamin D3 in 11 RCTs [44,46–49,52 ,54,55,58–60 ], calcifediol in 3”

“…while five trials [33,35–37, 43] As for length of hospitalization, four trials found no difference between the intervention and control group [33,38,41,43], one study [37] found it was shorter among treated individuals, whereas another study [35] found that it was longer, but with no difference…”

“The overall risk of bias was low [30] and with some concerns [29] (Table S2).”

“Among these, all-cause mortality was the only one in which COVID-19 vitamin-supplemented individuals seemed to have significant benefits, in line with a recent meta-analysis that found reduced mortality rates after vitamin C administration in many diseases [80].”

“No immunological difference was detected in both trials between the two arms, as well as no difference in hematological parameters or in organ function indexes [31,32].”

“Viral infections are a significant global health concern [1].”

“); in the second trial [27], vitamins C and E were administered orally once a discharge; in the last study [28], vitamins C and D were administered orally two day for 21 days.”

“…and the relatively safe profile of these substances, additional data could be produced in the near future, allowing a more conclusive judgment on the potential benefits of vitamin D as a prevention therapy and vitamin co-administration as a supplemental treatment for COVID-19 patients [75,76].”

“OH vitamin D levels may benefit to a different extent from the supplementation [68,88,89], we did not detect any increased effect, as already reported in the literature [68].”

“However, as several trials are still ongoing or have not been published yet [96], new data could soon become available that may allow us to alleviate some uncertainty about the findings and may contribute to making the funnel plot more balanced.”

“No immunological difference was detected in both trials between the two arms, as well as no difference in hematological parameters or in organ function indexes [31,32].”

“Public health practices [3], including handwashing, social distancing, and other non-pharmacological treatments, are a cornerstone in reducing the spread of viral infections and minimizing their impact on individuals and communities [4].”

“…of patients, provide effective treatments, and promote a path for full recovery While enhancing data sharing and strati fi ed patient management is pivotal, concerns about data privacy, interoperability of health information systems, and unequal access to care must be considered [117–119].”

“For instance, vitamin supplements are widely recognized for their ability to address nutrient deficiencies and improve immune function [43,44].”

“A meta-analysis investigating the preventive effects of vitamin supplementation during the acute phase of COVID-19 on the development of PASC concluded that no definitive conclusions could be drawn [51].”

“17–20 Therefore, we conducted a systematic review and network meta-analysis (NMA) of RCTs to investigate the effectiveness and safety of these interventions in reducing the incidence and severity of RTIs in adults.”

“Emerging evidence underscores the functional interplay between vitamin A (VA) and VD [74, 75].”

“Given that there is no universally established standard of care at present for neuropsychiatric manifestations in PCC, adjuvant strategies—particularly those involving natural antioxidant and anti-inflammatory compounds—are of increasing interest in mitigating long-term sequelae [19,20].”

“Benefits of the regular use of vitamin C and vitamin D were reported only in decreasing all-cause mortality among patients with COVID-19 [103,104].”

“B vitamins (especially B6, B9, and B12) are thought to support cellular immunity and reduce inflammation, but clinical data on their role in COVID-19 remain sparse [20].”

“In addition, there are contradictory results of several clinical trials about VitD supplementation to prevent SARS-CoV-2 infections [15].”

“Further, a recent SR(MA) on vitamins confirmed the lack of studies on the possible influence of vitamins A, B, C and D in PCS. 125 Additionally, research shows nutritional intake or status (ie, presence or absence of nutritional deficiencies) is often not included in longitudinal studies on acute…”

“Evidence on micronutrients and cognition in LC remains limited and heterogeneous [29–31], and studies in other clinical and community populations have likewise not shown a uniform cognitive benefit.”

“…oral involvement (39). ii) Immune support through the use of nutritional supplements, such as vitamins D and C, zinc and prebi‑ otics/probiotics (46), appropriate antiretroviral therapy (ART), typically a combination of drugs, such as non‑nucle‑ oside reverse transcriptase inhibitors,…”

“One of these avenues of diet and lifestyle research focused on micronutrients and vitamins, for instance witnessed by the large number of studies describing the effect of vitamin D intake in COVID-19 [1].”

“[102] This aspect may require more reliable clinical trials for verification.”

“Similarly, another meta-analysis conducted by Sinopoli et al. (Sinopoli et al. 2024) also showed that VC reduced the mortality in the overall analysis (RR: 0.84) and in the subgroup in which mortality was evaluated at day 14 from enrollement (RR: 0.84).”