Introduction
Interest in dietary supplement ingredients that might enhance immune function and reduce the risk of infectious diseases is high, especially after the emergence of COVID-19.
The immune system defends the body from pathogens that cause disease and is comprised of innate responses, which are the first line of defense, and adaptive responses, which become engaged later [1-3].
The innate immune system includes physical barriers, such as the skin and gut epithelium, that help prevent pathogen entry. It also includes leukocytes (white blood cells)—such as neutrophils, macrophages (which release cytokines), and natural killer cells—that attempt to find and eliminate foreign pathogens. However, these components are nonspecific, meaning that unlike the adaptive immune system, they do not recognize and respond to specific pathogens [1,2,4].
The adaptive immune system consists of B lymphocytes (B cells) that secrete antibodies (a process known as humoral immunity) and T lymphocytes, which are also known as T cells (a process known as cell-mediated immunity), both of which are pathogen specific [3-5]. The adaptive response takes several days or weeks to develop, but it generates immunological memory; as a result, a subsequent exposure to the same pathogen leads to a vigorous and rapid immune response [1,3,5]. Vaccinations stimulate the adaptive immune system, protecting the body from future exposures [2].
The body’s immune response to pathogens can lead to inflammation, causing redness, swelling, heat, pain, and possible loss of tissue function [6]. Inflammation helps eliminate the pathogen and initiate the healing process, but it can also cause symptoms and severe pathologies [6,7]. For example, activation of CD8 T cells as part of the adaptive immune response can increase inflammation and cause pulmonary damage. This process can lead to acute respiratory distress syndrome (ARDS), which has occurred in some patients with COVID-19 [7].
Consuming adequate amounts of several vitamins and minerals—including vitamin A, vitamin C, vitamin D, vitamin E, selenium, and zinc—is important for proper immune function, and clinical deficiencies of these nutrients weaken immunity and can increase susceptibility to infections [2,4,5,8-10]. Other ingredients (whether provided through foods or dietary supplements), such as botanicals and probiotics, are not essential in the body but might affect immune function.
Measuring the impact of dietary supplement ingredients, such as vitamins, minerals, or other substances, on the immune system is difficult because the immune system is a complex network of organs, tissues, and cells [11,12]. No single, straightforward measure of immune system function and resistance to disease exists. Indirectly, immune function can be assessed by examining a person’s risk and severity of infectious diseases.
This fact sheet summarizes the effects of various dietary supplement ingredients on immune function and the risk of selected infectious diseases, including the common cold, influenza and other respiratory tract infections, infectious diarrhea, and HIV infection. These diseases can be caused by numerous pathogens. For example, the common cold is caused by a wide variety of respiratory viruses, most commonly rhinovirus, but also coronaviruses, adenoviruses, and other virus serotypes [13].
Dietary supplement ingredients in each category are presented in alphabetical order. In some cases, cited research involves intravenous, enteral, or parenteral administration. Dietary ingredients administered by these routes are not classified as dietary supplements, but the information is included for completeness.
For information on dietary supplements and COVID-19, please see the Office of Dietary Supplements (ODS) health professional fact sheet, Dietary Supplements in the Time of COVID-19.
Vitamins and Minerals
Consuming a nutritious variety of foods helps maintain overall good health and a strong immune system [14]. Obtaining adequate amounts of vitamins and minerals is also important for good health, and deficiencies of certain vitamins and minerals—including vitamins A, B6, B12, C, D, E, and K; folate; and copper, iodine, iron, magnesium, selenium, and zinc—might adversely affect immune function.
Examples involving vitamins are as follows:
Folate deficiency affects thymus and spleen function and decreases T-lymphocyte levels, and vitamin B12 deficiency decreases the phagocytic capacity of neutrophils [15].
Vitamin A deficiency is associated with increased susceptibility to infections, altered immune responses, and an impaired ability of epithelial tissue to act as a barrier to pathogens [5,8,15].
Vitamin E deficiency impairs humoral and cell-mediated immunity and is associated with reduced natural killer cell activity [16-18].
Examples involving minerals are as follows:
Copper deficiency is associated with altered immune responses and an increased risk of infection, especially in infants and older adults [16,19,20].
Low magnesium status is associated with decreased immune cell activity, increased oxidative stress, and increased inflammation, including increased levels of some inflammatory cytokines, such as interleukin-6 [21-26].
Selenium deficiency might adversely affect immune response as well as the pathogenicity of viruses [5,10,27].
The European Society for Clinical Nutrition and Metabolism states that low intakes or status of several micronutrients—including vitamins A, E, B6, and B12; zinc; and selenium—are associated with worse outcomes in patients with viral infections [14]. If needed, vitamin and mineral supplementation can boost intakes to recommended levels. In the absence of deficiency, however, routine supplementation with micronutrients probably does little to prevent or treat specific infections [14,28].
The following subsections describe research on the effects of dietary supplements containing more commonly studied vitamins and minerals—vitamins A, C, D, and E, selenium, and zinc—on immune function.
Vitamins
Vitamin A
Many foods contain vitamin A, an essential nutrient. Two sources of vitamin A are available in the human diet: preformed vitamin A (retinol and retinyl esters) and provitamin A carotenoids (beta-carotene, alpha-carotene, and beta-cryptoxanthin). Preformed vitamin A is present in foods from animal sources, including dairy products, eggs, fish, and organ meats. Provitamin A carotenoids come from plant foods, including leafy green vegetables, orange and yellow vegetables, tomato products, fruits, and some vegetable oils. The Recommended Dietary Allowance (RDA) for vitamin A is 300 to 1,200 mcg retinol activity equivalents (RAE) for infants and children, depending on age, and 700 to 1,300 mcg RAE for adults, including women who are pregnant or lactating [29].
Vitamin A plays a critical role in vision and growth. It is also required for the formation and maintenance of epithelial tissue and the differentiation, maturation, and function of macrophages and other cells of the innate immune system [5,15,30]. Vitamin A’s impact on adaptive immunity is less clear, but it is involved in the maturation of CD4+ T cells, the function of B cells, and the regulation of inflammatory cytokines [5,15]. Vitamin A deficiency is associated with increased susceptibility to infections, altered immune responses, and impairment in the ability of epithelial tissue to act as a barrier to pathogens [5,15,30,31].
Although vitamin A deficiency is rare in the United States, it is common in many low- and middle-income countries and is one of the top causes of preventable blindness in children [32-36]. It is also associated with an increased risk of respiratory diseases, diarrhea, and measles. For this reason, the World Health Organization (WHO) and other expert groups recommend universal vitamin A supplementation for children younger than 5 years (including those who have HIV) in populations with a high risk of vitamin A deficiency [33,37]. Recommended doses in these populations are 30,000 mcg RAE (100,000 International Units [IU]) vitamin A once for infants age 6–11 months and 60,000 mcg RAE (200,000 IU) every 4–6 months for children age 1–5 years [37]. The authors of a 2022 analysis concluded that vitamin A supplementation has reduced child mortality rates in sub-Saharan Africa, although rates are still substantial in many countries in this region [38].
Efficacy
Diarrhea in children
Vitamin A deficiency can decrease resistance to pathogens in the mucosa of the digestive tract and increase the risk of diarrhea [30]. Vitamin A deficiency also increases the risk of mortality from diarrhea in young children [39]. A 2015 analysis of data from 83 countries found that 94,500 deaths from diarrhea in children were associated with vitamin A deficiency [39]. In addition, more than 95% of these deaths occurred in sub-Saharan Africa and south Asia.
For these reasons, researchers have examined the effects of vitamin A supplementation on childhood diarrhea. Results from these studies suggest that vitamin A supplementation reduces the risk and severity of diarrhea in children in low- and middle-income countries but does not appear to benefit very young infants.
A 2011 systematic review of studies that examined the effects of vitamin A on childhood diarrhea included 13 clinical trials in a total of 37,710 participants that examined risk of diarrhea and 7 clinical trials in a total of 90,951 children age 6 months to 5 years, mostly in low- or middle-income countries, that examined the risk of death from diarrhea [40]. Vitamin A doses ranged from 6,000 mcg RAE (20,000 IU) to 61,800 mcg RAE (206,000 IU), depending on age, and were administered in a single dose or in several doses administered weekly or every few months for up to 24 months. Vitamin A supplementation decreased the risk of diarrhea by 15% and the risk of death due to diarrhea by 28%. Similarly, a 2022 Cochrane Review that included 15 clinical trials in a total of 77,946 children age 6 months to 5 years found that 15,000 mcg RAE (50,000 IU) to 60,000 mcg RAE (200,000 IU) vitamin A, depending on age, reduced the risk of diarrhea by 15% [33]. In addition, results from 9 studies in a total of 1,098,538 children showed that vitamin A reduced the risk of death due to diarrhea by 12%.
In very young infants, however, limited evidence suggests that vitamin A supplementation does not affect diarrhea morbidity or mortality. A 2016 Cochrane Review that examined the effects of vitamin A supplementation in children age 1 to 6 months found that 7,500 mcg RAE (25,000 IU) to 15,000 mcg RAE (50,000 IU) vitamin A administered three times during the first few months of life did not reduce the risk of diarrhea or of death due to diarrhea [41]. However, these findings were based on only two clinical trials that examined the incidence of diarrhea in 5,183 participants and one trial that examined mortality from diarrhea in 210 participants.
HIV infection
HIV infection can lower appetite and impair the body’s absorption and use of nutrients. It can also increase the risk of comorbidities, including diarrhea and respiratory diseases [42]. HIV progression can be measured by CD4+ T-cell counts; lower cell counts indicate more advanced disease, and a count below 200 cells/microliter (mcL) indicates AIDS [43]. HIV is treated with a combination of medicines called antiretroviral therapy (ART), which can reduce the risk of HIV transmission from one individual to another by reducing viral load and help people with HIV live longer [44].
The results of studies of the effects of vitamin A supplementation on risk of HIV transmission or disease outcomes in children and adults have been mixed.
Two Cochrane Reviews found that vitamin A supplements improved some but not all outcomes examined in children but offered no benefit in adults with HIV infection. A 2013 Cochrane Review included three clinical trials in a total of 262 infants and children with HIV age 5 years or younger [45]. It found that vitamin A supplementation (15,000 mcg RAE [50,000 IU] to 60,000 mcg RAE [200,000 IU], depending on age, administered up to four times per year) reduced the risk of all-cause mortality by 45% but had inconsistent effects on the risk of diarrhea or respiratory infections. Another Cochrane Review examined the effects of vitamin A supplementation in four clinical trials that included a total of 919 adults with HIV infection (mostly women age 18 to 45) [46]. This review found that 90,000 mcg RAE (180,000 mcg) beta-carotene or 3,000 mcg RAE (10,000 IU) vitamin A supplementation daily for 4 to 6 weeks or a single dose of 60,000 mcg RAE (200,000 IU) or 90,000 mcg RAE (300,000 IU) vitamin A did not have clinically significant effects on CD4+ T-cell counts or viral load. None of the trials was adequately powered to assess mortality or morbidity outcomes.
Results were negative in another 2017 Cochrane Review [47]. It included five clinical trials conducted in sub-Saharan Africa with a total of 7,298 pregnant women with HIV. Participants took vitamin A daily during pregnancy (3,000 mcg RAE [10,000 IU] or 1,500 mcg RAE [5,000 IU] plus 30 mg beta-carotene), a single dose immediately after delivery (60,000 to 120,000 mcg RAE [200,000 to 400,000 IU] to the mother and/or 15,000 mcg RAE [50,000 IU] to the newborn), or both. Vitamin A supplementation did not affect the risk of mother-to-child transmission of HIV. Largely because of the findings from this analysis, the WHO does not recommend vitamin A supplementation in women with HIV who are pregnant in order to reduce the risk of mother-to-child transmission of HIV [48].
Most of the findings were also negative in a 2022 systematic review of vitamin A supplementation that included 17 clinical trials, conducted mostly in sub-Saharan Africa, in a total of 12,585 children and adults (mostly pregnant women) with HIV [31]. Vitamin A dosing schedules varied widely but commonly included 1,500 to 3,000 mcg RAE (5,000 to 10,000 IU) daily or one-time doses of 15,000 to 120,000 mcg RAE (50,000 to 400,000 IU) at baseline or delivery. Vitamin A supplementation did not affect viral load, CD4+ or CD8+ T-cell counts, or interleukin-1b levels. In addition, it did not affect rates of gastrointestinal and HIV symptoms. However, in one trial included in the review, vitamin A supplementation (120,000 mcg RAE [400,000 IU] at delivery) reduced the number of clinic visits for some health conditions in women with HIV postpartum and in another trial, supplementation with 15,000 to 60,000 mcg RAE (50,000 to 200,000 IU) vitamin A (depending on age) five times per year reduced rates of diarrhea in children with HIV. Supplements (1,500 mcg RAE [5,000 IU] daily plus 60,000 mcg RAE [200,000 IU] at delivery) also reduced the risk of preterm birth in one study in pregnant women with HIV.
Whether maternal vitamin A supplementation affects the morbidity and mortality of breastfed infants was the focus of a cross-sectional study in lactating women with HIV from sub-Saharan Africa [49]. The study included 838 mothers, 309 of whom took vitamin A supplements after giving birth (doses and frequency not reported); the other 529 did not. Vitamin A supplementation did not affect infant mortality rates or the risk of cough with difficulty breathing, diarrhea, or fever in the breastfed infants.
Measles in children
In 2023, measles was responsible for about 107,500 deaths worldwide, mostly in young children in low-income countries [50]. Vitamin A deficiency, which is rare in the United States, is a risk factor for severe measles [5,39]. A WHO analysis of data from 83 countries showed that 11,200 child deaths from measles were associated with vitamin A deficiency in 2013, and more than 95% of these deaths occurred in sub-Saharan Africa and south Asia [39].
Research suggests that vitamin A supplementation reduces the risk of measles in children who are at high risk of vitamin A deficiency. However, vitamin A supplementation does not appear to reduce the risk of death from measles. A 2022 Cochrane Review included six clinical trials that examined the effect of vitamin A supplementation on the risk of measles in children [33]. These studies enrolled a total of 19,566 children age 6 months to 5 years who lived in low- and middle-income countries. Vitamin A doses ranged from 15,000 mcg RAE (50,000 IU) to 60,000 mcg RAE (200,000 IU), depending on age. Supplements were administered as a single dose or every 4 to 6 months. Vitamin A supplementation reduced the risk of new cases of measles by 50%. However, the same Cochrane Review found that vitamin A supplementation did not affect the risk of death due to measles, based on the results from six clinical trials in a total of 1,088,261 children.
Pneumonia and other respiratory tract infections in children
Vitamin A deficiency is associated with recurrent respiratory tract infections in children [33,51]. However, findings have been mixed from trials of the effects of vitamin A supplementation on the risk and severity of pneumonia and other respiratory tract infections in children [33,52]. In addition, some evidence suggests that doses of vitamin A supplementation that are higher than the WHO recommends might increase the risk of respiratory tract infections among children with normal nutritional status [53].
Effects were mixed in a meta-analysis of 15 clinical trials in a total of 3,021 children (age not specified) that examined the effects of 450 mcg RAE (1,500 IU) to 120,000 mcg RAE (400,000 IU) vitamin A supplementation for several days or weeks on the risk of morbidity and mortality from pneumonia [52]. Vitamin A supplementation shortened the durations of hospital stays and of signs and symptoms, including fever, cough, and abnormal chest X-rays. However, it did not reduce the risk of death due to pneumonia.
Other clinical trials have found that vitamin A supplements do not reduce the risk of respiratory tract infections or of death from these infections. A 2022 Cochrane Review that included 11 clinical trials in a total of 27,540 children age 6 months to 5 years found that 15,000 mcg RAE (50,000 IU) to 60,000 mcg RAE (200,000 IU), depending on age, vitamin A supplementation did not significantly affect the risk of lower respiratory tract infections [33]. In addition, vitamin A supplements did not affect the risk of death due to these infections, according to the results of nine studies in a total of 1,098,538 children that examined this outcome. A separate Cochrane Review also found that vitamin A supplementation (7,500 mcg RAE [25,000 IU] or 15,000 mcg RAE [50,000 IU] given three times during the first 14 weeks of life) did not reduce the risk of respiratory tract infections or death due to such infections in very young infants age 1 to 6 months, although the review included only one trial for each outcome [41]. Similarly, a 2022 systematic review of 16 clinical trials that combined nine trials in a meta-analysis in a total of 32,129 children found that vitamin A supplementation did not reduce the risk of respiratory tract infections [54].
Another meta-analysis found that taking vitamin A supplements to reduce the risk of respiratory tract infections might even be harmful in some circumstances [53]. The analysis included 26 clinical trials that examined acute or lower respiratory tract infections in a total of 50,994 children from birth to age 11 years. Vitamin A doses ranged from 15,000 mcg RAE (50,000 IU) to 370,800 mcg RAE (1,236,000 IU) depending on age and were administered as a single dose or over days, weeks, months, or years. Overall, vitamin A supplementation did not affect the risk, severity, or duration of acute or lower respiratory tract infections. However, in subgroup analyses, higher-than-standard vitamin A doses (more than 30,000 mcg RAE [100,000 IU] for children up to 11 months of age and more than 60,000 mcg RAE [200,000 IU] every 4 to 6 months for children age 12 months to 11 years) increased the risk of acute respiratory tract infections by 66% in participants with normal nutritional status, but these doses did not affect this risk in participants with stunted and wasted nutritional status.
Safety
Up to 600 to 2,800 mcg/day preformed vitamin A in foods and dietary supplements is safe for children, depending on age, and up to 3,000 mcg/day is safe for adults, including women who are pregnant or lactating [29]. These tolerable upper intake levels (ULs, maximum daily intake unlikely to cause adverse health effects), however, do not apply to people taking vitamin A under the care of a physician.
Higher intakes can cause severe headache, blurred vision, nausea, dizziness, aching muscles, and coordination problems. In severe cases, cerebral spinal fluid pressure can increase, leading to drowsiness and, eventually, coma [55]. Regular consumption of high doses of preformed vitamin A from foods or supplements can cause dry skin, painful muscles and joints, fatigue, depression, and abnormal liver test results. High intakes of preformed vitamin A can also cause congenital birth defects [35].
Unlike preformed vitamin A, beta-carotene is not known to be teratogenic or lead to reproductive toxicity. Therefore, beta-carotene does not have an established UL [56].
Vitamin A might interact with some medications. For example, orlistat, a weight-loss medication, can decrease the absorption of vitamin A, resulting in low plasma levels in some patients [57]. In addition, synthetic retinoids derived from vitamin A that are used as oral prescription medicines, such as acitretin used to treat psoriasis, increase the risk of hypervitaminosis A when taken in combination with vitamin A supplements [57].
Vitamin C
Vitamin C, also called ascorbic acid, is an essential nutrient contained in many fruits and vegetables, including citrus fruits, tomatoes, potatoes, red and green peppers, kiwifruit, broccoli, strawberries, brussels sprouts, and cantaloupe. The RDA for vitamin C is 15 to 115 mg for infants and children, depending on age, and 75 to 120 mg for nonsmoking adults, including women who are pregnant or lactating; people who smoke need 35 mg more per day [56].
Vitamin C plays an important role in both innate and adaptive immunity, probably because of its antioxidant effects, antimicrobial and antiviral actions, and effects on immune system modulators [5,32,58-62]. Vitamin C helps maintain epithelial integrity, enhance the differentiation and proliferation of B cells and T cells, enhance phagocytosis, normalize cytokine production, and decrease histamine levels [4,5,60]. It might also inhibit viral replication [13].
Vitamin C deficiency impairs immune function and increases susceptibility to infections [5,58,60]. Some research suggests that supplemental vitamin C enhances immune function [63], but its effects might vary depending on an individual’s vitamin C status [64].
Vitamin C deficiency is uncommon in the United States, affecting only about 7% of individuals age 6 years and older [65]. People who smoke and those whose diets include a limited variety of foods (such as some older adults and people with alcohol or drug use disorders) are more likely than others to obtain insufficient amounts of vitamin C [61,63].
Efficacy
Common cold
Vitamin C’s antioxidant action might help reduce oxidative stress during infections. In addition, regular consumption of vitamin C might reduce the duration of the common cold and the severity of its symptoms, but taking vitamin C supplements only after symptom onset does not provide consistent benefits [5,59].
Several clinical trials have examined whether vitamin C supplementation reduces the risk of developing the common cold in the general population and those exposed to extreme physical stress. One trial included 92 runners and a control group of 92 nonrunners (mostly male, age 25 years or older) who took 600 mg per day vitamin C or placebo for 21 days before a 90-kilometer ultramarathon [66]. During the 2 weeks after the race, 68% of the runners who took a placebo but only 33% of those who took vitamin C reported developing an upper respiratory tract infection. Among nonrunners, however, the incidence of upper respiratory tract infections was not different between supplement and placebo users. In addition, the duration of symptoms in nonrunners who took vitamin C was shorter (mean 4.2 days) than in those who took a placebo (5.6 days), but symptom duration did not differ between the runners who took vitamin C and those who took a placebo.
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