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| Authors | Type of study | Subjects | Dosage | Results | Type of immunity Involved | Mechanism of action |
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| Turner; 2001 | Clinical study, randomized | Ninety-one volunteers | 41 treated with active medication (consisted of 33 mM zinc gluconate) and 50 treated with placebo for 3 days were inoculated with rhinovirus and then were treated with study medication for an additional 6 days, single nasal spray of 120 mL per nostril, at ∼4-h intervals, 5 times each day | Zinc treatment had no effect on total symptom score, rhinorrhea, nasal obstruction, or the proportion of infected volunteers who developed clinical colds | | |
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| Mahalanabis et al.; 2004 | Randomized, double-blind, placebo-controlled clinical trial | 153 children aged 2–24 | Four treatment: (1) zinc acetate (10 mg elemental Zn twice daily for 5 d) plus a placebo for vitamin A, (2) vitamin A as retinyl palmitate [10,000 μg retinol equivalents (RE) twice daily for 4 d] plus a placebo for zinc, (3) zinc plus vitamin A according to the above schedule, or (4) placebo for zinc and for vitamin A | Zinc treatment significantly reduces duration of fever and very ill status in boys, but not in girls, with severe acute lower respiratory infection (ALRI) | | Zinc as a micronutrient plays a key role at the catalytic sites of a wide range of enzymes and is critical to human growth, metabolism, and immune function. The diets of children in many developing countries are often deficient in zinc and a high phytate : zinc ratio in their diet reduces zinc bioavailability |
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| Barnett et al.; 2016 | A randomized double-blind, placebo-controlled trial | 53 nursing home elderly (aged ≥65 y) | Supplementation with 30 mg Zn/d for 3 mo | The increase in serum zinc concentration is associated with the enhancement
of T cell function | Adaptive immunity | Mainly because of an increase in the number of T cells and Zn improves T cell-mediated function by increasing the number of functional T cells in the periphery |
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| Prasad et al.; 2007 | Randomized, double-blind, placebo-controlled trial | Fifty healthy subjects of both sexes aged 55–87 y | Each day for 12 mo, subjects in the zinc-supplemented group received 1 capsule of zinc gluconate (15 mg elemental zinc) orally | The mean incidence of infections per subject in 12 mo was significantly lower in the zinc-supplemented group than in the placebo group. A significantly lower incidence of fever and a nonsignificant trend toward a lower incidence of the common cold were observed in the zinc-supplemented group than in the placebo group | Innate immunity | Zinc supplementation decreased not only the production of inflammatory cytokines but also that of oxidative stress marker: the increase of IL-2 production in zinc-deficient elderly subjects by increasing the gene expression of IL-2 and by a decrease in IL-10 production |
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| Pinna et al.; 2002 | Clinical study | 8 healthy men | The subjects were given a controlled 3-d rotating diet that contained 4.6 mg Zn/d. Zn intakes were adjusted by giving Zn gluconate supplements. During baseline periods and repletion periods, subjects’ Zn intakes totaled 13.7 mg/d. During restriction period, the subjects consumed 4.6 mg of highly available Zn | Changes in lymphocyte proliferation and IL-2R expression may be early markers of mild zinc deficiency | Innate immunity | Zinc restriction reduced peripheral blood mononuclear cells (PBMNC) proliferation at all mitogen concentrations tested except 10 mg/L. Dietary zinc restriction reduced IL-2R secretion by PBMNC stimulated at a suboptimal PHA concentration.
The secretion of IFN-γ and TNF-α was unchanged throughout the study |
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| Maggini et al.; 2012 | Data from two preliminary, double-blind, randomized, placebo-controlled trials, parallel-group | Study 1 included 30 patients: 13 males and 17 females
Study 2 enrolled 64 patients: 25 males and 39 females | 1000 mg vitamin C plus 10 mg zinc | Supplementation with vitamin C and zinc may represent an efficacious measure | | |
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| Prasad et al.; 2008 | Randomized, double-blind, placebo-controlled trial | Fifty ambulatory volunteers were recruited within 24 h of developing symptoms of the common cold | 1 lozenge containing 13.3 mg of zinc (as zinc acetate) or placebo every 2-3 h while being awake | Mean durations of cold symptoms, cough, nasal discharge, and muscle ache were significantly decreased in the zinc group compared with the placebo group thanks to its anti-inflammatory and antioxidant properties | Innate immunity | The decrease in sIL-1ra and sTNF-R1 levels in the zinc group only suggests that zinc decreased the oxidative stress, resulting in decreased activation of monocytes and macrophages
Zinc decreases ICAM-1 levels and induces the zinc-dependent transcription factor A20 in monocytes and macrophages, which inhibits NF-kB activation via the TNF-R-associated factor pathway
Zinc is an inhibitor of NADPH oxidase, an enzyme that initiates the generation of free radicals; it is essential for superoxide dismutase and for generation of metallothionein,
reduced the concentration of the oxidative stress markers, and inhibited the ex vivo induction of TNF-α and IL-1β mRNA in mononuclear cells; and it provided protection against TNF-α-induced NF-kB activation in isolated peripheral blood mononuclear cells |
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| Bhandari et al.; 2002 | Double masked, randomized placebo-controlled trial | 2482 children aged 6 to 30 months | Daily elemental zinc, 10 mg to infants and 20 mg to older children or placebo for four months. Zinc gluconate | Zinc supplementation substantially reduced the incidence of pneumonia in children who had received vitamin A | Skin Innate immunity and adaptive immunity | Supplementation improves immune functions, including delayed cutaneous hypersensitivity, and increases the number of CD4 (helper) lymphocytes
In experimental models zinc deficiency has been shown to impair cellular and humoral immune function |
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| Bogden et al.; 1990 | Double-blind partial crossover design | 63 subjects (age 60–89) | 3–6 month supply of placebo, 15 mg of Zn, or 100 mg Zn-capsules | Zinc had positive effects on one measure of cellular immune function but at the same time had an adverse effect on another measure of cellular immunity | Innate immunity | NK cell activity was enhanced, but, except for this cellular immune functions, were not significantly improved
Delayed dermal hypersensitivity (DDH) increased in the study in placebo group and the suppression of the increase in DDH by zinc persisted |
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| Mc Donald et al.; 2015 | A randomized, double-blind, placebo-controlled clinical trial | 2400 infants who were 6 wk of age and born to HIV-negative mothers in a low-malaria setting, Tanzania | Oral supplementation of MVs (vitamin B complex and vitamins C and E), zinc, zinc + MVs, or placebo for 18 mo.
From the time of randomization to 6 mo of age, infants received 1 capsule/d, and from 7 mo of age to the end of follow-up, 2 capsules were provided daily The capsule contained 5 mg of zinc | Acute upper respiratory infections were significantly lower for infants supplemented with zinc than for those who did not receive zinc | Adaptive immunity | Mean CD4 T cell percentage was slightly but significantly higher among children who received zinc and MVs in comparison with placebo |
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| Isbaniah et al.; 2010 | Double-blind, randomized, placebo-controlled trial | Chronic obstructive pulmonary disease (COPD) patients with acute upper respiratory tract infection (URTI)—108 mostly male patients (age 40–81) | Treatment: EP (Echinacea purpurea) or EP + zinc, selenium, and ascorbic acid or placebo zinc = 10 mg | The combination of EP—zinc, selenium, and ascorbic acid—alleviates exacerbation symptoms caused by URTI in COPD | Innate and adaptive response | It seems that both selenium and zinc act on T lymphocytes, through modulating IL-2 secretion, its receptor expression, and sensitivity, as well as the thymulin activity which is required for the differentiation of CD4+ T cells.
Zinc is included in the biosynthesis of leukotriene B4.
Finally, the transcriptional repressor Gfi1, a zinger finger protein, was identified as a regulator of the innate immune response and to be essential for the development of macrophages-dependent cytokine production and granulocytes |
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| Field et al.; 1987 | Clinical study | 15 female patients | Zinc supplements (50, 100, 150 mg) | Evidence in plasma and leucocyte zinc concentrations in an elderly population | Innate immunity | Decrease in granulocyte with high zinc doses probably thanks to the diminished phagocytic and chemotactic activity of polymorphonuclear cells |
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| Wintergerst et al.; 2005 | Review: a large number of randomized controlled intervention trials | Human | Daily intakes of 10–30 mg of zinc for children with infectious diseases | The authors explain that zinc and vitamin C play an important role in immune system: adequate intakes ameliorate symptoms and shorten the duration of respiratory tract infection, including the common cold, but there are discrepancies in trials that have been considered | Innate and adaptive immunity | Zinc is essential for the intracellular binding of tyrosine kinase to T cell receptors, which are required for T lymphocyte development and activation—lowered zinc status impairs cellular mediators of innate immunity such as phagocytosis by macrophages and neutrophils, natural killer cell activity, generation of the oxidative burst, and complement activity |
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| Sanchez et al.; 2014 | Randomized triple-blind community trial | 301 children, 2–5 years of age | Children were distributed in three groups receiving zinc amino acid chelate, zinc sulfate, and placebo five days a week for 16 weeks
7 mg of zinc for children with 2-3 years and 9,45 mg of zinc for children with 4-5 years | Zinc amino acid chelate had a better effect on reducing the incidence of acute respiratory infection in children | Innate immunity | Probably thanks to the production of interferon and the modulation of inflammatory cytokines |
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| Martinez- Estevez et al.; 2016 | 12-month randomized controlled trial, triple-blind | 355 children underwent randomization, with 174 assigned to the zinc supplementation group and 181 to the control group | Children in the active supplementation group received 5 mg of zinc oxide plus 525 mg of calcium carbonate plus 70 UI of vitamin D3 (Kid Cal), and children in the nonsupplemented control group received 525 mg of calcium carbonate plus 70 UI of vitamin D3 | Decreased the incidence of URTI | Innate immunity | Among the various mechanisms involved in the antiviral effects of zinc, the ICAM-1 receptor blocking has been considered as one of the most important actions |
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| Brooks et al.; 2004 | Double-blind placebo-controlled trial | 270 children (age 2–23 months) | Elemental zinc, 20 mg per day, or placebo | Zinc accelerates recovery from severe pneumonia in children and could help reduce antimicrobial resistance by decreasing multiple antibiotic exposures and lessen complications and deaths where second line drugs are unavailable | Innate immunity | Zinc has role in the acute phase response mediated by cytokines during acute infection, helping to boost the body’s immune response through a defense cascade, beginning with mobilization and sequestration of zinc to metallothionein-rich tissue, rapid upregulation of immune defense specific protein synthesis, activation of immune defense activity such as macrophages, lymphocytes, and NK cells and antibody-dependent cytotoxicity |
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| Sazawal et al.; 1997 | A double-blind, randomized controlled trial | Children (zinc 38, control 48) | Zinc gluconate to provide elemental zinc 10 mg daily and 20 mg during diarrhea | Zinc supplementation improves cellular immune status: regarding cell-mediated immunity (CMI), the percentage of anergic or hypoergic children (using induration score) decreased from 67% to 47% in the zinc group.
The zinc group had a significantly higher rise in the geometric means of CD3, CD4, and CD4/CD8 ratio with no difference in CD8 and CD20. The rise in CD4 was significantly higher in the zinc as compared to the control group | Adaptive immunity | The observation of an increase in the number of circulating T lymphocytes, especially CD4 cells, after zinc supplementation may be explained by direct effect of zinc ion on the lymphocyte membrane affecting maturation and differentiation of T lymphocytes or by a stimulation of thymus endocrine function. Once T lymphocytes leave the thymus their differentiation and maturation are thought to be regulated by zinc-thymulin and deficiency of zinc-thymulin has been associated with secondary cellular immune deficiency and with immune senescence. Thus terminal deoxynucleotidyl transferase or zinc-thymulin has been suggested as possible mechanism by which zinc may be affecting T cell development and function |
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| Sempertegui et al.; 1996 | A randomized double-blind placebo-controlled trial | 50 children (age 12–59 months old) | 10 mg of zinc sulfate or placebo | After treatment (on day 60), the cutaneous delayed-type hypersensitivity (DTH) was higher in treated group; the incidence of fever, cough, and upper respiratory tracts secretions was lower in S group, but after 120 days the incidence of fever and upper respiratory tracts secretions was the same in both groups, but the incidence of cough was higher in S group | Innate immunity | The mechanism is not clear, probably improving cellular immunity |
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| Bogden et al.; 1988 | Clinical study | 103 elderly subjects (age 60–89 years) | Three treatments: placebo, or 15 mg zinc/day or 100 mg/day for 3 months | In a subgroup (34,3%), Zn administration enhanced delayed dermal hypersensitivity (DDH) | Skin, innate immunity | cellular immunity will not be enhanced by Zn supplementation, but they argued that cellular immunity in subgroups of elderly people will be improved by Zn supplementation |
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| Fortes et al.; 1998 | A double-blind, randomized, controlled trial | 178 elderly patients | 4 treatments: (1) vit. A (800 μg retinol palmitate), (2) zinc (25 mg as zinc sulfate), (3) zinc + vit. A (800 μg retinol palmitate and 25 mg of zinc sulfate), (4) placebo | Zinc supplementation improves cell-mediated immune response, because it increases the number of CD4+DR+T cells and cytotoxic T lymphocytes | Immune and adaptive response | Effect on thymulin levels that promotes T cells functions, including suppressor function and interleukin-2 production.
Zn prevents the negativity effects of vit. A on immunity |
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| Turk et al.; 1998 | Clinical study | 26 patients in hemodialysis and 11 healthy patients (HP) were vaccinated with multivalent influenza vaccine (MIV) | Supplementation with 120 mg of ZnSO4 | Zn supplementation could not restore the immune parameters and enhance antibody response to MIV in HP | | |
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| Wieringa et al.; 2010 | Randomized, double-blind, controlled trial | 229 pregnant women with a gestational age <20 weeks, and infants and women were followed up monthly until the infants were 6 months old | In addition to iron (30 mg as ferrous fumarate) and folic acid (0,4 mg), one group of women received β- carotene (4,5 mg), one group zinc (30 mg as zinc sulfate), and one group β- carotene plus zinc (4,5 and 30 mg, resp.) | Maternal supplementation with zinc and β-carotene affected the newborn’s immune development, but only zinc supplementation affects morbidity in the infants | Innate immunity | Zinc gives higher interleukin-6 production |
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| Erickson et al.; 2000 | Review | Humans | Supplementation such as zinc, selenium, iron, copper, b-carotene, vitamins A, C, and E, and folic acid | Micronutrients have an important role in immunity | Innate immunity | Zinc enhances natural killer cell functions;
zinc supplementation directly induced cytokine production, predominantly IL-1, IL-6, and TNF-a, by mononuclear cells in vitro |
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| Maggini et al.; 2007 | Review | Humans | | Inadequate intake and status of vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates undernutrition. Therefore, supplementation with these selected micronutrients (including zinc) can support the body’s natural defense system by enhancing all three levels of immunity | Skin innate and adaptive immunity | It is involved in the cytosolic defense against oxidative stress (superoxide dismutase activity) and is an essential cofactor for thymulin which modulates cytokine release and induces proliferation. It helps to maintain skin and mucosal membrane integrity and increases cellular components of innate immunity (e.g., phagocytosis by macrophages and neutrophils, NK cell activity, generation of oxidative burst, DTH activity), antibody responses, and the numbers of cytotoxic CD8þT cells (Th1 response) |
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| Calder and Kew; 2002 | Review | | | Increasing intakes of some nutrients above habitual and recommended levels can enhance some aspects of immune function; low plasma Zn levels predicted the subsequent development of lower respiratory tract infections | Skin
innate and adaptive immunity | In patients with Zn deficiency related to sickle cell disease, natural killer cell activity is decreased.
Zinc supplementation increases thymus size, and topical application of Zn improves the DTH response in the area of skin on which the application was made
Zn administration to preterm-low-birth-weight infants increases the number of circulating T lymphocytes and their proliferation and a 5 mg Zn/d increases measures of cell-mediated immune function |
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| Singh and Das; 2013 | Review | Humans | There is a significant reduction in the duration of cold at a dose of ≥75 mg/day | Zinc administered within 24 hours of onset of symptoms reduces the duration of common cold symptoms in healthy people | Enhancement of innate as well as acquired immunity | Not clear |
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| Hojyo and Fukada; 2016 | Review | | | Zn has role in dendritic cells (that are important to present the peptide-MHC-II complex on their cell surface to antigen-specific CD4+ helper T (Th) cells to initiate immune responses) because a reduction in Zn is required for proper antigen presentation via MHC-II to elicit adaptive immune responses
Zn deficiency is characterized by immunodeficiency with thymic atrophy and lymphopenia
Zn controls antibody-mediated humoral immune responses and ZIP10-Zn has a role in early B-cell development and the maintenance of mature B cells
ZIP10-Zn signaling may control fate decisions in lymphocyte progenitors under physiological conditions and exacerbate malignancy under pathological conditions, according to the highly regulated pattern of ZIP10 expression | Innate and adaptive immunity | Zn facilitates the endocytosis of MHC-II but inhibits the trafficking of MHC-II from the lysosome/endosome compartments to the plasma membrane
the ZnD-induced thymic atrophy could result from the combination of increased glucocorticoid levels, an impairment of thymulin activity, and impaired cell-intrinsic survival function
ZIP10-Zn signaling regulates the expression of CD45R while simultaneously (and indirectly) enhancing the CD45R PTPase activity through a Zn-dependent process rather than by a direct effect on PTPase activity
The effect on development could be explained by glucocorticoids and ZIP10 maintains mature B cells through a LYN-independent mechanism
ZIP10-Zn signaling inhibits the apoptosis induced by activated caspases and promotes pro-B-cell survival in a cell-autonomous manner
Cytokine stimulation (the first signal) activates the JAK-STAT pathway (the second signal), which further induces ZIP10 expression and eventually generates ZIP10-Zn signals (the third signal) |
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