Table 3.

Studies on vitamin C, immunity, and common cold presented in the narrative review.

Authors	Type of study	Subjects	Dosage	Results	Type of immunity involved	Mechanism of action
Hemilä et al.; 2010	Review and meta-analysis	11306 men, woman and children	0.2 g daily for a single day or for a period	Twenty-nine comparisons examined the effect of prophylactic vitamin C on common cold duration (9649 episodes). In adults the duration of colds was reduced by 8% (3% to 12%), and in children by 13% (6% to 21%). The severity of colds was significantly reduced in the prophylaxis trials. Seven trial comparisons examined the effect of therapeutic vitamin C (3249 episodes). No consistent differences from the placebo group were seen in the duration or severity of colds.	All immunity	Regular ingestion of vitamin C had no effect on common cold incidence in the ordinary population. However, it had a modest but consistent effect in reducing the duration and severity of common cold symptoms. In trials with participants exposed to short periods of extreme physical stress (including marathon runners and skiers) vitamin C halved the common cold risk.
Maggini et al.; 2012	Double-blind, randomized, placebo-controlled pilot study	94 patients	1000 mg vitamin C plus 10 mg zinc	Rate of definite relief from rhinorrhoea was significantly higher in the active treatment group than in the placebo group over the 5-day assessment period (p = 0.03, Cox proportional hazard model).	All immunity	In view of the frequency of the common cold, coupled with the related social and economic costs and the limited treatment options, supplementation with vitamin C and zinc may represent an efficacious measure, with a good safety profile, to help ameliorate the symptoms of this infectious viral disease.
Penn et al.; 1991	Randomized controlled trial	Thirty elderly 30	100 mg for 28 days	Percentage of cells (mean ± SD) in peripheral blood   T cells: 6.58 ± 6.3 (before) 69.1 ± 9.7  (after) p = NS T4 cells: 45.2 ± 4.5 (before) 50.3 ± 8.8 (after) p < 0.05   T8 cells: 24.7 ± 5.3 (before) 19.7 ± 7.6  (after) p < 0.05   T4 : T8: 1.92 ± 0.49 (before) 2.88 ± 1.2 (after) p < 0.01   Proliferative response of lymphocytes to the mitogen PHA, at concentrations of 1/200 and 1/400, measured in decays per minute (dpm)   PHA 1/200: 9562 ± 11 (before) 15,690 ± 11,577 (after) p < 0.02   PHA 1/400: 3355 ± 3662 (before) 12,863 ± 11,872 (after) p < 0.01.	Innate immunity	Improvement in some aspects of cell-mediated immune function. In particular the number of T cells, T4 cells, and the T4 : T8 ratio increased significantly. The responsiveness of lymphocytes to the mitogen PHA also increased significantly and independently of the concentrations of the mitogen used. The results suggest that supplementation with physiological doses of vitamins A, C, and E in combination can improve cell-mediated immunity.
Schertling et al.; 1990	Randomized crossover trial	24 men and women	5 g/die for 35 days	The difference between the two groups (placebo period, ascorbic acid period) is statistically significant for the peak heights (p ~ 0.03). The changes in the alveolar macrophage activity measured on the basis of the formation of ROM do not correlate or only weakly correlate with the changes in peak flow values and symptom scores (|r| < 0.04 in all cases).	Innate immunity	In the presence of increased activity of the pulmonary inflammatory cells (e.g., alveolar macrophages, granulocytes) with bronchial asthma, the equilibrium between oxidative and antioxidative capacity in the lungs may be displaced in favor of the oxidative process, such that additional administration of ascorbic acid at a high dose (5 g/day) and over a longer period of time may be expected to provide a therapeutic effect.
Lauer et al.; 2013	placebo-controlled trial	33 healthy volunteers with skin types II and III according to the Fitzpatrick classification	100 or 180 mg for 4 weeks	Carotenoid values before and after 4 weeks of vitamin C supplementation measured on the inner forearm and the palm   (Δ = 10–4 AU) Vitamin C dose 100 mg Total carotenoids Palm: 1.5 (p = NS) Forearm: 0.5 (p = NS) Lycopene Palm: 0.3 (p = NS) Forearm: −0.1 (p < 0.05) Vitamin C dose 180 mg Total carotenoids Palm: 0.6 (p = NS) Forearm: 0.8 (p < 0.05) Lycopene Palm: −0.1 (p < 0.05) Forearm: −0.1 (p = NS).	Skin	Vitamin C increases the antioxidative activity of the skin, and there is an increase in cutaneous carotenoids though it was not significant. The increase in cutaneous antioxidative activity occurred fast after supplementation and was enhanced with higher doses of vitamin C. The study shows that dietary supplementation with vitamin C can has a significant effect on skin radical scavenging.
Sasazuki et al.; 2006	A double-blind, 5-year randomized controlled trial	244 men and women	50 mg (low-dose group) or 500 mg (high-dose group)	When the common cold was defined as occurring three or more times during the survey period, an approximately 70% reduction in relative risks (RR) was observed (0.34, 95% CI: 0.12–0.97, p = 0.04). The corresponding value for the common cold defined as occurring four or more times was 0.28 (95% CI: 0.06–1.28, p = 0.10), for which only 10 events were observed. The results were essentially the same in the intention-to-treat groups.	All immunity	Vitamin C supplementation significantly reduces the frequency of the common cold but had no apparent effect on the duration or severity of the common cold.
Harper et al.; 2002	Case series study	12 men and women	1 g/day for 10 days	Reduction in spontaneous generation of superoxide (pretreatment 8.41 ± 0.7 nmol/106 cells; posttreatment 5.64 ± 0.6 nmol/106; p < 0.05). Total antioxidant capacity increased significantly following treatment with vitamin C (555.4 ± 142 versus 668.6 ± 186 μmol/l trolox equivalent; p = 0.01) as did vitamin C concentration (56.5 ± 27 versus 137.7 ± 64 μmol/l; p = 0.002).	Innate immunity	The treatment of patients with antioxidants reduced neutrophil generation of superoxide and suggested that antioxidants may have an important role as adjuvant therapy.
Nieman et al.; 2002	Randomized study	28 men and women	1500 mg/die for 7 days	Plasma ascorbic acid was markedly higher in the vitamin C compared with placebo group prerace and rose more strongly in the vitamin C group during the race (postrace: 3.21 ± 0.29 and 1.28 ± 0.12 μg/100 μl, resp., p < 0.001). No significant group or interaction effects were measured for lipid hydroperoxide, F2-isoprostane, immune cell counts, plasma interleukin (IL)-6, IL-10, IL-1-receptor antagonist, or IL-8 concentrations, or mitogen-stimulated lymphocyte proliferation and IL-2 and IFN-γ production.	Innate immunity	Vitamin C supplementation does not serve as a countermeasure to postrace oxidative and immune changes in carbohydrate fed ultramarathon runners. Statistical correlations suggest that oxidative stress had little influence on the immune changes that take place during or after a competitive ultramarathon race.
Davison and Gleeson.; 2006	Single blind, randomized crossover design	9 men	1000 mg for 2 weeks	Main effects p values (trial; time; interaction) ACTH (adrenocorticotrophic hormone) (pg ml−1) 0.303; 0.002; 0.276 IL-6 (pg ml−1) 0.818; 0.000; 0.795 Cortisol (nM) 0.097; 0.004; 0.039. There was a significant trial-time interaction effect for plasma cortisol concentration (p = 0.039). There was a significantly lower postexercise neutrophilia (p < 0.014) in the VC trial, compared with the PLA trial.	Innate immunity	Vitamin C (VC) was effective at increasing antioxidant defence, modulating the leukocytosis and neutrophilia responses and possibly had some small effects on the plasma cortisol response. This suggests that supplementation with VC alone for a period of up to 2 weeks provides very limited or no protection against the depression of neutrophil function which is typically observed after prolonged exercise.
Du et al.; 2003	Randomized controlled study	84 men and women	Treatment group: vit C (10 g/day) was given intravenously for 5 days control group: vit C (1 g/day) was given intravenously for 5 days	The ratios of CD4/CD8 and CD4 positive cells were decreased, especially in severe acute pancreatitis (SAP) patients (p < 0.05. CD4/CD8, p = 0.041; CD4, p = 0.019). After treatment, the average value of concentration of plasma vitamin C (P-VC) was significantly higher and the values of SIL-2R, TNF-α, IL-6, and IL-8 were significantly lower in the treatment group than in the control group (p < 0.05  P-VC, p = 0.045; SIL-2R, p = 0.012; TNF-α, p = 0.030; IL-6, p = 0.015; and IL-8, p = 0.043).	Innate immunity	High-dose vitamin C has therapeutic efficacy on acute pancreatitis. Compared with the normal group, CD3 and CD4 positive cells in acute pancreatitis (AP) patients were significantly decreased. The potential mechanisms include promotion of antioxidizing ability of AP patients, blocking of lipid peroxidation in the plasma, and improvement of cellular immune function.
Dunstan et al.; 2007	A randomized controlled trial	54 allergic adults	1500 mg/day for 4 weeks	Antioxidant supplementation resulted in significant increases in serum levels of vitamin C, vitamin E, β-carotene, and selenium levels, compared with the placebo group (p < 0.001). There was no change in serum antioxidative capacity (AC), plasma F2-isoprostanes, exhaled nitric oxide (eNO), or immune responses following supplementation with antioxidants compared with placebo.	Acquired immunity	Although the dietary supplement achieved changes in antioxidant levels, it did not result in any significant changes in established immune responses over the study period.
Hunter et al.; 2012	Randomized crossover study	32 older individuals	362.4 mg for 4 weeks	No changes to innate immune function (natural killer cell activity, phagocytosis) or inflammation markers (high-sensitivity C-reactive protein, homocysteine) were detected. p = 0.03 (significant value was defined a priori at p < 0.001).	Innate immunity	Consumption of gold kiwifruit enhanced the concentrations of several dietary plasma analytes, which may contribute to reduced duration and severity of selected URTI (upper respiratory tract infections) symptoms, offering a novel tool for reducing the burden of URTI in older individuals.
Vojdani et al.; 2000	Randomized clinical trial	20 men and women	500, 1000, or 5000 mg for 2 weeks	Intracellular levels of ascorbic acid in human leukocytes   (μg/5 × 106 cells)   Dosage 500 mg: (mean ± SD) Day 0: 6.8 ± 2.1   Day 1: 9.1 ± 1.1  p = 0.03 (p from day 0 to day 1)   Day 7: 10 ± 1.4  p = 0.01 (p from day 1 to day 7) Day 15: 10.1 ± 1.2  p = 0.01 (p from day 7 to day 15) Day 21: 7.2 ± 1.7  p = 0.18 (p from day 15 to day 21) Dosage 1000 mg: (mean ± SD) Day 0: 7.4 ± 2.4   Day 1: 10 ± 2.6  p = 0.01 (p from day 0 to day 1) Day 7: 10.3 ± 2.7  p = 0.01 (p from day 1 to day 7) Day 15: 10.7 ± 2.8  p = 0.01 (p from day 7 to day 15) Day 21: 7.3 ± 2.3  p = 0.26 (p from day 15 to day 21) Dosage 5000 mg: (mean ± SD) Day 0: 7 ± 2.3   Day 1: 9.1 ± 1.8  p = 0.01 (p from day 0 to day 1) Day 7: 9.2 ± 1.7  p = 0.03 (p from day 1 to day 7) Day 15: 9.5 ± 1.9  p = 0.01 (p from day 7 to day 15) Day 21: 7 ± 2.6  p = 0.91 (p from day 15 to day 21) NK cell cytotoxic activity (LU)   Dosage 500 mg: (mean ± SD) Day 0: 35.6 ± 27.6   Day 1: 55.8 ± 18.8  p = 0.07 (p from day 0 to day 1) Day 7: 50.6 ± 12.8 p = 0.19 (p from day 1 to day 7) Day 15: 52.4 ± 24.4  p = 0.05 (p from day 7 to day 15) Day 21: 39.6 ± 26.4  p = 0.01 (p from day 15 to day 21) Dosage 1000 mg: (mean ± SD) Day 0: 34.2 ± 22.5   Day 1: 72.6 ± 39.12  p = 0.04 (p from day 0 to day 1) Day 7: 82 ± 46.4  p = 0.04 (p from day 1 to day 7) Day 15: 77.6 ± 36.4  p = 0.04 (p from day 7 to day 15) Day 21: 43.2 ± 29.6  p = 0.17 (p from day 15 to day 21) Dosage 5000 mg: (mean ± SD) Day 0: 33.4 ± 28.8   Day 1: 67.4 ± 39  p = 0.19 (p from day 0 to day 1) Day 7: 56.6 ± 29.5 p = 0.21 (p from day 1 to day 7) Day 15: 58.8 ± 26.2 p = 0.24 (p from day 7 to day 15) Day 21: 35 ± 24.9  p = 0.60 (p from day 15 to day 21).	Innate immunity	We concluded that ascorbic acid in an antioxidant and doses up to 5000 mg neither induce mutagenic lesion nor have negative effects on NK cell activity.
McComsey et al.; 2003	Pilot trials	8 men and women	1000 mg/die for 24 weeks	CD 4 + cell count (cell/mm 3)   (mean ± SD) Study entry: 627 ± 316   Week 24: 605 ± 460 (p = 0.49).	Innate immunity	There is a rationale for testing of antioxidant but there is no statistical significance.