Zinc plays a critical role in the normal functioning of the immune system. We investigated whether zinc sulfate administered orally to adult zinc-replete volunteers modulates systemic and intestinal immune responses to an oral killed cholera toxoid B subunit (CTB) whole-cell cholera vaccine. The 30 participants were immunized twice, with a 17-day interval. The vaccinees in the intervention group ingested 45 mg of elemental zinc thrice daily for 9 days starting 2 days before each vaccine dose. The median serum anti-CTB immunoglobulin A (IgA) and IgG responses from day 0 to day 30, i.e. after two vaccine doses, were 13-fold lower (P value for identical distribution, <0.005) in the zinc-supplemented compared to the nonsupplemented vaccinees. The median serum vibriocidal responses from baseline to after one (day 0 to day 17) and two (day 0 to day 30) vaccine doses were at least sixfold (P ؍ 0.033) and fourfold (P ؍ 0.091) higher, while the median fecal anti-CTB IgA response after two doses was estimated to be fourfold higher (P ؍ 0.084) in the zinc-supplemented vaccinees. These observations show that zinc reduces the antitoxin and may enhance the antibacterial responses in serum. Zinc may also improve the intestinal antitoxin immune response. Oral zinc administration has the potential to modify critical immune responses to antigens applied to mucosal surfaces.As a constituent of many biological systems, zinc is an essential nutrient and plays a critical role in the normal functioning of the immune system (4,25,31,38). Several in vitro studies have shown that the immunomodulatory effects of zinc closely resemble the actions of several well-characterized adjuvants (e.g., aluminum salts) that selectively activate specific T-cell subpopulations controlling immune responses (3,13).In vitro studies indicate that there is a delicate zinc concentration dependency for lymphocyte and monocyte activation (22,31,38). Zinc dosage regimens for achieving modulation of these processes in vivo are not established and may differ depending on the desired outcome. To achieve adequate immunomodulation, zinc supplementation should probably coincide with the 7 to 10 days of maximum clonal expansion of lymphocytes following immunization (14,15,22,36). The dose administered has to induce adequate zinc concentrations in the appropriate lymphoid tissues (8, 34).The clinical effects of zinc are known from several studies in developing countries, where zinc supplementation substantially reduces the severity and duration of diarrhea in children and also reduces the incidence of diarrhea (6). Somewhat surprisingly, these effects do not seem to be limited to those who are malnourished or zinc deficient; zinc also has substantial preventive effects in children with normal plasma zinc levels (5).In order to be efficacious, vaccines against enteric infections should induce a specific secretory immunoglobulin A (S-IgA) as well as an adequate systemic immune response (24). To exploit the practicality of oral immunization and the superiorability o...