Oral Typhoid Vaccination With Live-Attenuated Salmonella Typhi Strain Ty21a Generates Ty21a-Responsive and Heterologous Influenza Virus-Responsive CD4+ and CD8+ T Cells at the Human Intestinal Mucosa.

BACKGROUND: Oral vaccination with live-attenuated Salmonella Typhi strain Ty21a is modestly efficacious, but the mechanisms of protection are currently unknown. While humoral and cellular immune responses are well described in peripheral blood, the cellular response at the intestinal mucosa has never been directly assessed. METHODS: We vaccinated healthy adults with Ty21a and assessed humoral and cellular immunity in vaccinated volunteers and controls after 18 days. Immunoglobulin levels were assessed in peripheral blood by an enzyme-linked immunosorbent assay. Cellular responses were assessed in peripheral blood and at the duodenal and colonic mucosa by flow cytometry. RESULTS: We demonstrate the generation of Ty21a-responsive and heterologous influenza virus-responsive CD4(+) and CD8(+) T cells at the duodenal mucosa. All duodenal responses were consistently correlated, and no responses were observed at the colonic mucosa. Peripheral anti-lipopolysaccharide immunoglobulin G and immunoglobulin A responses were significantly correlated with duodenal responses. The assessment of integrin ß7 expression intensity among peripheral and duodenal T-cell subsets revealed varied capacities for mucosal homing and residence. CONCLUSIONS: The breadth of duodenal cellular responses was not reflected peripherally. The direct evaluation of mucosal immune defense may yield functional correlates of protection and could provide insight into mechanisms that may be manipulated to enhance vaccine immunogenicity.

Longevity of duodenal and peripheral T-cell and humoral responses to live-attenuated Salmonella Typhi strain Ty21a.

BACKGROUND: We have previously demonstrated that polyfunctional Ty21a-responsive CD4+ and CD8+ T cells are generated at the duodenal mucosa 18 days following vaccination with live-attenuated S. Typhi (Ty21a). The longevity of cellular responses has been assessed in peripheral blood, but persistence of duodenal responses is unknown. METHODS: We vaccinated eight healthy adults with Ty21a. Peripheral blood and duodenal samples were acquired after a median of 1.5 years (ranging from 1.1 to 3.7 years) following vaccination. Cellular responses were assessed in peripheral blood and at the duodenal mucosa by flow cytometry. Levels of IgG and IgA were also assessed in peripheral blood by enzyme-linked immunosorbent assay. RESULTS: No T-cell responses were observed at the duodenal mucosa, but CD4+ T-cell responses to Ty21a and FliC were observed in peripheral blood. Peripheral anti-lipopolysaccharide IgG and IgA responses were also observed. Early immunoglobulin responses were not associated with the persistence of long-term cellular immune responses. CONCLUSIONS: Early T-cell responses which we have previously observed at the duodenal mucosa 18 days following oral vaccination with Ty21a could not be detected at a median of 1.5 years. Peripheral responses were observed at this time. Immunoglobulin responses observed shortly after vaccination were not associated with cellular immune responses at 1.5 years, suggesting that the persistence of cellular immunity is not associated with the strength of the initial humoral response to vaccination.