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

Salmonella enterica serovar Typhi is a human-host-restricted intracellular pathogen and the causative agent of typhoid fever. Following ingestion, the bacteria cause systemic illness following invasion via the mucosal surface of the small intestine [1]. In the 1970s, through chemical mutagenesis of pathogenic S. Typhi strain Ty2, a live-attenuated oral typhoid vaccine, Ty21a, was developed [2]. Vaccination with 3 doses of Ty21a is moderately protective, and although estimates of efficacy vary [3–5], a recently published review calculated a cumulative efficacy of 48% 3 years following vaccination [6]. Ty21a is able to induce humoral and cellular immune responses, both of which have been implicated in protection against disease. While opsonophagocytic antibody function [7], cellular cytotoxicity, proliferation, and cytokine production functionality have been assessed in peripheral blood following vaccination with Ty21a [8–13], cellular immunity at the human intestinal mucosa has never been directly assessed. Numerous studies have demonstrated that cellular immune responses generated through vaccination with Ty21a are primed for mucosal homing [13–15], highlighting the importance of mucosal immunity in defense against disease. Furthermore, it has been demonstrated that the assessment of vaccine immunogenicity by peripheral sampling alone provides an incomplete reflection of vaccine immunogenicity [16]. It has previously been observed in murine models that previously primed T cells of heterologous specificities are recruited to the lung during influenza virus infection [17]. Although this phenomenon has not been observed in humans, we hypothesized that vaccination with Ty21a could enhance T-cell responses to heterologous antigens at the mucosal surface by a similar mechanism. Through the direct assessment of immunity at the intestinal mucosa, it may be possible to identify mechanisms involved in the induction of protective immunity, which may be manipulated to improve oral vaccine immunogenicity. Here, we have assessed cellular immunity in vaccinated volunteers and controls at the duodenal and colonic mucosa and in peripheral blood after 18 days. We have compared and correlated peripheral and mucosal cellular responses with accepted peripheral humoral measures of vaccine efficacy, providing a unique insight into the relationship between human mucosal and peripheral immune defense.