Correlation of T cell response and bacterial clearance in human volunteers challenged with Helicobacter pylori revealed by randomised controlled vaccination with Ty21a-based Salmonella vaccines

Abstract

Background:Helicobacter pylori remains a global health hazard, and vaccination would be ideal for its control. Natural infection appears not to induce protective immunity. Thus, the feasibility of a vaccine for humans is doubtful.Methods:In two prospective, randomised, double-blind, controlled studies (Paul Ehrlich Institute application nos 0802/02 and 1097/01), live vaccines against H pylori were tested in human volunteers seronegative for, and without evidence of, active H pylori infection. Volunteers (n = 58) were immunised orally with Salmonella enterica serovar Typhi Ty21a expressing H pylori urease or HP0231, or solely with Ty21a, and then challenged with 2×105 cagPAI− H pylori. Adverse events, infection, humoral, cellular and mucosal immune response were monitored. Gastric biopsies were taken before and after vaccination, and postchallenge. Infection was terminated with antibiotics.Results:Vaccines were well tolerated. Challenge infection induced transient, mild to moderate dyspeptic symptoms, and histological and transcriptional changes in the mucosa known from chronic infection. Vaccines did not show satisfactory protection. However, 13 of 58 volunteers, 8 vaccinees and 5 controls, became breath test negative and either cleared H pylori (5/13) completely or reduced the H pylori burden (8/13). H pylori-specific T helper cells were detected in 9 of these 13 (69%), but only in 6 of 45 (13%) breath test-positive volunteers (p = 0.0002; Fisher exact test). T cells were either vaccine induced or pre-existing, depending on the volunteer.Conclusion:Challenge infection offers a controlled model for vaccine testing. Importantly, it revealed evidence for T cell-mediated immunity against H pylori infection in humans.

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

“…The finding that control mice vaccinated with the S. Typhimurium 'carrier' also exhibit reductions in H. pylori numbers is consistent with previous reports from studies in both mice and humans [16,24,32]. While vaccinating with the carrier alone had some protective effect, it was seldom as effective as vaccination with H. pylori-specific antigen, which consistently results in a further 1 log reduction in bacterial numbers.…”

“…This observation has also been supported by data from a recent trial of a recombinant attenuated Salmonella enterica serovar Typhi (S. Typhi)-based H. pylori vaccine in human volunteers. In this study, healthy (H. pylori negative) adult volunteers were vaccinated orally with recombinant S. Typhi expressing H. pylori antigen, and later challenged with a well-characterised H. pylori strain [16]. Vaccine-specific CD4 1 T-cell responses were detected and found to correlate with reductions in colonisation in some vaccinated volunteers.…”

“…On the one hand vaccination causes 'post-immunisation gastritis' a local inflammatory responses in the stomach in many animal and human recipients, and indeed concerns have been raised about the safety of a prophylactic or therapeutic vaccine [9]. On the other, while a recent trial of a combined CagA/ NapA/alum formulation delivered via the intramuscular route was reported to induce strong antibody T-cell responses after four doses [10], most studies investigating mucosal vaccination approaches with live or protein-adjuvanted vaccines have been reported to induce weak, systemic immune responses in humans, as reflected by measurable antibody and T-cell responses [6,[11][12][13]. A better understanding of the immunological mechanisms underlying vaccination is therefore essential to aid development of an effective vaccine for humans.…”

A mutation burst during the acute phase of Helicobacter pylori infection in humans and rhesus macaques

“…The corresponding mutation rate of 7.5 Â 10 À 6 , which is similar to that during chronic infection, implies the lack of an inflammatory response in this patient for reasons that are currently unknown, but possibly involved a low number of 10 5 colony-forming units (c.f.u.) in the inoculum 32 in comparison with 10 9 c.f.u. in this re-infection study and to 7.5 Â 10 8 c.f.u.…”

The C-Terminally Encoded, MHC Class II-Restricted T Cell Antigenicity of the Helicobacter pylori Virulence Factor CagA Promotes Gastric Preneoplasia

“…Several vaccination regimens induce protective immunity in animal models; these include subunit vaccines containing H. pylori urease (8), neutrophil-activating protein (9), or adhesin A (10), but also recombinant live Salmonella vaccines expressing Helicobacter Ags (11). Clinical trials have demonstrated the immunogenicity of experimental vaccines in human volunteers (12)(13)(14). However, all current vaccine development efforts are hampered by their failure to achieve sterilizing immunity in rodent models, let alone in humans.…”