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

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 Hpylori (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

Subversion of immunity by schistosomes

Chronic parasitic disease affects millions of people worldwide. Helminth infections are seldom fatal but cause chronic disease that may range from asymptomatic to debilitating. One of the hallmarks of the immune response to parasitic infections is the tendency to suppress inflammation and control tissue damage. The overall effect of this is not only to reduce or inactivate the activities of the parasite, but even to skew immune responses to other infectious agents. This article discusses the state of our understanding of the complex regulationandcontrol ofimmuneresponses inducedby schistosomes

Leptin, CD4(+) T(reg) and the prospects for vaccination against H.pylori infection

Helicobacter pylori infection induces chronic inflammation which is characterized not only by infiltrations of inflammatory cells such as neutrophils and CD4+ T cells, but also significant populations of regulatory T cells (Treg). These cells are important for disease pathogenesis because they are believed to contribute to the persistence of the infection. Despite encouraging results in animal models, the prospects for an effective H. pylori vaccine are currently poor because of generally disappointing results in preclinical and phase 1 trials. As a result, a current major focus of basic research on vaccination is to better understand the mechanisms regulating the inflammatory response with the view it can inform future vaccine design. Our studies in this area have focused on gastric CD4+ Treg in vaccinated mice, and raised the hypothesis that adipokines in particular leptin are involved the establishment of a protective gastric immune response. Here we discuss the hypothesis that vaccination deregulatesTreg responses in the gastric mucosa, and that this process is mediated by leptin.We propose that reduced suppression permits a protective sub population of H. pylori-specific CD4+ T cells to exert protective effects, presumably via the gastric epithelium. Evidence from the literature and experimental approaches will be discusse

Immunity and Vaccine Development Against Helicobacter pylori

Helicobacter pylori is a highly-adapted gastrointestinal pathogen of humans and the immunology of this chronic infection is extremely complex. Despite the availability of antibiotic therapy, the global incidence of H. pylori infection remains high, particularly in low to middle-income nations. Failure of therapy and the spread of antibiotic resistance among the bacteria are significant problems and provide impetus for the development of new therapies and vaccines to treat or prevent gastric ulcer, and gastric carcinoma. The expansion of knowledge on gastric conventional and regulatory T cell responses, and the role of TH17 in chronic gastritis from studies in mouse models and patients have provided valuable insights into how gastritis is initiated and maintained. The development of human challenge models for testing candidate vaccines has meant a unique opportunity to study acute infection, but the field of vaccine development has not progressed as rapidly as anticipated. One clear lesson learned from previous studies is that we need a better understanding of the immune suppressive mechanisms in vivo to be able to design vaccine strategies. There is still an urgent need to identify practical surrogate markers of protection that could be deployed in future field vaccine trials. Important developments in our understanding of the chronic inflammatory response, progress and problems arising from human studies, and an outlook for the future of clinical vaccine trials will be discussed

Proteomic and gene profiling approaches to study host responses to bacterial infection

Infectious disease is the result of an intimate relationship between the pathogen and host, which involves cross-talk. After an initial flood of mainly descriptive reports on the influence of acute bacterial infection on cells, transcriptome and proteome studies are now becoming more refined in their approach, and are shedding light on the role of pathogen-specific mechanisms/structures in pathogenesis. In addition, studies of gene expression in vivo have shed new light on how the host influences the niche occupied by bacteria. Elegant refinements to proteomics using beads coated with bacterial invasins, or purifying subcellular fractions are producing a picture of invasion specific processes. Such approaches combined with modern functional genomics technologies such as RNAi represent the next phase in understanding host-bacteria interactions

Transcription profiling analysis of the mechanisms of vaccine-induced protection against H. pylori.

C1 - Journal Articles Referee