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Background: Helicobacter pylori is one of the most common gastric pathogens, affecting at least half the world's population, and is strongly associated with gastritis, peptic ulcer, gastric adenocarcinoma, and lymphoma. We aimed to assess the efficacy, safety, and immunogenicity of a three-dose oral recombinant H pylori vaccine in children in China.Methods: We did this randomised, double-blind, placebo-controlled, phase 3 trial at one centre in Ganyu County, Jiangsu Province, China. Healthy children aged 6-15 years without past or present H pylori infection were randomly assigned (1:1), via computer-generated randomisation codes in blocks of ten, to receive the H pylori vaccine or placebo. Participants, their guardians, and study investigators were masked to treatment allocation. The primary efficacy endpoint was the occurrence of H pylori infection within 1 year after vaccination. We did analysis in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02302170.Findings: Between Dec 2, 2004, and March 19, 2005, we randomly assigned 4464 participants to either the vaccine group (n=2232) or the placebo group (n=2232), of whom 4403 (99%) participants completed the three-dose vaccination schedule and were included in the per-protocol efficacy analysis. We extended follow-up to 3 years. We recorded 64 events of H pylori infection within the first year (14 events in 2074·3 person-years at risk in the vaccine group vs 50 events in 2089·6 person-years at risk in the placebo group), resulting in a vaccine efficacy of 71·8% (95% CI 48·2-85·6). 157 (7%) participants in the vaccine group and 161 (7%) participants in the placebo group reported at least one adverse reaction. Serious adverse events were reported in five (<1%) participants in the vaccine group and seven (<1%) participants in the placebo group, but none was considered to be vaccination related.Interpretation: The oral recombinant H pylori vaccine was effective, safe, and immunogenic in H pylori-naive children. This vaccine could substantially reduce the incidence of H pylori infection; however, follow up over a longer period is needed to confirm the protection of the vaccine against H pylori-associated diseases.Funding: Chongqing Kangwei Biological Technology. [ABSTRACT FROM AUTHOR]

Abstract: Urease plays a crucial role in the survival and pathogenesis of Helicobacter pylori (H. pylori), and antibody neutralizing the urease activity may be implicated for the protection against H. pylori infection. Previously, a neutralizing monoclonal antibody (MAb) 6E6 against UreB of H. pylori was developed. In this work, we try to identify the B-cell epitope recognized by neutralizing MAb 6E6. Following screening a series of truncated proteins of UreB, an epitope was primarily localized in the aa 200–230 of UreB. Subsequently, we screened the overlapping synthetic peptides covering the aa 200–230 and identified a novel B-cell epitope (U211–225, IEAGAIGFKIHEDWG) that was recognized by specific MAb 6E6. The newly identified epitope may help understanding of the protective immunity against H. pylori and be implicated for vaccine development. [Copyright &y& Elsevier]

Helicobacter pylori, an etiological agent of gastroduodenal diseases, undergoes drastic morphological transition from spiral shape to coccoid form under oxidative stress. However, the knowledge of the specific expression profile in response to oxidative stress is relatively limited. Here, we report global proteomic analysis of H. pylori coccoids under oxidative stress. Two-dimensional gel electrophoresis analysis of H. pylori featuring coccoid revealed that 10 unique protein spots exhibit different expression profiles with comparison of that under normal microaerophilic condition. In total, seven proteins including superoxide dismutase, alkyl hydroperoxide reductase, urease G, and so forth were confirmed using matrix-assisted laser desorption/ionization time-of-flight/mass spectroscopy and then validated by reverse transcription–polymerase chain reaction, indicating that they play key roles in the physiological adaptation mechanisms of H. pylori to oxygen challenge. These data provide preliminary insights into H. pylori on coccoid generation under oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer is one of the most common malignant diseases worldwide. Emerging evidence has shown that microRNAs (miRNAs) are associated with tumor development and progression. Our previous studies have revealed that H. pylori infection was able to induce the altered expression of miR-30b in gastric epithelial cells. However, little is known about the potential role of miR-30b in gastric cancer. Methods: We analyzed the expression of miR-30b in gastric cancer cell lines and human gastric cancer tissues. We examined the effect of miR-30b mimics on the apoptosis of gastric cancer cells in vitro by flow cytometry (FCM) and caspase-3/7 activity assays. Nude mouse xenograft model was used to determine whether miR-30b is involved in tumorigenesis of gastric cancer. The target of miR-30b was identified by bioinformatics analysis, luciferase assay and Western blot. Finally, we performed the correlation analysis between miR-30b and its target expression in gastric cancer. Results: miR-30b was significantly down-regulated in gastric cancer cells and human gastric cancer tissues. Enforced expression of miR-30b promoted the apoptosis of gastric cancer cells in vitro, and miR-30b could significantly inhibit tumorigenicity of gastric cancer by increasing the apoptosis proportion of cancer cells in vivo. Moreover, plasminogen activator inhibitor-1 (PAI-1) was identified as the potential target of miR-30b, and miR-30b level was inversely correlated with PAI-1 expression in gastric cancer. In addition, silencing of PAI-1 was able to phenocopy the effect of miR-30b overexpression on apoptosis regulation of cancer cells, and overexpression of PAI-1 could suppressed the effect of promoting cell apoptosis by miR-30b, indicating PAI-1 is potentially involved in miR-30b-induced apoptosis on cancer cells. Conclusion: miR-30b may function as a novel tumor suppressor gene in gastric cancer by targeting PAI-1 and regulating the apoptosis of cancer cells. miR-30b could serve as a potential biomarker and therapeutic target against gastric cancer. [ABSTRACT FROM AUTHOR]

Abstract: Little is known about the potential role of microRNAs (miRNAs) in the carcinogenesis of gastric cancer induced by Helicobacter pylori (H. pylori). Here, we showed that microRNA-222 (miR-222) was up-regulated in H. pylori-infected gastric mucosa and gastric cancer. Ectopic expression of miR-222 promoted cell proliferation and colony formation in vitro. Mechanistically, we identified RECK as a novel target of miR-222, and also confirmed their relationship by the inverse correlation of mRNA expression ex vivo. Furthermore, we found that RNA interference silencing of RECK can mimic the oncogenic effects of miR-222. Collectively, H. pylori may function as an initiator in the process of carcinogenesis by up-regulating miR-222, which further participates in the progression of cancer by promoting proliferation and inhibiting RECK. [Copyright &y& Elsevier]

Abstract: Therapeutic vaccination is a desirable alternative for controlling Helicobacter pylori (H. pylori) infection. In the present study, attenuated Salmonella vector vaccines were constructed that expressed fusion proteins complexed with H. pylori CagA, VacA and UreB in different arrangements, and their therapeutic efficacy was evaluated in H. pylori-infected mice. Oral therapeutic immunization with attenuated Salmonella, which expressed the fused protein CVU, significantly decreased H. pylori colonization in the stomach; protection was related to specific CD4+ T cell Th1 type responses and serum IgG and mucosal sIgA antibody responses. These findings suggested that therapeutic efficacy was related to the arrangement of the fusion protein. It is possible that arrangement decides the expression of recombinant antigen in mice, and the latter results in different therapeutic efficacy. The attenuated Salmonella vector vaccine, which expressed the fused protein arrangement CVU, is superior to others, and could be a candidate vaccine against H. pylori. [Copyright &y& Elsevier]

Abstract: Th17 cells represent a novel subset of CD4+ T cells, which is associated with Helicobacter pylori infection. In the present study, we investigated the potential role of Urease subunit B (UreB) in the induction of Th17 cell response. Co-cultured splenic lymphocytes from H. pylori-infected mice with the recombinant UreB (rUreB) elevated IL-17 secretion and caused an increase in the number of Th17 cells. The expression of IL-6 and IL-23 p19 was significantly increased in rUreB-stimulated macrophages. Whole cell protein (WCP) of UreB-deficient strain (UreB− strain) induced less Th17 cell responses than that of wild-type strain. In addition, subcutaneous and intranasal immunization of rUreB elicited antigen-specific Th17 cell responses. Intranasal immunization of rUreB reduced H. pylori colonization in the stomach, which was closely related with the increased rUreB-specific Th17 cell responses. These results suggest that UreB is an important protein which is able to elicit Th17 cell responses against H. pylori both in vivo and in vitro. [Copyright &y& Elsevier]

Abstract: Th17 cells represent a novel subset of CD4+ T cells, which is associated with chronic inflammation. The present study evaluated Th17 cell responses to Helicobacter pylori infection in mouse model and CD4+ T cell differentiation in response to H. pylori-infected macrophages. Th17 cells were observed in the H. pylori-infected gastric tissue. Co-culture of CD4+ T cells with H. pylori-infected macrophages elevated IL-17 and IFN-γ secretion, up-regulated retinoid-related orphan receptor gamma t (RORγt) and T box expressed in T cells (T-bet) expression and increased the numbers of Th17 and Th1 cells. The expression of CD40, CD80, and CD86 and the secretion of IL-6, TGF-β1, IL-23, and CCL20 were significantly increased in H. pylori-stimulated macrophages. NF-κB pathway participated in the production of IL-6, IL-23, and CCL20 from macrophages in response to H. pylori, and inhibition of NF-κB pathway of macrophages resulted in less Th17 cell differentiation. Taken together, these results suggest that H. pylori induces Th17 cell differentiation via infected macrophages. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNA-155 (miR-155) has been implicated as a central regulator of the immune system. We have previously reported that miR-155 negatively regulates Helicobacter pylori (H. pylori)-induced inflammation, but the molecular mechanism of miR-155 regulating the inflammation is not fully clear. Here, we identified myeloid differentiation protein 88 (MyD88) as a target gene of miR-155, and found that miR-155 decreased MyD88 expression at the protein but not the mRNA message level, suggesting that the miR-155-mediated inhibition is a post-transcriptional event. Furthermore, the overexpression of miR-155 led to significantly reduced IL-8 production induced by H. pylori infection. Thus, we have demonstrated that miR-155 can negatively regulate inflammation by targeting a key adaptor molecule MyD88 in inflammatory pathways. [Copyright &y& Elsevier]

Abstract: Epitope vaccine is a promising option for therapeutic vaccination against Helicobacter pylori (H. pylori) infection. In this study, we constructed a multi-epitope vaccine with five epitopes and mucosal adjuvant E. coli heat-labile enterotoxin B subunit (LTB) named HUepi-LTB and evaluated its therapeutic effect against H. pylori infection in BALB/c mice model. HUepi-LTB containing three Th epitopes from UreB and two B cell epitopes from UreB and HpaA was constructed and expressed in E. coli. Oral therapeutic immunization with HUepi-LTB significantly decreased H. pylori colonization compared with oral immunization with PBS, and the protection was correlated with antigen-specific CD4+ T cells and IgG and mucosal IgA antibody responses. This multi-epitope vaccine may be a promising vaccine candidate that may help to control H. pylori infection. [Copyright &y& Elsevier]

Background: Development of Helicobacter pylori vaccine would be a new effective strategy for prevention and treatment of H. pylori infection. Recombinant H. pylori vaccine comprising a single subunit antigen can only induce immune response with limited protection efficiency. In this study, the protective effect of H. pylori multicomponent vaccines consisting of three recombinant subunit antigens was investigated using the Mongolian gerbil model. Materials and methods: Mongolian gerbils were immunized with different formulations of three recombinant H. pylori antigens (UreB, HspA, and HpaA) with two different adjuvants (Al(OH)3, LTR72DITH) by intragastric (i.g.) or intramuscular (i.m.) routes. The protective effects of multicomponent vaccines were assessed after H. pylori challenge in different studies. The specific IgG antibodies in serum were monitored by ELISA, and the mRNA expressions of IL-4 and IFN-γ in spleen tissue were detected by reverse transcribed polymerase chain reaction (RT-PCR). Results: The protective effect against H. pylori challenge in gerbils immunized with three recombinant antigens and LTR72DITH or Al(OH)3 was significantly higher than that in single- or double-antigen vaccine-immunized and control gerbils. Furthermore, the protective effect of the triple-antigen vaccine combined with the LTR72DITH adjuvant (average 86.3%) was significantly greater than that of vaccine combined with the Al(OH)3 adjuvant (average 53.4%). After the first immunization, the anti-UreB/HspA/HpaA serum IgG level in gerbils immunized with triple-antigen vaccine combined with Al(OH)3 was higher than that in gerbils immunized with the vaccine combined with LTR72DITH. Splenic interferon (IFN)-γ and interleukin (IL)-4 transcript levels were significantly increased in LTR72DITH vaccine-immunized gerbils as compared to the Al(OH)3 vaccine group. Moreover, splenic IL-4 mRNA levels were higher than IFN-γ in gerbils immunized with triple-antigen vaccine with either LTR72DITH or Al(OH)3. Conclusions: This study indicated that the recombinant multicomponent vaccine provided effective protection against H. pylori infection as compared to the single-antigen vaccine. This protective immunity would be closely associated with a predominant Th2-type response. [ABSTRACT FROM AUTHOR]

Abstract: CD4+ T cells play important roles in protection against Helicobacter pylori (H. pylori) infection. In order to better understand the immune responses of H. pylori infection and improve immune interventions against this pathogen, we identified the Th epitopes in UreB of H. pylori, an excellent vaccine candidate antigen. By using the RANKPEP prediction algorithm, we have identified and characterized three Th epitopes within the UreB antigen, which can be recognized by CD4+ T cells from BALB/c (H-2d) mice. They were U546–561, U229–244, and U237–251. These epitopes have important value for studying the immune response of H. pylori infection and for designing effective vaccine against H. pylori. [Copyright &y& Elsevier]