https://www.gastrojournal.org/article/S0016-5085(07)00990-0/pdf

Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(15)60310-5.pdf

Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial

Despite the fact that the adjuvant properties of the heat-labile enterotoxins of Escherichia coli (LT) and Vibrio cholerae (CT) have been known for more than 20 years, there are no available oral vaccines containing these molecules as adjuvants, primarily because they are both very potent enterotoxins. A number of attempts with various degrees of success have been made to reduce or eliminate the enterotoxicity of LT and CT so they can safely be used as oral adjuvants or immunogens. In this report we characterize the structural, enzymatic, enterotoxic, and adjuvant properties of a novel mutant of LT, designated LT(R192G/L211A), or dmLT. dmLT was not sensitive to trypsin activation, had reduced enzymatic activity for induction of cyclic AMP in Caco-2 cells, and exhibited no enterotoxicity in the patent mouse assay. Importantly, dmLT retained the ability to function as an oral adjuvant for a coadministered antigen (tetanus toxoid) and to elicit anti-LT antibodies. In vitro and in vivo data suggest that the reduced enterotoxicity of this molecule compared to native LT or the single mutant, LT(R192G), is a consequence of increased sensitivity to proteolysis and rapid intracellular degradation in mammalian cells. In conclusion, dmLT is a safe and powerful detoxified enterotoxin with the potential to function as a mucosal adjuvant for coadministered antigens and to elicit anti-LT antibodies without undesirable side effects. Bacterially derived enterotoxins, such as the heat-labile enterotoxin (LT) produced by enterotoxigenic Escherichia coli (ETEC) and the closely related cholera enterotoxin (CT) produced by Vibrio cholerae, promote secretory diarrhea during microbial infection. Each enterotoxin is composed of an enzymatically active A-subunit noncovalently associated with a pentameric B-subunit. Induction of intestinal fluid secretion occurs after a series of events involving both changes to toxin structure and activation of intracellular signaling pathways (reviewed in reference 14). The B-subunit mediates binding and internalization of the toxin to cells; subsequent proteolytic cleavage and disulfide bond reduction separate the A-subunit into two domains, the enzymatically active A1 subunit and a smaller A2 peptide. Transport of A1 into the cytoplasm results in ADP-ribosylation of Gs, followed by irreversible activation of adenylate cyclase and increases in intracellular levels of cyclic AMP (cAMP). In intestinal epithelial cells, this induction of cAMP causes a disregulation of cAMP-sensitive ion transport mechanisms, inhibiting intracellular salt absorption, increasing electrolyte transport into the gut lumen, and creating an osmotic gradient favoring intestinal water secretion (12). An enzymatically active A-subunit is required for intestinal fluid secretion but also enables LT to act as an oral adjuvant, boosting the immune response to coadministered antigens and inducing both humoral and cellular immune responses in both the systemic and mucosal compartments. However, even low doses of LT (and CT) induce side effects, such as diarrhea,

https://cvi.asm.org/content/cdli/18/4/546.full.pdf

Characterization of a Mutant Escherichia coli Heat-Labile Toxin, LT(R192G/L211A), as a Safe and Effective Oral Adjuvant

This guideline updates a prior concensus recommendation of the German Society for Digestive and Metabolic Diseases (DGVS) from 1996. It was developed by an interdisciplinary cooperation with representatives of the German Society for Microbiology, the Society for Pediatric Gastroenterology and Nutrition (GPGE) and the German Society for Rheumatology. The guideline is methodologically based on recommendations of the Association of the Scientific Medical Societies in Germany (AWMF) for providing a systematic evidence-based consensus guideline of S 3 level and has also implemented grading criteria according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). Clinical applicability of study results as well as specifics for Germany in terms of epidemiology, antibiotic resistance status, diagnostics and therapy were taken into account.

/pdf/s2k-guideline-helicobacter-pylori-and-gastroduodenal-ulcer-17tk1qfbpn.pdf

[S2k-guideline Helicobacter pylori and gastroduodenal ulcer disease].

Perhaps the best-studied mucosal adjuvants are the bacterially derived ADP-ribosylating enterotoxins. This adjuvant family includes heat-labile enterotoxin of Escherichia coli (LT), cholera toxin (CT), and mutants or subunits of LT and CT. These proteins promote a multifaceted antigen-specific response, including inflammatory Th1, Th2, Th17, cytotoxic T lymphocytes (CTLs), and antibodies. However, more uniquely among adjuvant classes, they induce antigen-specific IgA antibodies and long-lasting memory to coadministered antigens when delivered mucosally or even parenterally. The purpose of this minireview is to describe the general properties, history and creation, preclinical studies, clinical studies, mechanisms of action, and considerations for use of the most promising enterotoxin-based adjuvant to date, LT(R192G/L211A) or dmLT. This review is timely due to completed, ongoing, and planned clinical investigations of dmLT in multiple vaccine formulations by government, nonprofit, and industry groups in the United States and abroad.

https://msphere.asm.org/content/msph/3/4/e00215-18.full.pdf

The Mucosal Vaccine Adjuvant LT(R192G/L211A) or dmLT.

Background and aims: Escherichia coli heat labile enterotoxin (LT) at doses of 5 μg or 10 μg has adjuvant activity for oral immunisation in humans infected with Helicobacter pylori, but causes severe diarrhoea. This study was undertaken to establish a safe and effective dose of LT, to confirm the safety of recombinant urease, and to compare the immunogenicity of orally compared with enterically delivered urease. Methods: 42 healthy adults without present or past H pylori infection were randomised to receive 60 mg recombinant H pylori urease in soluble or in encapsulated form, given with doses of LT ranging from 0 μg to 2.5 μg. Four oral doses were administered at day 1, 8, 29, and 57. Specific IgG, IgA, and antibody secreting cells were measured as well as total α4β7 integrin positive lymphocyte responses. Results: Enterically delivered urease was well tolerated and no serious adverse events occurred. Mild diarrhoea (one to four loose stools) occurred after the first immunisation in 50% (6 of 12) of the volunteers exposed to 2.5 μg LT (p=0.06; paired t test, compared with baseline) but not in volunteers exposed to lower LT doses. Immune responses occurred in five (p=0.048; Fisher’s exact test), one, two, and one of six subjects exposed to 2.5 μg, 0.5 μg, 0.1 μg, and no LT, respectively. Significant CD4 + , CD69 + , and CD45RO hi responses occurred over time among α4β7 hi lymphocytes in volunteers receiving 2.5 μg LT. Enterically delivered urease induced higher lymphocyte responses than soluble urease. Conclusions: The safety of H pylori urease is confirmed. Oral LT may conserve its adjuvant activity at low doses with minimal side effects.

https://gut.bmj.com/content/gutjnl/51/5/634.full.pdf

Safety and efficacy of low dose Escherichia coli enterotoxin adjuvant for urease based oral immunisation against Helicobacter pylori in healthy volunteers.

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Safety and efficacy of low dose Escherichia coli enterotoxin adjuvant for urease based oral immunisation against Helicobacter pylori in healthy volunteers.