Safety and Immunogenicity of Oral Inactivated Whole-Cell Helicobacter pylori Vaccine with Adjuvant among Volunteers with or without Subclinical Infection

Abstract

Helicobacter pylori infection of the gastric mucosa can be found in approximately 50% of the world's population and is associated with a range of pathology, including peptic ulcer, atrophic gastritis, and gastric cancer. To explore immunization as a strategy for preventing and treating H. pylori-associated disease, we assessed the safety and immunogenicity in healthy adults of a formalin-inactivated, oral H. pylori whole-cell (HWC) vaccine, administered with or without mutant Escherichia coli heat-labile toxin (LT R192G ) as a mucosal adjuvant. In a dose-response study, 23 subjects with or without H. pylori infection were vaccinated with either 2.5 ؋ 10 6 HWC, 2.5 ؋ 10 8 HWC, or 2.5 ؋ 10 10 HWC, plus 25 g of LT R192G . Thereafter, a randomized study was conducted in which 18 H. pylori-infected subjects were assigned, in a double-blind fashion, to receive either 2.5 ؋ 10 10 HWC plus placebo-adjuvant, placebo-vaccine plus 25 g of LT R192G , placebo-vaccine plus placeboadjuvant, or 2.5 ؋ 10 10 HWC plus 25 g of LT R192G . Diarrhea (six subjects), low-grade fever (five subjects), and vomiting (two subjects) were observed, usually after the first dose. Significant rises in geometric mean mucosal (fecal and salivary) anti-HWC immunoglobulin A antibodies occurred among H. pylori-infected and uninfected subjects following inoculation with 2.5 ؋ 10 10 HWC plus 25 g of LT R192G . Moreover, among H. pylori-negative volunteers, this regimen induced significant lymphoproliferative responses in 5 of 10 subjects and gamma interferon production responses to H. pylori sonicate in 7 of 10 subjects. There was no evidence that vaccination eradicated H. pylori in infected volunteers. These results suggest that it is possible to stimulate mucosal and systemic immune responses in humans to H. pylori antigens by using an HWC vaccine.

Therapeutic Vaccination againstHelicobacter pyloriin the Beagle Dog Experimental Model: Safety, Immunogenicity, and Efficacy

“…Unfortunately, it is known that an antibody response does not necessarily correlate with protection against H. pylori (7). In fact, in spite of the previously observed good immunogenicity in humans and both immunogenicity and efficacy in animals, when other H. pylori vaccines were assessed for therapeutic efficacy in humans (15,23), neither H. pylori eradication nor an amelioration of gastric pathology was achieved. It is unclear whether the failure of these attempts of therapeutic vaccination was due to the antigen (soluble urease or whole-cell vaccine), to the route of administration (oral), or to the necessity of limiting the dose of the adjuvants (E. coli heat-labile enterotoxin or its mutant LTR192G) because of their intrinsic toxicity.…”

“…Some vaccines against H. pylori have already been determined to be safe and immunogenic in humans (15,23), although in some cases unwanted side effects have been observed due to the toxicity of the adjuvant. In particular, a vaccine consisting of the same antigens used here, formulated with alum for intramuscular injection, was recently tested in H. pylori-negative human volunteers, showing high safety and immunogenicity (19,31), in agreement with the results described here in dogs.…”

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

“…Oral (mucosal route) vaccination is desirable for a human H. pylori vaccine because of the ease of delivery and, for a live vaccine, the necessity of a single dose is also attractive. Phase 1 clinical trials in human volunteers have in general yielded disappointing results with issues such as poor immunogenicity [6], and adverse reactions [7], presenting serious obstacles to further progression of a human vaccine [8]. The reasons for this failure probably result from apparently opposing aspects of the immune response to vaccination.…”

“…with issues such as poor immunogenicity [6], and adverse reactions [7], presenting serious obstacles to further progression of a human vaccine [8]. The reasons for this failure probably result from apparently opposing aspects of the immune response to vaccination.…”

Construction of expression systems forflaAandflaBgenes ofHelicobacter pyloriand determination of immunoreactivity and antigenicity of recombinant proteins

“…So far, no vaccine preventing H pylori infection has been commercially available. The majority of studies attempting to produce a vaccine have focused on urease enzyme, heat shock protein, and vacuolating cytotoxin [35,[48][49][50] , but rarely on H pylori flagellin. H pylori flagellin is composed of two subunits, named as FlaA with 53KDa and FlaB with 54 KDa respectively.…”