Therapeutic intragastric vaccination against Helicobacter pylori in mice eradicates an otherwise chronic infection and confers protection against reinfection

Abstract

Chronic infection of the gastroduodenal mucosae by the gram-negative spiral bacterium Helicobacter pylori is responsible for chronic active gastritis, peptic ulcers, and gastric cancers such as adenocarcinoma and low-grade gastric B-cell lymphoma. The success of eradication by antibiotic therapy is being rapidly hampered by the increasing occurrence of antibiotic-resistant strains. An attractive alternative approach to combat this infection is represented by the therapeutic use of vaccines. In the present work, we have exploited the mouse model of persistent infection by mouse-adapted H. pylori strains that we have developed to assess the feasibility of the therapeutic use of vaccines against infection. We report that an otherwise chronic H. pylori infection in mice can be successfully eradicated by intragastric vaccination with H. pylori antigens such as recombinant VacA and CagA, which were administered together with a genetically detoxified mutant of the heat-labile enterotoxin of Escherichia coli (referred to as LTK63), in which the serine in position 63 was replaced by a lysine. Moreover, we show that therapeutic vaccination confers efficacious protection against reinfection. These results represent strong evidence of the feasibility of therapeutic use of VacA-or CagA-based vaccine formulations against H. pylori infection in an animal model and give substantial preclinical support to the application of this kind of approach in human clinical trials.

Therapeutic Oral Vaccination Induces Mucosal Immune Response Sufficient to Eliminate Long‐Term Helicobacter pylori Infection

“…The therapeutic vaccination of H. pylori-infected mice using H. pylori-whole cell sonicate together with the mucosal adjuvant CT induced a high level of eradication. This is in full agreement with previous studies (2,3,6,9,23) (Table 1).…”

“…In the present study, we demonstrated that chronic gastric infection by H. pylori in mice can be successfully cured with the oral administration of H. pylori-whole cell sonicate plus CT as an adjuvant. Several investigators have recently suggested that therapeutic oral vaccination against H. pylori infection is effective for bacterial eradication (2,3,6,9,11,23). Doidge et al firstly indicated the feasibility of therapeutic vaccination against H. felis infection in a mouse model.…”

“…Therefore, the therapeutic use of vaccines against ongoing Helicobacter infection might be an alternative approach to the use of antibiotics. Several studies have shown that therapeutic vaccination induces successful eradication of persistent Helicobacter infection using similar immunogen to the prophylactic vaccine in experimental animal models (2,3,6,9,11,23). In the present study, we evaluated the efficacy of oral vaccination with H. pylori-whole cell sonicate as a therapeutic use for long-term H. pylori-infected mice and demonstrated that the efficacy of oral therapeutic vaccination was due to the induction of local secretory IgA in the stomach, similar to that of oral prophylactic vaccination.…”

Exploring novel vaccines against Helicobacter pylori: protective and therapeutic immunization

“…Bacterial mechanism of protection or whether other aspects of the immune system, such as IgG from mucosa in-ghosts have been produced from a variety of bacteria including E. coli and H. pylori. Oral, aerogenic or filtrated B cells or cell mediated responses, are more important remains to be established (87). Prophylactic parenteral administration of (recombinant) ghosts (Rghosts) in experimental animals induced specific and therapeutic immunity against H. pylori obtained with various formulations, in rodent, cat and monkey humoral and cellular immune responses against bacterial and target components including protective mu-models have been attributed to an expression of MHC II-restricted T cell effectors rather than sIgA (88).…”

Analysis of host responses of guinea pigs during Helicobacter pylori infection

“…In mice, orogastric vaccination with mucosal adjuvants and H. pylori whole cell sonicate or individual antigens, such as urease or vacuolating cytotoxin (VacA), prevented H. pylori infection [4]. Orogastric vaccination with VacA also eradicated chronic H. pylori infection in mice [5]. In human volunteers, experimental vaccination with urease resulted in a decrease of the H. pylori infective load of the stomach only [6].…”