Possible Correlates of Long-Term Protection againstHelicobacter pylorifollowing Systemic or Combinations of Mucosal and Systemic Immunizations

Abstract

The ability to induce long-term immunity to Helicobacter pylori is necessary for an effective vaccine. This study was designed to establish the most efficient route(s) (systemic, mucosal, or a combination) of immunization for induction of long-term immunity and to define correlates of protection. Mice were immunized orally alone (oral group), intramuscularly (i.m.) alone (i.m. group), orally followed by i.m. (oral/i.m. group), or i.m. followed by orally (i.m./oral group). Long-term protective immunity to oral H. pylori challenge was observed 3 months after immunization through the i.m. or oral/i.m. route. Protection correlated with an increase in H. pylori-specific interleukin-12 and both immunoglobulin G1 (IgG1) and IgG2a serum titers following challenge. Mice that were not protected (oral or i.m./oral) had increased levels of IgA in both sera and Peyer's patches. This study demonstrates the ability to induce long-term immunity against H. pylori, provides correlates of protection, and illustrates the crucial role of the immunization route(s).Helicobacter pylori is a gram-negative spiral bacterium that colonizes the gastric epithelium in nearly 50% of the world's population. Infection is typically acquired early in childhood and continues throughout the life of the host, leading to chronic gastritis and in some cases peptic ulcer disease or gastric cancer (32, 37). In spite of the development of H. pylori-specific immune responses, the bacteria are rarely eliminated from the gastric epithelium (6). Treatment for H. pylori infection includes a combination of a proton pump inhibitor and two antibiotics. However, antibiotic resistance, high cost, and recurrence of infection make world-wide eradication through drug therapy problematic. While development of a vaccine is ideal, the challenge lies in inducing long-lasting immunity. Various routes of immunization have been used to demonstrate protection against H. pylori in mice: oral, intranasal, intrarectal, intradermal, and subcutaneous (11,13,15,20,24,34,35,43). Most H. pylori vaccine studies challenge animals 2 to 4 weeks after immunization, when the immune response is still in the acute effector phase (13, 15, 18, 20-22, 35, 36), and this does not test generation and maintenance of immunologic memory. Thus, results from previous studies cannot be used to predict long-term protection.Mucosal immunization is a route commonly used to induce mucosal immunity. While immunizing through a mucosal route seems optimal for eliciting mucosal immunity, no studies have reported its success in the generation of H. pylori immunologic memory. Unlike for Helicobacter felis, against which long-term protection can be achieved through immunization, a longterm-protection model for H. pylori has yet to be reported (27,33). Recent studies have demonstrated that immunization through a combination of mucosal and systemic routes may increase mucosal immunity (22,25,39,40).The mechanisms by which protection against H. pylori occurs are still unknown. In general, immune responses, such as l...

Prolonged Protection against Intranasal Challenge with Influenza Virus following Systemic Immunization or Combinations of Mucosal and Systemic Immunizations with a Heat-Labile Toxin Mutant

“…Although LT or CT and their mutants have been extensively used as mucosal adjuvants, their use as systemic adjuvants has been far more limited. CT has been shown as an effective systemic adjuvant in several studies (16,26,48,53,58). Interestingly, it was shown that, whereas the systemic administration of CT induced both TH1-and TH2-type responses, the nontoxic moiety of CT, CTB, induced TH1-type responses (2).…”

“…CT has been shown as an effective systemic adjuvant in several studies (16,26,48,53,58). If combinations of mucosal and systemic vaccinations should be used for humans, it would be more practical to use the same vaccine formulation for both mucosal and systemic vaccination regimens.…”

Mucosal Immune Regulation and Vaccines for Helicobacter-associated Gastritis

“…It has been reported that intramuscular immunization is most effective and produces the most longlasting effects against infection with respect to the induction of anti-H. pylori-specific antibodies [54]. Since the protective effect correlated with increased IL-12 production in splenocytes, systemic activation of Th1 responses may be required to increase the duration of protection from immunization.…”

“…The expression level of B7-H1 in H. pylori infected gastric epithelium is much higher than that of uninfected cells. B7-H1 was identified as a programmed death-ligand 1, PDL-1 belonging to the B7 family of molecules [26][27][28]. PDL-1 binds to the programmed death-1 (PD-1) receptor, which results in the down-regulation of T cell activation [29].…”

Helicobacter pylori: A Brief History of a Still Lacking Vaccine

“…Since H. pylori colonization occurs at the mucosal level, particular emphasis has been given to oral immunization, although other mucosal routes of immunization [36], as well as the parenteral route [35] or prime-boost regimens, have been considered [37][38][39]. Mucosal immunization requires the use of strong mucosal adjuvants, as proteins are poor immunogens when administered mucosally.…”