Vaccines

Jacques Pappo; Steven Czinn; John Nedrud

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Mobley HLT, Mendz GL, Hazell SL, editors. Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press; 2001.

Helicobacter pylori: Physiology and Genetics.

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Chapter 37Vaccines

Jacques Pappo, Steven Czinn, and John Nedrud.

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The Immune Response against Helicobacter pylori: Implications for Vaccination

The immune response to H. pylori is remarkably diverse. Evidence from human and animal studies has shown that the immune system expends substantial energy in response to H. pylori. Yet, the infection is commonly lifelong, and the immune response activated against this organism does not effect clearance or prevent reinfection after successful antimicrobial treatment (131). The immune functions in cases of spontaneous "clearance" in pediatric populations (92, 109) or in animal models (37) are unknown. However, mathematical (16) and animal (38) infection models describe a central role for the host response in the regulation of H. pylori load throughout the course of the infection, and thus, predict that shifts in the host response can affect the dynamics of this host-microbial equilibrium.

Gastric Mucosal Immune Response to Infection

In the absence of H. pylori antigenic stimulation, the stomach appears as a relatively quiescent organ, with little evidence of immunologic activity. Even after oral immunization, which supports the trafficking and migration into mucosal organs of antigen-specific T cells and IgA B cells originating in gut-associated lymphoid tissues (GALT), the uninfected stomach is segregated from the continuous entry of lymphocytes into mucosal sites (112, 128). These findings indicate a paucity of local gastric cytokines and chemokines involved in guiding integrin expression, leukocyte homing, and influx in the absence of H. pylori-driven inflammation. On the other hand, there is substantial evidence that H. pylori delivers powerful stimuli that profoundly restructure gastric cell composition and signaling. Early events in H. pylori binding to gastric epithelial cells are mediated by interactions of epithelial cell glycoconjugate and integrin receptors with their cognate H. pylori ligands (83, 148, 149, 152). Adhesion induces translocation of H. pylori protein antigens into epithelial cells by type IV secretion (125) and the focal reorganization of cytoskeletal proteins into membrane pedestals (44). Tyrosine phosphorylation of host proteins (45) and activation of NF-κB transcription factor (90) then promote the production of inflammatory cytokines and chemokines. Accordingly, gastric biopsies from infected subjects exhibit elevated levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-12, tumor necrosis factor alpha (TNF-α), growth-related oncogene, monocyte chemotactic protein-1, macrophage inflammatory protein-1 alpha, and regulated-upon-activation T expressed and secreted (RANTES) chemokines (reviewed in reference 81). The chemical gradients created by these molecules finely tune the expression of cell adhesion receptor-ligand pairs and favor leukocyte recruitment, accumulation, and activation.

It is clear that infection activates immune mechanisms that ordinarily lie dormant in gastric tissue. H. pylori upregulates expression of the CD11b/CD18 integrin and its receptor, intercellular-adhesion molecule-1 (ICAM-1; CD54) used for leukocyte transmigration into inflammatory sites (25, 71, 73). H. pylori can also increase gastric epithelial cell expression of CD80 and CD86 (164) required for T cell costimulation and upregulates class II major histocompatibility complex (MHC) in vivo (47, 159). Importantly, the class II MHC heterodimer may itself function as a receptor for H. pylori (52). Thus, H. pylori reprograms the stomach to function as a target end organ for leukocyte homing and amplifies the immunologic machinery to buttress local T-cell activation during infection. These observations also raise the possibility that vaccine-specific effectors may accumulate and undergo local activation in the infected stomach.

B-cell recruitment and local proliferation

The compartments where H. pylori antigens are scanned by the immune system are not completely understood, but these antigens must permeate both mucosal and peripheral lymphoid organs, as evidenced by the development of heterogeneous serum IgG and mucosal IgA antibody responses during infection (24, 95, 114). H. pylori-infected gastric tissue harbors increased numbers of H. pylori-specific antibody-secreting cells (113). The polymeric Ig receptor, involved in transport of IgA dimers into the lumen, is substantially upregulated in infected gastric epithelium and permits concomitant secretion of elevated levels of anti-H. pylori secretory IgA (2, 59, 84). The gastric B cells and their clonal progeny commonly assemble into mucosal follicles (147), but these B cells appear unable to convert gastric epithelial cells into the specialized M cell lineage (93) found elsewhere at mucosal surfaces overlying lymphoid aggregates in GALT (127). The chemokine B lymphocyte chemoattractant and its receptor, CXCR5, direct B-cell movement and follicle formation (54). This receptor-ligand pair localizes to B-cell aggregates in H. pylori-induced mucosa-associated lymphoid tissue (MALT) lymphoma and gastric lymphoma (115) and thus appears to be involved in shaping H. pylori follicular reactions. The size of the B-cell repertoire for H. pylori is not known, but substantially diverse antibody specificities are used during infection (95), including specificities directed against epithelial and Ig self-epitopes (67, 155).

Commitment and activation of specialized gastric T cells

H. pylori infection leads to the progressive accumulation of T cells in the proximal and distal stomach. These T-cell infiltrates are frequently dominated by the CD4⁺T helper (Th) cell phenotype (7) and may organize into discrete parafollicular T-cell regions resembling the GALT architecture (59). Gastric resident T cells exhibit upregulated IL-2 receptor expression (82) and recognize H. pylori peptide ligands using various T-cell receptor (TCR) Vβ chains (35), although only a relatively small (ca. 20%) proportion of gastric T-cell clones derived from infected subjects is able to proliferate to H. pylori antigens in a class II MHC-restricted fashion (32). The infected gastric tissue constitutes an enriched source of effector T cells, with frequencies of H. pylori-specific mucosal T cells in the range of 1 to 10% compared with a frequency of ≤ 0.05% antigen-specific T cells in the peripheral lymphocyte pool (33, 35). Functionally, these gastric T cells display Th-cell function for B-cell proliferation and IgA production (32, 33), but also appear to mediate CD95 (APO-1/Fas) interactions resulting in apoptosis of B lymphocytes and epithelial target cells (33, 135).

Another response to H. pylori infection is characterized by the emergence of gastric intraepithelial lymphocytes (gIEL) (74). The vast majority of murine gIEL derived from infected tissue are TCR αβ⁺CD4⁺, exhibit a memory/activation phenotype, and display ubiquitous signaling/adhesion molecules CD2 and CD28. These gIEL are well equipped for transendothelial migration, as evidenced by the expression of CD11a^hi, CD44, and lymphocyte-Peyer's patch adhesion molecule 1 (LPAM-1) and LPAM-2 (79). The homing of αβ⁺CD4⁺ into the stomach has been established in vivo, and gradual acquisition of CD103, which mediates adhesive interactions with gastric epithelial cell Ecadherin, marks the conversion of αβ⁺CD4⁺T-cell emigrants into resident gIEL postinfection (80).

Programming by H. pylori for Host Persistence during Natural Infection

The type and magnitude of immune responses are governed by cytokines derived from functionally polarized Th-cell subsets. The Th1 subset drives cell-mediated immunity and inflammatory responses through the production of interferon-γ (IFN-γ), IL-2, IL-12, IL-18, lymphotoxin α, and TNF-α, while Th2 cells are associated preferentially with mucosal IgA induction and secrete IL-4, IL-5, IL-6, IL-10, IL-13, and transforming growth factor β. Little is known about the sorting of H. pylori peptides and the strength of TCR signaling throughout the course of the infection. However, there is increasing evidence that H. pylori biases Th-cell differentiation and that the ensuing polarization toward a Th1-type response contributes to H. pylori gastric disease.

Live H. pylori differentially stimulates secretion of IL-12 (70), a cytokine produced by antigen-presenting cells (APCs) involved in Th1-cell generation via upregulation of IFN-γ production (108). Populations of gastric T cells analyzed from H. pylori-infected biopsies show an overabundance of IFN-γ⁺ cells and IFN-γ-secreting cells relative to IL-4-producing cells (7, 105), a profile consistent with a Th1 phenotype. Further, IFN-γ appears to predominate in the stomach even in the absence of H. pylori gastritis (88), raising the possibility that the gastric microenvironment itself may select for Th1-cell development. The skewing of the Th response is also observed in the clonal progeny of gastric CD4⁺T cells isolated from infected stomach tissue, since a majority of the H. pylori-specific T-cell clones established from infected subjects display a Th1 type (33, 146). Recent evidence points to the ability of chemokines and their receptors to control the selective migration of polarized Th subsets (126). The C-C chemokine RANTES, which is upregulated during H. pylori infection (142), mediates transendothelial migration of Th1 but not Th2 cells (89). Therefore, proinflammatory Th1-type cells predominate in the infected stomach not only because Th1 cells are expanded by their encounters with H. pylori, but also because the repertoire of chemokines may exclude Th2-cell influx.

Immune evasion strategies employed by H. pylori

To explain its persistence in human populations, H. pylori has been suggested either to tolerize the host from mounting a protective immune response or to interfere with immune responses that would otherwise result in its elimination (15). While H. pylori carriage does not induce peripheral tolerance (60), several studies indicate the ability of H. pylori to downregulate T-cell proliferation (97) and IL-15 transcription (106) and to restrict cognate interactions for T-cell activation through perturbation of endocytosis and antigen processing (122). Recent findings show that the survival of H. pylori may also be linked to its capacity to negatively select T cells via induction of apoptosis (156). It is precisely because H. pylori polarizes the type and magnitude of the host response that immunization may be viewed as a means to deviate a Th1-dominant response resulting in infection and gastritis to another immunologic state capable of interfering with H. pylori persistence and disease.

Preventive and Therapeutic Vaccines

Rationale for Vaccination

The global H. pylori burden is estimated at 10¹⁶ organisms (23). The rising rate of antimicrobial-resistant strains (65, 116), the emergence of multidrug-resistant strains (30), and the development of adverse events to treatment (20) represent important causes of primary treatment failures and pose formidable challenges for the successful treatment of this infection. Vaccination to prevent infection or to treat an already established infection has surfaced as an increasingly viable approach for the clinical management of H. pylori infection. Vaccination should prove efficacious against drug-resistant strains and may well limit the development of drug-resistant H. pylori. As shown in experimental models (see "Experimental Models of Immunization and Vaccine Efficacy," below), immunization also protects against reinfection and can interfere with transmission. Although the prevalence of H. pylori infection in the developed world appears to be declining, estimates from a mathematical model indicate that the disappearance of H. pylori in the United States will take in excess of a century (137). Indeed, a recent study designed to evaluate the impact of a vaccine on the cost of H. pylori disease argues for a very favorable cost-benefit ratio (136). However, a salient and compelling argument for vaccination lies in its ability to modulate the host immune response programmed by infection, and thus, in the potential to avert the development of long-term inflammatory sequelae. There is now direct evidence that the proinflammatory cytokine macrophage migration inhibitory factor inactivates transcription of the p53 tumor suppressor (77) and that immune deviation can lessen the severity of chronic gastritis and limit the evolution of gastric atrophy (56). Furthermore, recent studies have suggested that polymorphisms in the IL-1β gene cluster, controlling the magnitude of the host immune and inflammatory responses, may explain clinical outcomes of H. pylori gastroduodenal disease (46). Therefore, vaccination against H. pylori is currently poised as a singularly advantageous strategy for infection management with the potential to prevent the development of gastric adenocarcinoma.

Feasibility of Vaccination against H. pylori

The first studies on oral immunization with H. pylori antigens (27) were stimulated by observations that IgA responses can protect against mucosal infections and that H. pylori is a noninvasive pathogen that remains at the mucosal surface. The existence of a surrogate H. pylori model based on murine Helicobacter felis infection (100) enabled the rapid expansion of immunization studies for the control of helicobacter infection (Table 1). Observations of immune protection from challenge in orally vaccinated mice were generated in short order (18, 19, 28). In the piglet H. pylori model available at that time, mucosal or parenteral vaccinations were found to diminish the infection density, but systemic vaccination resulted in a more severe neutrophilic and lymphocytic gastritis than that of unimmunized animals (41). Although the nature of the protective immune response was not understood, subsequent experiments using the murine H. felis model firmly established the principle of oral vaccination in the context of a mucosal adjuvant for prevention (53, 104, 118, 128) and treatment (21, 36) of the infection. The seminal observations of interference with helicobacter infection by immunization represent the scaffold for human vaccine development aimed at control of H. pylori disease on a global scale.

Table 1

Animal models of helicobacter vaccine immunity.

Experimental Models of Immunization and Vaccine Efficacy

The recognition that H. felis lacks the cag pathogenicity island and that it must signal the host in an epithelial pedestal-independent fashion (141) accelerated the development of murine H. pylori models and widened the search of predictive models of human infection and vaccination outcome. In recent years, experimental models of H. pylori vaccine immunity have been described in mice, felines, germ-free piglets, and nonhuman primates (Table 1). The utilization of murine models, in particular, has confirmed the protective effect of vaccination against H. pylori infection with adapted cagA⁺or cagA mutant strains of varying colonization densities (96, 110, 130). Not only can immunization protect against challenge with H. pylori, but it may also eradicate or substantially diminish the extent of an established infection and confer protection against rechallenge (61). In ferrets, oral immunization can result in cure of natural Helicobacter mustelae infection in approximately one-third of the treated animals (26). Recent findings in gnotobiotic piglets (43) and in cats (9) have provided further cues on the ability of vaccination to limit H. pylori colonization. Sequential oral immunizations in rhesus monkeys appear to prevent the natural transmission of H. pylori in about 30% of vaccinated animals (39). However, vaccination of rhesus monkey hosts has little (102) or no effect (145) in preventing colonization upon deliberate challenge, and treatment of a chronic infection by immunization in this animal model remains unproven (103).

A survey of outcomes from vaccine studies in experimental H. pylori models reveals a gradient of vaccine efficacy from murine to nonhuman primates. This therapeutic gradient may reflect the degree of genetic adaptation of H. pylori strains for colonization of murine hosts not naturally susceptible to infection (101, 110) when compared with H. pylori strains naturally fit for long-term survival in susceptible rhesus monkey hosts (38). On the other hand, vaccination outcomes ranging from complete immune protection in murine models (63, 110) to minimal vaccine efficacy in rhesus monkeys (103) could simply be reasoned on the basis of our limited knowledge of mucosal immunization of nonhuman primates. Thus, while the proposition of immune intervention for control of H. pylori infection is supported by the available evidence, to what extent, or indeed which animal model of H. pylori infection is predictive of vaccination outcomes in humans is presently unknown. A human challenge model (66), while limited to an acute infection, may now enable preventive vaccination trials to be conducted in a human population.

What Is Meant by Immune Protection? Effect on Infection Density and Gastritis

Important features of animal models of vaccine efficacy are the endpoints that are measured and how these endpoints relate to human bacterial burden and disease. It is now recognized that the vaccination outcome must be interpreted carefully and that "immune protection" is not necessarily synonymous with the abstract notion of "sterilizing immunity," i.e., absolute blockade or eradication of the infection. For experimental models involving H. felis, complete prevention or cure of the infection has been judged by quantitation of the bacterial population by using histological methods, urea hydrolysis assays, or both. However, both of these methods appear unable to reliably detect low levels of infection (below 10⁴ to 10⁵ organisms/g). Indeed, antimicrobial treatment of immunized "protected" mice effects resolution of the underlying gastritis driven by residual organisms (49). In H. pylori models, a common readout of the vaccination outcome is determination of bacterial burden by quantitative culture of hosts challenged with a single H. pylori strain within weeks postvaccination. While bacterial culture is considered to be a reproducible "gold standard" to measure the presence of viable organisms, it is apparent that characteristics of the host genetic background and the H. pylori challenge strain can specify for a wide range of infection density (29, 38, 101, 110, 154). Therefore, the determination of vaccine efficacy in murine models might be more instructive if examined in host strains of various genetic backgrounds challenged with different H. pylori strains. Further, the observation of transient experimental infections (29, 37) raises the possibility that "immune protection" in certain models may represent the accelerated rate of clearance of an otherwise transient infection.

Vaccination can provide a complete barrier to infection in some murine models with modest colonization efficiency (110, 140), but immune protection when the infection burden is comparable to that of humans (6) ordinarily involves the attenuation of infection density by 1 to 3 log CFU/g of stomach (50, 96, 111, 129). Because the H. pylori density is associated with the extent of gastritis and epithelial injury (6), the findings of immune protection also point to vaccination as a means to downregulate H. pylori-mediated inflammation and support the notion that a histological readout of gastritis should be investigated in vaccine studies. This is particularly germane in view of observations of increased leukocytic influx upon immunization against H. mustelae (162) and H. pylori (41, 103). In murine H. felis models, this phenomenon of "postimmunization gastritis" has been described months postvaccination and is characterized by increased corpus infiltration of IgA⁺B cells and CD4⁺ and CD8⁺T-cell populations (49, 118) of unknown antigen specificity. On the other hand, recent findings from vaccination against H. pylori in nonhuman primates (39) and humans (119) suggest that oral immunization does not power the development of gastritis. Further studies are required to fully understand the relationships of animal model, antigen-adjuvant combination, and in particular, vaccine efficacy on the onset of gastritis postimmunization.

Targeted Sites for Immune Induction and Antigen Recognition

MALT is largely represented by the organized lymphoid tissue in the oropharyngeal, intestinal, and genital tracts. These structures contain discrete cytokine microenvironments that direct mucosal T-cell activation and IgA B-cell differentiation upon appropriate antigenic stimulation. Early studies on immunization suggested that immune protection requires the genesis of effectors from GALT (18, 19, 28). In more recent studies, it has been further shown that vaccine delivery to oral/buccal, nasal, Peyer's patch, and rectal tissues confers immune protection from infection (40, 96). During mucosal immunization, IgA⁺B cells and CD4⁺T cells are recruited and expanded in the gastric mucosa (49, 63, 128). Gastric localization of vaccine-specific leukocytes requires the upregulation of homing receptor-ligand pairs signaled by challenge with live organisms or by the presence of an underlying infection (see "Gastric Mucosal Immune Response to Infection," above). However, it has not been conclusively established that the gastric resident leukocytes generated by vaccination are MALT emigrants. Indeed, recent phenotypic studies of gastric α4⁺ TCRαβ⁺ cells after oral immunization point to the peripheral lymphoid pool as a contributor of gastric vaccine effectors (129) and support findings of parenteral immunization, especially at subcutaneous sites that target the lymph nodes draining the stomach, as an additional route that promotes immune protection (69) and accretion of IgA⁺ cells and T cells in gastric tissue (50).

Antigens, Adjuvants, and Delivery Systems for H. pylori Vaccines

The initial vaccine studies employed bacterial lysates delivered orally with cholera toxin (CT) as a prototype mucosal adjuvant (reviewed in references 11, 51). However, the complex nature of whole-cell vaccines and their potential for eliciting undesirable immune reactions have favored the use of purified recombinant antigens for vaccine development. Several approaches have guided the identification of H. pylori vaccine antigens, including in silico prediction from genomic analyses, comparison of antigenic patterns using proteomics or libraries of H. pylori genomic DNA, and theoretical and experimental analyses of putative virulence factors.

Genomic analyses have revealed five paralogous gene families of outer membrane proteins represented in both sequenced H. pylori strains. These gene families comprise from 3 to 33 members, display a C-terminal hydrophobic motif, and consist of potential vaccine candidates with porin function and adhesive properties (3). The genomics approach has also revealed that candidate vaccine proteins may be susceptible to antigenic diversification, since expression of these antigens may be switched on and off by a slipped-strand mispairing repair mechanism, as found in the fucosyltransferase genes encoding the enzyme required for Lewis X and Y side chain addition on lipopolysaccharide (5). By proteomic analyses, the screening of sera from infected subjects has resulted in the identification of about 30 immunodominant H. pylori antigens, including the neutrophil-activating protein HP-NAP, flagellar and heat shock proteins, the urease B subunit, and elongation factors (95). Screening of sera from vaccinated mice against an H. pylori expression library has likewise identified urease, the heat shock protein HspB, putative membrane proteins, and the lipoprotein Lpp20 (75). In vitro assays with antibody-secreting cells (113) or with T-cell clones (32) derived from infected subjects have further identified membrane proteins, the hemagglutinin HpaA, and CagA and VacA as potential candidates. Of these, the enzymes urease and catalase, the UreB subunit of urease, the heat shock proteins HspA and HspB, the leukocyte-activating HP-NAP, the lipoprotein Lpp20, and the CagA and VacA antigens have been shown to be protective in infection models (21, 53, 91, 104, 110, 118, 128, 130, 139).

Virtually all of the vaccine studies reporting efficacy have shown a strict adjuvant requirement. The mucosal adjuvants CT and the closely related E. coli heat-labile toxin (LT) are AB₅ molecules with superior capacity for driving Th2 differentiation and IgA production when delivered to MALT (107). Multiple immunizations in the absence of CT adjuvant, even at high antigen doses, generate appreciable levels of serum IgG and mucosal IgA antibody but fail to mediate immune protection (161). The toxicity of CT and LT molecules in humans has stimulated the investigation of alternative adjuvants and delivery systems for H. pylori vaccination. Dissection of the AB₅ toxin adjuvant activity has shown that genetic detoxification of LT via site-directed replacement of serine to lysine at position 63 is consistent with vaccine efficacy (61, 111), while immunization with the recombinant CTB or LTB subunits is not (13, 160). Immunization with the orally active adjuvant muramyl dipeptide has no measurable effect on antibody induction or H. mustelae infection, but instead appears to lead to mucosal damage (162). Oral delivery of antigen encapsulated in poly (d-l-lactide-coglycolide) microspheres, aimed at augmenting M cell-dependent uptake (48), enhances the anti-H. pylori antibody responses (94), but the value of this strategy in protection against infection has not been established. The construction of additional mutant LT molecules (reviewed in reference 132), as well as the design of novel CTA-based fusion protein adjuvants (1) and nanoparticulate delivery systems with IL-12-dependent adjuvant activity (144), should further encourage work into the search for clinically viable mucosal adjuvants for H. pylori vaccines.

Several adjuvants exhibit efficacy in parenteral immunization protocols. Alum, complete Freund's adjuvant, and incomplete Freund's adjuvant effect immune protection of varying magnitude when delivered subcutaneously or intraperitoneally with H. pylori antigens (41, 50, 64, 163), although repeated intramuscular injections of a conventional alum-based vaccine appear ineffective (102). Immunization by the subcutaneous route with the saponin adjuvant QS21 is protective against challenge, and highly efficacious when used therapeutically in a murine model (68, 69). Recent studies have shown subcutaneous immunization with the LT adjuvant, or with combinations of LT and LTB, to have equivalent protective activity to oral vaccination with LT (160).

An alternative approach to the use of mucosal adjuvants for recombinant subunit vaccines involves the use of live vectors. A replication-defective adenovirus vector delivered by intramuscular injection reduces the extent of H. felis infection (85). Injection of poliovirus replicons encoding the urease B subunit generates specific IgG2a antibody and IFN-γ responses (124), but its effect on protection is currently unknown. Oral or intranasal immunization with a live attenuated Salmonella enterica serovar Typhimurium-vectored vaccine is also efficacious in controlling the extent of H. pylori colonization (22, 62).

Whether employing mucosal, parenteral, or combined immunization routes, vaccine studies accompanied by a histopathology readout of the target end organ should reveal whether a particular antigen-adjuvant pair has the instrinsic ability to further drive the proinflammatory Th1 response committed during infection. Studies using CD4⁺T cells and mucosal APC (70, 72) have the potential to guide the selection of antigens, adjuvants, and delivery systems as a function of their effects on Th-cell differentiation and may ultimately aid in the rational design of H. pylori vaccines.

Mechanisms of Immune Protection

B Cells and Antibody Induction

In murine H. pylori infection models, the gastric B-cell pool is in the order of 1 to 2 × 10⁶ IgA B cells/stomach (29); this population of IgA⁺ cells harbors a very high frequency (ca. 10%) of specific antibody-containing cells that cluster in gastric mucosa after immunization (96). Local salivary gland immunity appears to contribute substantially to the overall IgA antibody level during oral immunization (143), and administration of high concentrations of IgA monoclonal antibody can protect from challenge (28). In humans, IgA antibody may delay the onset of H. pylori infection in some populations (153), and its fine specificity can be shown to differ after immunization and during spontaneous clearance (14). On the other hand, IgA deficiency does not increase the susceptibility to infection (17), and B-cell deficiency in μMT mice has little effect on the severity of the infection (12) and, in fact, may be compatible with spontaneous clearance (134). While a frequent outcome of protective immunization against H. pylori is the generation of elevated serum IgG and mucosal IgA antibody responses (19, 28, 104, 128), careful analysis reveals that the relationship between IgA antibody level and the extent of immune protection is discordant (96, 161). Indeed, recent studies in B-cell-deficient μMT mice now indicate that both prophylactic and therapeutic vaccinations mediate immune protection in a B-cell- and antibody-independent fashion (14, 50, 151).

Gastric T Cells and the Th-Cell Theorem

If effector mucosal IgA responses are not central to immune protection, what then mediates H. pylori vaccine immunity? The evidence has suggested, and more recently established, the involvement of T cells in vaccine-directed protection. Approximately 10⁶ CD4⁺T cells/stomach are generated during experimental infection of mice (29), and this CD4⁺ population is substantially expanded during protective vaccination (49, 96). The mucosal adjuvant CT, frequently employed in protective vaccination trials, requires CD4⁺T cells for demonstrable adjuvant activity (76). Direct evidence from studies in MHC gene knockout mice shows that T cells regulate the infection burden (129) and that vaccine efficacy is strictly dependent on the genesis of activated CD4⁺T cells (129) and governed by intact class II MHC function (50, 129). Furthermore, adoptive transfer of Th cells from vaccinated donors into unimmunized recipient mice reduces the severity of the infection (64, 87, 121) (Fig. 1). The frequency of antigen-specific T cells has not been estimated, but the homing into gastric tissue of about 2×10⁴ TCRαβ⁺CD4⁺ cells after adoptive transfer is sufficient to confer immune protection (87). Interestingly, adoptive transfer of Th-cell effectors circumvents CD4 deficiency and protects from challenge, but adoptive transfer into class II MHC gene knockout mice does not, even though transferred CD4⁺T cells can be shown to populate the stomach (Fig. 1). These observations suggest that CD4⁺T-cell effectors must experience interactions between the TCR and the MHC to result in persistence and expression of their Th-cell program.

Figure 1

Vaccination with H. pylori. Groups of C57BL/6 wild-type donor mice were immunized intranasally with 100 μg H. pylori lysate antigen and 10 μg CT adjuvant, or with CT adjuvant alone. H. pylori immunization protected from infection relative (more...)

The polarization of Th-cell effectors during antigenic stimulation constitutes an important determinant of immune protection. In vaccine studies using CT adjuvant, sequential oral immunizations give rise to a progressive increase in IL-4 and downregulation of IFN-γ production (138). Oral immunization may also increase IFN-γ expression (22, 63), but immune protection is only associated with the gastric expression of IL-4 and IL-5 (63) or with secretion of IL-10 by peripheral CD4⁺T cells (22). Other studies supporting a role of Th2 responses in mucosal protection against infection have shown that infected IL-4 knockout mice exhibit a greater H. felis load than wild-type mice (121), and treatment in vivo with anti-IL-4 increases H. pylori colonization and thwarts the protective effect of vaccination (86). While immunization of Fas-L-deficient mice (a Th2-prone strain) does not result in enhanced protective activity relative to that observed in immunized wild-type mice (78), the adoptive transfer of a Th2 cell line suppresses the subsequent infection resulting from H. felis challenge (121). Indeed, a disabled Th1 response, as observed in IFN^−/− mutant mice, still permits the development of protective vaccine immunity (140). Factors such as host genetic background (150, 154), and nature, intensity, and duration of antigenic stimulation (133) effect Th-cell differentiation and likely account for differences in Th usage observed in the various vaccine models. Nevertheless, the induction of Th-cell responses, whether involving a dominant Th2 program or a Th2 phenotype superimposed on a Th1 response, appears to be temporally associated with vaccine protection. How these Th cells signal the gastric microenvironment to effect protection from H. pylori infection is unknown.

Can Immune Protection Exist Independently of Gastritis?

A number of studies have evinced an association between vaccination and the evolution of gastritis of greater severity than that observed in nonimmunized hosts (see "What Is Meant by Immune Protection? Effect on Infection Density and Gastritis," above). In H. pylori-infected SCID mice, the adoptive transfer of spleen cells triggers marked gastritis and metaplasia and progressively stunts colonization (42) to a level comparable to that achieved after immunization. Results from the H. felis model using CD54 knockout mice likewise suggest that recruitment of inflammatory cells is required to effect immune protection from challenge (117), but studies with H. pylori infection reveal no effect of ICAM-1 deficiency on vaccine-mediated efficacy (87). It has been recently shown that immune protection can occur in a strictly IFN-γ and IL-12-dependent fashion without the coordinate exacerbation of gastritis in a short-term protection model (85). Furthermore, vaccine protection can develop in the absence of demonstrable gastritis (140). It is not clear whether the gastric infiltrate in vaccinated hosts is composed of Th1 cells, Th2 cells, or both. Phenotypic characterization of the Th-cell effectors resident in the postvaccinal infiltrate should elucidate the relative contribution of polarized Th cells to gastric inflammation. These analyses have important implications for dissecting and understanding the downstream effects of vaccination, since IFN-γ and IL-12 strongly pattern the development of gastritis and mucosal injury (120, 123), while Th2 responses attenuate chronic gastritis and mucosal atrophy (10, 56). Taken together, the evidence suggests that the inflammatory response mounted against infection is dissociable from the vaccine response leading to the accumulation of protective T cells. The advent of models of gastric atrophy, metaplasia, and cancer in insulin-gastrin transgenic mice infected with H. felis (157) and in gerbils colonized with H. pylori (158) now enables testing directly whether vaccine immunity modifies the nature of long-term gastritis and prevents the development of gastric malignancy.

Clinical Trials

The safety and immunogenicity of oral immunization with recombinant H. pylori urease and LT adjuvant have been tested in a double-blind, placebo-controlled trial in H. pylori-infected adults (119). The vaccination schedule resembled that devised for mice and resulted in the induction of IgA antibody-secreting cells, but only in a modest reduction of bacterial load in some subjects. However, approximately two-thirds of the volunteers experienced significant diarrhea attributable to LT administration. The observations in a murine model of immune protection with a genetically detoxified LT molecule (61, 111) have led to a clinical trial using H. pylori whole cells and the mutant LT192G adjuvant administered three times at 2-week intervals (98). This oral immunization protocol resulted in mild adverse events and in elevated serum and gastric IgG and IgA antibody levels. However, no protective effect was achieved at trial completion. An alternative delivery system under investigation in uninfected subjects involves salmonella-vectored oral immunization. While protective in murine models (22, 62), the early clinical experience with a phoP/phoQ attenuated S. enterica serovar Typhimurium (4) or Typhi (34), has shown little or no effect on antibody induction.

The active search for effective but nontoxic mucosal adjuvants and the recent reports of immune protection by intranasal and parenteral vaccination (see "Antigens, Adjuvants, and Delivery Systems for H. pylori Vaccines," above) are certain to stimulate future clinical vaccine trials.

References

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Pappo J, Czinn S, Nedrud J. Vaccines. In: Mobley HLT, Mendz GL, Hazell SL, editors. Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press; 2001. Chapter 37.

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The Immune Response against Helicobacter pylori: Implications for Vaccination
Preventive and Therapeutic Vaccines
Mechanisms of Immune Protection
Clinical Trials
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