Key points

The need for an Helicobacter pylori vaccine: late diagnosis of Helicobacter pylori -associated gastric cancer

The gram-negative bacterium H pylori remains prevalent, infecting the stomachs of more than half the world’s population. More than 80% of infected individuals experience no untoward effects from being infected, and some studies indicate that infection may actually be beneficial for resistance to childhood asthma or esophageal diseases. H pylori is, however, a major cause of significant pathologic conditions, such as gastritis, gastric and duodenal ulcers, and gastric cancer. For most of these individuals, a diagnosis of H pylori infection followed by an appropriate course of antimicrobial therapy would be sufficient treatment, as eradication rates can exceed 90%. Nevertheless, many would benefit from an H pylori vaccine. Treatment, however, requires several antibiotics in combination with a proton pump inhibitor (PPI) taken several times a day for at least 7 days. In addition, the most common antibiotics for H pylori eradication, clarithromycin and metronidazole, are becoming less effective in some countries because of the increasing prevalence of antibiotic-resistant strains, and eradication of H pylori infection does not provide continued protection against reinfection. Some countries have reported rates of reinfection as high as 15% to 30% per year.

A more compelling justification for development of an H pylori vaccine is the relationship between H pylori and gastric cancer. Individuals who develop gastric cancer typically remain asymptomatic until cancer is well established. Therefore, by the time they have been diagnosed with H pylori infection the prognosis is poor. Approximately 1% of H pylori -infected individuals develop gastric adenocarcinoma and less than 1% develop mucosa-associated lymphoid tissue lymphoma. Identifying these individuals is impossible, but the costs of identifying all infected people within a country and providing antimicrobial therapy to all infected individuals would be prohibitive, particularly in many of the African and south Asian countries where H pylori and its associated diseases are most prevalent. A vaccine administered in early life therefore would provide the most cost-effective means of preventing gastric cancer in a nation where the incidence is high.

The need for an Helicobacter pylori vaccine: late diagnosis of Helicobacter pylori -associated gastric cancer

The gram-negative bacterium H pylori remains prevalent, infecting the stomachs of more than half the world’s population. More than 80% of infected individuals experience no untoward effects from being infected, and some studies indicate that infection may actually be beneficial for resistance to childhood asthma or esophageal diseases. H pylori is, however, a major cause of significant pathologic conditions, such as gastritis, gastric and duodenal ulcers, and gastric cancer. For most of these individuals, a diagnosis of H pylori infection followed by an appropriate course of antimicrobial therapy would be sufficient treatment, as eradication rates can exceed 90%. Nevertheless, many would benefit from an H pylori vaccine. Treatment, however, requires several antibiotics in combination with a proton pump inhibitor (PPI) taken several times a day for at least 7 days. In addition, the most common antibiotics for H pylori eradication, clarithromycin and metronidazole, are becoming less effective in some countries because of the increasing prevalence of antibiotic-resistant strains, and eradication of H pylori infection does not provide continued protection against reinfection. Some countries have reported rates of reinfection as high as 15% to 30% per year.

A more compelling justification for development of an H pylori vaccine is the relationship between H pylori and gastric cancer. Individuals who develop gastric cancer typically remain asymptomatic until cancer is well established. Therefore, by the time they have been diagnosed with H pylori infection the prognosis is poor. Approximately 1% of H pylori -infected individuals develop gastric adenocarcinoma and less than 1% develop mucosa-associated lymphoid tissue lymphoma. Identifying these individuals is impossible, but the costs of identifying all infected people within a country and providing antimicrobial therapy to all infected individuals would be prohibitive, particularly in many of the African and south Asian countries where H pylori and its associated diseases are most prevalent. A vaccine administered in early life therefore would provide the most cost-effective means of preventing gastric cancer in a nation where the incidence is high.

High incidence of gastric cancer in developing nations

Gastric cancer disproportionately affects developing nations. The prevalence of H pylori infection ranges from 10% to 60% in Western countries but can approach 100% in developing countries. This prevalence is consistent with data demonstrating that infection rates increase significantly within the US population for individuals living below the poverty level and even higher for those living in overcrowded homes or individuals without an education. The high incidence of H pylori in many nations translates to a high incidence of gastric cancer. The incidence of gastric cancer in the United States is 7.5 per 100,000 people, whereas many South and Central American countries have rates of more than 10 per 100,000 and many Asian countries have rates more than 20 per 100,000, including China at 22.7, Japan at 29.9, and The Republic of Korea at 41.8. The lifetime risk of developing gastric cancer in these countries (approximately 10% in some districts of Japan and Korea) illustrates the dire need of developing preventive therapies. A model developed in 2001 predicted the benefits to the United States of a vaccine administered in childhood if available by 2010. It predicted a decrease in prevalence to only 0.7% by the year 2100 with a concomitant decrease in gastric cancer incidence of only 0.4 per 100,000. Extrapolating this model to countries with a higher cancer incidence predicted a decrease in Japan to 1 per 100,000 and for countries with a higher incidence a reduction to 5.8 per 100,000. Therefore, despite the low incidence of H pylori in the West, most of the world would benefit greatly from vaccination against H pylori .

Challenges in inducing protective Helicobacter pylori immunity at the gastric mucosa

All vaccines must meet at least 4 requirements to optimize efficacy; an appropriate antigen, an optimum dose and frequency of administration, an optimum route of vaccination, and strong immunogenicity typically achieved by inclusion of an adjuvant or carrier. However, in the case of inducing immunity in the gastrointestinal tract, there is an additional impediment. Most traditional immunizations are designed to increase the immunogenicity of something already treated as foreign by the host, whereas a vaccine designed to stimulate immunity in the gastrointestinal tract must overcome the inherent natural local immune mechanisms to suppress immunity to luminal antigens, food, and microbes. The propensity of the host to limit immunity at mucosal surfaces may explain the paucity of vaccines for venereal diseases and gastrointestinal pathogens. It was against this background that much of the experimental H pylori vaccine research in animals was performed, primarily in mice but including some larger animals as well. Results from all these animal studies are too numerous to recount in detail, but several findings should be highlighted for their influence on the design of vaccines against H pylori in clinical trials.

Results from the mouse model that contributed to vaccine development

First, protective immunity against H pylori in mice can be achieved through almost any route of delivery. Early dogma held that oral or mucosal vaccination would be required to induce immunity in the stomach because H pylori resides in the lumen and is noninvasive. The first challenge studies, therefore, using the Helicobacter felis mouse model in the years before development of mouse-adapted H pylori strains, delivered live H felis to the peritoneal cavity or H felis lysate and cholera toxin (CT) adjuvant by oral gavage before challenge. Immunized mice achieved significant reductions in bacterial load compared with nonvaccinated control mice. Subsequent studies by many laboratories confirmed these results and used this model to study the protective host immune response. In the process it was also determined that protection could be induced through vaccination targeting other mucosal tissues including orogastric, intranasal, and rectal. Protective immunity in these models is generally defined as a significant reduction in bacterial load, although sterilizing immunity has been reported in some mice in gerbil studies using intranasal, oral, and rectal immunizations. Intranasal immunization has been demonstrated to be at least as good as orogastric immunization with the added benefit of requiring less antigen and with less risk of detrimental effects due to bacterial exotoxin adjuvants such as CT or Escherichia coli heat labile toxin (LT); yet this technology has not been incorporated into human clinical trials (see later discussion). Perhaps most surprising has been the observation that protective immunity equivalent to orogastric delivery can be induced through the use of systemic routes, including subcutaneous and intraperitoneal. These results are in contrast to the failure of systemic immunization to protect against other mucosal pathogens but have been the impetus for at least 1 phase 3 clinical trial using parenteral immunization described later.

Second, protection in mice can be achieved using numerous distinct H pylori protein antigens. It is likely that protection is mediated by a cellular inflammatory response promoted by T _H 1 and T _H 17 cells ( Fig. 1 ). In addition, several laboratories have demonstrated that vaccine-induced protective immunity can be achieved in the absence of antibodies. A partial list of antigens demonstrated to afford protection against H pylori in mice includes the urease subunits, CagA, VacA, catalase, flagellin, heat shock proteins, H pylori adhesion A, and neutrophil activating protein (NAP). Killed whole-cell bacteria may also suffice, as whole-cell lysates have been used extensively in mice as described in the original Helicobacter vaccine reports. Such whole-cell preparations have been incorporated into the clinical trial described later. The large number of antigens may prove beneficial if it is determined that a multivalent vaccine provides better efficacy in clinical trials. Ferrero and colleagues demonstrated that improved efficacy could be achieved in mice by combining heat shock protein A (HspA) with a urease subunit vaccine to achieve protection in 100% of mice compared with 80% of mice when immunized with either urease or HspA alone. This concept has been supported by a study using a canine model. As stated earlier, complete protection has been difficult to achieve in animal models. However, a multivalent vaccine consisting of VacA, CagA, and NAP was shown to be completely protective when given therapeutically in beagle dogs as determined by immunohistochemical detection of H pylori in histologic sections.

Protection against H pylori mediated by distinct T-helper-cell responses. Immunizations delivered therapeutically or prophylactically with adjuvant systems that activate T _H 17 or T _H 1 immune responses promote robust inflammation and granulocyte recruitment and activity that can reduce the bacterial load or eradicate infection. Immunizations that activate T _H 2 cells and humoral-based immune responses may prevent infection through antibody-mediated clearance of low-load bacterial challenge.

A third principal derived from numerous animal studies, which has already been incorporated into clinical trials, is the use of therapeutic immunization to treat a preexisting Helicobacter infection. The initial experiment was performed in mice using the H felis infection model and demonstrated that protection was not limited to the timing of immunization but rather to the activation of an immune response that is not activated by chronic Helicobacter infection. This experiment was subsequently performed using H pylori in mice. In addition, as noted earlier, a trivalent subunit vaccine was used to eradicate H pylori from beagle dogs through systemic immunization. Therapeutic immunization was also tested in the ferret model for treatment of Helicobacter mustelae infection. H mustelae is an indigenous infection of the ferret stomach and induces gastric disease with high similarity to H pylori infection of humans. It was speculated that unlike the H felis and H pylori animal models mentioned earlier, the nature of the H mustelae ferret model would more closely approximate the host pathogen relationship of human H pylori infection and give a better impression of vaccine efficacy. In this light, although sterilizing immunity was achieved for some animals, this protection was observed in only 30% of immunized ferrets. This study was performed with purified recombinant H pylori urease plus CT, similar to 1 of the 2 reported therapeutic immunization clinical trials described later.

Lastly, prophylactic immunization against H pylori is effective when administered to neonatal mice. This experiment has important implications if a vaccine is to be administered to humans at an early age. Although there may be utility in administering a therapeutic vaccine to the adult population in countries where H pylori -associated gastric cancer remains prevalent, a more effective strategy for long-term reductions in H pylori infections and associated pathology may be to immunize children because most infections occur in early childhood. As mentioned earlier, there is a consensus that eradication of H pylori requires a T _H 1- or T _H 17-mediated inflammatory response. Immunization of neonatal mice has historically been associated with the induction of immune tolerance. Early exposure in life to infectious agents can also lead to tolerance that can result in the inability of adults to clear the infection. In this light, the number and activity of regulatory T cells is increased in the stomachs of children infected with H pylori relative to infected adults. Therefore, the ability to protect neonatally immunized mice from challenge with H pylori at levels comparable to vaccinated adult mice is encouraging. These mice responded with strong interferon γ, interleukin (IL)-4, and IL-5 responses when immunized subcutaneously or intraperitoneally and with either Freund incomplete or complete adjuvant.

Clinical trials

To date there have been 4 major published clinical studies to test the efficacy of an H pylori vaccine ( Table 1 ) in addition to several studies to determine safety and immunogenicity. Each of these trials was distinguishable from the others based on the antigens used, the adjuvant or delivery system used, the route of delivery, or the timing of immunization compared with initiation of infection. Although all are considered unsuccessful based on the lack of protective immunity induced, some insight may be gained from an evaluation of the detailed results. The first of these studies used recombinant urease B in combination with E coli LT to treat volunteers already demonstrated to be naturally infected with H pylori . A range of doses was tested (180, 60, and 20 mg) by the oral route, but none of the vaccine formulations induced protective immunity. However, immunization induced a significant increase in urease-specific circulating IgA-producing B cells compared with placebo. The group of volunteers receiving the lowest dose of urease antigen had a significant reduction in bacterial load. These data demonstrate that it is possible to positively affect the host immune response to H pylori through oral immunization. It is particularly meaningful because the volunteers had long-standing H pylori infections and therefore a well-established downregulated immune response to H pylori that could be overcome, if not to the degree necessary to achieve bacterial eradication. Another aspect of this study is that more than 60% of volunteers receiving the LT adjuvant experienced diarrhea after only a single dose, resulting in the discontinuation of the protocol that used the higher 10-μg dose of LT before completion of the study. Many individuals receiving the 5-μg dose, however, also experienced diarrhea. A subsequent study on safety and immunogenicity with human volunteers determined that a dose of 2.5 μg of LT was necessary to achieve immune induction but that 50% of the subjects still experienced diarrhea. A separate study by the same group tested H pylori urease and LT combinations delivered by enema in an attempt to circumvent toxicity. Volunteers received 3 immunizations during the course of 4 weeks, with no adverse events reported even in the group receiving 25 μg of LT. Unfortunately, although an immunologic response to LT was achieved as measured by LT-specific B cells in the blood that were induced, no immunologic response to H pylori urease was achieved, even in individuals receiving 60 mg of urease.

Table 1

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