1. Helicobacter pylori Vaccine Development Catherine O. Johnson March 9, 2006

2. Pathogen Background Gram negative bacteria Colonizes the human gastrointestinal tract and stomach Oral-Oral or Oral-Fecal routes of person- to-person transmission

3. Requisite Nasty Pictures

4. Nasty Pictures (2)

5. Mechanism of Infection H. pylori is able to establish long-term infection in most individuals  Colonizes the mucus layer of the stomach lumen  Goes through adherent and non-adherent phases Mechanism used to evade host defenses is not completely understood  Able to modulate host immune system to favor a TH1-type inflammatory response; able to specifically modulate the immune responses that would clear the bacteria  Extensive intrastrain and interstrain diversity  Genetic variation in hosts

6. Burden of Disease Most of the time, infected individuals are asymptomatic 15-20% of infected individuals will develop severe gastrointestinal disease  Gastric tumors (particularly stomach body)  Peptic ulcers & active gastritis Approximately 50% of the global population is infected with H. pylori  Higher rates in those of lower SES status  80-90% of persons living in developing countries are infected by early adulthood

7. Worldwide Prevalence of Infection

8. Treatment Triple Therapy  Proton pump inhibitor, amoxicillin and clarithromycin  Dosed 2 times per day for 1 week Results in eradication of the organism in >80% of individuals Does not prevent recolonization; antibiotic resistance is becoming problematic

9. Vaccine Development Interest in both preventive and therapeutic vaccines Relatively good results in animal models Problems with extending vaccines to human subjects  Multiple doses required; incomplete protection  Route of immunization: oral, rectal, intranasal  Genetic diversity of the organism

10. Genetic Diversity of H. pylori Most genetically diverse bacterial species Strains differ in  Genome size  Gene order  Genetic content  Allelic profile Associations between specific strains and increased incidence of severe sequelae  Cag pathogenicity island  Specific VacA cytotoxin alleles

11. Vaccine Delivery Difficult to generate an immunologic response in the stomach/gut with a systemic inoculation Small studies have shown results with oral vaccines Rectal, intranasal, intrajejunal vaccines are also being explored

12. Clinical Trial of Vaccine Trial of an oral therapeutic vaccine Four doses of either 20, 60, or 180mg of recombinant H. pylori urease was given to infected subjects Trial demonstrated immunogenicity of the vaccine; however a high proportion of the subjects reported diarrhea