Download Helicobacter Pylori Vaccine Development [Catherine Johnson]

Helicobacter pylori Vaccine
Development
Catherine O. Johnson
March 9, 2006
Pathogen Background
• Gram negative bacteria
• Colonizes the human gastrointestinal tract
and stomach
• Oral-Oral or Oral-Fecal routes of personto-person transmission
Requisite Nasty Pictures
Nasty Pictures (2)
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
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
Worldwide Prevalence of
Infection
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
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
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
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
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