2004N-0355 - Scientific Considerations Related to Developing Biotechnology Products
FDA Comment Number : EC3
Submitter : Ms. J LeClair Date & Time: 09/23/2004 04:09:10
Organization : Ms. J LeClair
Health Professional
Category :
Issue Areas/Comments
GENERAL
GENERAL
3. Cancer Prevention Vaccine (continuation from previous comments 7995)
3. Helicobacter pylori (gastric lymphoma and gastric cancer)
Disease burden. In 1982 the isolation of Helicobacter pylori (HP) radically changes the conceptualization of several chronic gastrointestinal illnesses including gastritis, peptic ulcer, gastric lymphoma and gastric cancer. HP is a Gram-negative, spiral, microaerophilic, and flagellated bacterium, with a unique ecological niche, the stomach, almost exclusively extracellular, and whose unique host is human being (very ancient adaptation and co-evolution). HP may be now considered as one of the most widespread infection worldwide, approaching a 50-60% prevalence rate of the population. Initially thought to be restricted to developed countries, evidence came that developing countries not only were affected but even more heavily: seroprevalences were 4-6 times higher in subjects from developing countries at early as 10 years of age and remained constantly and significantly higher in older persons . Its transmission is from person to person, oral-oral and fecal-oral. It affects high-density population with lower socio-economic status including in developed countries. A natural reservoir in an animal species has not been identified to date. Most newly acquired HP infections happen before the age of 10 years or even below the age of 2 years (Turkish in Germany and developing countries). The acquisition is mainly intrafamilial, mother-to-child , or also child-to-child . Its persistence is life-long.
HP is responsible for several pathological features: chronic (antral) gastritis, atrophic gastritis, chronic gastritis, up to 15% of them evolving into duodenal ulcer , gastric ulcer, gastric B-cell lymphoma, gastric adenocarcinoma (defined "carcinogen" by WHO in 1994): more than 1 million new cases each year (IARC 1997).
The treatment is based on the inhibition of the proton pump and antibiotherapy using two to three of the following antibiotics for one to two weeks: amoxicillin, clarthromycin, motronidazole, tetracycline, bismuth salts. Although in controlled trials, the treatment is more than 90% efficient, the efficacy at the level of general practictionners is likely lower. In addition, the treatment cost is high and the compliance poor (several tablets / day depending on the therapeutic scheme), accompanied by side effects (abdominal pain, nausea, diarrhoea, etc), and increased resistance (50% or more to metronidazole; 20% or more to macrolides; 20-40% to ampicillin). Moreover, reinfections are possible (from 1% to 50% reported). There is a high proportion of severe gastric pathology without previous history of symptoms.
Vaccines. The organism has been shown to be heterogeneous at a genetic level (Jordan Report 2000). Micro heterogeneity can indeed be very high at the level of single genes or at the level of some specific areas in these genes; however, at the genomic level, the variability is no higher than about 7%. Several vaccine approaches are being pursued and prophylactic vaccination has been proven feasible in animal models (mice, dogs, etc). Whole-cell vaccines and selected antigens (urease, VacA, CagA, NAP, hsp, catalase, etc) are efficacious by mucosal (oral, nasal) and parenteral (intramuscular) immunisations, but there is no known correlate of protection. It is of note that the above aantigens are relatively well conserved among various bacterial strains. In humans, several Phase I studies have been conducted: (i) oral live-attenuated Salmonella expressing urease showing no to poor immunogenicity (Oravax, now Acambis ), project discontinued), (ii) oral whole-cell plus LT mutant as adjuvant, immunogenic but eliciting diarrhoea (Antex ), (iii) purified urease co-administered with wild type LT (Acambis, on hold), (iv) intramuscular delivery of recombinant VacA, CagA & NAP in alum, safe and strongly immunogenic (Chiron ), Commonwealth Serum Labs (Australia)and Institute of Medicine,DC.