Sterilizing immunity against experimental Helicobacter pylori infection is challenge-strain dependent.
The development of a murine model of Helicobacter pylori infection through serial in vivo passage of candidate strains has enabled a quantitative assessment of vaccine efficacy. In this study we compare infection with and protection against challenge from both CagA(+) type I, and CagA(-) type II in vivo adapted isolates. In vivo passage of a type II H. pylori isolate resulted in a highly infectious strain (X47-2AL), capable of reproducibly infecting mice to high density (10(7) CFU/g of gastric tissue). Similarly adapted type I strains were found to colonize mice at a significantly lower level (10(4)-10(5) CFU/g tissue). Mucosal immunization with recombinant urease (rUre) significantly protected animals against both types. Protection against X47-2AL was characterized by a > or =100-fold (or 2 log) reduction in bacterial density. However, the presence of a residual infection highlighted the inability to achieve sterilizing immunity against this strain. The level of protection appeared independent of challenge dose, and was stable for up to 6 months, all animals exhibiting a low-level residual infection that did not recrudesce with time. Similarly immunized mice challenged with isolates representing the residual infection were also protected, confirming that they did not represent a sub-population of H. pylori that could escape immunity. Immunization and challenge studies with type I adapted-isolates, demonstrated a similar 2-3 log reduction in the bacterial burden, but that in this instance resulted in sterilizing immunity. These results suggest varied specificity for the murine host by different Helicobacter strains that can influence the outcome of both infection and immunity.
Kleanthous
H
H
Acambis, Inc., 38 Sidney Street, Cambridge, MA 02139, USA. harry.kleanthous@acambis.com
Tibbitts
T J
TJ
Gray
H L
HL
Myers
G A
GA
Lee
C K
CK
Ermak
T H
TH
Monath
T P
TP
D000284:Administration, Oral; D000285:Administration, Rectal; D000818:Animals; D021461:Animals, Outbred Strains; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000032:analysis / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D002371:Cat Diseases / Q000382:microbiology; D002415:Cats; D005753:Gastric Mucosa / Q000276:immunology / Q000382:microbiology; D005756:Gastritis / Q000382:microbiology / Q000628:therapy* / Q000662:veterinary; D016481:Helicobacter Infections / Q000382:microbiology / Q000628:therapy* / Q000662:veterinary; D016480:Helicobacter pylori / Q000145:classification / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity; D007114:Immunization / Q000379:methods; D016233:Immunotherapy, Active; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D008992:Monkey Diseases / Q000382:microbiology; D009061:Mouth Mucosa / Q000276:immunology; D010641:Phenotype; D011706:Pyloric Antrum / Q000382:microbiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D014510:Urease / Q000032:analysis / Q000235:genetics / Q000502:physiology; D014774:Virulence / Q000276:immunology
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D011993:Recombinant Fusion Proteins; C080866:cagA protein, Helicobacter pylori; D014510:Urease