Correlation of T cell response and bacterial clearance in human volunteers challenged with H. pylori revealed by randomized controlled vaccination with Ty21a-based Salmonella vaccines
Toni Aebischer 1, Dirk Bumann 1, Hans-Joerg Epple 2, Wolfram Metzger 1, Thomas Schneider 2, Georgy Cherepnev 1, Anna K Walduck 1, Desiree Kunkel 2, Verena Moos 2, Christoph Loddenkemper 2, Irina Jiadze 2, Michael Panasyuk 3, Manfred Stolte 4, David Y Graham 5, Martin Zeitz 2 and Thomas F. Meyer 1*
1 Max Planck Institute for Infection Biology, Berlin, Germany
2 Charite Campus Benjamin Franklin, Berlin, Germany
3 Kazan State University, Kazan, Russian Federation
4 Klinikum Bayreuth, Bayreuth, Germany
5 Veterans Affairs Medical Center Houston, Texas, United States
* To whom correspondence should be addressed. E-mail: tfm{at}mpiib-berlin.mpg.de.
Accepted 18 March 2008
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Background: H. pylori remains a global health hazard and vaccination would be ideal for its control. Natural infection appears not to induce protective immunity. Thus, the feasibility of a vaccine for humans is doubtful.
Methods: In two prospective, randomized, double blind, controlled studies (Paul Ehrlich Institute application no. 0802/02, no. 1097/01) live vaccines against H. pylori were tested in human volunteers seronegative for, and without evidence of active H. pylori infection. Volunteers (n=58) were immunized orally with Salmonella enterica serovar Typhi Ty21a expressing H. pylori urease or HP0231, or solely with Ty21a and then challenged with 2x105 cagPAI- H. pylori. Adverse events, infection, humoral, cellular and mucosal immune response were monitored. Gastric biopsies were taken before and after vaccination, and post challenge. Infection was terminated with antibiotics.
Results: Vaccines were well tolerated. Challenge infection induced transient, mild to moderate dyspeptic symptoms, and histological and transcriptional changes in the mucosa known from chronic infection. Vaccines did not show satisfactory protection. However, 13 of 58 volunteers, 8 vaccinees and 5 controls, became breath test negative and either cleared H. pylori (5/13) completely, or reduced H. pylori burden (8/13). H. pylori-specific T helper cells were detected in 9 of these 13 (69%), but only in 6 of 45 (13%) breath test positive volunteers (P=0.0002; Fisher's exact test). T cells were either vaccine induced or pre-existing, depending on volunteer.
Conclusion: Challenge infection offers a controlled model for vaccine testing. Importantly, it revealed evidence for T cell mediated immunity against H. pylori infection in humans.
