This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Radosevic, K.
Right arrow Articles by Goudsmit, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Radosevic, K.
Right arrow Articles by Goudsmit, J.

 Previous Article  |  Next Article 

Infection and Immunity, August 2007, p. 4105-4115, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00004-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Protective Immune Responses to a Recombinant Adenovirus Type 35 Tuberculosis Vaccine in Two Mouse Strains: CD4 and CD8 T-Cell Epitope Mapping and Role of Gamma Interferon{triangledown}

Katarina Radosevic,1* Catharina W. Wieland,2 Ariane Rodriguez,1 Gerrit Jan Weverling,1 Ratna Mintardjo,1 Gert Gillissen,1 Ronald Vogels,1 Yasir A. W. Skeiky,3 David M. Hone,3 Jerald C. Sadoff,3 Tom van der Poll,2 Menzo Havenga,1 and Jaap Goudsmit1

Crucell Holland BV, P.O. Box 2048, 2301 CA Leiden, The Netherlands,1 Center of Infection and Immunity, Amsterdam Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands,2 Aeras Global TB Vaccine Foundation, 1405 Research Blvd., Rockville, Maryland 208503

Received 2 January 2007/ Returned for modification 12 February 2007/ Accepted 16 May 2007

There is an urgent need for an efficacious vaccine against tuberculosis (TB). Cellular immune responses are key to an effective protective response against TB. Recombinant adenovirus (rAd) vectors are especially suited to the induction of strong T-cell immunity and thus represent promising vaccine vehicles for the prevention of TB. We have previously reported on rAd vector serotype 35, the serotype of choice due to low preexisting immunity worldwide, which expresses a unique fusion protein of Mycobacterium tuberculosis antigens Ag85A, Ag85B, and TB10.4 (Ad35-TBS). Here, we demonstrate that Ad35-TBS confers protection against M. tuberculosis when administered to mice through either an intranasal or an intramuscular route. Histological evaluation of lung tissue corroborated the protection and, in addition, demonstrated differences between two mouse strains, with diffuse inflammation in BALB/c mice and distinct granuloma formation in C57BL/6 mice. Epitope mapping analysis in these mouse strains showed that the major T-cell epitopes are conserved in the artificial fusion protein, while three novel CD8 peptides were discovered. Using a defined set of T-cell epitopes, we reveal differences between the two mouse strains in the type of protective immune response, demonstrating that different antigen-specific gamma interferon (IFN-{gamma})-producing T cells can provide protection against M. tuberculosis challenge. While in BALB/c (H-2d) mice, a dominant CD8 T-cell response was detected, in C57BL/6 (H-2b) mice, more balanced CD4/CD8 T-cell responses were observed, with a more pronounced CD4 response in the lungs. These results unify conflicting reports on the relative importance of CD4 versus CD8 T-cell responses in protection and emphasize the key role of IFN-{gamma}.

* Corresponding author. Mailing address: Crucell Holland BV, Archimedesweg 4-6, 2333 CN Leiden, The Netherlands. Phone: 31 (0)71 5199286. Fax: 31 (0)71 5199800. E-mail: katarina.radosevic{at}crucell.com

{triangledown} Published ahead of print on 25 May 2007.

Editor: R. P. Morrison

Infection and Immunity, August 2007, p. 4105-4115, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00004-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Mir, F.-A., Kaufmann, S. H. E., Eddine, A. N. (2009). A Multicistronic DNA Vaccine Induces Significant Protection against Tuberculosis in Mice and Offers Flexibility in the Expressed Antigen Repertoire. CVI 16: 1467-1475 [Abstract] [Full Text]  
  • Tchilian, E. Z., Desel, C., Forbes, E. K., Bandermann, S., Sander, C. R., Hill, A. V. S., McShane, H., Kaufmann, S. H. E. (2009). Immunogenicity and Protective Efficacy of Prime-Boost Regimens with Recombinant {Delta}ureC hly+ Mycobacterium bovis BCG and Modified Vaccinia Virus Ankara Expressing M. tuberculosis Antigen 85A against Murine Tuberculosis. Infect. Immun. 77: 622-631 [Abstract] [Full Text]  
  • Forbes, E. K., Sander, C., Ronan, E. O., McShane, H., Hill, A. V. S., Beverley, P. C. L., Tchilian, E. Z. (2008). Multifunctional, High-Level Cytokine-Producing Th1 Cells in the Lung, but Not Spleen, Correlate with Protection against Mycobacterium tuberculosis Aerosol Challenge in Mice. J. Immunol. 181: 4955-4964 [Abstract] [Full Text]  
  • Rodriguez, A., Goudsmit, J., Companjen, A., Mintardjo, R., Gillissen, G., Tax, D., Sijtsma, J., Weverling, G. J., Holterman, L., Lanar, D. E., Havenga, M. J. E., Radosevic, K. (2008). Impact of Recombinant Adenovirus Serotype 35 Priming versus Boosting of a Plasmodium falciparum Protein: Characterization of T- and B-Cell Responses to Liver-Stage Antigen 1. Infect. Immun. 76: 1709-1718 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»