title: 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.
abstract: 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-2(d)) mice, a dominant CD8 T-cell response was detected, in C57BL/6 (H-2(b)) 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.
authors.affiliation: Crucell Holland BV, Archimedesweg 4-6, 2333 CN Leiden, The Netherlands. katarina.radosevic@crucell.com
authors.forename: Katarina
authors.initials: K
authors.lastname: Radosevic
authors.forename: Catharina W
authors.initials: CW
authors.lastname: Wieland
authors.forename: Ariane
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Weverling
authors.forename: Ratna
authors.initials: R
authors.lastname: Mintardjo
authors.forename: Gert
authors.initials: G
authors.lastname: Gillissen
authors.forename: Ronald
authors.initials: R
authors.lastname: Vogels
authors.forename: Yasir A W
authors.initials: YA
authors.lastname: Skeiky
authors.forename: David M
authors.initials: DM
authors.lastname: Hone
authors.forename: Jerald C
authors.initials: JC
authors.lastname: Sadoff
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Menzo
authors.initials: M
authors.lastname: Havenga
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000276:immunology; D000256:Adenoviridae / Q000235:genetics; D000281:Administration, Intranasal; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000276:immunology*; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000382:microbiology; D014376:Tuberculosis / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D018984:Epitopes, T-Lymphocyte; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D007371:Interferon-gamma; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis