title: Protection against tuberculosis with homologous or heterologous protein/vector vaccine approaches is not dependent on CD8+ T cells.
abstract: Considerable effort has been directed to develop Mycobacterium tuberculosis vaccines to boost bacille Calmette-Guérin or for those who cannot be immunized with bacille Calmette-Guérin. We hypothesized that CD4(+) and CD8(+) T cell responses with a heterologous prime/boost vaccine approach could induce long-lived vaccine efficacy against M. tuberculosis in C57BL/6 mice. We produced an adenovirus vector expressing ID93 (Ad5-ID93) for induction of CD8 T cells to use with our candidate tuberculosis vaccine, ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE), which induces potent Th1 CD4 T cells. Ad5-ID93 generates ID93-specific CD8(+) T cell responses and induces protection against M. tuberculosis. When Ad5-ID93 is administered in a prime-boost strategy with ID93/GLA-SE, both CD4(+) and CD8(+) T cells are generated and provide protection against M. tuberculosis. In a MHC class I-deficient mouse model, all groups including the Ad5-ID93 group elicited an Ag-specific CD4(+) T cell response and significantly fewer Ag-specific CD8(+) T cells, but were still protected against M. tuberculosis, suggesting that CD4(+) Th1 T cells could compensate for the loss of CD8(+) T cells. Lastly, the order of the heterologous immunizations was critical. Long-lived vaccine protection was observed only when Ad5-ID93 was given as the boost following an ID93/GLA-SE prime. The homologous ID93/GLA-SE prime/boost regimen also induced long-lived protection. One of the correlates of protection between these two approaches was an increase in the total number of ID93-specific IFN-γ-producing CD4(+) T cells 6 mo following the last immunization. Our findings provide insight into the development of vaccines not only for tuberculosis, but other diseases requiring T cell immunity.
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, WA, USA 98102.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Baldwin
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, WA, USA 98102.
authors.forename: Lance K
authors.initials: LK
authors.lastname: Ching
authors.affiliation: Allergan, Inc. 2525 Dupont Dr., Irvine, CA USA 92612.
authors.forename: Samuel O
authors.initials: SO
authors.lastname: Pine
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, WA, USA 98102.
authors.forename: Magdalini
authors.initials: M
authors.lastname: Moutaftsi
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, WA, USA 98102.
authors.forename: Elyse
authors.initials: E
authors.lastname: Lucas
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, WA, USA 98102.
authors.forename: Aarthy
authors.initials: A
authors.lastname: Vallur
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, WA, USA 98102.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Orr
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bertholet
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, WA, USA 98102.|Department of Global Health, University of Washington, Seattle, WA, USA 98195.|Immune Design Corp., 1124 Columbia Street, Suite 700, Seattle, WA, USA 98104.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, WA, USA 98102.|Department of Global Health, University of Washington, Seattle, WA, USA 98195.
authors.forename: Rhea N
authors.initials: RN
authors.lastname: Coler
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D007117:Immunization, Secondary / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines
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