title: Optimizing HIV-1-specific CD8+ T-cell induction by recombinant BCG in prime-boost regimens with heterologous viral vectors.
abstract: The desire to induce HIV-1-specific responses soon after birth to prevent breast milk transmission of HIV-1 led us to propose a vaccine regimen which primes HIV-1-specific T cells using a recombinant Mycobacterium bovis bacillus Calmette-Guérin (rBCG) vaccine. Because attenuated live bacterial vaccines are typically not sufficiently immunogenic as stand-alone vaccines, rBCG-primed T cells will likely require boost immunization(s). Here, we compared modified Danish (AERAS-401) and Pasteur lysine auxotroph (222) strains of BCG expressing the immunogen HIVA for their potency to prime HIV-1-specific responses in adult BALB/c mice and examined four heterologous boosting HIVA vaccines for their immunogenic synergy. We found that both BCG.HIVA(401)  and BCG.HIVA(222)  primed HIV-1-specific CD8(+)  T-cell-mediated responses. The strongest boosts were delivered by human adenovirus-vectored HAdV5.HIVA and sheep atadenovirus-vectored OAdV7.HIVA vaccines, followed by poxvirus MVA.HIVA; the weakest was plasmid pTH.HIVA DNA. The prime-boost regimens induced T cells capable of efficient in vivo killing of sensitized target cells. We also observed that the BCG.HIVA(401)  and BCG.HIVA(222)  vaccines have broadly similar immunologic properties, but display a number of differences mainly detected through distinct profiles of soluble intercellular signaling molecules produced by immune splenocytes in response to both HIV-1- and BCG-specific stimuli. These results encourage further development of the rBCG prime-boost regimen.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Hopkins
authors.forename: Anne
authors.initials: A
authors.lastname: Bridgeman
authors.forename: Charles
authors.initials: C
authors.lastname: Bourne
authors.forename: Alice
authors.initials: A
authors.lastname: Mbewe-Mvula
authors.forename: Jerald C
authors.initials: JC
authors.lastname: Sadoff
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Both
authors.forename: Joan
authors.initials: J
authors.lastname: Joseph
authors.forename: John
authors.initials: J
authors.lastname: Fulkerson
authors.forename: Tomáš
authors.initials: T
authors.lastname: Hanke
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D046808:Atadenovirus / Q000276:immunology; D001500:BCG Vaccine / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors / Q000276:immunology; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D007114:Immunization / Q000379:methods; D007117:Immunization, Secondary / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D012756:Sheep; D015398:Signal Transduction / Q000276:immunology; D014611:Vaccination / Q000379:methods; D014614:Vaccines, Synthetic / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D001500:BCG Vaccine; D018984:Epitopes, T-Lymphocyte; D014614:Vaccines, Synthetic; D014765:Viral Vaccines