title: Recombinant Mycobacterium bovis BCG prime-recombinant adenovirus boost vaccination in rhesus monkeys elicits robust polyfunctional simian immunodeficiency virus-specific T-cell responses.
abstract: While mycobacteria have been proposed as vaccine vectors because of their persistence and safety, little has been done systematically to optimize their immunogenicity in nonhuman primates. We successfully generated recombinant Mycobacterium bovis BCG (rBCG) expressing simian immunodeficiency virus (SIV) Gag and Pol as multigenic, nonintegrating vectors, but rBCG-expressing SIV Env was unstable. A dose and route determination study in rhesus monkeys revealed that intramuscular administration of rBCG was associated with local reactogenicity, whereas intravenous and intradermal administration of 10(6) to 10(8) CFU of rBCG was well tolerated. After single or repeat rBCG inoculations, monkeys developed high-frequency gamma interferon enzyme-linked immunospot responses against BCG purified protein derivative. However, the same animals developed only modest SIV-specific CD8(+) T-cell responses. Nevertheless, high-frequency SIV-specific cellular responses were observed in the rBCG-primed monkeys after boosting with recombinant adenovirus 5 (rAd5) expressing the SIV antigens. These cellular responses were of greater magnitude and more persistent than those generated after vaccination with rAd5 alone. The vaccine-elicited cellular responses were predominantly polyfunctional CD8(+) T cells. These findings support the further exploration of mycobacteria as priming vaccine vectors.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cayabyab
authors.forename: Birgit
authors.initials: B
authors.lastname: Korioth-Schmitz
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.forename: Angela
authors.initials: A
authors.lastname: Carville
authors.forename: Harikrishnan
authors.initials: H
authors.lastname: Balachandran
authors.forename: Ayako
authors.initials: A
authors.lastname: Miura
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Carlson
authors.forename: Adam P
authors.initials: AP
authors.lastname: Buzby
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001500:BCG Vaccine / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015684:Gene Products, pol / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D007117:Immunization, Secondary / Q000379:methods*; D008253:Macaca mulatta / Q000276:immunology*; D009163:Mycobacterium bovis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D017186:Titrimetry; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D001500:BCG Vaccine; D015686:Gene Products, env; D015683:Gene Products, gag; D015684:Gene Products, pol; D014614:Vaccines, Synthetic