title: Immunogenicity of recombinant adenovirus serotype 35 vaccine in the presence of pre-existing anti-Ad5 immunity.
abstract: The high prevalence of pre-existing immunity to adenovirus serotype 5 (Ad5) in human populations may substantially limit the immunogenicity and clinical utility of recombinant Ad5 vector-based vaccines for HIV-1 and other pathogens. A potential solution to this problem is to use vaccine vectors derived from adenovirus (Ad) serotypes that are rare in humans, such as Ad35. However, cross-reactive immune responses between heterologous Ad serotypes have been described and could prove a major limitation of this strategy. In particular, the extent of immunologic cross-reactivity between Ad5 and Ad35 has not previously been determined. In this study we investigate the impact of pre-existing anti-Ad5 immunity on the immunogenicity of candidate rAd5 and rAd35 vaccines expressing SIV Gag in mice. Anti-Ad5 immunity at levels typically found in humans dramatically blunted the immunogenicity of rAd5-Gag. In contrast, even high levels of anti-Ad5 immunity did not substantially suppress Gag-specific cellular immune responses elicited by rAd35-Gag. Low levels of cross-reactive Ad5/Ad35-specific CD4(+) T lymphocyte responses were observed, but were insufficient to suppress vaccine immunogenicity. These data demonstrate the potential utility of Ad35 as a candidate vaccine vector that is minimally suppressed by anti-Ad5 immunity. Moreover, these studies suggest that using Ad vectors derived from immunologically distinct serotypes may be an effective and general strategy to overcome the suppressive effects of pre-existing anti-Ad immunity.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. dbarouch@bidmc.harvard.edu
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
authors.forename: Maria G
authors.initials: MG
authors.lastname: Pau
authors.forename: Jerome H H V
authors.initials: JH
authors.lastname: Custers
authors.forename: Wouter
authors.initials: W
authors.lastname: Koudstaal
authors.forename: Stefan
authors.initials: S
authors.lastname: Kostense
authors.forename: Menzo J E
authors.initials: MJ
authors.lastname: Havenga
authors.forename: Diana M
authors.initials: DM
authors.lastname: Truitt
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Sumida
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kishko
authors.forename: Janelle C
authors.initials: JC
authors.lastname: Arthur
authors.forename: Birgit
authors.initials: B
authors.lastname: Korioth-Schmitz
authors.forename: Michael H
authors.initials: MH
authors.lastname: Newberg
authors.forename: Darci A
authors.initials: DA
authors.lastname: Gorgone
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lifton
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Panicali
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
mesh_terms: D000256:Adenoviridae / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D000257:Adenoviridae Infections / Q000276:immunology* / Q000517:prevention & control*; D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D018604:Epitope Mapping / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000097:blood; D015683:Gene Products, gag / Q000008:administration & dosage / Q000097:blood / Q000276:immunology; D005822:Genetic Vectors; D007110:Immunity, Active; D007115:Immunization Schedule; D007117:Immunization, Secondary; D007273:Injections, Intramuscular; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D012703:Serotyping; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D010446:Peptide Fragments; D014614:Vaccines, Synthetic; D014765:Viral Vaccines