title: Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity.
abstract: A common viral immune evasion strategy involves mutating viral surface proteins in order to evade host neutralizing antibodies. Such immune evasion tactics have not previously been intentionally applied to the development of novel viral gene delivery vectors that overcome the critical problem of anti-vector immunity. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens have proved highly immunogenic in preclinical studies but will probably be limited by the high prevalence of pre-existing anti-Ad5 immunity in human populations, particularly in the developing world. Here we show that rAd5 vectors can be engineered to circumvent anti-Ad5 immunity. We constructed novel chimaeric rAd5 vectors in which the seven short hypervariable regions (HVRs) on the surface of the Ad5 hexon protein were replaced with the corresponding HVRs from the rare adenovirus serotype Ad48. These HVR-chimaeric rAd5 vectors were produced at high titres and were stable through serial passages in vitro. HVR-chimaeric rAd5 vectors expressing simian immunodeficiency virus Gag proved comparably immunogenic to parental rAd5 vectors in naive mice and rhesus monkeys. In the presence of high levels of pre-existing anti-Ad5 immunity, the immunogenicity of HVR-chimaeric rAd5 vectors was not detectably suppressed, whereas the immunogenicity of parental rAd5 vectors was abrogated. These data demonstrate that functionally relevant Ad5-specific neutralizing antibodies are focused on epitopes located within the hexon HVRs. Moreover, these studies show that recombinant viral vectors can be engineered to circumvent pre-existing anti-vector immunity by removing key neutralizing epitopes on the surface of viral capsid proteins. Such chimaeric viral vectors may have important practical implications for vaccination and gene therapy.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Roberts
authors.forename: Anjali
authors.initials: A
authors.lastname: Nanda
authors.forename: Menzo J E
authors.initials: MJ
authors.lastname: Havenga
authors.forename: Peter
authors.initials: P
authors.lastname: Abbink
authors.forename: Diana M
authors.initials: DM
authors.lastname: Lynch
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Ewald
authors.forename: Jinyan
authors.initials: J
authors.lastname: Liu
authors.forename: Anna R
authors.initials: AR
authors.lastname: Thorner
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Swanson
authors.forename: Darci A
authors.initials: DA
authors.lastname: Gorgone
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lifton
authors.forename: Angelique A C
authors.initials: AA
authors.lastname: Lemckert
authors.forename: Lennart
authors.initials: L
authors.lastname: Holterman
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.forename: Athmanundh
authors.initials: A
authors.lastname: Dilraj
authors.forename: Angela
authors.initials: A
authors.lastname: Carville
authors.forename: Keith G
authors.initials: KG
authors.lastname: Mansfield
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
mesh_terms: D000256:Adenoviridae / Q000145:classification / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics* / Q000276:immunology*; D004274:DNA, Recombinant / Q000235:genetics; D005818:Genetic Engineering; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology*; D008253:Macaca mulatta / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D014612:Vaccines
chemical_list: D036022:Capsid Proteins; D004274:DNA, Recombinant; D014612:Vaccines; C018315:hexon capsid protein, Adenovirus