title: Neutralizing antibodies to adenovirus serotype 5 vaccine vectors are directed primarily against the adenovirus hexon protein.
abstract: The utility of recombinant adenovirus serotype 5 (rAd5) vector-based vaccines for HIV-1 and other pathogens will likely be limited by the high prevalence of pre-existing Ad5-specific neutralizing Abs (NAbs) in human populations. However, the immunodominant targets of Ad5-specific NAbs in humans remain poorly characterized. In this study, we assess the titers and primary determinants of Ad5-specific NAbs in individuals from both the United States and the developing world. Importantly, median Ad5-specific NAb titers were >10-fold higher in sub-Saharan Africa compared with the United States. Moreover, hexon-specific NAb titers were 4- to 10-fold higher than fiber-specific NAb titers in these cohorts by virus neutralization assays using capsid chimeric viruses. We next performed adoptive transfer studies in mice to evaluate the functional capacity of hexon- and fiber-specific NAbs to suppress the immunogenicity of a prototype rAd5-Env vaccine. Hexon-specific NAbs were remarkably efficient at suppressing Env-specific immune responses elicited by the rAd5 vaccine. In contrast, fiber-specific NAbs exerted only minimal suppressive effects on rAd5 vaccine immunogenicity. These data demonstrate that functionally significant Ad5-specific NAbs are directed primarily against the Ad5 hexon protein in both humans and mice. These studies suggest a potential strategy for engineering novel Ad5 vectors to evade dominant Ad5-specific NAbs.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Sumida
authors.forename: Diana M
authors.initials: DM
authors.lastname: Truitt
authors.forename: Angelique A C
authors.initials: AA
authors.lastname: Lemckert
authors.forename: Ronald
authors.initials: R
authors.lastname: Vogels
authors.forename: Jerome H H V
authors.initials: JH
authors.lastname: Custers
authors.forename: Marylyn M
authors.initials: MM
authors.lastname: Addo
authors.forename: Shahin
authors.initials: S
authors.lastname: Lockman
authors.forename: Trevor
authors.initials: T
authors.lastname: Peter
authors.forename: Fred W
authors.initials: FW
authors.lastname: Peyerl
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kishko
authors.forename: Shawn S
authors.initials: SS
authors.lastname: Jackson
authors.forename: Darci A
authors.initials: DA
authors.lastname: Gorgone
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lifton
authors.forename: Myron
authors.initials: M
authors.lastname: Essex
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
authors.forename: Menzo J E
authors.initials: MJ
authors.lastname: Havenga
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000328:Adult; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D036022:Capsid Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D016036:Seroepidemiologic Studies; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D036022:Capsid Proteins; D016056:Immunodominant Epitopes; D007166:Immunosuppressive Agents; D019444:Vaccines, DNA; D014765:Viral Vaccines; C018315:hexon capsid protein, Adenovirus