title: Attenuation of Replication-Competent Adenovirus Serotype 26 Vaccines by Vectorization.
abstract: Replication-competent adenovirus (rcAd)-based vaccine vectors may theoretically provide immunological advantages over replication-incompetent Ad vectors, but they also raise additional potential clinical and regulatory issues. We produced replication-competent Ad serotype 26 (rcAd26) vectors by adding the E1 region back into a replication-incompetent Ad26 vector backbone with the E3 or E3/E4 regions deleted. We assessed the effect of vectorization on the replicative capacity of the rcAd26 vaccines. Attenuation occurred in a stepwise fashion, with E3 deletion, E4 deletion, and human immunodeficiency virus type 1 (HIV-1) envelope (Env) gene insertion all contributing to reduced replicative capacity compared to that with the wild-type Ad26 vector. The rcAd26 vector with E3 and E4 deleted and containing the Env transgene exhibited 2.7- to 4.4-log-lower replicative capacity than that of the wild-type Ad26 in vitro. This rcAd26 vector is currently being evaluated in a phase 1 clinical trial. Attenuation as a result of vectorization and transgene insertion has implications for the clinical development of replication-competent vaccine vectors.
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Lori F
authors.initials: LF
authors.lastname: Maxfield
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Abbink
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Stephenson
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Erica N
authors.initials: EN
authors.lastname: Borducchi
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ng'ang'a
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Marinela M
authors.initials: MM
authors.lastname: Kirilova
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Noelix
authors.initials: N
authors.lastname: Paulino
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boyd
authors.affiliation: PaxVax, San Diego, California, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Shabram
authors.affiliation: PaxVax, San Diego, California, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ruan
authors.affiliation: PaxVax, San Diego, California, USA.
authors.forename: Mayank
authors.initials: M
authors.lastname: Patel
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA dbarouch@bidmc.harvard.edu.
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
mesh_terms: D062705:Adenovirus Vaccines / Q000235:genetics* / Q000276:immunology; D000260:Adenoviruses, Human / Q000235:genetics* / Q000502:physiology*; D017321:Clinical Trials, Phase I as Topic; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D016254:Mutagenesis, Insertional; D065288:Serogroup; D014779:Virus Replication; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D062705:Adenovirus Vaccines; D054299:env Gene Products, Human Immunodeficiency Virus