title: Disrupted adenovirus-based vaccines against small addictive molecules circumvent anti-adenovirus immunity.
abstract: Adenovirus (Ad) vaccine vectors have been used for many applications due to the capacity of the Ad capsid proteins to evoke potent immune responses, but these vectors are often ineffective in the context of pre-existing anti-Ad immunity. Leveraging the knowledge that E1(-)E3(-) Ad gene transfer vectors are potent immunogens, we have developed a vaccine platform against small molecules by covalently coupling analogs of small molecules to the capsid proteins of disrupted Ad (dAd5). We hypothesized that the dAd5 platform would maintain immunopotency even in the context of anti-Ad neutralizing antibodies. To test this hypothesis, we coupled cocaine and nicotine analogs, GNE and AM1, to dAd5 capsid proteins to generate dAd5GNE and dAd5AM1, respectively. Mice were pre-immunized with Ad5Null, resulting in high titer anti-Ad5 neutralizing antibodies comparable to those observed in the human population. The dAd5GNE and dAd5AM1 vaccines elicited high anti-cocaine and anti-nicotine antibody titers, respectively, in both naive and Ad5-immune mice, and both functioned to prevent cocaine or nicotine from reaching the brain of anti-Ad immune mice. Thus, disrupted Ad5 evokes potent humoral immunity that is effective in the context of pre-existing neutralizing anti-Ad immunity, overcoming a major limitation for current Ad-based vaccines.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: De
authors.forename: Odelya E
authors.initials: OE
authors.lastname: Pagovich
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hicks
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Rosenberg
authors.forename: Amira Y
authors.initials: AY
authors.lastname: Moreno
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.forename: Stefan
authors.initials: S
authors.lastname: Worgall
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Kaminsky
authors.forename: Dolan
authors.initials: D
authors.lastname: Sondhi
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D015153:Blotting, Western; D002208:Caproates / Q000276:immunology* / Q000378:metabolism; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D046912:Multiprotein Complexes / Q000276:immunology* / Q000378:metabolism; D009538:Nicotine / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics; D014612:Vaccines / Q000276:immunology*
chemical_list: C582060:6-((1-methyl-2-(pyridin-3-yl)pyrrolidin-3-yl)methoxy)hexanoic acid; C582059:6-(3-(benzoyloxy)-8-methyl-8-azabicyclo(3.2.1)octane-2-carboxoamido)hexanoic acid; D057134:Antibodies, Neutralizing; D002208:Caproates; D036022:Capsid Proteins; D046912:Multiprotein Complexes; D014612:Vaccines; D009538:Nicotine; D003042:Cocaine