title: Anti-nicotine vaccines: Comparison of adjuvanted CRM197 and Qb-VLP conjugate formulations for immunogenicity and function in non-human primates.
abstract: Anti-nicotine vaccines comprise nicotine-like haptens conjugated to a carrier protein plus adjuvant(s). Unfortunately, those tested clinically have failed to improve overall long term quit rates. We had shown in mice that carrier, hapten, linker, hapten load (number of haptens per carrier molecule), aggregation and adducts, as well as adjuvants influence the function of antibodies (Ab) induced. Herein, we tested an optimized antigen, NIC7-CRM, comprised of 5-aminoethoxy-nicotine (NIC7) conjugated to genetically detoxified diphtheria toxin (CRM197), with hapten load of ~16, no aggregation (~100% monomer) and minimal adducts. NIC7-CRM was tested in non-human primates (NHP) and compared to NIC-VLP, which has the same hapten and carrier as the clinical-stage CYT002-NicQb but a slightly different linker and lower hapten load. With alum as sole adjuvant, NIC7-CRM was superior to NIC-VLP for Ab titer, avidity and ex vivo function (83% and 27% nicotine binding at 40ng/mL respectively), but equivalent for in vivo function after intravenous [IV] nicotine challenge (brain levels reduced ~10%). CpG adjuvant added to NIC7-CRM/alum further enhanced the Ab responses and both ex vivo function (100% bound) and in vivo function (~80% reduction in brain). Thus, both optimal antigen design and CpG adjuvant were required to achieve a highly functional vaccine. The compelling NHP data with NIC7-CRM with alum/CpG supported human testing, currently underway.
authors.affiliation: Pfizer Vaccine Immunotherapeutics, Ottawa Laboratories, Ottawa, ON, Canada. Electronic address: michael.mccluskie@pfizer.com.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCluskie
authors.affiliation: Pfizer Biotherapeutics Pharmaceutical Sciences, St. Louis, MO, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thorn
authors.affiliation: Pfizer Vaccine Immunotherapeutics, La Jolla, CA, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Gervais
authors.affiliation: Pfizer Vaccine Immunotherapeutics, La Jolla, CA, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Stead
authors.affiliation: Pfizer Vaccine Immunotherapeutics, Ottawa Laboratories, Ottawa, ON, Canada.
authors.forename: Ningli
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Pfizer Vaccine Immunotherapeutics, Ottawa Laboratories, Ottawa, ON, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Benoit
authors.affiliation: Pfizer Vaccine Immunotherapeutics, Ottawa Laboratories, Ottawa, ON, Canada.
authors.forename: Janna
authors.initials: J
authors.lastname: Cartier
authors.affiliation: Pfizer Vaccine Immunotherapeutics, Ottawa Laboratories, Ottawa, ON, Canada.
authors.forename: In-Jeong
authors.initials: IJ
authors.lastname: Kim
authors.affiliation: Pfizer Biotherapeutics Pharmaceutical Sciences, St. Louis, MO, USA.
authors.forename: Keshab
authors.initials: K
authors.lastname: Bhattacharya
authors.affiliation: Pfizer Biotherapeutics Pharmaceutical Sciences, St. Louis, MO, USA.
authors.forename: Jari I
authors.initials: JI
authors.lastname: Finneman
authors.affiliation: Pfizer Vaccine Immunotherapeutics, La Jolla, CA, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Merson
authors.affiliation: Pfizer Vaccine Immunotherapeutics, Ottawa Laboratories, Ottawa, ON, Canada.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Davis
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000906:Antibodies / Q000097:blood*; D001426:Bacterial Proteins / Q000276:immunology*; D001921:Brain; D005260:Female; D006241:Haptens / Q000276:immunology; D018796:Immunoconjugates / Q000737:chemistry; D008252:Macaca fascicularis; D008297:Male; D009538:Nicotine / Q000276:immunology*; D009841:Oligonucleotides; D013997:Time Factors; D014612:Vaccines / Q000276:immunology*; D014614:Vaccines, Synthetic
chemical_list: D000276:Adjuvants, Immunologic; D000906:Antibodies; D001426:Bacterial Proteins; D006241:Haptens; D018796:Immunoconjugates; D009841:Oligonucleotides; D014612:Vaccines; D014614:Vaccines, Synthetic; C448865:hapten 7; C028581:CRM197 (non-toxic variant of diphtheria toxin); D009538:Nicotine