title: A CpG-Ficoll Nanoparticle Adjuvant for Anthrax Protective Antigen Enhances Immunogenicity and Provides Single-Immunization Protection against Inhaled Anthrax in Monkeys.
abstract: Nanoparticulate delivery systems for vaccine adjuvants, designed to enhance targeting of secondary lymphoid organs and activation of APCs, have shown substantial promise for enhanced immunopotentiation. We investigated the adjuvant activity of synthetic oligonucleotides containing CpG-rich motifs linked to the sucrose polymer Ficoll, forming soluble 50-nm particles (DV230-Ficoll), each containing >100 molecules of the TLR9 ligand, DV230. DV230-Ficoll was evaluated as an adjuvant for a candidate vaccine for anthrax using recombinant protective Ag (rPA) from Bacillus anthracis. A single immunization with rPA plus DV230-Ficoll induced 10-fold higher titers of toxin-neutralizing Abs in cynomolgus monkeys at 2 wk compared with animals immunized with equivalent amounts of monomeric DV230. Monkeys immunized either once or twice with rPA plus DV230-Ficoll were completely protected from challenge with 200 LD50 aerosolized anthrax spores. In mice, DV230-Ficoll was more potent than DV230 for the induction of innate immune responses at the injection site and draining lymph nodes. DV230-Ficoll was preferentially colocalized with rPA in key APC populations and induced greater maturation marker expression (CD69 and CD86) on these cells and stronger germinal center B and T cell responses, relative to DV230. DV230-Ficoll was also preferentially retained at the injection site and draining lymph nodes and produced fewer systemic inflammatory responses. These findings support the development of DV230-Ficoll as an adjuvant platform, particularly for vaccines such as for anthrax, for which rapid induction of protective immunity and memory with a single injection is very important.
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Kachura
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and.
authors.forename: Colin
authors.identifier: http://orcid.org/0000-0001-5524-2523
authors.initials: C
authors.lastname: Hickle
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and.
authors.forename: Sariah A
authors.initials: SA
authors.lastname: Kell
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and.
authors.forename: Atul
authors.initials: A
authors.lastname: Sathe
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and.
authors.forename: Carlo
authors.initials: C
authors.lastname: Calacsan
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and.
authors.forename: Radwan
authors.initials: R
authors.lastname: Kiwan
authors.affiliation: Amnis Corp., EMD Millipore, Seattle, WA 98119.
authors.forename: Brian
authors.initials: B
authors.lastname: Hall
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Milley
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and.
authors.forename: Gary
authors.initials: G
authors.lastname: Ott
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and RCoffman@dynavax.com DCampbell@dynavax.com.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and.
authors.forename: Holger
authors.initials: H
authors.lastname: Kanzler
authors.affiliation: Dynavax Technologies, Berkeley, CA 94710; and RCoffman@dynavax.com DCampbell@dynavax.com.
authors.forename: John D
authors.identifier: http://orcid.org/0000-0002-8526-3330
authors.initials: JD
authors.lastname: Campbell
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D022122:Anthrax Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology; D051940:B7-2 Antigen / Q000096:biosynthesis; D001408:Bacillus anthracis / Q000276:immunology / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005362:Ficoll / Q000276:immunology; D020862:GC Rich Sequence / Q000235:genetics; D037181:Lectins, C-Type / Q000096:biosynthesis; D008252:Macaca fascicularis; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D009504:Neutrophils / Q000276:immunology; D009841:Oligonucleotides / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D012141:Respiratory Tract Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D000276:Adjuvants, Immunologic; D022122:Anthrax Vaccines; D000942:Antigens, Bacterial; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051940:B7-2 Antigen; D001427:Bacterial Toxins; D005362:Ficoll; D037181:Lectins, C-Type; D009841:Oligonucleotides; D011994:Recombinant Proteins; D014614:Vaccines, Synthetic; D000099192:CD69 Antigens; C030325:anthrax toxin