title: Adjuvant-carrying synthetic vaccine particles augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release.
abstract: Augmentation of immunogenicity can be achieved by particulate delivery of an antigen and by its co-administration with an adjuvant. However, many adjuvants initiate strong systemic inflammatory reactions in vivo, leading to potential adverse events and safety concerns. We have developed a synthetic vaccine particle (SVP) technology that enables co-encapsulation of antigen with potent adjuvants. We demonstrate that co-delivery of an antigen with a TLR7/8 or TLR9 agonist in synthetic polymer nanoparticles results in a strong augmentation of humoral and cellular immune responses with minimal systemic production of inflammatory cytokines. In contrast, antigen encapsulated into nanoparticles and admixed with free TLR7/8 agonist leads to lower immunogenicity and rapid induction of high levels of inflammatory cytokines in the serum (e.g., TNF-a and IL-6 levels are 50- to 200-fold higher upon injection of free resiquimod (R848) than of nanoparticle-encapsulated R848). Conversely, local immune stimulation as evidenced by cellular infiltration of draining lymph nodes and by intranodal cytokine production was more pronounced and persisted longer when SVP-encapsulated TLR agonists were used. The strong local immune activation achieved using a modular self-assembling nanoparticle platform markedly enhanced immunogenicity and was equally effective whether antigen and adjuvant were co-encapsulated in a single nanoparticle formulation or co-delivered in two separate nanoparticles. Moreover, particle encapsulation enabled the utilization of CpG oligonucleotides with the natural phosphodiester backbone, which are otherwise rapidly hydrolyzed by nucleases in vivo. The use of SVP may enable clinical use of potent TLR agonists as vaccine adjuvants for indications where cellular immunity or robust humoral responses are required.
authors.affiliation: Selecta Biosciences, Watertown, MA 02472, USA. Electronic address: PIlyinskii@selectabio.com.
authors.forename: Petr O
authors.initials: PO
authors.lastname: Ilyinskii
authors.affiliation: Selecta Biosciences, Watertown, MA 02472, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Roy
authors.affiliation: Selecta Biosciences, Watertown, MA 02472, USA.
authors.forename: Conlin P
authors.initials: CP
authors.lastname: O'Neil
authors.affiliation: Selecta Biosciences, Watertown, MA 02472, USA.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Browning
authors.affiliation: Selecta Biosciences, Watertown, MA 02472, USA.
authors.forename: Lynnelle A
authors.initials: LA
authors.lastname: Pittet
authors.affiliation: Selecta Biosciences, Watertown, MA 02472, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Altreuter
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Alexis
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Tonti
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Shi
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Basto
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Iannacone
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
authors.forename: Aleksandar F
authors.initials: AF
authors.lastname: Radovic-Moreno
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Langer
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.affiliation: Selecta Biosciences, Watertown, MA 02472, USA.
authors.forename: Lloyd P M
authors.initials: LP
authors.lastname: Johnston
authors.affiliation: Selecta Biosciences, Watertown, MA 02472, USA.
authors.forename: Takashi Kei
authors.initials: TK
authors.lastname: Kishimoto
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000917:Antibody Formation; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage; D007111:Immunity, Cellular; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D013154:Spleen / Q000166:cytology; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists; D051217:Toll-Like Receptor 9 / Q000819:agonists; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; C423449:CpG ODN 1826; D016207:Cytokines; D007093:Imidazoles; D009838:Oligodeoxyribonucleotides; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D014614:Vaccines, Synthetic; C402365:resiquimod
keywords: Adjuvant; CpG; R848; Resiquimod; Synthetic nanoparticle vaccine; TLR agonist