Adjuvant-carrying synthetic vaccine particles augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release

被引：132

作者：

Ilyinskii, Petr O. ^{[1
]}

Roy, Christopher J. ^{[1
]}

O'Neil, Conlin P. ^{[1
]}

Browning, Erica A. ^{[1
]}

Pittet, Lynnelle A. ^{[1
]}

Altreuter, David H. ^{[1
]}

Alexis, Frank ^{[2
]}

Tonti, Elena ^{[3
]}

Shi, Jinjun ^{[2
]}

Basto, Pamela A. ^{[4
,5
]}

Iannacone, Matteo ^{[3
]}

Radovic-Moreno, Aleksandar F. ^{[4
,5
]}

Langer, Robert S. ^{[4
,5
]}

Farokhzad, Omid C. ^{[2
]}

von Andrian, Ulrich H. ^{[3
]}

Johnston, Lloyd P. M. ^{[1
]}

Kishimoto, Takashi Kei ^{[1
]}

机构：

[1] Selecta Biosci, Watertown, MA 02472 USA

[2] Brigham & Womens Hosp, Lab Nanomed & Biomat, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA

[4] David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[5] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA

来源：

VACCINE | 2014年 / 32卷 / 24期

关键词：

Synthetic nanoparticle vaccine; TLR agonist; Adjuvant; CpG; R848; Resiquimod; T-CELL RESPONSES; SINGLE-STRANDED RNA; IMMUNOSTIMULATORY DNA-SEQUENCES; RESIQUIMOD 0.01-PERCENT GEL; BACTERIAL-DNA; CPG MOTIFS; NONHUMAN-PRIMATES; DENDRITIC CELLS; INNATE IMMUNITY; TLR9; AGONIST;

D O I：

10.1016/j.vaccine.2014.02.027

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 nanopartides 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-alpha 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. (C) 2014 The Authors. Published by Elsevier Ltd.

引用

页码：2882 / 2895

页数：14

共 73 条

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