In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity

被引：385

作者：

Lynn, Geoffrey M. ^{[1
,2
]}

Laga, Richard ^{[2
,3
]}

Darrah, Patricia A. ^{[1
]}

Ishizuka, Andrew S. ^{[1
]}

Balaci, Alexandra J. ^{[1
]}

Dulcey, Andres E. ^{[4
]}

Pechar, Michal ^{[3
]}

Pola, Robert ^{[3
]}

Gerner, Michael Y. ^{[5
]}

Yamamoto, Ayako ^{[1
]}

Buechler, Connor R. ^{[1
]}

Quinn, Kylie M. ^{[1
]}

Smelkinson, Margery G. ^{[6
]}

Vanek, Ondrej ^{[7
]}

Cawood, Ryan ^{[2
]}

Hills, Thomas ^{[2
]}

Vasalatiy, Olga ^{[4
]}

Kastenmueller, Kathrin ^{[1
]}

Francica, Joseph R. ^{[1
]}

Stutts, Lalisa ^{[8
]}

Tom, Janine K. ^{[8
]}

Ryu, Keun Ah ^{[8
]}

Esser-Kahn, Aaron P. ^{[8
]}

Etrych, Tomas ^{[3
]}

Fisher, Kerry D. ^{[2
]}

Seymour, Leonard W. ^{[2
]}

Seder, Robert A. ^{[1
]}

机构：

[1] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA

[2] Univ Oxford, Dept Oncol, Oxford, England

[3] Acad Sci Czech Republic, Inst Macromol Chem, Prague, Czech Republic

[4] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD USA

[5] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA

[6] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA

[7] Charles Univ Prague, Fac Sci, Dept Biochem, Prague, Czech Republic

[8] Univ Calif Irvine, Dept Chem, Irvine, CA 92717 USA

来源：

NATURE BIOTECHNOLOGY | 2015年 / 33卷 / 11期

基金：

美国国家卫生研究院;

关键词：

T-CELL IMMUNITY; DENDRITIC CELLS; INNATE IMMUNITY; LYMPH-NODES; ADJUVANT; RESPONSES; ANTIGEN; PROTECTION; ACTIVATION; COPOLYMERS;

D O I：

10.1038/nbt.3371

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer-TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer-TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer-TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.

引用

页码：1201 / +

页数：13

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