Characterization and biological evaluation of a microparticle adjuvant formulation for plasmid DNA vaccines

被引:22
作者
Evans, RK
Zhu, DM
Casimiro, DR
Nawrocki, DK
Mach, H
Troutman, RD
Tang, AM
Wu, SL
Chin, S
Ahn, C
Isopi, LA
Williams, DM
Xu, Z
Shiver, JW
Volkin, DB
机构
[1] Merck Res Labs, Dept Vaccine Pharmaceut Res, West Point, PA 19486 USA
[2] Merck Res Labs, Dept Viral Vaccine Res, West Point, PA 19486 USA
关键词
DNA; DNA delivery; vaccine adjuvants; microparticles; particle sizing; light-scattering; immunology;
D O I
10.1002/jps.20112
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
We describe the physiochemical characterization and immunological evaluation of plasmid DNA vaccine formulations containing a nonionic triblock copolymer adjuvant (CRL1005) in the presence and absence of a cationic surfactant, benzalkonium chloride (BAK). CRL1005 forms particles of I - 10 microns upon warming above its phase-transition temperature (similar to6-8degreesC) and the physical properties of the particles are altered by BAK. DNA/CRL1005 vaccines formulated with and without BAK were evaluated in rhesus macaques to determine the effect of CRL1005 and BAK on the ability of plasmid DNA to induce a cellular immune response. Immunogenicity results indicate that the addition of CRL1005 to human immunodeficiency virus-1 gag plasmid DNA formulated in phosphate-buffered saline leads to an enhancement in the gag-specific cellular immune response. Moreover, the addition of BAK to human immunodeficiency virus-1 gag plasmid DNA/CRL1005 formulations produces an additional enhancement in gag-specific cellular immunity. In vitro characterization studies of DNA/CRL1005 formulations indicate no detectable binding of DNA to CRL1005 particles in the absence of BAK, suggesting that the enhancement Of Cellular immunity induced by DNA/CRL1005 formulations is not due to enhanced DNA delivery. In the presence of BAK, however, results indicate that BAK binds to CRL1005 particles, producing cationic microparticles that bind DNA through electrostatic interactions. If BAK is present at the phase-transition temperature, it reduces the particle size from similar to2 microns to similar to300 mn, presumably by binding to hydrophobic surfaces during particle formation. Zeta potential measurements indicate that the surface charge of CRL1005-BAK particles changes from positive to negative upon DNA binding, and DNA bound to the surface of CRL1005-BAK particles was visualized by fluorescence microscopy. These results indicate that the addition of BAK to DNA/CRL1005 formulations leads to the formation of similar to300 nm CRL1005-BAK-DNA particles that enhance the cellular immune response in rhesus monkeys. (C) 2004 Wiley-Liss, Inc. and the American Pharmacists Association.
引用
收藏
页码:1924 / 1939
页数:16
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