Injection route and TLR9 agonist addition significantly impact heroin vaccine efficacy.
Injection route and TLR9 agonist addition significantly impact heroin vaccine efficacy.
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DOI：
10.1021/mp400631w
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发表时间：
2014-03-03
影响因子：
4.9
通讯作者：
Janda KD
中科院分区：
文献类型：
--
作者：
Bremer PT;Schlosburg JE;Lively JM;Janda KD
主动免疫是阻断药物药效学作用的有效手段，有望成为治疗海洛因成瘾的一种方法。先前，我们证明了第一代疫苗在阻断大鼠海洛因自我给药方面的功效，然而，许多疫苗成分可以被修改以进一步提高性能。在这里，我们检查不同的海洛因疫苗注射途径和佐剂配方的影响。皮下注射免疫小鼠的抗海洛因效价低于腹腔注射和皮下注射/腹腔注射。在原明矾佐剂中添加TLR9激动剂胞嘧啶-鸟嘌呤寡脱氧核苷酸1826 (CpG ODN 1826)，与单独添加明矾相比，可获得更高的抗体滴度和阿片亲和力。为了全面评估疫苗的有效性，在热板试验和尾浸试验中生成了海洛因诱导镇痛的全剂量-反应曲线。用CpG ODN 1826治疗的小鼠表现出极大的剂量-反应曲线偏移（与未接种的对照组相比，偏移10 - 13倍），而非CpG ODN疫苗组没有表现出同样强劲的效果（ip和combo的偏移2 - 7倍，sc的偏移2 - 3倍）。结果表明，CpG ODN 1826是一种高效佐剂，开发小分子蛋白结合疫苗应考虑注射途径。最后，本研究建立了滥用疫苗药物评估的新标准，其中应在适当的行为任务中执行完整的剂量-反应曲线。
Active immunization is an effective means of blocking the pharmacodynamic effects of drugs and holds promise as a treatment for heroin addiction. Previously, we demonstrated the efficacy of our first-generation vaccine in blocking heroin self-administration in rats, however, many vaccine components can be modified to further improve performance. Herein we examine the effects of varying heroin vaccine injection route and adjuvant formulation. Mice immunized via subcutaneous (sc) injection exhibited inferior anti-heroin titers compared to intraperitoneal (ip) and sc/ip coadministration injection routes. Addition of TLR9 agonist cytosine-guanine oligodeoxynucleotide 1826 (CpG ODN 1826) to the original alum adjuvant elicited superior antibody titers and opioid affinities compared to alum alone. To thoroughly assess vaccine efficacy, full dose–response curves were generated for heroin-induced analgesia in both hot plate and tail immersion tests. Mice treated with CpG ODN 1826 exhibited greatly shifted dose–response curves (10–13-fold vs unvaccinated controls) while non-CpG ODN vaccine groups did not exhibit the same robust effect (2–7-fold shift for ip and combo, 2–3-fold shift for sc). Our results suggest that CpG ODN 1826 is a highly potent adjuvant, and injection routes should be considered for development of small molecule–protein conjugate vaccines. Lastly, this study has established a new standard for assessing drugs of abuse vaccines, wherein a full dose–response curve should be performed in an appropriate behavioral task.
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影响因子：
3.7
作者：
Mullen GE;Ellis RD;Miura K;Malkin E;Nolan C;Hay M;Fay MP;Saul A;Zhu D;Rausch K;Moretz S;Zhou H;Long CA;Miller LH;Treanor J
通讯作者：
Treanor J
影响因子：
9.1
作者：
Cooper, CL;Davis, HL;Heathcote, J
通讯作者：
Heathcote, J
影响因子：
5.5
作者：
Duryee, Michael J.;Bevins, Rick A.;Sanderson, Sam D.
通讯作者：
Sanderson, Sam D.
DOI：
10.1073/pnas.95.26.15553
发表时间：
1998-12-22
影响因子：
11.1
作者：
Millan, CLB;Weeratna, R;Davis, HL
通讯作者：
Davis, HL
影响因子：
4.2
作者：
Mark, TL;Woody, GE;Kleber, HD
通讯作者：
Kleber, HD