Efficacy, but not antibody titer or affinity, of a heroin hapten conjugate vaccine correlates with increasing hapten densities on tetanus toxoid, but not on CRM197 carriers.
Efficacy, but not antibody titer or affinity, of a heroin hapten conjugate vaccine correlates with increasing hapten densities on tetanus toxoid, but not on CRM197 carriers.
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DOI：
10.1021/acs.bioconjchem.5b00085
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发表时间：
2015-06-17
影响因子：
4.7
通讯作者：
Matyas, Gary R.
中科院分区：
文献类型：
--
作者：
Jalah, Rashmi;Torres, Oscar B.;Mayorov, Alexander V.;Li, Fuying;Antoline, Joshua F. G.;Jacobson, Arthur E.;Rice, Kenner C.;Deschamps, Jeffrey R.;Beck, Zoltan;Alving, Carl R.;Matyas, Gary R.
针对滥用药物的疫苗已经在动物体内诱导出抗体，通过将药物隔离在血液中并阻止其越过血脑屏障来阻止药物的生物效应。滥用的药物太小，不能诱导抗体，因此，需要将药物半抗原类似物与载体蛋白结合。这些结合疫苗的效力取决于几个因素，包括半抗原设计、偶联策略、半抗原密度、载体蛋白选择和疫苗佐剂。以前，我们已经证明，海洛因/吗啡半抗原1(MorHap)与破伤风类毒素(TT)偶联，并与含有单磷脂A(MPLA)的脂质体混合作为佐剂，部分阻断海洛因对小鼠的抗伤害感受作用。在这里，我们扩展了这些发现；展示了显著改善的疫苗诱导的抗伤害效应高达3%的平均最大潜在效应(%MPE)。这是通过使用两种不同的常用载体蛋白TT和交叉反应材料197(CRM197)评估不同半抗原密度的半抗原1疫苗结合物的疫苗效力而获得的。用这些结合物与L混合免疫小鼠，可以诱导出很高的抗1Ig G峰值，可与海洛因及其代谢产物6-乙酰吗啡和吗啡结合，峰值为400-1500微克/毫升。除每个载体的半抗原密度最低外，抗体效价和亲和力均与半抗原密度无关。TT载体疫苗可长期抑制海洛因诱导的抗伤害性感觉，这种抑制作用与增加半抗原密度有关。最佳处方含有≥-30半抗原/TT分子的半抗原密度最高的TT，海洛因攻击后诱导%MPE约为3%。相反，使用CRM197的最佳配方是中等密度(10-15个半抗原/CRM197分子)，但%MPE约为13%。此外，还介绍了化合物1的化学合成、偶联方法的优化以及半抗原密度的精确定量方法。
Vaccines against drugs of abuse have induced antibodies in animals that blocked the biological effects of the drug by sequestering the drug in the blood and preventing it from crossing the blood-brain barrier. Drugs of abuse are too small to induce antibodies and, therefore, require conjugation of drug hapten analogs to a carrier protein. The efficacy of these conjugate vaccines depends on several factors including hapten design, coupling strategy, hapten density, carrier protein selection, and vaccine adjuvant. Previously, we have shown that 1 (MorHap), a heroin/morphine hapten, conjugated to tetanus toxoid (TT) and mixed with liposomes containing monophosphoryl lipid A [L(MPLA)] as adjuvant, partially blocked the antinociceptive effects of heroin in mice. Herein, we extended those findings; demonstrating greatly improved vaccine induced antinociceptive effects up to 3% mean maximal potential effect (%MPE). This was obtained by evaluating the effects of vaccine efficacy of hapten 1 vaccine conjugates with varying hapten densities using two different commonly used carrier proteins, TT and cross-reactive material 197 (CRM197). Immunization of mice with these conjugates mixed with L(MPLA) induced very high anti-1 IgG peak levels of 400 – 1,500 µg/mL that bound to both heroin and its metabolites, 6-acetylmorphine and morphine. Except for the lowest hapten density for each carrier, the antibody titers and affinity were independent of hapten density. The TT carrier based vaccines induced long-lived inhibition of heroin-induced antinociception that correlated with increasing hapten density. The best formulation contained TT with the highest hapten density of ≥30 haptens/TT molecule and induced %MPE of approximately 3% after heroin challenge. In contrast, the best formulation using CRM197 was with intermediate 1 densities (10–15 haptens/ CRM197 molecule), but the %MPE was approximately 13%. In addition, the chemical synthesis of 1; the optimization of the conjugation method; and the methods for the accurate quantification of hapten density are described.
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影响因子：
5.5
作者：
Matyas, Gary R.;Rice, Kenner C.;Cheng, Kejun;Li, Fuying;Antoline, Joshua F. G.;Iyer, Malliga R.;Jacobson, Arthur E.;Mayorov, Alexander V.;Beck, Zoltan;Torres, Oscar B.;Alving, Carl R.
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通讯作者：
SCHUSTER, CR
影响因子：
5.5
作者：
Alving, Carl R.;Matyas, Gary R.;Torres, Oscar;Jalah, Rashmi;Beck, Zoltan
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