Effect of Currently Approved Carriers and Adjuvants on the Pre-Clinical Efficacy of a Conjugate Vaccine against Oxycodone in Mice and Rats
Effect of Currently Approved Carriers and Adjuvants on the Pre-Clinical Efficacy of a Conjugate Vaccine against Oxycodone in Mice and Rats
复制标题
DOI：
10.1371/journal.pone.0096547
复制
发表时间：
2014-05-05
期刊：
影响因子：
3.7
通讯作者：
Pentel, Paul R.
中科院分区：
文献类型：
--
作者：
Pravetoni, Marco;Vervacke, Jeffrey S.;Pentel, Paul R.
针对高度滥用的处方阿片类羟考酮的疫苗接种显示出阻断羟考酮效应的临床前疗效。本研究进一步评价了由在C6位衍生化的羟考酮（6 OXY）与天然匙孔血蓝蛋白（nKLH）载体蛋白偶联组成的候选疫苗。为了提供一种适用于人体研究的羟考酮疫苗制剂，我们研究了替代载体和佐剂对羟考酮特异性血清抗体和B细胞应答产生的影响，以及免疫对小鼠和大鼠中羟考酮分布和羟考酮诱导的抗伤害感受的影响。在小鼠和大鼠中，与破伤风类毒素（TT）或GMP级KLH二聚体（dKLH）缀合的6 OXY与与nKLH十聚体缀合的6 OXY一样有效，而与TT衍生肽缀合的6 OXY半抗原在预防小鼠中羟考酮诱导的抗伤害感受方面无效。用60 XY-TT s.c.免疫吸收在明矾佐剂上的60 XY-TT在大鼠中提供与60 XY-TT和弗氏佐剂腹膜内施用相似的保护。toll样受体4（TLR 4）激动剂单磷酰脂质A（MPLA）佐剂单独或与明矾组合，对于在用6 OXY-nKLH或6 OXY-TT接种的小鼠中产生羟考酮特异性血清抗体或分泌6 OXY特异性抗体的B细胞，没有提供优于单独明矾的优势。羟考酮疫苗的免疫原性可通过TLR 4信号传导调节，因为在TLR 4缺陷小鼠中对明矾中的6 OXY-nKLH的应答降低。这些数据表明，TT、nKLH和dKLH载体在不同种属、毒株和通过不同给药途径提供一致的6 OXY缀合物疫苗免疫原性，而佐剂制剂可能需要针对个体免疫原或患者群体进行定制。
Vaccination against the highly abused prescription opioid oxycodone has shown pre-clinical efficacy for blocking oxycodone effects. The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the C6 position (6OXY) conjugated to the native keyhole limpet hemocyanin (nKLH) carrier protein. To provide an oxycodone vaccine formulation suitable for human studies, we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses, and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats. 6OXY conjugated to tetanus toxoid (TT) or a GMP grade KLH dimer (dKLH) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats, while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice. Immunization with 6OXY-TT s.c. absorbed on alum adjuvant provided similar protection to 6OXY-TT administered i.p. with Freund's adjuvant in rats. The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, alone or in combination with alum, offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY-specific antibody secreting B cells in mice vaccinated with 6OXY-nKLH or 6OXY-TT. The immunogenicity of oxycodone vaccines may be modulated by TLR4 signaling since responses to 6OXY-nKLH in alum were decreased in TLR4-deficient mice. These data suggest that TT, nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species, strains and via different routes of administration, while adjuvant formulations may need to be tailored to individual immunogens or patient populations.