Efficacy and Selectivity of Monovalent and Bivalent Vaccination Strategies to Protect against Exposure to Carfentanil, Fentanyl, and Their Mixtures in Rats
Efficacy and Selectivity of Monovalent and Bivalent Vaccination Strategies to Protect against Exposure to Carfentanil, Fentanyl, and Their Mixtures in Rats
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DOI：
10.1021/acsptsci.1c00260
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发表时间：
2022-05-13
影响因子：
--
通讯作者：
Pravetoni, Marco
中科院分区：
文献类型：
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作者：
Crouse, Bethany;Wu, Mariah M.;Pravetoni, Marco
在过去十年中，由于非法芬太尼和卡芬太尼等其他强效合成阿片类药物的广泛供应，与毒品有关的致命过量大大增加。故意或意外摄入或暴露于卡芬太尼、芬太尼及其混合物会引起呼吸抑制和心动过缓，这很难用阿片受体拮抗剂纳洛酮逆转。疫苗为减少与芬太尼相关物质相关的死亡率以及治疗阿片类药物使用障碍提供了一种很有希望的策略。本研究报告了单价和二价疫苗接种策略，可引起多肽抗体反应，有效防止卡芬太尼、芬太尼或卡芬太尼/芬太尼混合物的药理作用。用含有卡芬太尼半抗原或基于芬太尼半抗原或它们在二价疫苗制剂中的组合的单独结合疫苗对大鼠进行预防性免疫，然后用卡芬太尼、芬太尼或它们的混合物进行刺激。首先，这些研究确定了一种预防卡芬太尼诱导的抗痛觉、呼吸抑制和心动过缓的铅疫苗。然后，对卡芬太尼和芬太尼的有效性通过二价疫苗接种策略实现，该策略通过异种初始/增强或联合免疫方案将抗卡芬太尼和抗芬太尼铅疫苗结合起来。这些临床前数据支持开发疫苗作为一种可行的策略，以防止暴露于过量的卡芬太尼、芬太尼或其混合物引起的毒性。
Drug-related fatal overdoses have significantly increased in the past decade due to the widespread availability of illicit fentanyl and other potent synthetic opioids such as carfentanil. Deliberate or accidental consumption or exposure to carfentanil, fentanyl, and their mixture induces respiratory depression and bradycardia that can be difficult to reverse with the opioid receptor antagonist naloxone. Vaccines offer a promising strategy to reduce the incidence of fatalities associated with fentanyl-related substances, as well as treatment for opioid use disorder (OUD). This study reports monovalent and bivalent vaccination strategies that elicit polydonal antibody responses effective in protecting against the pharmacological actions of carfentanil, fentanyl, or carfentanil/fentanyl mixtures. Rats were prophylactically immunized with individual conjugate vaccines containing either carfentanil- or fentanyl-based haptens, or their combination in bivalent vaccine formulations, and then challenged with carfentanil, fentanyl, or their mixture. First, these studies identified a lead vaccine protective against carfentanil-induced antinociception, respiratory depression, and bradycardia. Then, efficacy against both carfentanil and fentanyl was achieved through bivalent vaccination strategies that combined lead anti-carfentanil and anti-fentanyl vaccines via either heterologous prime/boost or co-administration immunization regimens. These preclinical data support the development of vaccines as a viable strategy to prevent toxicity from exposure to excessive doses of carfentanil, fentanyl, or their mixtures.