Open SPR助力疫苗动物模型评估

Title: A synthetic opioid vaccine attenuates fentanyl-vs-food choice in male and female rhesus monkeys

题目：合成阿片类疫苗减弱了雄性和雌性恒河猴的芬太尼与食物选择

Journal: Drug and Alcohol Dependence

IF:3.951

Date: 2020/10/20

Abstract

Aim: Opioid-targeted vaccines are under consideration as candidate Opioid Use Disorder medications. We recently reported that a fentanyl-targeted vaccine produced a robust and long-lasting attenuation of fentanyl-vsfood choice in rats. In the current study, we evaluated an optimized fentanyl-targeted vaccine in rhesus monkeys to determine whether vaccine effectiveness to attenuate fentanyl choice translated to a species with greater phylogenetic similarity to humans.

Methods: Adult male (2) and female (3) rhesus monkeys were trained to respond under a concurrent schedule of food (1 g pellets) and intravenous fentanyl (0, 0.032− 1 μg/kg/injection) reinforcement during daily 2 h sessions. Fentanyl choice dose-effect functions were determined daily and 7-day buprenorphine treatments (0.0032− 0.032 mg/kg/h IV; n = 4–5) were determined for comparison to vaccine effects. Subsequently, a fentanyl-CRM197 conjugate vaccine was administered at week 0, 3, 8, 15 over a 29-week experimental period during which fentanyl choice dose-effect functions continued to be determined daily.

Results: Buprenorphine significantly decreased fentanyl choice and reciprocally increased food choice. Vaccination eliminated fentanyl choice and increased food choice in four-of-the-five monkeys. A transient and less robust vaccine effect was observed in the fifth monkey. Fentanyl-specific antibody concentrations peaked after the third vaccination to approximately 50 μg/mL while anti-fentanyl antibody affinity increased to a sustained low nanomolar level.

Conclusion: These results translate fentanyl vaccine effectiveness from rats to rhesus monkeys to decrease fentanyl-vs-food choice, albeit with greater individual differences observed in monkeys. These results support the potential and further clinical evaluation of this fentanyl-targeted vaccine as a candidate Opioid Use Disorder medication.

目的

阿片类药物靶向疫苗可能成为阿片类药物使用障碍治疗药物。我们最近报道芬太尼疫苗能强而持久地让小鼠减弱对芬太尼与食物选择。在最近的研究中，我们在与人类有更相似的发育系统的恒河猴中对优化后的芬太尼疫苗进行评估，以确定疫苗是否能有效降低恒河猴对芬太尼的选择。

方法

2只雄性和3只雌性成年恒河猴在每天2小时的会议时间内进行食物(1g丸剂)和静脉内芬太尼(0, 0.032− 1 μg/kg/注射)强化的同时做出反应的训练。每天确定芬太尼选择剂量，7天的丁丙诺啡治疗(0.0032− 0.032 mg/kg/h IV; n = 4–5)作为疫苗效果的对照。随后，在29周的实验中，在第 0、3、8、15 周接种芬太尼结合疫苗，在此期间每天继续确定芬太尼选择剂量。

结果

丁丙诺啡显着减少了芬太尼的选择并相应地增加了食物的选择。在五分之四的猴子中，接种疫苗消除了芬太尼的选择并增加了食物的选择。在第五只猴子中观察到短暂且不太强烈的疫苗效果。芬太尼特异性抗体浓度在第三次接种后达到峰值50μg/mL，同时抗芬太尼抗体亲和力提高到低纳摩尔水平。

结论

这些结果将芬太尼疫苗减少芬太尼与食物的选择的有效性从大鼠转移到恒河猴，虽然在猴子中观察到更大的个体差异。这些结果表明，芬太尼疫苗具有治疗阿片类药物滥用的潜力，有进一步进行临床评估的意义。