Crouse Bethany, Miller Shannon M, Muelken Peter, Hicks Linda, Vigliaturo Jennifer R, Marker Cheryl L, Guedes Alonso G P, Pentel Paul R, Evans Jay T, LeSage Mark G, Pravetoni Marco
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA.
Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, USA.
NPJ Vaccines. 2023 Jul 24;8(1):107. doi: 10.1038/s41541-023-00697-9.
Opioid use disorders (OUD) and overdose are public health threats worldwide. Widespread access to highly potent illicit synthetic opioids such as fentanyl is driving the recent rise in fatal overdoses. Vaccines containing fentanyl-based haptens conjugated to immunogenic carrier proteins offer a long-lasting, safe, and cost-effective strategy to protect individuals from overdose upon accidental or deliberate exposure to fentanyl and its analogs. Prophylactic or therapeutic active immunization with an anti-fentanyl vaccine induces the production of fentanyl-specific antibodies that bind the drug in the blood and prevent its distribution to the brain, which reduces its reinforcing effects and attenuates respiratory depression and bradycardia. To increase the efficacy of a lead anti-fentanyl vaccine, this study tested whether the incorporation of synthetic toll-like receptor (TLR) 4 and TLR7/8 agonists as vaccine adjuvants would increase vaccine efficacy against fentanyl challenge, overdose, and self-administration in either rats or Hanford miniature pigs. Formulation of the vaccine with a nucleolipid TLR7/8 agonist enhanced its immunogenicity and efficacy in preventing fentanyl-induced respiratory depression, analgesia, bradycardia, and self-administration in either rats or mini-pigs. These studies support the use of TLR7/8 adjuvants in vaccine formulations to improve their clinical efficacy against OUD and potentially other substance use disorders (SUD).
阿片类药物使用障碍（OUD）和过量用药是全球范围内的公共卫生威胁。芬太尼等高效非法合成阿片类药物的广泛可得性导致近期致命过量用药事件增多。含有与免疫原性载体蛋白偶联的基于芬太尼的半抗原的疫苗，为保护个体在意外或故意接触芬太尼及其类似物时免于过量用药提供了一种持久、安全且具有成本效益的策略。用抗芬太尼疫苗进行预防性或治疗性主动免疫可诱导产生芬太尼特异性抗体，这些抗体在血液中与药物结合，阻止其分布到大脑，从而降低其强化作用，并减轻呼吸抑制和心动过缓。为提高一种先导抗芬太尼疫苗的效力，本研究测试了将合成的Toll样受体（TLR）4和TLR7/8激动剂作为疫苗佐剂是否会提高疫苗对芬太尼攻击、过量用药及自我给药的效力，实验对象为大鼠或汉福德小型猪。用一种核脂质TLR7/8激动剂配制疫苗，可增强其免疫原性以及在预防大鼠或小型猪芬太尼诱导的呼吸抑制、镇痛、心动过缓和自我给药方面的效力。这些研究支持在疫苗制剂中使用TLR7/8佐剂，以提高其针对阿片类药物使用障碍以及可能的其他物质使用障碍（SUD）的临床效力。
