Stone Addison E, Scheuermann Sarah E, Haile Colin N, Cuny Gregory D, Velasquez Marcela Lopez, Linhuber Joshua P, Duddupudi Anantha L, Vigliaturo Jennifer R, Pravetoni Marco, Kosten Therese A, Kosten Thomas R, Norton Elizabeth B
Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA.
Department of Psychology, University of Houston, Houston, TX, USA.
NPJ Vaccines. 2021 May 13;6(1):69. doi: 10.1038/s41541-021-00329-0.
Fentanyl is a major contributor to the devastating increase in overdose deaths from substance use disorders (SUD). A vaccine targeting fentanyl could be a powerful immunotherapeutic. Here, we evaluated adjuvant and delivery strategies for conjugate antigen vaccination with fentanyl-based haptens. We tested adjuvants derived from the heat-labile toxin of E. coli including dmLT and LTA1 by intramuscular, sublingual or intranasal delivery. Our results show anti-fentanyl serum antibodies and antibody secreting cells in the bone-marrow after vaccination with highest levels observed with an adjuvant (alum, dmLT, or LTA1). Vaccine adjuvanted with LTA1 or dmLT elicited the highest levels of anti-fentanyl antibodies, whereas alum achieved highest levels against the carrier protein. Vaccination with sublingual dmLT or intranasal LTA1 provided the most robust blockade of fentanyl-induced analgesia and CNS penetration correlating strongly to anti-FEN IgA. In conclusion, this study demonstrates dmLT or LTA1 adjuvant as well as mucosal delivery may be attractive strategies for improving the efficacy of vaccines against SUD.
芬太尼是导致物质使用障碍（SUD）所致过量死亡灾难性增加的主要因素。一种靶向芬太尼的疫苗可能是一种强大的免疫疗法。在此，我们评估了基于芬太尼半抗原的共轭抗原疫苗接种的佐剂和递送策略。我们通过肌肉注射、舌下给药或鼻内给药测试了源自大肠杆菌不耐热毒素的佐剂，包括dmLT和LTA1。我们的结果显示，接种疫苗后骨髓中出现抗芬太尼血清抗体和抗体分泌细胞，使用佐剂（明矾、dmLT或LTA1）时观察到最高水平。用LTA1或dmLT佐剂的疫苗引发了最高水平的抗芬太尼抗体，而明矾对载体蛋白产生的抗体水平最高。舌下给予dmLT或鼻内给予LTA1进行疫苗接种对芬太尼诱导的镇痛和中枢神经系统渗透提供了最强有力的阻断，这与抗芬太尼IgA密切相关。总之，本研究表明dmLT或LTA1佐剂以及黏膜递送可能是提高针对SUD疫苗疗效的有吸引力的策略。
