Preclinical Efficacy and Selectivity of Vaccines Targeting Fentanyl,Alfentanil, Sufentanil, and Acetylfentanyl in Rats

The ongoing public health emergency of opioid use disorders (OUD) and overdose in the United States is largelydriven by fentanyl and its related analogues and has resulted in over 75 673 deaths in 2021. Immunotherapeutics such as vaccineshave been investigated as a potential interventional strategy complementary to current pharmacotherapies to reduce the incidence ofOUD and opioid-related overdose. Given the importance of targeting structurally distinct fentanyl analogues, this study compared apreviously established lead conjugate vaccine (F1-CRM) to a series of novel vaccines incorporating haptens derived from alfentaniland acetylfentanyl (F8, 9a, 9b, 10), and evaluated their efficacy against drug-induced pharmacological effects in rats. While no vaccinetested provided significant protection against alfentanil, lead formulations were effective in reducing antinociception, respiratorydepression, and bradycardia elicited by fentanyl, sufentanil, and acetylfentanyl. Compared with control, vaccination with F1-CRMalso reduced drug levels in the brain of rats challenged with lethal doses of fentanyl. These data further support investigation of F1-CRM as a candidate vaccine against fentanyl and selected analogues