Pharmacological mechanisms underlying the efficacy of antibodies generated by a vaccine to treat oxycodone use disorder

Raleigh, Michael D.; King, Samantha J.; Baruffaldi, Federico; Saykao, Amy; Hamid, Fatima A.; Winston, Scott; LeSage, Mark; Pentel, P.R.; Pravetoni, Marco

doi:10.1016/j.neuropharm.2021.108653

Cited by 16 publications

(11 citation statements)

References 45 publications

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“…For instance, we have previously reported that immunization with OUD vaccines increases antibody-bound opioid in the serum, reducing the free circulating opioid. 25,48,49 This study extended these findings by showing that vaccination resulted in a decrease in free circulating fentanyl and carfentanil in the heart and lungs, which may contribute to protection against druginduced effects on respiratory and cardiovascular functions. Previous reports showed that nicotine vaccines elicit functional drug-specific antibody IgG and IgA responses in various organs including the lungs.…”

Section: ■ Discussionsupporting

confidence: 56%

Efficacy and Selectivity of Monovalent and Bivalent Vaccination Strategies to Protect against Exposure to Carfentanil, Fentanyl, and Their Mixtures in Rats

Crouse

Gradinati

et al. 2022

ACS Pharmacol. Transl. Sci.

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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 polyclonal 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.

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Section: ■ Discussionsupporting

confidence: 56%

Efficacy and Selectivity of Monovalent and Bivalent Vaccination Strategies to Protect against Exposure to Carfentanil, Fentanyl, and Their Mixtures in Rats

Crouse

Gradinati

et al. 2022

ACS Pharmacol. Transl. Sci.

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“…A vaccine targeting oxycodone is currently being investigated in subjects with OUD in Phase I clinical trials. 12 Antifentanyl vaccines targeting OUD have shown efficacy in reducing antinociception, respiratory depression, and brain distribution of fentanyl in mice and rats, 13 − 16 and in some studies were effective against potentially lethal fentanyl doses (i.e., 2–4 mg/kg) in mice. 16 Because of their selectivity for the target drug, antifentanyl vaccines did not interfere with pharmacological activity of off-target opioids such as methadone and naloxone, or critical care medications such as anesthetics.…”

Section: Introductionmentioning

confidence: 99%

“…Such vaccines, which consist of an opioid-based hapten conjugated to an immunogenic carrier protein, have shown substantial preclinical efficacy as a strategy to combat OUD and drug-related overdose (reviewed in refs and ). A vaccine targeting oxycodone is currently being investigated in subjects with OUD in Phase I clinical trials . Antifentanyl vaccines targeting OUD have shown efficacy in reducing antinociception, respiratory depression, and brain distribution of fentanyl in mice and rats, − and in some studies were effective against potentially lethal fentanyl doses (i.e., 2–4 mg/kg) in mice .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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The ongoing public health emergency of opioid use disorders (OUD) and overdose in the United States is largely driven by fentanyl and its related analogues and has resulted in over 75 673 deaths in 2021. Immunotherapeutics such as vaccines have been investigated as a potential interventional strategy complementary to current pharmacotherapies to reduce the incidence of OUD and opioid-related overdose. Given the importance of targeting structurally distinct fentanyl analogues, this study compared a previously established lead conjugate vaccine (F 1 –CRM) to a series of novel vaccines incorporating haptens derived from alfentanil and acetylfentanyl (F 8, 9a, 9b, 10 ), and evaluated their efficacy against drug-induced pharmacological effects in rats. While no vaccine tested provided significant protection against alfentanil, lead formulations were effective in reducing antinociception, respiratory depression, and bradycardia elicited by fentanyl, sufentanil, and acetylfentanyl. Compared with control, vaccination with F 1 –CRM also reduced drug levels in the brain of rats challenged with lethal doses of fentanyl. These data further support investigation of F 1 –CRM as a candidate vaccine against fentanyl and selected analogues.

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“…Previous studies have shown that conjugate vaccines elicit opioid-specific B cell population subsets including switched memory B cells (Laudenbach et al ., 2015), and that B cell formation is dependent upon germinal center formation and involvement of cognate CD4+ T cells (Laudenbach et al ., 2015; Baruffaldi et al ., 2019). Furthermore, vaccination could boost antibodies well-beyond the disappearance of the first antibody response (Raleigh et al ., 2021). Here, VAST-elicited memory B cells are persistent as they can be recalled in mice through at least 16 weeks after the second prime injection, which renders this platform flexible for different vaccine regiments and experimental set-ups.…”

Section: Discussionmentioning

confidence: 99%

An Epitope-Focused Trypanosome-Derived Vaccine Platform Elicits High-Affinity Antibodies and Immunity Against Fentanyl Effects

Triller

Vlachou

Hashemi

et al. 2022

Preprint

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SummaryPoorly antigenic small molecules pose challenges for the production of clinically efficacious antibodies. To address this, we have developed an immunization platform derived from the antigenic surface coat of the African trypanosome. Through sortase-based conjugation of antigens to the trypanosome surface coat protein variant surface glycoprotein (VSG), we created the VAST (VSG-immunogen Array by Sortase Tagging). We used VAST to elicit protective immunity to the effects fentanyl. Immunizing mice with fentanyl-VAST generated serological memory and protection from fentanyl challenge. Employing single-cell RNAseq, we then developed a streamlined method that synergizes with the VAST to identify immunization-elicited memory B cells and the antibodies they encode. All antibodies selected by this method displayed picomolar affinities for fentanyl. Passive immunization protected animals from fentanyl, while crystallography revealed that the mAbs bind fentanyl in an unusually deep pocket suited to small molecules, demonstrating the ability of the VAST to elicit high-quality therapeutic antibodies.

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Pharmacological mechanisms underlying the efficacy of antibodies generated by a vaccine to treat oxycodone use disorder

Cited by 16 publications

References 45 publications

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

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

An Epitope-Focused Trypanosome-Derived Vaccine Platform Elicits High-Affinity Antibodies and Immunity Against Fentanyl Effects

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