Vaccines for fentanyl and its derivatives: A strategy to reduce illicit use and overdose

芬太尼及其衍生物疫苗：减少非法使用和过量服用的策略

• 批准号: 10523190
• 负责人: Marco Pravetoni
• 金额: $ 400.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523190
• 关键词: Address; Adjuvant; Agonist; Antibodies; Antibody Affinity; Antibody Response; B-Lymphocytes; Behavior; Benchmarking; Bradycardia; Brain; Buprenorphine; Canada; Carrier Proteins; Categories; Chemicals; Clinical Trials; Cocaine; Conjugate Vaccines; Conjugated Carrier; Contracts; Data; Development; Drug Prescriptions; Epidemic; Escherichia coli; Europe; Exposure to; Family; Fentanyl; Follow-Up Studies; Formulation; Funding; Guidelines; Haptens; Heroin; Human Resources; Immunization; Immunize; Incidence; Individual; Industry Standard; Keyhole Limpet Hemocyanin; Law Enforcement; Lead; Licensing; Maintenance; Manufacturer Name; Methadone; Modeling; Mus; Naloxone; Naltrexone; Occupational Exposure; Occupations; Opioid; Overdose; Overdose reduction; Oxycodone; Pharmaceutical Preparations; Pharmacotherapy; Phase; Positioning Attribute; Public Health; Rattus; Recombinants; Regimen; Risk; Safety; Security; Self Administration; Series; Site; TLR9 gene; Testing; Toxicology; United States; Vaccines; Ventilatory Depression; abuse liability; aluminum sulfate; analog; antagonist; base; carfentanil; clinical toxicology; cost effective; cost effective intervention; cross reacting material 197; cross reactivity; drug distribution; efficacy testing; endogenous opioids; fentanyl overdose; high risk; illicit opioid; in vivo; industry partner; lead optimization; medication-assisted treatment; opioid overdose; opioid use; opioid user; pre-clinical; preclinical development; prescription opioid; remifentanil; research clinical testing; response; tetanus toxin fragment C; vaccine development; vaccine efficacy; vaccine evaluation; vaccine formulation; vaccine trial

ABSTRACT. This UG3/UH3 project will develop vaccines against fentanyl and fentanyl-like compounds as a strategy to reduce illicit opioid use and the incidence of fatal overdoses. Proposed activities will include lead vaccine selection and optimization, manufacturing of GMP vaccines, and IND-enabling GLP toxicology studies. The US has seen dramatic increases in fatal overdoses due to heroin, counterfeit prescription drugs, and cocaine adulterated with fentanyl or fentanyl-like analogs. Current medications may not be sufficient to address the opioid overdose epidemic. As a complementary strategy to current medications, we will develop vaccines against fentanyl and fentanyl-like compounds to reduce their abuse liability and lethality. Our team has already developed vaccines against heroin and oxycodone that induce antibodies effective in reducing opioid distribution to the brain, opioid-induced behaviors, and opioid-induced respiratory depression. Vaccines effectively and selectively target the intended opioid but do not interfere with endogenous opioids nor with approved pharmacotherapies. Opioid vaccines offer a long-lasting, safe and cost-effective intervention complementary to medication assisted treatment (MAT). Vaccines may reduce overdoses in opioid users as well as protect those in professions (e.g., law enforcement, airport security, postal workers) at risk of accidental exposure to fentanyl and fentanyl analogs. Our team has identified a candidate fentanyl vaccine consisting of a fentanyl-based hapten (F0) conjugated to the keyhole limpet hemocyanin (KLH) carrier protein, and adsorbed onto alum adjuvant. Immunization with F0-KLH reduces fentanyl distribution to the brain, and selectively reduces fentanyl-induced antinociception and respiratory depression in rats. We will further optimize the lead F0-KLH by testing alternative carrier proteins. In parallel we will develop other conjugate vaccines containing a new series of haptens (Fn) to target carfentanil, remifentanil, and other fentanyl analogs. Development will be staggered across UG3/UH3 phases, and we expect that the first lead F0-carrier conjugate vaccine will be ready for IND filing by the end of Year 3. AIM1 focuses on optimization of vaccines containing the lead F0 and new Fn haptens conjugated to industry-standard carrier proteins, including two E. coli-expressed carriers obtained from our industry partner FinaBiosolutions. Leads are identified for efficacy in inducing antibodies that will reduce fentanyl (or fentanyl analog) distribution to the brain as well as reducing antinociception, respiratory depression and lethality in rats. AIM1 also characterizes additional immunization regimens and vaccine efficacy in fentanyl self-administration rat models. As a contingency plan, AIM2 tests whether AIM1 leads containing F0 and Fn haptens can be co-administered in a multicomponent vaccine formulation to simultaneously target fentanyl and its analogs. AIM3 focuses on manufacturing of GMP vaccines and evaluate their safety in GLP pre-clinical toxicology studies through CMO and CRO partners. AIM3 will then file an IND for at least one vaccine formulation against fentanyl and/or its analogs.

摘要。这个UG3/UH3项目将开发针对芬太尼和芬太尼样化合物的疫苗