Bacteriophage virus-like particle vaccines for fentanyl and heroin overdose

用于治疗芬太尼和海洛因过量的噬菌体病毒样颗粒疫苗

• 批准号: 10157937
• 负责人: Bryce C Chackerian
• 金额: $ 157.27万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157937
• 关键词: 6-O-monoacetylmorphine; Address; Adjuvant; Affinity; Animal Model; Antibodies; Antibody Affinity; Antibody titer measurement; Bacteriophages; Binding; Blood; Buprenorphine; Chemicals; Clinical; Collaborations; Combined Vaccines; Contracts; Data; Development; Development Plans; Dose; Engineering; Fentanyl; Funding; General Population; Generations; Guidelines; Heroin; Human; Immunization; Ingestion; Inhalation; Injections; International; Intramuscular; Intravenous; Kinetics; Laboratories; Lead; Length; Life; Longevity; Methadone; Modeling; Modification; Monitor; Morphine; Mus; Naloxone; Neuraxis; New Mexico; Nociception; Opioid; Oral; Oryctolagus cuniculus; Overdose; Oxycodone; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacy facility; Phase; Preparation; Process; Production; Protocols documentation; Rattus; Rivers; Route; Running; Safety; Savings; Self Administration; Serum; Site; Specificity; Surface; Testing; Toxic effect; Toxicology; United States; United States National Institutes of Health; Universities; Vaccination; Vaccine Adjuvant; Vaccines; Ventilatory Depression; Virus-like particle; base; blood-brain barrier crossing; cell bank; college; density; drug of abuse; efficacy study; efficacy testing; endogenous opioids; experience; fentanyl overdose; heroin overdose; immunogenic; immunogenicity; industry partner; interest; lead candidate; medical schools; nonhuman primate; novel strategies; novel vaccines; opioid epidemic; opioid overdose; opioid use disorder; overdose death; peptide drug; preclinical development; prevent; product development; programs; response; vaccine candidate; vaccine development; vaccine efficacy

PROJECT SUMMARY Opioids account for close to 70% of overdose deaths in the United States, with fentanyl and heroin two of the most common causes. Treatment of opioid overdose currently relies on rapid administration of naloxone. New strategies to prevent opioid overdose are desperately needed as a part of a comprehensive approach to address the opioid epidemic in the United States. Opioid vaccines are an attractive approach to prevent opioid overdose and Opioid Use Disorder (OUD). These vaccines act by eliciting serum antibodies that bind and sequester the drug in the blood, preventing it from crossing the blood-brain barrier where it acts on the central nervous system. Current opioid vaccine strategies require multiple boosts and months to reach peak titers, and have yet to show protection against lethal overdose. Here, we propose to use a bacteriophage virus-like particle (VLP) vaccine platform to elicit high titer antibodies quickly to protect against lethal overdose with fentanyl and heroin. We have preliminary data showing the feasibility of this approach for oxycodone, with peak titers reached within 14 days after a single intramuscular immunization, and protection from lethal overdose with oxycodone. In this two phase UG3/UH3 proposal, we will engineer a combined vaccine to protect against fentanyl and heroin by displaying modified fentanyl, heroin, and two active metabolites of heroin (6-acetylmorphine and morphine) on our bacteriophage VLP platform. In Phase 1, we will explore the impact of attachment site on the specificity and affinity of the antibodies elicited and the efficacy of the combined vaccine to protect against lethal overdose, drug-induced respiratory depression, and drug-induced anti- nociception. At the end of Phase 1, we will have a lead candidate combined vaccine against fentanyl and heroin. In Phase 2, we will further explore the addition of adjuvants and administration site on vaccine efficacy. We will also examine the protection offered by our vaccine against lethal fentanyl and heroin overdose administered by oral, intravenous, inhalation routes. We will also develop a comprehensive Product Development Plan, a master cell bank (MCB), and engage industry partners to establish a process and non- GLP production runs of our VLP vaccines and a non-GLP safety pharmacology functional observation battery. Overall these studies will identify a lead fentanyl and heroin vaccine candidate that can protect against fatal overdose of these drugs, and provide the critical data necessary to move into IND-enabling studies by the end of the 5 years of funding.

项目概要 阿片类药物占美国服药过量死亡人数的近 70%，其中芬太尼和海洛因是其中两种 最常见的原因。目前阿片类药物过量的治疗依赖于纳洛酮的快速给药。新的 迫切需要制定预防阿片类药物过量的策略，作为综合方法的一部分 解决美国的阿片类药物流行问题。阿片类疫苗是预防阿片类药物的一种有吸引力的方法 药物过量和阿片类药物使用障碍 (OUD)。这些疫苗通过引发血清抗体来发挥作用，这些抗体可以结合并 将药物隔离在血液中，防止其穿过血脑屏障，作用于中枢神经系统 神经系统。目前的阿片类疫苗策略需要多次加强和数月才能达到峰值滴度，并且 尚未显示出针对致命过量用药的保护作用。在这里，我们建议使用类似噬菌体病毒 颗粒（VLP）疫苗平台可快速引发高滴度抗体，以防止致命的过量服用 芬太尼和海洛因。我们有初步数据显示这种方法对羟考酮的可行性， 单次肌内免疫后 14 天内达到峰值滴度，并防止致命 羟考酮过量。在这个两阶段的 UG3/UH3 提案中，我们将设计一种联合疫苗 通过展示改性芬太尼、海洛因和海洛因的两种活性代谢物来预防芬太尼和海洛因 （6-乙酰吗啡和吗啡）在我们的噬菌体 VLP 平台上。在第一阶段，我们将探讨影响 附着位点对引发的抗体的特异性和亲和力以及组合的功效的影响 疫苗可预防致命的过量用药、药物引起的呼吸抑制和药物引起的抗 伤害感受。在第一阶段结束时，我们将拥有针对芬太尼和 海洛因。在第二阶段，我们将进一步探讨佐剂的添加和给药部位对疫苗功效的影响。 我们还将检查我们的疫苗对致命的芬太尼和海洛因过量服用的保护作用 通过口服、静脉注射、吸入途径给药。我们还将开发全面的产品 开发计划、主细胞库（MCB），并与行业合作伙伴合作建立流程和非 我们的 VLP 疫苗和非 GLP 安全药理学功能观察组的 GLP 生产运行。 总体而言，这些研究将确定一种可预防致命的芬太尼和海洛因候选疫苗 过量服用这些药物，并提供最终进入 IND 研究所需的关键数据 5年的资助。