Bacteriophage virus-like particle vaccines for fentanyl and heroin overdose

项目总结 阿片类药物占美国过量死亡的近70%，芬太尼和海洛因是其中的两种 最常见的原因。阿片类药物过量的治疗目前依赖于纳洛酮的快速给药。新的 迫切需要防止阿片类药物过量的战略，作为综合办法的一部分 解决阿片类药物在美国的流行问题。阿片疫苗是一种有吸引力的预防阿片类药物的方法 过量和阿片类药物使用障碍(OUD)。这些疫苗的作用是通过诱导血清抗体结合和 将药物隔离在血液中，防止它越过作用于中枢神经系统的血脑屏障 神经系统。目前的阿片类药物疫苗战略需要多次免疫和数月才能达到峰值滴度，并且 尚未显示出针对致命过量的保护措施。在这里，我们建议使用一种类似噬菌体病毒 颗粒(VLP)疫苗平台可快速诱导高滴度抗体，以防止致命的过量使用 芬太尼和海洛因。我们有初步数据表明羟考酮这种方法的可行性， 在单次肌肉免疫后14天内达到峰值滴度，并保护免受致死 羟考酮过量。在这两个阶段的UG3/UH3提案中，我们将设计一种联合疫苗来 通过展示改良的芬太尼、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，我们将探讨其影响 结合结合部位对抗体的特异性和亲和力的影响 预防致命过量、药物引起的呼吸抑制和药物引起的抗病毒的疫苗 伤害性感受。在第一阶段结束时，我们将有一个领先的候选联合疫苗来对抗芬太尼和 海洛因。在第二阶段，我们将进一步探索佐剂的添加和给药部位对疫苗效力的影响。 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。我们还将开发一种全面的产品 发展计划、主细胞库(MCB)，并与行业合作伙伴建立流程和非 GLP生产我们的VLP疫苗和一个非GLP安全药理功能观察电池。 总体而言，这些研究将确定一种主要的芬太尼和海洛因疫苗候选药物，可以预防致命的 这些药物的过量使用，并提供必要的关键数据，以便在年底之前进入支持IND的研究 在五年的资金投入中。

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.