Bacteriophage virus-like particle based vaccines against oxycodone

基于噬菌体病毒样颗粒的羟考酮疫苗

• 批准号: 10750819
• 负责人: Isabella Romano
• 金额: $ 3.71万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750819
• 关键词: American; Animal Model; Animals; Antibodies; Antibody Avidity; Antibody Response; Bacteriophages; Binding; Blood; Blood - brain barrier anatomy; Brain; Carrier Proteins; Cessation of life; Clinical Trials; Conjugate Vaccines; Data; Development; Dose; Drug Exposure; Drug Targeting; Effectiveness; Engineering; Enzyme-Linked Immunosorbent Assay; Fellowship; Fentanyl; Foundations; Goals; Haptens; High Pressure Liquid Chromatography; Human; Immunization; Immunize; Immunology; In Vitro; Individual; Intervention; Intravenous; Investigation; Keyhole Limpet Hemocyanin; Knowledge; Mass Spectrum Analysis; Mediating; Modeling; Naloxone; Opioid; Opioid Antagonist; Opioid Receptor; Overdose; Oxycodone; Patients; Pharmaceutical Preparations; Phase; Prevention; Public Health; Rattus; Research; Research Project Grants; Research Proposals; Route; Safety; Serum; Severities; Structure; Surface; Techniques; Tetanus Toxoid; United States; Vaccinated; Vaccination; Vaccine Design; Vaccines; Ventilatory Depression; Virus-like particle; Whole Body Plethysmography; blood-brain barrier crossing; chemical conjugate; clinically relevant; combat; cross reactivity; drug distribution; exposure route; immunogenic; improved; in vivo; interest; liquid chromatography mass spectrometry; medication for opioid use disorder; medication-assisted treatment; novel; novel strategies; novel therapeutic intervention; novel vaccines; opioid epidemic; opioid overdose; opioid use disorder; pre-clinical; prescription opioid abuse; prevent; protective efficacy; self assembly; skills; subcutaneous; translational applications; treatment strategy; vaccine development; vaccine platform; vaccinology

PROJECT SUMMARY Opioid use disorder (OUD) and associated opioid overdoses are public health crises of increasing severity, reflected by a staggering 80,000 opioid overdose associated deaths in the United States alone in 2021. Despite the availability of current treatment strategies including medications for opioid use disorder and medication assisted treatment (MOUD and MAT), opioid overdoses continue to skyrocket at an alarming rate. Recently, vaccines targeting opioids were proposed as a novel intervention to combat the growing crisis. Vaccines targeting opioids have been developed using traditional protein carrier approaches and are entering human clinical trials. The overall goal of this fellowship is to investigate the efficacy of a Qβ bacteriophage virus-like particle (VLP) based vaccine targeting oxycodone as a novel treatment to prevent oxycodone overdose. Bacteriophage VLPs are highly immunogenic vaccine platforms that are well-established to be safe and effective in humans. This project will be conducted under the central hypothesis that a Qβ VLP conjugated vaccine targeting oxycodone will offer protection upon cognate drug challenge with limited cross-reactivity. This hypothesis will be investigated by the following specific aims: Specific Aim 1: Determine the impact of immunization on drug distribution across the blood-brain barrier. Using high-performance liquid chromatography mass spectrometry (HPLC-MS), drug concentrations will be determined in the blood and brain compartments of immunized animals. Specific Aim 2: Investigate protection elicited by Qβ-oxycodone upon intravenous drug challenge. Utilizing whole-body plethysmography (WBP), I will investigate Qβ-oxycodone mediated protection from opioid induced respiratory depression upon intravenous drug challenge. Specific Aim 3: Examine the impact of immunization on naloxone efficacy. Using in-vitro and in-vivo approaches, the cross-reactivity of vaccine elicited antibodies with the opioid receptor antagonist naloxone will be determined. Together, these aims are focused on the long-term goal to inform effective vaccine design and offer new treatment options for OUD patients.

项目摘要 阿片类药物使用障碍（OUD）和相关的阿片类药物过量是日益严重的公共卫生危机， 这反映在2021年仅在美国就有惊人的80，000例阿片类药物过量相关死亡。尽管 目前治疗策略的可用性，包括阿片类药物使用障碍的药物和 尽管有许多辅助治疗（MOUD和MAT），阿片类药物过量继续以惊人的速度飙升。最近， 针对类阿片的疫苗被提议作为应对日益严重的危机的一种新的干预措施。疫苗 已经使用传统的蛋白质载体方法开发了靶向阿片类药物， 临床试验该研究的总体目标是研究Qβ噬菌体病毒样 靶向羟考酮的基于VLP的疫苗作为预防羟考酮过量的新型治疗。 噬菌体VLP是高度免疫原性的疫苗平台，其被公认为是安全有效的 在人类身上。本项目将在中心假设下进行，即Qβ VLP结合疫苗 靶向羟考酮将在具有有限交叉反应性的同源药物攻击时提供保护。这 假设将通过以下具体目标进行研究：具体目标1：确定 免疫对药物穿过血脑屏障分布的影响。使用高效液相色谱 通过质谱法（HPLC-MS），将在血液和脑隔室中测定药物浓度， 免疫动物具体目的2：研究Qβ-羟考酮对静脉给药的保护作用 挑战.利用全身体积描记法（WBP），我将研究Qβ-羟考酮介导的保护作用 阿片类药物诱导的呼吸抑制。具体目标3：审查影响 对纳洛酮疗效的影响。使用体外和体内方法，疫苗的交叉反应性 将测定阿片样物质受体拮抗剂纳洛酮引起的抗体。这些目标合在一起是 重点关注长期目标，为有效的疫苗设计提供信息，并为OUD提供新的治疗选择 患者