Development of novel vaccines against drug abuse - Proof of concept study for vac

开发新型抗药物滥用疫苗 - 疫苗概念验证研究

• 批准号: 8133603
• 负责人: CHENMING M ZHANG
• 金额: $ 19.27万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133603
• 关键词: Adverse effects; Affinity; American; Animal Testing; Antibodies; Antibody Formation; Antigens; Benchmarking; Binding; Budgets; Carbon; Carrier Proteins; Cessation of life; Chemicals; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical Trials; Cocaine; Development; Dialysis procedure; Disease; Drug Addiction; Drug abuse; Enzyme-Linked Immunosorbent Assay; Epitopes; Equilibrium; Escherichia coli; Evaluation; Haptens; Health; Heroin; Human; Immune response; Immunology; Intranasal Administration; Legal; Lipid Bilayers; Lipids; Liposomes; Malignant Neoplasms; Medical Societies; Mental Depression; Modeling; Modification; Mus; Nanotechnology; Nature; Nicotine; Nicotine Dependence; Oral; Oral Administration; Particulate; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Phospholipids; Preparation; Process; Proteins; Psychotropic Drugs; Route; Smoker; Smoking; Solutions; Stress; Stroke; Structure; Study models; Substance abuse problem; Succinic Acids; Surface; Technology; Testing; TimeLine; Tobacco; Tobacco use; United States; Ursidae Family; Vaccinated; Vaccines; Virus; addiction; base; bioprocess; combat; cross reactivity; density; env Gene Products; immunogenic; immunogenicity; improved; innovation; macrophage; mouse model; nanohorn; nanomaterials; nanoparticle; novel; novel vaccines; particle; safety study; small molecule; social; success; suicidal behavior; uptake; vaccine candidate; vaccine effectiveness; vaccine efficacy; virus envelope

DESCRIPTION (provided by applicant): Development of novel vaccines against drug abuse - Proof of concept study for vaccines against nicotine addiction Project Summary Drug abuse is a growing global problem particularly in the United States. The addiction of psychoactive drugs has caused significant social and economical stresses. Among all drugs, tobacco, cocaine, and heroin are the most addictive ones. Tobacco is the most widely abused substance, yet smoking is legal and causes arguably the most serious health-related problems in the United States and around the world. Chronic use of tobacco is considered a responsible factor for serious diseases such as chronic obstructive pulmonary disease, stroke, chronic lung disease, and cancer. There are more than 60 million smokers currently in the U.S. and 400,000 related deaths per year. In addition, there are more than 2 million American abusers of heroin and cocaine. Due to the nature of the chemicals (as small molecules), finding ways to combat the problem has been a constant challenge to the society and the medical field. Current pharmacological therapies have shown very limited success with some accompanying serious side-effects, such as depression with suicidal behavior. On the other hand, immunopharmacotherapy has emerged as a promising alternative to combat drug addiction. Evidently, the success of drug vaccines is directly correlated with the antibody titer in the vaccinated subjects. All current vaccines, particularly the three in human clinical trials, have shown limited efficacy depending on the vaccine's ability to elicit antibody response, and thus there is undoubtedly a need for improved nicotine vaccines that can elicit strong immune response. In this project, we propose an unprecedented approach to develop potentially very potent vaccines against small molecule drugs. As a model study, we propose to develop vaccines against nicotine addiction. The innovation of this project involves the use of a new class of carbon nanomaterial, nanohorn, as support for lipid and carrier protein assembly. The carrier protein will be conjugated with a target compound (nicotine hapten) to elicit nicotine specific antibodies in vaccinated subjects. The assembled particles will bear strong resemblances as enveloped viruses, which are commonly strong immunogens. Using carbon nanohorn as support will enable us to control the size of the vaccine, which will possess unparalleled stability and could be suitable for oral or intranasal administration. This proof- of-concept project is focused on developing the particle assembly process and test the immunogenicity of the particles. The specific aims are to 1) prepare carbon nanohorns with controlled size and surface modifications, 2) assemble nanohorn supported lipid particle with carrier protein embedded and conjugate hapten molecules to the carrier protein, and 3) evaluate the immunogenicity of the vaccine in mice. Antibody titer and antibody-nicotine binding affinity of current vaccines, particularly NicQb by Cytos AG, will be used as the benchmarks to evaluate the success of this vaccine candidate. Success of this project will pave the way for investigating the effects of various parameters, such as nanohorn size, lipid composition, and number of embedded carrier protein per particle, on the efficacy of the vaccine. Moreover, we fully recognize the importance for the toxicological study of the assembled particles. However, due to the limited timeline and budget, only basic toxicological signs will be observed and assessed during the animal test. Full scale toxicological and safety study will be carried out in the next phase of the project. In addition, the possibility of administering the vaccine through oral or intranasal route will be evaluated in the next phase of study if this proof-of-concept study is successful. The broad impact of this project resides in the potential of a new platform technology for producing much needed and effective vaccines against various drug molecules. It is highly possible that this technology will revolutionize the treatment of psychoactive drug addiction. PUBLIC HEALTH RELEVANCE: Psychoactive drug addiction is a growing global problem and causes significant social and economical stresses. Pharmacological treatments of drug addiction have limited success with serious side effects. On the other hand, immunopharmacotherapy has shown tremendous promises, but current vaccines have not been able to elicit high antibody titers in the vaccinated subject for the vaccines to be highly effective. Thus, there is a strong need for developing highly effective vaccines against drug additions. This project will target this need directly by developing novel vaccines for the treatment of drug addiction. These vaccines will likely possess greater stability and immunogenicity when compared with the current vaccines.

描述（由申请人提供）：开发针对药物滥用的新型疫苗 - 针对尼古丁成瘾项目的概念证明研究概念研究摘要滥用药物滥用是一个日益增长的全球问题，尤其是在美国。精神药物的成瘾引起了巨大的社会和经济压力。在所有药物中，烟草，可卡因和海洛因是最令人上瘾的药物。烟草是最广泛滥用的物质，但吸烟是合法的，可以说是美国和世界各地最严重的健康问题。长期使用烟草被认为是严重疾病的负责因素，例如慢性阻塞性肺部疾病，中风，慢性肺部疾病和癌症。目前在美国有超过6000万吸烟者，每年有40万例相关死亡。此外，还有超过200万美国海洛因和可卡因的虐待者。由于化学物质的性质（作为小分子），寻找解决问题的方法一直是对社会和医疗领域的持续挑战。当前的药理学疗法在某些严重的副作用（例如具有自杀行为的抑郁症）中表现出非常有限的成功。另一方面，免疫药物治疗已成为打击药物成瘾的有前途的替代方法。显然，药物疫苗的成功与接种受试者中的抗体滴度直接相关。所有当前的疫苗，尤其是人类临床试验中的三种疫苗，根据疫苗引起抗体反应的能力的有限疗效，因此无疑需要改善尼古丁疫苗，以引起强烈的免疫反应。 在这个项目中，我们提出了一种前所未有的方法来开发针对小分子药物的潜在非常有效的疫苗。作为一项模型研究，我们建议开发针对尼古丁成瘾的疫苗。该项目的创新涉及使用新的碳纳米材料纳米霍恩（Nanohorn）作为对脂质和载体蛋白质组件的支持。载体蛋白将与靶化合物（尼古丁触觉）共轭，以引起疫苗接种受试者中的尼古丁特异性抗体。组装的颗粒将具有强烈的相似之处，因为这些病毒通常是强烈的免疫原子。使用碳纳米角作为支撑将使我们能够控制疫苗的大小，该疫苗将具有无与伦比的稳定性，并且可以适合口服或鼻内给药。概念概念项目的重点是开发颗粒组装过程并测试颗粒的免疫原性。具体目的是1）准备具有控制尺寸和表面修饰的碳纳米角，2）用载体蛋白嵌入了载体蛋白和结合蛋白的抗脂肪颗粒，并将纳米霍恩支撑脂质颗粒到载体蛋白上，并将其与固定性蛋白质分子组装到载体蛋白上，3）评估小鼠中该疫苗的免疫发育。当前疫苗的抗体滴度和抗体 - 纽约汀结合亲和力，尤其是Cytos Ag的NICQB，将用作评估该疫苗候选者成功的基准。该项目的成功将为研究各种参数的影响（例如纳米霍恩大小，脂质组成以及每个颗粒嵌入式载体蛋白的数量）对疫苗疗效的效果铺平道路。此外，我们完全认识到组装颗粒的毒理学研究的重要性。但是，由于时间表和预算有限，在动物测试期间只能观察和评估基本的毒理学体征。全面的毒理学和安全研究将在项目的下一阶段进行。此外，如果这项概念验证的研究成功，将在下一阶段进行通过口服或鼻内途径进行疫苗的可能性。该项目的广泛影响在于一种新的平台技术的潜力，即针对各种药物分子生产急需和有效的疫苗。这项技术很有可能会彻底改变精神活性药物成瘾的治疗。 公共卫生相关性：精神活性吸毒是一个日益增长的全球问题，会引起巨大的社会和经济压力。药物成瘾的药理治疗方法在严重的副作用和严重的副作用方面取得了有限的成功。另一方面，免疫药物疗法已显示出巨大的承诺，但是当前的疫苗无法在接种疫苗的受试者中引起高抗体滴度，以使疫苗非常有效。因此，强烈需要开发针对添加药物的高效疫苗。该项目将通过开发用于治疗药物成瘾的新型疫苗直接针对这种需求。与当前的疫苗相比，这些疫苗可能具有更大的稳定性和免疫原性。