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: 8233398
• 负责人: CHENMING M ZHANG
• 金额: $ 19.24万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233398
• 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; public health relevance; 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.

项目概述：药物滥用是一个日益严重的全球性问题，特别是在美国。精神药物成瘾已造成严重的社会和经济压力。在所有毒品中，烟草、可卡因和海洛因是最容易上瘾的。烟草是最广泛滥用的物质，然而吸烟是合法的，并且在美国和世界各地引起了最严重的健康问题。长期使用烟草被认为是导致慢性阻塞性肺病、中风、慢性肺病和癌症等严重疾病的一个负责因素。目前美国有6000多万吸烟者，每年有40万人死于吸烟。此外，美国还有200多万海洛因和可卡因滥用者。由于化学物质的性质（小分子），寻找解决这一问题的方法一直是社会和医学界面临的一个挑战。目前的药物治疗已经显示出非常有限的成功，并伴有一些严重的副作用，如抑郁症和自杀行为。另一方面，免疫药物疗法已经成为对抗药物成瘾的一种有希望的替代方法。显然，药物疫苗的成功与接种者的抗体滴度直接相关。目前所有的疫苗，特别是人体临床试验中的三种疫苗，都显示出有限的功效，这取决于疫苗引起抗体反应的能力，因此毫无疑问需要改进尼古丁疫苗，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，我们建议开发抗尼古丁成瘾的疫苗。该项目的创新之处包括使用一种新的碳纳米材料——纳米角，作为脂质和载体蛋白组装的支持。载体蛋白将与目标化合物（尼古丁半抗原）结合，在接种疫苗的受试者中引发尼古丁特异性抗体。组装的颗粒与包膜病毒非常相似，包膜病毒通常是强免疫原。使用碳纳米角作为支持将使我们能够控制疫苗的大小，这将具有无与伦比的稳定性，可以适用于口服或鼻内给药。这个概念验证项目的重点是开发粒子组装过程和测试粒子的免疫原性。具体目标是：1)制备具有可控尺寸和表面修饰的碳纳米角；2)组装纳米角负载的脂质颗粒，嵌入载体蛋白并将半抗原分子偶联到载体蛋白上；3)评估疫苗在小鼠体内的免疫原性。目前疫苗的抗体滴度和抗体-尼古丁结合亲和力，特别是Cytos AG的NicQb，将作为评估该候选疫苗成功的基准。该项目的成功将为研究各种参数的影响铺平道路，如纳米角大小、脂质组成和每个颗粒嵌入的载体蛋白数量，对疫苗效力的影响。此外，我们充分认识到组装颗粒的毒理学研究的重要性。然而，由于时间和预算有限，在动物试验期间只会观察和评估基本的毒理学迹象。该项目的下一阶段将进行全面的毒理学和安全性研究。此外，如果这项概念验证研究取得成功，将在下一阶段的研究中评估通过口服或鼻内途径接种疫苗的可能性。这一项目的广泛影响在于，有可能产生一种新的平台技术，用于生产针对各种药物分子的急需和有效的疫苗。这项技术极有可能给精神药物成瘾的治疗带来革命性的变化。

项目成果

Negatively Charged Carbon Nanohorn Supported Cationic Liposome Nanoparticles: A Novel Delivery Vehicle for Anti-Nicotine Vaccine.

带负电荷的碳纳米角支持的阳离子脂质体纳米颗粒：一种新型的抗尼古丁疫苗递送载体。

• DOI: 10.1166/jbn.2015.2156
• 发表时间: 2015
• 期刊: Journal of biomedical nanotechnology
• 影响因子: 2.9
• 作者: Zheng,Hong;Hu,Yun;Huang,Wei;deVilliers,Sabina;Pentel,Paul;Zhang,Jianfei;Dorn,Harry;Ehrich,Marion;Zhang,Chenming
• 通讯作者: Zhang,Chenming

The next-generation nicotine vaccine: a novel and potent hybrid nanoparticle-based nicotine vaccine.

• DOI: 10.1016/j.biomaterials.2016.08.028
• 发表时间: 2016-11
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Hu, Yun;Smith, Daniel;Frazier, Evan;Hoerle, Reece;Ehrich, Marion;Zhang, Chenming
• 通讯作者: Zhang, Chenming

In vitro controlled release of antigen in dendritic cells using pH-sensitive liposome-polymeric hybrid nanoparticles.

• DOI: 10.1016/j.polymer.2015.10.048
• 发表时间: 2015-12-02
• 期刊: Polymer
• 影响因子: 4.6
• 作者: Hu Y;Zhao Z;Ehrich M;Fuhrman K;Zhang C
• 通讯作者: Zhang C

Tuning the Size of Poly(lactic-co-glycolic Acid) (PLGA) Nanoparticles Fabricated by Nanoprecipitation.

• DOI: 10.1002/biot.201700203
• 发表时间: 2018-01
• 期刊: Biotechnology journal
• 影响因子: 4.7
• 作者: Huang W;Zhang C
• 通讯作者: Zhang C

Paradox of PEGylation in fabricating hybrid nanoparticle-based nicotine vaccines.

• DOI: 10.1016/j.biomaterials.2018.08.015
• 发表时间: 2018-11
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Hu Y;Zhao Z;Harmon T;Pentel PR;Ehrich M;Zhang C
• 通讯作者: Zhang C