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

描述(由申请者提供)：开发针对药物滥用的新型疫苗-针对尼古丁成瘾疫苗的概念验证研究项目摘要药物滥用是一个日益严重的全球问题，特别是在美国。精神活性药物的成瘾造成了巨大的社会和经济压力。在所有毒品中，烟草、可卡因和海洛因是最容易上瘾的。烟草是被滥用最广泛的物质，但吸烟是合法的，可以说是美国和世界各地最严重的与健康有关的问题。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主要因素。美国目前有6000多万吸烟者，每年有40万人死于与吸烟有关的疾病。此外，美国还有200多万人滥用海洛因和可卡因。由于化学物质(作为小分子)的性质，寻找解决问题的方法一直是社会和医学领域面临的一个持续挑战。目前的药物治疗显示出非常有限的成功，伴随着一些严重的副作用，如伴有自杀行为的抑郁症。另一方面，免疫药物疗法已经成为对抗药物成瘾的一种有前途的替代方案。可见，药物疫苗的成功与否与接种对象的抗体效价直接相关。目前所有的疫苗，特别是人体临床试验中的三种疫苗，都显示出有限的疗效，这取决于疫苗诱导抗体反应的能力，因此无疑需要改进的尼古丁疫苗来激发强烈的免疫反应。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。该项目的创新之处包括使用一种新型的碳纳米材料纳米角作为脂质和载体蛋白组装的载体。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诱导尼古丁特异性抗体。组装的颗粒将与包膜病毒具有很强的相似性，包膜病毒通常是强免疫原。使用碳纳米角作为载体将使我们能够控制疫苗的大小，它将具有无与伦比的稳定性，并可能适合于口服或鼻腔给药。这个概念验证项目的重点是开发颗粒组装工艺，并测试颗粒的免疫原性。其具体目的是：1)制备具有可控尺寸和表面修饰的碳纳米角；2)将纳米角蛋白负载的脂质颗粒与载体蛋白包埋和偶联到载体蛋白上；3)评价疫苗在小鼠体内的免疫原性。目前疫苗的抗体效价和抗体-尼古丁结合亲和力，特别是Cytos AG的NicQb，将被用作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对疫苗效力的影响铺平道路，例如纳米角大小、脂质成分和每颗粒嵌入的载体蛋白数量。此外，我们充分认识到对组装颗粒进行毒理学研究的重要性。然而，由于时间和预算有限，在动物试验期间只观察和评估基本的毒理学迹象。在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成功，将在下一阶段的研究中评估通过口服或鼻腔途径接种疫苗的可能性。该项目的广泛影响在于一种新的平台技术的潜力，用于生产针对各种药物分子的急需和有效的疫苗。这项技术极有可能彻底改变精神活性药物成瘾的治疗方法。 公共卫生相关性：精神活性药物成瘾是一个日益严重的全球性问题，并造成巨大的社会和经济压力。药物成瘾的药物治疗效果有限，副作用严重。另一方面，免疫药物治疗显示出巨大的前景，但目前的疫苗尚未能够在接种对象中诱导高抗体滴度，从而使疫苗具有高效性。因此，迫切需要开发针对药物添加的高效疫苗。该项目将通过开发治疗药物成瘾的新型疫苗直接针对这一需求。与目前的疫苗相比，这些疫苗可能具有更大的稳定性和免疫原性。

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.