Building novel vaccines on a borrowed coat

用借来的外套制造新型疫苗

• 批准号: 8181547
• 负责人: F. NINA Papavasiliou
• 金额: $ 42.38万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8181547
• 关键词: Active Immunization; Acute; Address; Adjuvant; Affinity; African; Alzheimer' s Disease; Amino Acid Sequence; Amyloid beta-Protein; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Basic Science; Binding; Blood Circulation; Brain; Childhood; Chronic; Chronic Disease; Cocaine; Communicable Diseases; Development; Disease; Engineering; Epitopes; Eye; Future; Generations; Goals; HIV; Human; Immune Sera; Immune response; Immune system; Immunity; Immunization; Individual; Infection; Infectious Agent; Injection of therapeutic agent; Learning; Malignant Neoplasms; Mediating; Medical; Membrane Glycoproteins; Memory; Memory B-Lymphocyte; Methods; Monoclonal Antibodies; Mus; Names; Neurodegenerative Disorders; Nicotine; Normal tissue morphology; Opiates; Organism; Parasites; Passive Immunization; Peptides; Pharmaceutical Preparations; PrP; PrPC Proteins; Proteins; Source; Structure; Surface; System; Therapeutic; Therapeutic antibodies; Tissues; Toxic effect; Transgenic Organisms; Trypanosoma; Trypanosoma brucei brucei; Vaccination; Vaccine Design; Vaccines; Variant; Work; acronyms; addiction; base; burden of illness; cancer cell; density; drug of abuse; extracellular; flu; immunogenic; interest; killings; link protein; neutralizing antibody; novel strategies; novel vaccines; overexpression; pathogen; protein aggregate; research study; response; small molecule; surface coating; tau Proteins; therapeutic vaccine; vector; vector vaccine

DESCRIPTION (provided by applicant): Vaccination (or active immunization) entails the introduction of a foreign material (antigen) into an individual in order to produce protection (immunity) to a particular disease. In simple terms, vaccination works by priming the immune system to recognize a particular antigen. One of the primary goals of vaccination is to generate protective titers of antibody, as well as long-term protection through the creation of memory B cells that can protect against the infectious agent. Successful vaccines must generate neutralizing antibody responses as well as B cell memory toward a specific pathogen. However, successful vaccines are the exception: it has been difficult to create a protective vaccine for a great number of infectious diseases (e.g. HIV) or even long lasting, protective vaccines against common diseases (e.g. flu). Despite many years of basic research, the reasons why most vaccines fail are not understood. In recent years, passive immunization against non-communicable diseases has also shown great promise. (This is best illustrated in the context of cancer, where the non-proprietary name for a majority of new drugs ends in -mab; an acronym that indicates the monoclonal antibody source). Active immunization to raise therapeutic antibodies is the next logical step. Therefore, understanding how to make good vaccines is of therapeutic interest both in the traditional context of infectious diseases and in the context of non- communicable diseases, most of which are currently incurable. To address this acute need for successful vaccines in both contexts, we propose to approach vaccine design in a completely new manner: rather than attempt to engineer an immunogenic vector, we sought to exploit an organism that has an inherent ability to stimulate a very strong B cell response in an infected individual, that results in tremendous antibody production and B cell memory. We have created a novel vaccine vector using the coat of the African trypanosome Trypanosoma brucei, an extracellular parasite that lives in the bloodstream of the infected mammalian host. T.brucei is completely exposed to the immune system and to evade it, it uses its coat as a decoy: it promotes the generation of antibody responses to it, and then switches coats, starting the cycle again, and establishing a chronic infection. Exploitation of T.brucei 's ability to elicit strong neutralizing antibody responses (and B cell memory) to its coat makes it an optimal (though clearly completely unconventional) vaccine vector, and we propose herein to use this in the development of therapeutic vaccines toward Alzheimer's and also toward drugs of abuse (nicotine; opiates). Finally, we hope to learn from T.brucei, so that in the future we can develop designer vaccines that successively mimic what this organism has evolved to achieve. PUBLIC HEALTH RELEVANCE: We have developed a way to display pieces of proteins, or even small molecules, in a way that these stimulate a strong antibody response. We propose here to use this new method as a therapeutic vaccine, to stimulate our bodies to generate specific antibodies against targets of medical relevance (such as protein aggregates in Alzheimer's disease, or drugs of abuse, in the case of addiction). If successful, our experiments have the potential to bring the promise of therapeutic vaccination to fruition and could thus have a profound impact on the way we treat a great many chronic diseases (not only the ones we will focus on here, but also cancer etc).

说明(申请人提供)：疫苗接种(或主动免疫)需要将外来物质(抗原)引入个人，以产生对特定疾病的保护(免疫力)。简单地说，疫苗接种的工作原理是启动免疫系统识别特定的抗原。疫苗接种的主要目标之一是产生保护性的抗体滴度，以及通过创造记忆B细胞来保护身体免受感染性病原体感染的长期保护作用。成功的疫苗必须产生中和抗体反应，以及对特定病原体的B细胞记忆。然而，成功的疫苗是个例外：很难为大量传染病(如艾滋病毒)或甚至针对常见疾病(如流感)的长效保护性疫苗研制出保护性疫苗。尽管进行了多年的基础研究，但大多数疫苗失败的原因尚不清楚。近年来，针对非传染性疾病的被动免疫也显示出了巨大的希望。(这在癌症的背景下得到了最好的说明，大多数新药的非专利名称以-MAB结尾；这是一个指示单抗来源的首字母缩写)。主动免疫以提高治疗性抗体是下一个合乎逻辑的步骤。因此，无论是在传染病的传统背景下，还是在非传染性疾病的背景下，了解如何制造良好的疫苗都具有治疗意义，目前大多数非传染性疾病是无法治愈的。为了解决这两种情况下对成功疫苗的迫切需求，我们建议以一种全新的方式进行疫苗设计：我们不是试图设计一种免疫原性载体，而是试图利用一种具有内在能力的生物体，这种生物体具有激发感染者非常强烈的B细胞反应的内在能力，从而导致大量抗体产生和B细胞记忆。我们利用非洲锥体布鲁氏锥虫的外壳创造了一种新的疫苗载体，这种锥虫是一种细胞外寄生虫，生活在受感染哺乳动物宿主的血液中。布鲁氏毛滴虫完全暴露在免疫系统中，为了躲避免疫系统，它用自己的皮毛作为诱饵：它促进对它的抗体反应的产生，然后交换皮毛，再次开始循环，并建立慢性感染。利用布氏毛滴虫的S对其外壳产生强大的中和抗体反应(和B细胞记忆)的能力，使其成为最佳(尽管显然完全非常规)疫苗载体，我们在此建议将其用于开发治疗阿尔茨海默氏症和滥用药物(尼古丁；阿片类)的疫苗。最后，我们希望向布氏毛滴虫学习，以便在未来我们可以开发出成功模仿这种生物进化而实现的设计疫苗。 与公共健康相关：我们已经开发出一种方法来展示蛋白质片段，甚至是小分子，以一种刺激强烈抗体反应的方式。我们在这里建议使用这种新方法作为治疗性疫苗，以刺激我们的身体产生针对与医学相关的靶点的特定抗体(例如阿尔茨海默病中的蛋白质聚集体，或者成瘾情况下的滥用药物)。如果成功，我们的实验有可能实现治疗性疫苗接种的承诺，从而可能对我们治疗许多慢性病的方式产生深远影响(不仅是我们将在这里关注的那些疾病，还有癌症等)。