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; 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).

描述（由申请人提供）：疫苗接种（或主动免疫）需要将异物（抗原）引入个体，以便对特定疾病产生保护（免疫）。简而言之，疫苗接种是通过启动免疫系统识别特定抗原的。疫苗接种的主要目标之一是通过创建可以保护感染剂的记忆B细胞来产生抗体的保护性滴度以及长期保护。 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。但是，成功的疫苗是一个例外：很难为多种传染病（例如艾滋病毒），甚至持久的保护性疫苗（例如流感）创建一种保护性疫苗。尽管经过多年的基础研究，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巨大的希望。 （这是在癌症的背景下最好地说明的，其中大多数新药的非专有名称以-MAB结束；表明单克隆抗体来源的首字母缩写）。主动免疫以提高治疗性抗体是下一个逻辑步骤。因此，在传统的传统疾病和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兴趣，其中大多数目前都是无法治愈的。 为了解决这两种情况下成功疫苗的急需需求，我们建议以一种全新的方式处理疫苗设计：而不是试图设计免疫原性载体，而是试图利用具有固有能力的生物体，具有固有的能力，可以刺激受感染个体非常强的B细胞反应，从而在巨大的抗体产生和B细胞存储中产生巨大的抗体。我们已经使用非洲锥虫锥虫的涂层创建了一种新型的疫苗载体，这是一种细胞外寄生虫，生活在感染的哺乳动物宿主的血液中。 T.Brucei完全暴露于免疫系统并逃避它，它将其外套用作诱饵：它促进了对其的抗体反应的产生，然后切换外套，再次开始周期并建立慢性感染。对T.Brucei对其外套的强烈中和抗体反应（和B细胞记忆）的能力的剥削使其成为最佳（尽管显然是完全非常规）的疫苗载体，我们在此提议将其用于开发治疗性疫苗，以对阿尔茨海默氏症的治疗性疫苗开发，并促进滥用滥用的药物（尼古丁； OpiateS）。最后，我们希望向T.Brucei学习，以便将来我们可以开发设计器疫苗，以依次模仿该生物体所发展的目标。 公共卫生相关性：我们已经开发了一种显示蛋白质甚至小分子的方法，以刺激强烈的抗体反应。我们在这里建议将这种新方法用作治疗性疫苗，以刺激身体，以生成针对医学相关性靶标的特定抗体（例如，在成瘾的情况下，在阿尔茨海默氏病中的蛋白质聚集体或滥用药物）。如果成功的话，我们的实验有可能将治疗性疫苗接种的承诺带来成果，从而可能对我们对待许多慢性疾病的方式产生深远的影响（不仅我们将重点关注这里的疾病，而且是癌症等）。