Building novel vaccines on a borrowed coat

用借来的外套制造新型疫苗

• 批准号: 8517573
• 负责人: F. NINA Papavasiliou
• 金额: $ 39.83万
• 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/8517573
• 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.

描述（由申请人提供）：疫苗接种（或主动免疫）需要将外来物质（抗原）引入个体，以产生对特定疾病的保护（免疫力）。简单地说，疫苗接种通过启动免疫系统来识别特定的抗原。疫苗接种的主要目标之一是产生抗体的保护性滴度，以及通过产生可以保护免受感染因子的记忆B细胞来产生长期保护。 成功的疫苗必须产生中和抗体反应以及针对特定病原体的B细胞记忆。然而，成功的疫苗是例外：很难为大量传染病（如艾滋病毒）创造保护性疫苗，甚至很难为常见疾病（如流感）创造持久的保护性疫苗。尽管进行了多年的基础研究，但大多数疫苗失败的原因仍不清楚。 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。(This在癌症的背景下得到了最好的说明，其中大多数新药的非专有名称以-mab结尾;这是一个表示单克隆抗体来源的首字母缩略词）。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，无论是在传统的传染病背景下还是在非传染性疾病背景下，了解如何制造良好的疫苗都具有治疗意义，其中大多数疾病目前是无法治愈的。 为了解决这两种情况下对成功疫苗的迫切需求，我们提出以全新的方式设计疫苗：而不是试图设计免疫原性载体，我们试图利用具有内在能力的生物体来刺激感染个体中非常强的B细胞应答，这导致巨大的抗体产生和B细胞记忆。我们已经创建了一种新的疫苗载体，使用非洲锥虫布氏锥虫的外壳，布氏锥虫是一种生活在受感染哺乳动物宿主血流中的细胞外寄生虫。布氏锥虫完全暴露在免疫系统中，为了逃避免疫系统，它用自己的外套作为诱饵：它促进抗体的产生，然后交换外套，再次开始循环，并建立慢性感染。利用布氏锥虫对其外壳引发强中和抗体应答（和B细胞记忆）的能力使其成为最佳的（尽管显然完全非常规的）疫苗载体，并且我们在此提出将其用于开发针对阿尔茨海默氏病以及针对滥用药物（尼古丁;阿片类）的治疗性疫苗.最后，我们希望从布氏锥虫身上学习，以便在未来我们能够开发出设计疫苗，成功模仿这种生物体的进化目标。