Engineered Nanoparticles for Protective Subunit Vaccine Delivery and Discovery

用于保护性亚单位疫苗递送和发现的工程纳米颗粒

基本信息

批准号：
9293233
负责人：
John Tanner Wilson
金额：
$ 18.93万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-10 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293233
关键词：
Address Adjuvant Agonist Antigen-Presenting Cells Antigens Artificial nanoparticles CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cellular Immunity Cessation of life Communicable Diseases Complement Cross Presentation Cues Cytosol Data Development Disease Drug Delivery Systems Endosomes Engineering Enhancement Technology Epitopes Genes Immune response Immunity Immunization Immunize Immunodominant Epitopes Immunologic Surveillance Infection Intranasal Administration Investigation Kinetics Lead Longevity Lung MHC Class I Genes Memory Mucosal Immunity Multi-Drug Resistance Mus Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Nucleic Acids Pathway interactions Pattern recognition receptor Peptides Phenotype Plague Population Positioning Attribute Process Proteomics RNA Research Research Personnel Respiratory Mucosa Retinoic Acid Receptor Shapes Subunit Vaccines System T cell differentiation T cell response T memory cell T-Lymphocyte Techniques Technology Tuberculosis Tuberculosis Vaccines Vaccination Vaccine Adjuvant Vaccine Design Vaccines Viral Vector Work adaptive immune response base clinical practice clinically relevant cohort cost cytokine cytotoxic design immunogenic immunogenicity improved innovation mouse model multidisciplinary nanoparticle next generation novel novel vaccines pathogen response synergism tool uptake vaccination strategy vaccine delivery vaccine development vaccine discovery vaccine efficacy

项目摘要

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb) is a bacterial pathogen that causes tuberculosis (TB), a disease that afflicts 2 billion people and results in 1.5 million deaths each year. The global burden of TB is enormous and growing, and an effective vaccine would provide the best long-term solution to this problem. However, such a vaccine still does not exist. Major barriers that have hindered the development of an effective TB vaccine include an incomplete understanding of which antigenic determinants confer protective immunity and a dearth of vaccination strategies capable of eliciting memory CD8+ and CD4+ T cell responses that can rapidly respond to and clear infection. The objective of this project is to design and evaluate an innovative nanoparticle (NP) vaccine engineered to elicit robust and durable pulmonary CD8+ and CD4+ Th1 memory T cell responses against Mtb antigens. NPs will be developed and optimized for dual-delivery of Mtb epitopes and 5' triphosphorylated RNA (5'ppp-RNA), an agonist of the cytosolic pattern recognition receptor (PRR) retinoic acid-inducible gene 1 (RIG-I) that has immense untapped potential as a vaccine adjuvant. Specifically, we propose to harness the unique delivery capabilities of NP vaccines to enhance pulmonary Th1 and CD8+ T cell responses to established and clinically relevant Mtb MHC class I- and class II-restricted epitopes as well as naturally processed class I-restricted epitopes recently discovered by our team. We have assembled a strong multidisciplinary team with expertise in drug delivery, vaccine design and development, RNA engineering, epitope discovery, and mouse models of Mtb infection. Therefore, we are ideally positioned to accomplish our objective through the following Specific Aims: 1) Develop a nanoparticle vaccine that elicits lung-resident CD8+ and Th1 memory T cell responses to Mtb subunit antigens; 2) Evaluate the immunogenicity and protective potential of naturally processed Mtb epitopes. In Aim 1, we will investigate the effect of intranasal NP immunization on the magnitude and kinetics of pulmonary antigen/adjuvant delivery and intracellular uptake, elucidate the immunostimulatory adjuvant effects of 5'ppp-RNA, and rigorously characterize pulmonary and systemic CD4+ and CD8+ T cell responses to Mtb antigens. In Aim 2, we will use NPs to deliver novel Mtb class I-restricted epitopes, both alone and in combination with an established immunodominant class II Mtb epitope, characterize local and systemic T cell responses, and assess the ability of vaccines to protect against pulmonary Mtb challenge. This project will result in a new vaccine technology for enhancing mucosal cellular immunity to subunit vaccines, will expand the armamentarium of vaccine adjuvants, and will provide a tool that empowers the discovery of immunogenic and protective Mtb epitopes. By combining epitope discovery efforts with rationally engineered delivery systems, successful completion of the proposed research will establish a new and potentially transformative paradigm for the rational design of T cell-targeted vaccines.

项目摘要结核分枝杆菌（MTB）是导致结核病（TB）的细菌病原体，一种疾病每年有20亿人，每年造成150万人死亡。结核病的全球负担是巨大的，正在增长，有效的疫苗将为此问题提供最佳的长期解决方案。但是，这样的疫苗仍然不存在。阻碍有效结核病疫苗开发的主要障碍包括对哪种抗原决定因素赋予保护性免疫和缺乏的不完全了解能够引起记忆CD8+和CD4+ T细胞反应的疫苗接种策略，可以快速响应和清除感染。该项目的目的是设计和评估创新的纳米颗粒（NP）疫苗设计为引起耐用且耐用的肺CD8+和CD4+ TH1记忆T细胞反应针对MTB抗原。 NP将用于MTB表位和5'的双重交付和优化三磷酸化RNA（5'ppp-RNA），胞质模式识别受体（PRR）视网膜的激动剂酸诱导的基因1（RIG-I）具有巨大的疫苗辅助潜力。具体来说，我们提议利用NP疫苗的独特输送能力增强肺TH1和CD8+ T细胞对建立和临床相关的MTB MHC I类和II类限制的表位的反应以及我们团队最近发现的自然加工了I类限制的表位。我们组装了一个强大的多学科团队具有药物输送，疫苗设计和开发，RNA工程的专业知识，表位发现和MTB感染的小鼠模型。因此，我们理想地有能力完成我们的通过以下特定目的进行目标：1）开发一种引起肺居民CD8+的纳米颗粒疫苗和Th1记忆T细胞对MTB亚基抗原的反应； 2）评估免疫原性和保护性自然加工的MTB表位的潜力。在AIM 1中，我们将研究鼻内NP的作用对肺抗原/辅助递送和细胞内摄取的大小和动力学的免疫接种，阐明5'PPP-RNA的免疫刺激佐剂作用，并严格地表征肺和系统性CD4+和CD8+ T细胞对MTB抗原的反应。在AIM 2中，我们将使用NP提供新颖的MTB I类限制的表位，无论是单独还是与已建立的免疫主导II类MTB结合在一起表位，表征局部和全身T细胞反应，并评估疫苗防止疫苗的能力肺MTB挑战。该项目将导致一种新的疫苗技术来增强粘膜细胞对亚基疫苗的免疫力将扩大疫苗佐剂的武器库，并将提供一种工具赋予了免疫原性和保护性MTB表位的能力。通过结合表位发现工作通过合理设计的交付系统，拟议研究的成功完成将建立用于T细胞靶向疫苗的合理设计的新的和潜在的变革范式。