Criteria-Directed Vaccine Generation Via Ag Mimicry, Adjuvancy, And APC-Targeting

通过 Ag 拟态、佐剂和 APC 靶向生成标准疫苗

基本信息

批准号：
9300826
负责人：
Edmund J Gosselin
金额：
$ 58.4万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-09 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9300826
关键词：
Adjuvant Adjuvanticity Adverse effects Aerosols Agonist Antigen Mimicry Antigen Presentation Pathway Antigen Targeting Antigen-Presenting Cells Antigens Awareness B-Lymphocytes Bacteria Brain C57BL/6 Mouse Categories Cell Maturation Cells Complement 3d Complement Receptor Dendritic Cells Dendritic cell activation Development Dose Emerging Communicable Diseases Fc Receptor Follicular Dendritic Cells Francisella tularensis Generations Goals Growth Heart Human Immune Immunization Immunologist In Vitro Infection Infectious Agent Infusion procedures Investigation Ligands Mediating Microbe Modality Modeling Organism Pathogenesis Preventive Medicine Process Public Health Respiratory Tract Infections Signal Transduction Smallpox Vaccine Stream Surface T-Lymphocyte TLR2 gene Testing Vaccines Virulent adaptive immunity base biothreat cytokine extracellular genetic manipulation humanized mouse improved in vivo innovation interdisciplinary approach microbial mucosal vaccine novel overexpression pathogen public health relevance response success vaccine development vaccine discovery vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Establishment of an effective and uniform vaccine development strategy such as we propose here is key to conquering current and emerging infectious diseases. Despite successes against an array of bacterial agents, current approaches to vaccine development are as diverse as the microbes they target and require adjuvants that often have limited efficacy and/or toxic side effects. As a consequence, vaccine discovery is often slow, inefficient, and unsuccessful in the case of many high priority pathogens. We propose/hypothesize that vaccine generation for bacterial pathogens can be unified and stream-lined through a highly innovative criteria-directed approach that maximizes three of the most important criteria for vaccine success: Antigen (Ag)-mimicry, Adjuvanticity, and Efficient targeting of immunogens to Antigen Presenting Cells (APCs). We will test our hypothesis in the context of a very stringent model (respiratory infection with human-virulent Francisella tularensis [Ft]) in which we have obtained highly encouraging results with an adjuvant-free, mucosal vaccine (up to 75% protection of C57BL/6 mice). In fact, this is the only instance thus far in which it has been demonstrated that inactivated Ft administered intranasally protects C57BL/6 mice against mucosal challenge with the highly virulent Category A Ft SchuS4 pathogen. Thus, we will use Ft SchuS4 as a model pathogen to establish a criteria-directed approach to vaccine development, which we strongly believe will result in a fully protective adjuvant-independent mucosal vaccine against Ft SchuS4. In Aim 1, we will use differential cultivation and genetic manipulation of Ft SchuS4 to modulate: i) the antigenic similarity between in vitro- cultivated Ft immunogen and the replicating infectious pathogen (host-adaptation), ii) the cell-stimulatory capacity of the immunogen via over-expression of TLR2 agonist, and iii) processing/presentation of immunogen via bacterial surface expression of C3d, a ligand for CR2 on APCs (B cells and follicular dendritic cells). In Aim 2, we will analyze the impact of: i) growt medium-induced host-adaptation, and ii) over- expression of TLR2 ligands on TLR2 signaling, as reflected in dendritic cell (DC) maturation and cytokine responses. The impact of antigenic host-adaptation and altered TLR2 signaling on the processing/presentation of immunogen to Ft-specific T cells by DCs will also be evaluated. In Aim 3, we will: i) determine and optimize the protective activity of immunogens generated in Aims 1-2, separately and in combination, and ii) optimize the efficiency of Ft immunogen processing/presentation via the targeting of immunogen to CR2 and/or Fc receptors on APCs. The most protective immunogen(s) will then be evaluated in wildtype and humanized mice via aerosol challenge and correlates/mechanisms of protection identified. This project will not only yield an adjuvant-free mucosal vaccine against a Category A biothreat agent, but will establish an innovative and unique criteria-directed approach/platform for vaccine development applicable to other infectious agents, thus profoundly impacting preventive medicine/public health and changing the paradigm for vaccine development.

描述（由申请人提供）：建立有效而统一的疫苗开发策略，例如我们在这里提出的是征服当前和新兴的传染病的关键。尽管对一系列细菌剂取得了成功，但目前的疫苗发育方法与它们靶向的微生物一样多样化，并且需要疗效和/或有毒副作用的辅助物。结果，在许多高优先病原体的情况下，疫苗的发现通常很缓慢，效率低下且失败。我们提出/假设，通过高度创新的标准指导的方法可以统一和溪流疫苗的生成疫苗，从而最大化疫苗成功的三个最重要的标准：抗原（AG）模拟，辅助性，辅助性和对抗原抗抗原的靶向抗抗原的靶向抗原呈现的细胞（APCS）。我们将在非常严格的模型的背景下检验我们的假设（呼吸道感染，伴有人毒的francisella tularensis [ft]）通过无辅助的粘膜疫苗获得了极大的令人鼓舞的结果（对C57BL/6小鼠的保护最高75％）。实际上，这是迄今为止唯一证明杀活的FT鼻内施用的唯一实例，可以通过高毒性类别A FT Schus4病原体保护C57BL/6小鼠免受粘膜挑战。因此，我们将使用FT SCHUS4作为模型病原体来建立以标准为疫苗发育的标准方法，我们坚信，这将导致完全保护性辅助辅助粘膜疫苗针对FT SCHUS4。在AIM 1中，我们将使用差异培养和FT Schus4的遗传操纵来调节：i）体外培养的FT免疫原和复制感染性病原体（宿主适应）之间的抗原性相似性，ii）通过对TLR2 Agonist和III的表现的过度表达的表现来表现出来的细胞刺激能力，以及III III的表现，并通过III的表现来表现出来。 APC上CR2的配体（B细胞和卵泡树突状细胞）。在AIM 2中，我们将分析：i）在树突状细胞（DC）成熟和细胞因子反应中反映的TLR2配体对TLR2信号传导的过度表达对TLR2配体对TLR2信号传导的过度表达。还将评估抗原宿主适应和改变TLR2信号传导对通过DC对FT特异性T细胞的处理/呈现的影响。在AIM 3中，我们将：i）确定和优化AIMS 1-2，分别和组合中产生的免疫原的保护活性，ii）优化通过将免疫原处理/表现的效率通过靶向APC上的CR2和/或FC受体的靶向。然后，最保护的免疫原将通过气溶胶挑战和鉴定的保护机制在野生型和人源化小鼠中评估。该项目不仅将针对生物治疗剂的类别产生无辅助的粘膜疫苗，而且还将建立适用于其他感染剂的疫苗开发的创新和独特的指导方法/平台，从而对预防医学/公共卫生产生深远的影响，从而改变疫苗开发的范式。