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）：建立我们在此提出的有效且统一的疫苗开发策略是征服当前和新出现的传染病的关键。尽管针对一系列细菌制剂取得了成功，但目前的疫苗开发方法与其针对的微生物一样多种多样，并且需要的佐剂通常功效有限和/或毒副作用。因此，对于许多高优先级病原体来说，疫苗的发现往往缓慢、低效且不成功。我们建议/假设，细菌病原体的疫苗生产可以通过高度创新的标准导向方法来统一和简化，该方法最大限度地提高疫苗成功的三个最重要的标准：抗原（Ag）模拟、佐剂性和有效靶向抗原呈递细胞（APC）的免疫原。我们将在一个非常严格的模型（人类毒性土拉弗朗西斯菌的呼吸道感染）的背景下检验我们的假设 [Ft]），其中我们使用无佐剂粘膜疫苗获得了非常令人鼓舞的结果（对 C57BL/6 小鼠的保护高达 75%）。事实上，这是迄今为止唯一一个证明鼻内施用灭活 Ft 可以保护 C57BL/6 小鼠免受高毒力 A 类 Ft SchuS4 病原体粘膜攻击的实例。因此，我们将使用 Ft SchuS4 作为模型病原体来建立标准导向的疫苗开发方法，我们坚信这将产生针对 Ft SchuS4 的完全保护性的、不依赖佐剂的粘膜疫苗。在目标 1 中，我们将利用 Ft SchuS4 的差异培养和遗传操作来调节：i）体外培养的 Ft 免疫原与复制的感染性病原体（宿主适应）之间的抗原相似性，ii）Ft SchuS4 的细胞刺激能力iii) 通过 C3d 的细菌表面表达处理/呈递免疫原，C3d 是 APC（B 细胞和滤泡细胞）上 CR2 的配体树突状细胞）。在目标 2 中，我们将分析以下因素的影响：i) 生长培养基诱导的宿主适应，ii) TLR2 配体的过度表达对 TLR2 信号传导的影响，如树突状细胞 (DC) 成熟和细胞因子反应所反映的。还将评估抗原宿主适应和改变的 TLR2 信号传导对 DC 向 Ft 特异性 T 细胞处理/呈递免疫原的影响。在目标 3 中，我们将：i) 单独或组合确定和优化目标 1-2 中产生的免疫原的保护活性，以及 ii) 通过将免疫原靶向 CR2 和/来优化 Ft 免疫原加工/呈递的效率或 APC 上的 Fc 受体。然后将通过气溶胶攻击在野生型和人源化小鼠中评估最具保护性的免疫原，并确定保护的相关性/机制。该项目不仅将产生针对 A 类生物威胁因子的无佐剂粘膜疫苗，还将建立一种创新且独特的标准导向方法/平台，用于适用于其他感染因子的疫苗开发，从而深刻影响预防医学/公共卫生和改变疫苗开发的范式。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aerosol prime-boost vaccination provides strong protection in outbred rabbits against virulent type A Francisella tularensis.

气溶胶初免加强疫苗接种为近交系兔子提供了针对强毒力 A 型土拉弗朗西斯菌的强大保护。

DOI：
发表时间：
2018
期刊：
影响因子：
3.7
作者：
O'Malley, Katherine J;Bowling, Jennifer D;Stinson, Elizabeth;Cole, Kelly S;Mann, Barbara J;Namjoshi, Prachi;Hazlett, Karsten R O;Barry, Eileen M;Reed, Douglas S
通讯作者：
Reed, Douglas S

Ex vivo antigen-pulsed PBMCs generate potent and long lasting immunity to infection when administered as a vaccine.

当作为疫苗施用时，离体抗原脉冲的 PBMC 会产生有效且持久的感染免疫力。

DOI：
发表时间：
2017-02-15
期刊：
影响因子：
5.5
作者：
Kumar, Sudeep;Sunagar, Raju;Pham, Giang;Gosselin, Edmund J;Nalin, David
通讯作者：
Nalin, David

Lipoxin A4, a 5-lipoxygenase pathway metabolite, modulates immune response during acute respiratory tularemia.

脂氧素 A4 是一种 5-脂氧合酶途径代谢物，可调节急性呼吸道兔热病期间的免疫反应。

DOI：
发表时间：
2017-02
期刊：
影响因子：
5.5
作者：
Singh, Anju;Rahman, Tabassum;Bartiss, Rose;Arabshahi, Alireza;Prasain, Jeevan;Barnes, Stephen;Musteata, Florin Marcel;Sellati, Timothy J
通讯作者：
Sellati, Timothy J

Francisella tularensis - Immune Cell Activator, Suppressor, or Stealthy Evader: The Evolving View from the Petri Dish.

土拉弗朗西斯菌 - 免疫细胞激活剂、抑制剂或隐形逃避者：培养皿中不断演变的观点。