Dissecting the mechanism of age-specific adjuvant synergy in vitro and in vivo

剖析年龄特异性佐剂体外和体内协同作用的机制

• 批准号: 9108575
• 负责人: OFER LEVY
• 金额: $ 55.6万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108575
• 关键词: Adjuvant; Adult; Age; Agonist; Aluminum; Animal Model; Antibody Response; Antigen-Presenting Cells; Antigens; Attenuated Live Virus Vaccine; Attenuated Vaccines; Binding; Biological Assay; Biological Markers; Biological Models; C Type Lectin Receptors; CD4 Positive T Lymphocytes; Calmette-Guerin Bacillus; Cervarix; Chimeric Proteins; Collaborations; Dendritic Cells; Denmark; Development; Formulation; Goals; Growth; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunocompromised Host; Immunologics; In Vitro; Infection; Laboratories; Learning; Leukocytes; Licensing; Life; Lipid A; Lymphocyte Activation; Mediating; Modeling; Molecular; NF-kappa B; Names; Newborn Infant; Pathway interactions; Pattern; Pattern recognition receptor; Production; Public Health; Risk; Safety; Salts; Serum; System; TLR4 gene; TLR7 gene; TLR8 gene; Testing; Tissues; Toll-like receptors; Trehalose; Vaccine Adjuvant; Vaccines; Virus; Whole Blood; Work; adaptive immunity; age group; aluminum sulfate; combinatorial; cytokine; immunogenicity; in vitro Model; in vivo; insight; monocyte; named group; nonhuman primate; novel; novel strategies; novel vaccines; pathogen; public health intervention; public health relevance; receptor; receptor expression; respiratory; response; small molecule; vaccine development; vaccine response; vaccine safety; vaccinology

 DESCRIPTION (provided by applicant): Vaccines are a crucial public health intervention, yet to date their development has been largely ad hoc and empiric. Infections are most common at the extremes of age and vaccine adjuvantation can be a key approach to enhance immunogenicity for special populations that have distinct immunity. Adjuvants, molecules that boost immune response, can greatly enhance immunity but much remains to be learned regarding adjuvant action that can vary markedly with age. To identify promising adjuvantation systems and characterize their mechanisms of action, the Levy Lab has established novel human in vitro model systems, including whole- blood assays, monocyte-derived dendritic cell (MoDC) arrays, and microphysiologic three-dimensional tissue constructs, which model innate and adaptive immune responses. In preliminary in vitro studies employing human newborn, infant and adult leukocytes, we have identified certain Toll-like receptor agonist (TLRA) and C-type lectin receptor agonist (CLRA) combinations that synergistically enhance NF-kB and inflammasome activation as well as Th1 cytokine production in early life: the synthetic imidazoquinoline TLR7/8 agonist R848 and the Mincle (CLR) agonist Trehalose-6,6-dibehenate (TDB). In the propose studies, we will work in collaboration Dr. Peter Andersen (Statens Serum Institut (SSI); Copenhagen, Denmark), whose laboratory has world class expertise in adjuvant formulation and vaccinology, to further characterize the mechanisms underlying the synergistic activity of this combination adjuvantation system using Respiratory Syncitial Virus (RSV) pre-fusion protein as a model antigen. Our hypothesis is that TLRAs and CLRAs synergistically activate the NF-κB and inflammasome pathways to induce robust Th1 immune responses in vitro and in vivo. Our goal is to test this hypothesis employing our novel human in vitro platforms and in vivo safety immunogenicity of our adjuvant combination in using RSV pre-fusion protein as model antigen. We will achieve this goal by pursuing the following Specific Aims (SAs): Aim 1: Characterize mechanisms of combination adjuvant synergy in activating human DCs in vitro. Aim 2: Assess the ability of combination adjuvants to enhance DC-mediated lymphocyte activation in vitro. Aim 3: Evaluate the impact of combinatorial adjuvants on biomarkers of vaccine reactogenicity and immunogenicity in vitro and in vivo. Overall, successful pursuit of these Specific Aims will provide fresh insight into mechanisms of age-specific adjuvant synergy in vitro and in vivo thereby advancing new approaches to enhance protective immune responses in special populations, including the very young, against key pathogens.

 说明(申请人提供)：疫苗是一种重要的公共卫生干预措施，但到目前为止，它们的开发主要是临时和经验性的。感染最常见于年龄极端的人群，疫苗佐剂可以是提高具有不同免疫力的特殊人群免疫原性的关键途径。佐剂是增强免疫反应的分子，可以极大地增强免疫力，但关于佐剂的作用仍有许多需要了解，这种作用可能会随着年龄的变化而显著变化。为了识别有前景的佐剂系统并确定其作用机制，Levy实验室建立了新的人类体外模型系统，包括全血检测、单核细胞来源的树突状细胞(MoDC)阵列和微生理学三维组织结构，以模拟先天和获得性免疫反应。在使用人类新生儿、婴儿和成人白细胞的初步体外研究中，我们已经确定了某些Toll样受体激动剂(TLRA)和C型凝集素受体激动剂(CLRA)的组合，它们可以协同增强核因子-kB和炎症体激活以及Th1细胞因子的早期产生：合成咪唑喹啉TLR7/8激动剂R848和Mincle(CLR)激动剂海藻糖-6，6-二苯乙酸酯(TDB)。在拟议的研究中，我们将与Peter Andersen博士(位于丹麦哥本哈根的斯塔滕斯血清研究所)合作，进一步研究以呼吸道合胞病毒(RSV)预融合蛋白为模型抗原的这种联合佐剂系统协同活性的机制。我们的假设是，TLRAs和CLRAs协同激活了NF-κB和炎症体途径，在体外和体内诱导了强大的Th1型免疫反应。我们的目标是利用我们的新型人体体外平台来验证这一假说 以RSV预融合蛋白为模型抗原的佐剂组合物的体内安全免疫原性。我们将通过追求以下特定目标(SA)来实现这一目标：目标1：在体外研究联合佐剂协同激活人DC的机制。目的：评价联合佐剂在体外增强DC介导的淋巴细胞活化的能力。目的：评价联合佐剂在体内外对疫苗反应性和免疫原性生物标志物的影响。总体而言，成功地追求这些特定的目标将为体外和体内年龄特异性佐剂协同作用的机制提供新的见解，从而推动新的方法来增强特殊人群(包括非常年轻的人群)对关键病原体的保护性免疫反应。