New DC-targeting Vaccine Constructs and Antibody Reagents

新型 DC 靶向疫苗构建体和抗体试剂

基本信息

批准号：
8377855
负责人：
GERARD ZURAWSKI
金额：
$ 34.54万
依托单位：
BAYLOR RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8377855
关键词：
Adjuvant Affinity Agonist Antibodies Antigen Receptors Antigen Targeting Antigens Area B-Lymphocyte Epitopes Binding Biology Bispecific Antibodies CD8B1 gene Chemicals Chimeric Proteins Clinical Trials Contractor Data Dendritic Cells Dendritic cell activation Development Ensure Epitopes Flagellin Funding Future Generations Goals Hemagglutinin Human Immune response In Vitro Individual Influenza Influenza Hemagglutinin Knowledge LOX gene Link Macaca mulatta Monkeys Monoclonal Antibodies Mucosal Immunity Mus Nucleoproteins Phase Phase I Clinical Trials Polyvalent Vaccine Property Reagent Recombinant Antibody Secure Specificity TLR5 gene TLR7 gene TNFRSF5 gene Technology Testing Triage Vaccine Antigen Vaccines Viral Hemagglutinins base dectin 1 flu immunogenicity improved in vivo in vivo Model influenza virus vaccine langerin man novel vaccines programs prototype receptor response vaccine candidate vaccine development vaccine evaluation

项目摘要

In the 1st U19, we established panels of high specificity and high affinity monoclonal antibodies against the following human DC receptors: LOX-1, BDCA-2, DC-SIGN/L, Dectin-1, CD1d, DC-ASGPR, Langerin, CLEC-6, MARCO, CD40 and DCIR. These human DC receptor reagents uncovered fundamental new biology and were used for development of prototype vaccines that target antigens directly to DCs. Based on extensive efficacy data in vitro, as well as preliminary studies in two in vivo models, the Humouse and Rhesus macaque, we hypothesize that the most potent antigen-targeting vaccines will deliver multiple antigens, engage two receptors simultaneously, and will be directly linked to adjuvants. We envision three areas for improvement that are the basis of Aims 1-3. In Aim 1, we will construct polyvalent vaccines composed of influenza viral hemagglutinin (HA), nucleoprotein (NP), and matrix protein2 (M2). Triple vaccines will induce broad repertoires of both cellular and humoral immune responses. In Aim 2, we will generate vaccines that target two DC receptors to enhance the immunogenicity of vaccines. In Aim 3, adjuvant-linked DC-targeting vaccines will be produced. The vaccines generated herein will undergo analysis of DC binding, activation, and internalization through Aim 4, and then undergo further studies within Projects 1-4. Projects 1 and 2 serve, through in vitro analysis, to discover the most potent candidate vaccines - particularly those that will evoke mucosal immunity. The selected vaccines will be tested thoroughly in vivo via Projects 3 and 4.

在第一届U19中，我们建立了具有高特异性和高亲和力单克隆抗体的面板遵循人类直流受体：LOX-1，BDCA-2，DC-SIGN/L，DECTIN-1，CD1D，DC-ASGPR，LANGERIN，LANGERIN， CLEC-6，Marco，CD40和DCIR。这些人类直流受体试剂发现了基本的新型生物学，用于开发直接针对DC的抗原的原型疫苗。基于体外广泛的疗效数据，以及两个体内模型的初步研究，恒河猕猴，我们假设最有效的抗原疫苗将提供多种抗原，同时接合两个受体，并将直接与佐剂联系起来。我们设想三个改进领域是目标1-3的基础。在AIM 1中，我们将构建多价疫苗由流感病毒血凝素（HA），核蛋白（NP）和基质蛋白2（M2）组成。三倍疫苗将诱导细胞和体液免疫反应的广泛曲目。在AIM 2中，我们将产生靶向两个DC受体的疫苗，以增强疫苗的免疫原性。在AIM 3中，将产生与辅助DC靶向疫苗。本文生成的疫苗将接受通过目标4分析直流结合，激活和内在化，然后在内部进行进一步的研究项目1-4。通过体外分析，项目1和2的服务以发现最有力的候选人疫苗 - 尤其是那些会引起粘膜免疫的疫苗。选定的疫苗将进行测试通过项目3和4彻底在体内。