Vaccine Adjuvant/ Delivery Systems Core

疫苗佐剂/输送系统核心

基本信息

批准号：
8492635
负责人：
Darrell J Irvine
金额：
$ 31.09万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2013-02-07 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8492635
关键词：
Adjuvant Agonist Animals Antibody Formation Antigens Automobile Driving Avidity B-Lymphocytes Caliber Cell membrane Cells Cellular Immunity Clinical Data Dendritic Cells Development Dose Effectiveness Engineering Ensure Epitopes Face Generations Guanine HIV HIV Antigens HIV vaccine Human Humoral Immunities Immune response Immunity Immunization Injection of therapeutic agent Instruction Label Life Lipids Liposomes Lymphoid Malaria Membrane Micelles Modeling Molecular Mus Organ Peptide Vaccines Peptides Proteins Recombinants Route Safety Scaffolding Protein Signal Transduction Structure Subunit Vaccines System T cell response T memory cell T-Lymphocyte TLR3 gene TLR7 gene TLR8 gene Tail Toll-like receptors Toxic effect Vaccination Vaccine Adjuvant Vaccines Water aluminum sulfate base design human DNA immunogenicity leukocyte activation lymph nodes monophosphoryl lipid A mouse model nanocapsule nanoparticle nonhuman primate novel novel vaccines plasmid DNA programs response success tool vaccine delivery vaccine development vector

项目摘要

New adjuvant/delivery strategies that could enable protein and peptide vaccines to elicit both potent cellular and humoral immunity would be highly complementary to existing approaches in HIV vaccine development. In this Core, we will supply and further develop two classes of potent novel adjuvants recently developed in the Irvine lab to support the subunit vaccine studies of projects 1 and 2 in studying human immune responses to HIV immunogens in BLT humanized mice: stabilized lipid nanocapsules (SLNCs) and membrane-targeted micelles (MTMs). SLNCs are a lipid nanocapsule system for delivery of protein or peptide antigens together with molecular danger signals such as TLR agonists (TLRa), which retain entrapped antigen/TLRa much more effectively than traditional liposomes, leading to enhanced antigen/adjuvant delivery to dendritic cells and sustained accumulation of antigen in draining lymph nodes following vaccination. The second adjuvant system, membrane-targeted micelles (MTM), is based on the conjugation of molecular adjuvants or peptide antigen cargos to a micelle-forming lipid tail. These amphiphilic molecules self-assemble to form nanoparticles -15 nm in diameter in water, but also dynamically dis-assemble to anchor their lipid tails in the membrane on contact with cells. MTMs dramatically target TLRa or peptides to lymph nodes, forming intranodal vaccine depots following s.c. injection, and driving strongly enhanced immune responses to co-administered protein antigens. We will provide these potent adjuvants on demand for BLT humanized mouse immunization studies for projects 1 and 2. In addition, we will further develop these adjuvants to maximize the effectiveness in BLT mice while designing for negligible toxicity/reactogenicity, to ensure their relevance for human vaccine development. Results from these studies will further the BLT humanized mouse model as a tool for vaccine development, by identifying effective adjuvants and routes of administration for vaccine delivery, and provide new adjuvants applicable to diverse subunit vaccines beyond HIV.

新的佐剂/递送策略可以使蛋白质和肽疫苗同时引发有效的细胞体液免疫将与艾滋病毒疫苗开发的现有方法高度互补。在此核心中，我们将提供并进一步开发两类最近在尔湾实验室支持项目 1 和 2 的亚单位疫苗研究，以研究人类免疫 BLT 人源化小鼠对 HIV 免疫原的反应：稳定脂质纳米胶囊 (SLNC) 和膜靶向胶束（MTM）。 SLNC 是一种脂质纳米胶囊系统，用于输送蛋白质或肽抗原与分子危险信号如 TLR 激动剂 (TLRa) 一起，保留比传统脂质体更有效地包埋抗原/TLRa，从而增强抗原/佐剂递送至树突状细胞并在引流淋巴结中持续积累抗原接种疫苗后。第二种佐剂系统，膜靶向胶束 (MTM)，基于将分子佐剂或肽抗原货物与形成胶束的脂质尾缀合。这些两亲性分子在水中自组装形成直径-15 nm的纳米粒子，而且还可以动态地在与细胞接触时分解，将其脂质尾锚定在膜上。 MTM 显着瞄准 TLRa 或肽到达淋巴结，在皮下注射后形成结内疫苗库。注射、驾驶强烈增强对共同施用的蛋白质抗原的免疫反应。我们将提供这些有力的项目 1 和 2 的 BLT 人源化小鼠免疫研究所需的佐剂。此外，我们将进一步开发这些佐剂，以最大限度地提高 BLT 小鼠的有效性，同时设计可忽略不计的毒性/反应原性，以确保其与人类疫苗开发的相关性。这些研究的结果将通过鉴定有效的方法，进一步将 BLT 人源化小鼠模型作为疫苗开发的工具疫苗递送的佐剂和给药途径，并提供适用于多种疫苗的新佐剂 HIV 以外的亚单位疫苗。