BASE AWARD

基础奖

基本信息

批准号：
10935816
负责人：
GREGORY SORENSON
金额：
$ 189.67万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE COUNTY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10935816
关键词：
Acute Pneumonia Adjuvant Adult Agonist Antigen Targeting Antigens Award Bacterial Proteins Chimeric Proteins Contractor Development Dose Drug Metabolic Detoxication Elderly Formulation Helper-Inducer T-Lymphocyte Hemagglutinin Hemolysin Humoral Immunities Immune Immune response Immunity Immunocompetent Immunologic Adjuvants Immunologics Individual Influenza A virus Innate Immune System Ligands Lipid A Lung Mediating Modeling Mus Population Preclinical Testing Process Production Proliferating Proteins Pseudomonas Pseudomonas aeruginosa Safety Shapes Signal Transduction Staphylococcus aureus Staphylococcus aureus infection System T-Lymphocyte TLR4 gene Technology Type III Secretion System Pathway Vaccine Adjuvant Vaccine Antigen Vaccines Viral Proteins aging population alpha Toxin base biophysical properties combinatorial chemistry immunogenic immunogenicity influenza virus vaccine novel vaccines rational design response vaccine formulation

项目摘要

For effective next-generation vaccines, the identification of high-quality target antigens combined with effective adjuvants will be critical. Immunoadjuvants are key components in vaccine formulations since they enhance and shape immune responses to vaccines in both immunocompetent and immunosenescent individuals. Bacterial Enzymatic Combinatorial Chemistry (BECC) technology allows for the efficient production of rationally designed lipid A agonists which signal through the host innate immune system via toll-like receptor 4 (TLR4). BECC-based adjuvants generate a balanced Th1/Th2 response yielding antigen and dose sparing, increased T-cell mediated effector immunity, enhanced proliferation of T follicular helper (Tfh) cells, and the establishment of a longer-lasting humoral immunity in adult and aged populations. BECC470s is a rationally designed synthetic TLR4-based ligand from this process. The objective of this proposal is to develop the adjuvant potential of BECC470s and evaluate it for preclinical testing with three established immunogenic vaccine antigens: 1) Influenza A HA protein, 2) Staphylococcus aureus detoxified α-hemolysin, and 3) Pseudomonas spp. T3SS fusion protein (L-PaF). BECC470s will be evaluated for biophysical properties, safety, immune stimulatory potential, and antigen sparing when developed as independent vaccine formulations that include Antigen System (AS) biosimilars (AS01, AS03, and AS04 biosimilars, and micellular) in both adult and elderly populations. These studies will allow for IND-enabling development of BECC470s through immunological characterization studies, as well as compound optimization for three separate and unique component vaccines.

为了有效的下一代疫苗，至关重要的是，鉴定高质量靶抗原与有效佐剂是至关重要的。免疫添加剂是疫苗配方中的关键组成部分，因为它们可以增强并塑造免疫调查的免疫能力和免疫味个体中的疫苗。细菌酶合剂化学（BECC）技术允许有效地生产合理设计的脂质A激动剂，通过Toll样受体4（TLR4）通过宿主先天免疫抑制器系统发出信号。基于BECC的调节器会产生平衡的Th1/Th2反应，从而产生抗原和剂量的稀疏，增加T细胞介导的效应子免疫史免疫，增强T Follicular Helper（TFH）细胞的增殖，并在成人群体中建立较长的体液免疫疗法。 BECC470S是一个合理设计的基于合成TLR4的配体，来自此过程。该提案的目的是开发BECC470S的可调节电位，并用三种已建立的免疫原性疫苗抗原进行临床前测试评估：1）流感A HA HA蛋白，2）金黄色葡萄球菌排毒的氧化氧化物氧化氧化物氧化物氧化氧化葡萄球菌，以及3）Pseudomonas spp。 T3SS融合蛋白（L-PAF）。将评估BECC470的生物物理性能，安全性，免疫刺激潜力和抗原较高的抗原，并以独立的疫苗配方（包括抗原系统（AS）生物仿制药（AS01，AS03和AS04生物仿制药）以及成人和老年人群中的抗原系统（AS01，AS03和AS04生物仿制药））进行评估。这些研究将通过免疫特征研究来促进BECC470的开发，以及针对三种独特和独特的组成疫苗的化合物优化。