BASE AWARD

基础奖

• 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
• 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

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.

对于有效的下一代疫苗来说，鉴定高质量的靶抗原与有效佐剂相结合将是关键。免疫佐剂是疫苗配方中的关键成分，因为它们增强和塑造了免疫能力和免疫衰退者对疫苗的免疫反应。细菌酶组合化学(BECC)技术可以有效地生产设计合理的脂质A激动剂，这些激动剂通过Toll样受体4(TLR4)通过宿主天然免疫系统发出信号。基于BecC的佐剂产生平衡的Th1/Th2应答，产生抗原和剂量节省，提高T细胞介导的效应器免疫，促进T滤泡辅助细胞(TFH)的增殖，并在成人和老年人群中建立更持久的体液免疫。BECC470是在此基础上设计合理的合成TLR4配体。 这项建议的目的是开发BECC470的佐剂潜力，并用三种已建立的免疫原性疫苗抗原对其进行临床前试验：1)甲型流感HA蛋白，2)金黄色葡萄球菌解毒的α-溶血素，3)假单胞菌。T3SS融合蛋白(L-PAF)。BECC470将作为包括成人和老年人群中的抗原系统(AS)生物仿制药(AS01、AS03和AS04生物仿制药以及微细胞)的独立疫苗配方开发时，将在生物物理特性、安全性、免疫刺激潜力和抗原保护方面进行评估。这些研究将通过免疫学特性研究以及三种独立和独特成分疫苗的化合物优化，使BECC470能够实现IND开发。