VACCINES ADJUVANT DEVELOPMENT PROGRAM IN INFECTIOUS AND IMMUNE MEDIATED DISEASES

传染病和免疫介导疾病的疫苗佐剂开发计划

• 批准号: 10935774
• 负责人: TYSON HEILHERKER
• 金额: $ 181.85万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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/10935774
• 关键词: Adjuvant; Adjuvanticity; Agonist; Animal Model; Antigens; Austria; Boston; Cells; Chemistry; Contractor; Development; Disease; Family suidae; Ferrets; Formulation; Good Manufacturing Process; Hemagglutinin; Human; Immune; Immune response; Immune signaling; In Vitro; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Intervention; Investigational New Drug Application; Leukocytes; Licensing; Malignant Neoplasms; Mediating; Mus; Pattern recognition receptor; Pediatric Hospitals; Process; Production; Program Development; Proteins; Readiness; Research Activity; System; TLR7 gene; Vaccination; Vaccine Adjuvant; Vaccines; Wisconsin; analog; cytokine; efficacy study; good laboratory practice; high throughput screening; immune activation; immunogenicity; in vivo; in vivo Model; influenza virus strain; influenza virus vaccine; manufacture; novel; programs; response; scale up; small molecule

Vaccination is a key biomedical intervention to reduce infection, cancer, and other diseases, but responses to vaccines may be inadequate in breadth, magnitude and/or durability. Agents that activate innate immune signaling via selective activation of pattern recognition receptors (PRRs) can serve as adjuvants to enhance vaccine-induced immune responses and protection. High throughput screening on primary human cells in culture (in vitro) identified a novel imidazopyrimidine adjuvant, Precision Vaccines Program (PVP)-037, which demonstrated broad innate immune activation via the PRR Toll-like receptor-7 (TLR7), including cytokine induction from human leukocytes in vitro as well as enhancement of influenza antigen-specific humoral responses in mice in vivo. As Contractor, the Precision Vaccine Program (PVP) at Boston Children’s Hospital (BCH) will supervise, coordinate, and undertake research activities aimed at developing a novel small molecule imidazopyridine TLR7 agonist analog, optimizing adjuvant formulation and stability as well as adjuvanticity in combination with licensed HA protein-based influenza vaccine towards human leukocytes in vitro and in animal models in vivo. The production of adjuvant formulation will be completed under good laboratory practice (GLP), to support Investigational New Drug application (IND)-enabling activities in preparedness for chemistry, manufacturing, and control (CMC) process-development and pre-current Good Manufacturing Practice (cGMP) production-grade formulation scaled up.

疫苗接种是减少感染、癌症和其他疾病的关键生物医学干预措施，但对疫苗的反应在广度、程度和/或持久性方面可能不足。通过模式识别受体（PRR）的选择性激活来激活先天免疫信号传导的试剂可以用作佐剂以增强疫苗诱导的免疫应答和保护。对培养（体外）中的原代人细胞的高通量筛选鉴定了一种新型咪唑并嘧啶佐剂，精密疫苗计划（PVP）-037，其证明了通过PRR Toll样受体-7（TLR 7）的广泛先天免疫激活，包括体外人白细胞的细胞因子诱导以及体内小鼠流感抗原特异性体液应答的增强。作为承包商，波士顿儿童医院（BCH）的精准疫苗项目（PVP）将监督、协调和开展研究活动，旨在开发一种新型小分子咪唑并吡啶TLR 7激动剂类似物，优化佐剂配方和稳定性，以及与已获许可的基于HA蛋白的流感疫苗结合在体外和体内动物模型中对人白细胞的佐剂性。佐剂制剂的生产将根据药物非临床研究质量管理规范（GLP）完成，以支持研究性新药申请（IND）-使能活动，为化学、生产和控制（CMC）工艺开发和前现行药品生产质量管理规范（cGMP）生产级制剂的规模扩大做准备。