An adjuvant that promotes TH1/TH17 and CD8 T cells in a tuberculosis vaccine

一种在结核疫苗中促进 TH1/TH17 和 CD8 T 细胞的佐剂

• 批准号: 9208083
• 负责人: JoAnne L. Flynn
• 金额: $ 113.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208083
• 关键词: Adjuvant; Animal Model; Antibodies; Antibody Response; Antigens; Autopsy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cations; Cessation of life; Chimeric Proteins; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Communicable Diseases; Country; Data; Development; Disease; Environment; Formulation; Generations; Goals; Human; Immune response; Immunologics; Infection; Institutes; Lipids; Macaca; Modeling; Monkeys; Mus; Mycobacterium tuberculosis; Newborn Infant; PET/CT scan; Pathology; Pattern recognition receptor; Production; Protein Subunits; Recording of previous events; Route; Series; Serum; Subunit Vaccines; T cell response; Testing; Toxic effect; Toxicity Tests; Tuberculosis; Tuberculosis Vaccines; Universities; Vaccination; Vaccine Antigen; Vaccines; base; cytokine; cytotoxic; efficacy testing; experience; immunogenicity; improved; killings; medical schools; mouse model; nanoparticle; nonhuman primate; novel; pathogen; pre-clinical; prevent; public health relevance; response; safety testing; scale up; stability testing; translation to humans; vaccine candidate; vaccine development

DESCRIPTION (provided by applicant): There are two major components of effective vaccines: adjuvants and antigens. The adjuvant for a vaccine must induce the immune responses that are protective, while the antigens must be those against which an immune response can provide protection from infection or disease. Most currently available adjuvants for humans, of which there are very few, induce antibody responses and primarily Th2 T cell responses. For many infections, including M. tuberculosis, Th1 CD4 T cell response and a cytotoxic or cytokine-producing CD8 T cell response are needed. Adjuvants that can induce such responses against subunit proteins and are also safe are urgently needed to tackle the most stubborn infectious diseases. Here, we propose to optimize a promising new adjuvant developed by Statens Serum Institute (SSI), CAF09, which builds on the CAF platform of cationic nanoparticles composed of bioactive lipids. This adjuvant induces both CD4 (Th1, Th17) and CD8 T cells. Optimization of CAF09 formulation and route of vaccination will be performed, using an established subunit vaccine, H56, which was developed by SSI and has been demonstrated to provide protection in several animal models, including non-human primates. Following optimization, the best candidates, based on mouse studies, will be tested for immunogenicity in non-human primates, to provide better translation to humans. The best formulation of CAF09/H56 will be scaled up and toxicity and stability studies will be performed. Finally, one formulation of CAF09/H56, as determined by the iterative studies in mice and monkeys, will be tested in a rigorous non-human primate M. tuberculosis challenge model. These studies will provide the crucial pre-clinical data for moving CAF09/H56 forward into human clinical trials as an improved TB vaccine candidate.

描述（申请人提供）：有效疫苗有两个主要成分：佐剂和抗原。疫苗的佐剂必须诱导具有保护性的免疫反应，而抗原必须是免疫反应能够提供针对感染或疾病的保护的抗原。目前大多数可用的人类佐剂（数量很少）诱导抗体反应，主要是 Th2 T 细胞反应。对于包括结核分枝杆菌在内的许多感染，需要 Th1 CD4 T 细胞反应和细胞毒性或产生细胞因子的 CD8 T 细胞反应。迫切需要能够诱导针对亚基蛋白的此类反应并且安全的佐剂来应对最顽固的传染病。在这里，我们建议优化 Statens Serum Institute (SSI) 开发的一种有前景的新型佐剂 CAF09，它建立在由生物活性脂质组成的阳离子纳米颗粒的 CAF 平台上。该佐剂可诱导 CD4（Th1、Th17）和 CD8 T 细胞。将使用已建立的亚单位疫苗 H56 来优化 CAF09 配方和疫苗接种途径，该疫苗由 SSI 开发，已被证明可以在包括非人类灵长类动物在内的多种动物模型中提供保护。经过优化后，基于小鼠研究的最佳候选者将在非人类灵长类动物中测试免疫原性，以便为人类提供更好的翻译。 CAF09/H56的最佳配方将被放大并进行毒性和稳定性研究。最后，通过小鼠和猴子的迭代研究确定的 CAF09/H56 的一种配方将在严格的非人类灵长类结核分枝杆菌攻击模型中进行测试。这些研究将为 CAF09/H56 作为改进的结核病候选疫苗进入人体临床试验提供关键的临床前数据。