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: 8994259
• 负责人: JoAnne L. Flynn
• 金额: $ 112.49万
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8994259
• 关键词: Adjuvant; Animal Model; Antibodies; Antibody Response; Antigens; Autopsy; CD4 Positive T Lymphocytes; CD8B1 gene; Cessation of life; Chimeric Proteins; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Communicable Diseases; Country; Data; Development; Disease; Environment; Formulation; Generations; Goals; Health; Human; Immune response; 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; Scanning; Series; Serum; Subunit Vaccines; T cell response; T-Lymphocyte; Testing; Toxic effect; Toxicity Tests; Translations; Tuberculosis; Tuberculosis Vaccines; Universities; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; base; cytokine; cytotoxic; efficacy testing; experience; immunogenicity; improved; killings; medical schools; mouse model; nanoparticle; nonhuman primate; novel; pathogen; pre-clinical; prevent; response; safety testing; scale up; stability testing; 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（由申请人提供）：有效疫苗有两个主要成分：佐剂和抗原。疫苗的佐剂必须诱发具有保护作用的免疫反应，而抗原必须是免疫反应能够防止感染或疾病的抗原。目前大多数可用的人类佐剂，其中很少，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。迫切需要能够诱导这种针对亚基蛋白的反应并且安全的佐剂来治疗最顽固的传染病。在此，我们建议对Statens Serum Institute (SSI) CAF09开发的一种有前景的新佐剂进行优化，该佐剂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。这种佐剂同时诱导CD4 （Th1, Th17）和CD8 T细胞。将对CAF09的配方和接种途径进行优化，使用SSI开发的已建立的亚单位疫苗H56，该疫苗已被证明在几种动物模型（包括非人灵长类动物）中提供保护。在优化之后，基于小鼠研究的最佳候选药物将在非人类灵长类动物中进行免疫原性测试，以更好地为人类提供翻译。将扩大CAF09/H56的最佳配方，并进行毒性和稳定性研究。最后，在小鼠和猴子的反复研究中确定的一种CAF09/H56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。这些研究将为将CAF09/H56作为一种改进的结核病候选疫苗推进人体临床试验提供关键的临床前数据。