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.

说明(申请人提供)：有效疫苗有两个主要组成部分：佐剂和抗原。疫苗的佐剂必须诱导具有保护性的免疫反应，而抗原必须是那些免疫反应可以防止感染或疾病的抗原。目前大多数可用于人类的佐剂，其中很少，诱导抗体反应，主要是Th2 T细胞反应。对于许多感染，包括结核分枝杆菌，Th1CD4T细胞反应和细胞毒或产生细胞因子的CD8T细胞反应是必需的。迫切需要能够诱导对亚单位蛋白产生这种反应且安全的佐剂来治疗最顽固的传染病。在这里，我们建议优化由斯塔滕斯血清研究所(SSI)开发的一种有前景的新佐剂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。该佐剂可同时诱导CD4(Th1、Th17)和CD8T细胞。将使用已建立的亚单位疫苗H56对CAF09的配方和接种路线进行优化，H56是由SSI开发的，已被证明在包括非人类灵长类动物在内的几个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基因将在非人类灵长类动物中进行免疫原性测试，以提供更好的人类翻译。将扩大CAF09/H56的最佳配方，并进行毒性和稳定性研究。最后，通过对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挑战模型中进行测试。这些研究将为将CAF09/H56作为改进的结核病候选疫苗推进到人类临床试验提供关键的临床前数据。