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（申请人提供）：有效疫苗有两种主要成分：佐剂和抗原。疫苗的佐剂必须诱导保护性的免疫应答，而抗原必须是免疫应答可以提供保护免受感染或疾病的抗原。大多数目前可用于人类的佐剂（其中很少）诱导抗体应答并且主要是Th 2 T细胞应答。对于包括M.需要Th 1 CD 4 T细胞应答和细胞毒性或产生嘌呤的CD 8 T细胞应答。迫切需要能够诱导针对亚基蛋白的这种反应并且也是安全的佐剂来应对最顽固的感染性疾病。在这里，我们建议优化Statens血清研究所（SSI）开发的一种有前途的新佐剂CAF 09，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。该佐剂诱导CD 4（Th 1，Th 17）和CD 8 T细胞。将使用已确定的亚单位疫苗H56进行CAF 09制剂和疫苗接种途径的优化，H56由SSI开发，并已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物将在非人灵长类动物中进行免疫原性测试，以提供更好的人类翻译。CAF 09/H56的最佳制剂将按比例放大，并将进行毒性和稳定性研究。最后，将在严格的非人灵长类动物M.结核病挑战模型这些研究将为CAF 09/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。