Adjuvant combination for SARS-CoV-2 vaccine for the elderly

老年人SARS-CoV-2疫苗的佐剂组合

• 批准号: 10662196
• 负责人: Elena Vassilieva
• 金额: $ 19.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662196
• 关键词: 2019-nCoV; Address; Adjuvant; Adult; Affect; Age Years; Agonist; Animals; Antigens; Authorization documentation; COVID-19 vaccine; Cells; Cessation of life; Clinical Research; Combined Vaccines; Cytotoxic T-Lymphocytes; Data; Development; Disease; Dose; Elderly; Emergency Situation; Formulation; Immune response; Immunity; Individual; Influenza; Interferons; Licensing; MF59; Mus; Outcome; Pathway interactions; Persons; Production; Proteins; Quil A; RNA vaccine; Recombinant Proteins; Research; Safety; Saponins; Stimulator of Interferon Genes; Subunit Vaccines; Testing; Translations; Universities; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; aged; aging population; authority; coronavirus disease; cytokine; experience; high risk; immunogenicity; immunosenescence; improved; influenza virus vaccine; middle age; mouse model; neutralizing antibody; novel; older patient; pandemic disease; response; sex; vaccine candidate; vaccine development; vaccine response; young adult

PROJECT SUMMARY Severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is currently causing the coronavirus disease (COVID-19) in pandemic proportion. According to John Hopkins university data tracker, there were 120,217,175 global cases and 2,660,456 deaths worldwide on March 15, 2021. The disease ranges from asymptomatic to lethal, with the elderly patients most severely affected. Finding a successful strategy to protect most vulnerable aged population is vital. However, it is possible that protein-based vaccines will not be as effective in individuals over 65 years of age as in healthy younger adults. There are also indications that RNA vaccines that are currently used under emergency authorization elicit vaccine responses appear weaker in elderly . Protein-based vaccines are considered safe but they lack the ability to elicit Th1 type of responses especially needed for protection in aged populations. Recently we developed a novel combination adjuvant for use with a licensed influenza subunit vaccine in high-risk aged population and tested it in an aged mouse model. The formulation combines an agonist of the stimulator of interferon gene (STING) pathway 2,3’-cGAMP and saponin Quil-A. Activation of the STING pathway leads to production of interferons and cytokines in target cells, and enhances development of the immune response to vaccine antigens, while saponins stimulate both the Th1 immune response and cytotoxic T lymphocyte production against protein antigens. By co-delivering these two compounds, cGAMP and Quil-A, with the vaccine we combined their adjuvant potential and improved the protective immunity of influenza vaccine in the aged mice more effectively than either a 4x antigen dose or MF-59-like adjuvant, which are two current vaccination options for persons over 65 years of age. We propose that this combination will also potentiate the protective responses to a candidate SARS-CoV-2 vaccine and will test this in aged mice. We will test this hypothesis using both sexes of aged mice. As saponins have been previously shown to increase the duration of immune response we will also determine the persistence of neutralizing antibodies in vaccinated animals. Although we do not anticipate reactogenicity of this formulation based on our experience, we will also test if a novel and safer saponin Titerquil 1-0-5-5 can be used instead of Quil-A. The results will be directly relevant for development of SARS-CoV-2 protein vaccines for high-risk aged populations. The combination adjuvant can be directly added to existing vaccines.

项目概要 严重急性呼吸综合征 - 冠状病毒 2 (SARS-CoV-2) 目前正在引起 冠状病毒病（COVID-19）已成为大流行病。根据约翰·霍普金斯大学 数据跟踪器，那里 3 月 15 日，全球确诊病例为 120,217,175 例，死亡病例为 2,660,456 例， 2021 年。 这种疾病的范围从无症状到致命，其中老年患者最严重 做作的。找到一个成功的策略来保护最脆弱的老年人口至关重要。 然而，基于蛋白质的疫苗对于 65 岁以上的个体可能不会那么有效 岁数与健康年轻人一样。 还有迹象表明，RNA 疫苗 目前在紧急授权下使用的疫苗在老年人中的反应似乎较弱 。 基于蛋白质的疫苗被认为是安全的，但它们缺乏引发 Th1 型反应的能力 尤其需要保护老年人口。最近我们开发了一种新颖的组合 佐剂与获得许可的流感亚单位疫苗一起用于高危老年人群并经过测试 它在老年小鼠模型中。该制剂结合了干扰素刺激剂的激动剂 基因 (STING) 途径 2,3'-cGAMP 和皂苷 Quil-A。 STING 通路的激活导致 促进靶细胞中干扰素和细胞因子的产生，并促进细胞的发育 对疫苗抗原的免疫反应，而皂苷则刺激 Th1 免疫反应 以及针对蛋白质抗原的细胞毒性 T 淋巴细胞的产生。通过共同交付这两个 化合物 cGAMP 和 Quil-A，我们将它们的佐剂潜力与疫苗结合起来 与流感疫苗相比，更有效地提高老年小鼠的保护性免疫力 4 倍抗原剂量或 MF-59 样佐剂，这是当前的两种疫苗接种选择 65岁以上的人。我们建议这种组合也将增强保护作用 对候选 SARS-CoV-2 疫苗的反应并将在老年小鼠中进行测试。我们将测试这个 使用老年小鼠的两种性别的假设。由于皂苷先前已被证明可以增加 免疫反应的持续时间我们还将确定中和的持续时间 接种疫苗的动物体内产生抗体。尽管我们预计该配方不会产生反应原性 根据我们的经验，我们还将测试是否可以使用一种新颖且更安全的皂苷 Titerquil 1-0-5-5 用于代替 Quil-A。结果将与 SARS-CoV-2 的开发直接相关 针对高危老年人群的蛋白质疫苗。组合助剂可直接添加 现有疫苗。