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

项目摘要 严重急性呼吸道综合征-冠状病毒2（SARS-CoV-2）目前正在引起 冠状病毒病（COVID-19）占大流行比例。根据约翰霍普金斯大学 数据跟踪器， 截至3月15日，全球病例为120,217,175例，死亡2,660,456例， 2021. 这种疾病的范围从无症状到致命，老年患者最严重 影响。找到一个成功的战略来保护最脆弱的老年人口至关重要。 然而，基于蛋白质的疫苗可能对65岁以上的人不那么有效。 年龄与健康的年轻人一样。 也有迹象表明，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型应答的能力 尤其需要保护老年人。最近我们开发了一种新的组合 在高风险老年人群中与许可的流感亚单位疫苗一起使用的佐剂， 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 干扰素和细胞因子在靶细胞中的产生，并增强 免疫应答，而皂苷刺激Th1免疫应答 和针对蛋白抗原的细胞毒性T淋巴细胞产生。通过共同交付这两个 化合物，cGAMP和Quil-A，与疫苗结合，我们结合了它们的佐剂潜力， 提高流感疫苗在老年小鼠中的保护性免疫力， 4x抗原剂量或MF-59样佐剂，这是目前用于 65岁以上的人。我们认为，这种组合也将加强保护性 研究人员将在老年小鼠中测试对候选SARS-CoV-2疫苗的反应。我们将测试这个 使用老年小鼠的两性假设。由于皂苷先前已被证明增加 免疫反应的持续时间，我们还将确定中和的持续时间， 免疫动物体内的抗体。虽然我们不预期该制剂的反应原性 根据我们的经验，我们还将测试一种新的和更安全的皂苷Titerquil 1 - 0 - 5 - 5是否可以 使用而不是Quil-A。这些结果将直接关系到SARS-CoV-2的发展 针对高危老年人群的蛋白质疫苗。组合佐剂可直接加入 现有的疫苗。

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.