Countermeasures against COVID-19

针对 COVID-19 的对策

• 批准号: 10272280
• 负责人: Andrea Marzi
• 金额: $ 9.49万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10272280
• 关键词: 2019-nCoV; Agonist; Animal Diseases; Animals; Antibody-Dependent Enhancement; Antiviral Agents; COVID-19; Cells; Containment; Coronavirus; Data; Data Set; Development; Dose; Ebola virus; Ecology; Glycoproteins; Hamsters; Human; Immune response; Immunobiology; Immunoglobulin G; Indiana; Infection; Intramuscular; Knowledge; Laboratories; Lesion; Lung; Macaca mulatta; Microbiology; Molecular Virology; Nature; Pathogenesis; Patients; Play; Proteins; Research; Rodent; Role; Route; SARS coronavirus; Sampling; Serum; System; TLR4 gene; TLR7 gene; Testing; Therapeutic; Time; Vaccinated; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Virus; Virus Diseases; base; cytokine; influenzavirus; innovation; mouse model; pandemic disease; particle; pathogenic virus; receptor; response; vaccine candidate

The lab developed 2 vaccine candidates expressing the SARS-CoV-2 spike protein alone or in combination with the Ebola virus glycoprotein (EBOV GP). Hamster studies revealed that a single dose of either vaccine administered intranasally or intramuscularly (IM) protected the animals from disease after SARS-CoV-2 challenge. When we vaccinated rhesus macaques 10 days prior to SARS-CoV-2 challenge with a single dose of the VSV-SARS2-EBOV vaccine, only animals vaccinated by the IM route showed no signs of COVID-19, whereas the IN vaccinated animals did including lung lesions (Furuyama et al., unpublished data). Together with Dr. Munsters Virus Ecology Section, we studied the receptor usage of beta-coronaviruses using a VSV-based pseudoparticle system. We found that SARS-CoV-2 uses ACE2 as an entry receptor into cells (Letko et al., Nature Microbiology 2020). Furthermore, we collaborated with Dr. Munster on the establishment of a mouse model for SARS-CoV-2 in order to be able to test antivirals and vaccines (Yinda et al., 2020; PMID 32803199). In order to expand our understanding of human cytokine responses during COVID-19, we are analyzing human serum samples collected over time from patients from Indiana. In addition, we are determining IgG responses to SARS-CoV-2 in these samples and are looking into the potential of antibody-dependent enhancement of infection in these samples (Shifflett, Furuyama et al., unpublished data). Lastly, TLR4 and TLR7/8 agonists have shown to be beneficial as a treatment against influenza virus infections. In addition, TLR7/8 have been demonstrated to play a role in SARS-CoV-1 infection and pathogenesis. Therefore, we are testing both agonists as a potential treatment against SARS-CoV-2 infections in rodents. This project is in very early stages.

该实验室开发了 2 种候选疫苗，可单独表达 SARS-CoV-2 刺突蛋白或与埃博拉病毒糖蛋白 (EBOV GP) 结合表达。仓鼠研究表明，鼻内或肌内 (IM) 注射单剂疫苗可以保护动物在 SARS-CoV-2 攻击后免受疾病侵害。当我们在 SARS-CoV-2 攻击前 10 天用单剂 VSV-SARS2-EBOV 疫苗对恒河猴进行疫苗接种时，只有通过 IM 途径接种的动物没有表现出 COVID-19 的迹象，而 IN 疫苗接种的动物则表现出包括肺部病变（Furuyama 等人，未发表的数据）。 我们与 Munsters 病毒生态学部博士一起，使用基于 VSV 的伪粒子系统研究了 β 冠状病毒的受体使用。我们发现 SARS-CoV-2 使用 ACE2 作为进入细胞的受体（Letko 等人，Nature Microbiology 2020）。此外，我们与 Munster 博士合作建立了 SARS-CoV-2 小鼠模型，以便能够测试抗病毒药物和疫苗（Yinda 等人，2020；PMID 32803199）。 为了扩大我们对 COVID-19 期间人类细胞因子反应的了解，我们正在分析一段时间内从印第安纳州患者收集的人类血清样本。此外，我们正在确定这些样本中对 SARS-CoV-2 的 IgG 反应，并研究这些样本中抗体依赖性增强感染的潜力（Shifflett、Furuyama 等人，未发表的数据）。 最后，TLR4 和 TLR7/8 激动剂已被证明可有效治疗流感病毒感染。此外，TLR7/8已被证明在SARS-CoV-1感染和发病机制中发挥作用。因此，我们正在测试这两种激动剂作为啮齿动物 SARS-CoV-2 感染的潜在治疗方法。该项目尚处于早期阶段。