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IM route showed no signs of COVID-19, whereas the IN vaccinated animals did including lung lesions (Furuyama et al., unpublished data).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.

该实验室开发了两种单独表达SARS-CoV-2刺突蛋白或与埃博拉病毒糖蛋白(EBOV GP)联合表达的候选疫苗。仓鼠的研究表明，在SARS-CoV-2攻击后，单剂量鼻内或肌肉注射疫苗(IM)可以保护动物免受疾病的侵袭。当我们在SARS-CoV-2攻击前10天用单剂VSV-SARS2-EBOV疫苗接种恒河猴时，只有IM途径接种的动物没有出现新冠肺炎的迹象，而IN接种的动物出现了肺部损害(Furuyama等人，未发表的数据)。 我们与蒙斯特尔斯博士的病毒生态学部分一起，使用基于VSV的伪粒子系统研究了β冠状病毒的受体用途。我们发现SARS-CoV-2使用ACE2作为进入细胞的受体(Letko等人，自然微生物学2020)。此外，我们与蒙斯特博士合作建立了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年；PMID 32803199)。 为了扩大我们对新冠肺炎期间人类细胞因子反应的理解，我们正在分析从印第安纳州患者那里收集的一段时间的人类血清样本。此外，我们正在测定这些样本中对SARS-CoV-2的免疫球蛋白反应，并正在研究这些样本中抗体依赖的感染增强的可能性(Shifflett，Furuyama等人，未发表的数据)。 最后，TLR4和TLR7/8激动剂已被证明是治疗流感病毒感染的有益药物。此外，TLR7/8已被证实在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一种潜在的治疗鼠类SARS-CoV-2感染的方法。这个项目还处于非常早期的阶段。