Assessing the Risk of SARS-CoV-2 Remdesivir Resistance

评估 SARS-CoV-2 瑞德西韦耐药性风险

• 批准号: 10442701
• 负责人: Judd F Hultquist
• 金额: $ 20万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442701
• 关键词: 2019-nCoV; Active Sites; Animal Model; Antiviral Agents; Antiviral Therapy; Antiviral resistance; Binding; Binding Sites; Biochemical; Biological Assay; COVID-19; COVID-19 monitoring; COVID-19 pandemic; COVID-19 patient; COVID-19 treatment; Cell Culture Techniques; Cells; Cessation of life; Clinic; Clinical; Collection; Complement; Coronavirus; Data; Dexamethasone; Disease; Dyspnea; Ebola virus; Emergency Situation; Enrollment; Evolution; FDA Emergency Use Authorization; Funding; General Population; Genetic Variation; Goals; Grant; Haplotypes; Hospitalization; Hospitals; In Vitro; Infection; Lead; Measures; Mediating; Medical Records; Middle East Respiratory Syndrome Coronavirus; Monitor; Monoclonal Antibodies; Mutation; Nature; Nucleotides; Oligonucleotides; Outcome; Patients; Persons; Pneumonia; Polymerase; Population; Population Dynamics; Probability; Prodrugs; RNA Viruses; RNA-Directed RNA Polymerase; Recording of previous events; Recovery; Reporting; Research Personnel; Resistance; Respiratory distress; Risk; SARS coronavirus; Sampling; Seeds; Series; Specimen; Symptoms; Testing; Therapeutic; Time; Variant; Viral; Viral Load result; Virus; Work; biobank; deep sequencing; design; genome sequencing; global health; in silico; mimicry; molecular sequence database; mutant; nasal swab; nasopharyngeal swab; nucleotide analog; online repository; pandemic disease; pathogen; patient population; pressure; remdesivir; research clinical testing; resistance mutation; respiratory pathogen; response; severe COVID-19; therapeutic evaluation; treatment comparison; treatment strategy; viral RNA; viral resistance; virology; whole genome

PROJECT SUMMARY The rapid spread of the SARS-CoV-2 pandemic around the globe has led to an urgent and ongoing evaluation of therapeutic strategies for the treatment of Coronavirus Disease 2019 (COVID-19). While a handful of host- directed therapies are being used for the treatment of severe disease, including monoclonal antibodies and dexamethasone, there is only one antiviral with emergency use authorization, the nucleotide analog remdesivir (GS-5734). Remdesivir is thought to inhibit the viral RNA-dependent RNA polymerase, Nsp12, through nucleotide mimicry and early chain termination. As use of remdesivir for the treatment of COVID-19 escalates, it is essential to understand the nature and risk of developing antiviral resistance. We hypothesize that intra-host variation in Nsp12 could allow for the evolution of remdesivir resistance. In this exploratory grant, we propose to test this hypothesis by quantifying the SARS-CoV-2 viral diversity that arises in hospitalized patients over time with and without remdesivir treatment (Aim 1), and by determining the impact of known Nsp12 mutations on polymerase activity and sensitivity to remdesivir (Aim 2). In Aim 1, we will leverage a biobank of longitudinally collected nasopharyngeal swabs from hospitalized COVID-19 patients at Northwestern Memorial Hospital. Specimens were collected every 4 days after enrollment for up to one month, including specimens from 8 patients given remdesivir. We are continuing to collect specimens and intend to enroll an additional 50 COVID-19 patients over the coming months. Deep, whole genome sequencing of SARS-CoV-2 viruses from each specimen will be performed to classify the viral variants detected within each patient over time. The nature and extent of variation will be compared by time point, viral load, and treatment course as determined from medical record data. These studies will be complemented with deep sequencing of viruses produced ex vivo in the presence of varying concentrations of remdesivir. Overall, this work will determine the nature and extent of SARS-CoV-2 intra-host variation that develops in hospitalized patients and will determine the impact of remdesivir treatment on that variation. In Aim 2, in vitro oligonucleotide extension assays will be used to assess the impact of previously described Nsp12 mutations on polymerase activity and remdesivir efficacy. Documented mutations near the remdesivir binding pocket and Nsp12 active site, newly documented haplotypes arising in our patient population, and Nsp12 mutants found to be under selective pressure will be assessed first for polymerase activity followed by remdesivir sensitivity. The phylodynamic histories of impactful mutations and haplotypes will be followed to look for evidence of selection in the population. Together, these results will assess the risk of emergent remdesivir resistance and additionally identify potential resistance mutations for active monitoring.

项目摘要 SARS-COV-2大流行在全球范围内的迅速传播导致了紧急和持续的评估 2019年冠状病毒病治疗的治疗策略（Covid-19）。虽然少数主人 - 定向疗法用于治疗严重疾病，包括单克隆抗体和 地塞米松，只有一种具有紧急使用授权的抗病毒药 （GS-5734）。人们认为remdesivir抑制病毒RNA依赖性RNA聚合酶NSP12，通过 核苷酸模仿和早期链终止。随着使用Remdesivir进行Covid-19的治疗，它升级了，它 对于理解发展抗病毒药抗性的性质和风险至关重要。我们假设那个主持人 NSP12的变化可以允许Remdesivir抗性的演变。在这项探索性赠款中，我们建议 通过量化住院患者随时间出现的SARS-COV-2病毒多样性来检验这一假设 有和不进行Remdesivir处理（AIM 1），并通过确定已知NSP12突变对 聚合酶活性和对Remdesivir的敏感性（AIM 2）。在AIM 1中，我们将利用纵向的生物库 西北纪念医院从住院的199例患者中收集了鼻咽拭子。 注册后每4天收集标本，最多一个月，包括来自8例患者的标本 给定remdesivir。我们将继续收集标本，并打算招募50名Covid-19患者 在接下来的几个月中。每个标本的SARS-COV-2病毒的深层，全基因组测序将是 随着时间的推移，进行了每位患者中检测到的病毒变体的分类。变异的性质和程度 将按时间点，病毒负荷和治疗过程比较，根据病历数据确定。这些 在存在变化的情况下，研究将与对离体产生的病毒的深度测序进行补充 remdesivir的浓度。总体而言，这项工作将确定SARS-COV-2宿主内部的性质和程度 住院患者发展的变异，并将确定Remdesivir治疗对此的影响 变化。在AIM 2中，体外寡核苷酸扩展测定将用于评估先前的影响 描述了NSP12在聚合酶活性和remdesivir疗效上的突变。附近有记录的突变 Remdesivir Binding Pocket和NSP12活跃部位，在我们的患者人群中出现新记录的单倍型， 发现处于选择性压力下的NSP12突变体将首先评估。 通过remdesivir敏感性。影响力突变和单倍型的系统动力学历史将遵循 寻找人口选择的证据。这些结果将共同评估出现的风险 Remdesivir抗性，并鉴定出潜在的电阻突变以进行主动监测。

项目成果

Overlapping Delta and Omicron Outbreaks During the COVID-19 Pandemic: Dynamic Panel Data Estimates.

• DOI: 10.2196/37377
• 发表时间: 2022-06-03
• 期刊: JMIR PUBLIC HEALTH AND SURVEILLANCE
• 影响因子: 8.5
• 作者: Lundberg, Alexander L.;Lorenzo-Redondo, Ramon;Hultquist, Judd F.;Hawkins, Claudia A.;Ozer, Egon A.;Welch, Sarah B.;Prasad, P. V. Vara;Achenbach, Chad J.;White, Janine, I;Oehmke, James F.;Murphy, Robert L.;Havey, Robert J.;Post, Lori A.
• 通讯作者: Post, Lori A.

Covid-19: is omicron less lethal than delta?

• DOI: 10.1136/bmj.o1806
• 发表时间: 2022-08-02
• 期刊: BMJ-BRITISH MEDICAL JOURNAL
• 影响因子: 105.7
• 作者: Lorenzo-Redondo, Ramon;Ozer, Egon A.;Hultquist, Judd F.
• 通讯作者: Hultquist, Judd F.

Has Omicron Changed the Evolution of the Pandemic?

• DOI: 10.2196/35763
• 发表时间: 2022-01-31
• 期刊: JMIR public health and surveillance
• 影响因子: 8.5
• 作者: Lundberg AL;Lorenzo-Redondo R;Ozer EA;Hawkins CA;Hultquist JF;Welch SB;Prasad PVV;Oehmke JF;Achenbach CJ;Murphy RL;White JI;Havey RJ;Post LA
• 通讯作者: Post LA