Monitoring the emergence and origin of SARS-CoV-2 mutations – Genetic Inter- and Intrahost SARS-CoV-2 diversity in immunocompetent and immunocompromised patients

最近出现的SARS-CoV-2变体具有潜在的增加的传播性（即，英国（UK）变体VOC 202012/01和南非变体501.V2）清楚地强调了跟踪变体的出现及其传播的重要性。VOC 20 2012/01可能在短时间内获得了异常高数量的突变，这一事实导致人们推测该变体可能在长期感染的患者中迅速进化，例如接受抗病毒治疗的免疫抑制患者。然而，在感染和传播事件中新变异演变或出现的动力学研究不足。在这项提案中，我们将通过系统和全面地调查来自当地感染集群的大量样本中的变体出现和传播性，以及评估长期（40-140天）SARS-CoV-2感染住院患者纵向样本中的宿主内基因组多样性，来解决SARS-CoV-2变体的出现和起源。除了通过汉堡艾本德大学医学中心（UKE）获得的患者样本收集外，这项工作还将利用SARS-CoV-2基因组监测平台，该平台与当地卫生当局密切合作，已经由UKE和Heinrich Pette研究所（HPI）建立。到目前为止，该平台已经从汉堡的普通人群中产生了1，400多个全长SARS-CoV-2序列，并将在2021年6月之前产生另外约4，500个序列。我们希望我们的数据将大大有助于我们目前对变异出现的理解，以及复杂变异（如VOC 202012/01和501.V2）可能造成的威胁。只有在确定了促进潜在变异演变的确切机制和患者群体之后，我们才能够减轻它们的出现和传播，例如通过卫生管理和/或优化患者治疗方案。

The recent emergence of SARS-CoV-2 variants with potentially increased transmissibility (i.e., the United Kingdom (UK) variant VOC202012/01 and the South African variant 501.V2) clearly emphasize the importance of tracking the emergence of variants and their spread. The fact that VOC202012/01 might have acquired an unusually high number of mutations within a short period of time has led to the speculation that this variant may have rapidly evolved in patients suffering from a prolonged infection, e.g. immunosuppressed patients under antiviral therapy. However, the dynamics with which novel variants evolve or emerge during infection and transmission events are understudied. In this proposal, we will address the emergence and origin of SARS-CoV-2 variants by systematic and comprehensive investigation of variant emergence and transmissibility across a substantial number of samples from local infection clusters, as well as evaluation of intra-host genomic diversity in longitudinal samples from hospitalized patients suffering from long-term (40-140 days) SARS-CoV-2 infection. In addition to patient sample collections that are available via the University Medical Center Hamburg Eppendorf (UKE), this work will take advantage of a SARS-CoV-2 genome surveillance platform that, in close collaboration with local health authorities, has already been established by UKE and the Heinrich Pette Institute (HPI). The platform has so far produced more than 1,400 full-length SARS-CoV-2 sequences from the general population in Hamburg and will produce an additional ~4,500 sequences until June 2021. We expect that our data will strongly contribute to our current understanding of variant emergence and the threats that may be posed by complex variants such as VOC202012/01 and 501.V2. Only after identification of the precise mechanisms and patient populations that promote the evolution of potential variants of concern will we be able to mitigate their emergence and spread, e.g. by means of hygiene management and/or optimized patient treatment regimen.