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

最近出现的具有潜在增加传播性的SARS-CoV-2变种(即英国变种VOC202012/01和南非变种501.V2)清楚地强调了跟踪变种出现及其传播的重要性。VOC202012/01可能在短时间内获得了异常多的突变，这一事实导致了人们的猜测，即该变异可能在长期感染的患者中迅速演变，例如接受抗病毒治疗的免疫抑制患者。然而，新变种在感染和传播事件中进化或出现的动力学研究不足。在这项建议中，我们将通过系统和全面地调查大量来自局部感染集群的样本的变异出现和传播性，以及评估长期(40-140天)SARS-CoV-2住院患者的纵向样本的宿主内基因组多样性，来解决SARS-CoV-2变异的出现和起源问题。除了通过汉堡大学医学中心(UKE)提供的患者样本采集外，这项工作还将利用英国汉堡医学中心和海因里希·皮特研究所(HPI)与当地卫生当局密切合作建立的SARS-CoV-2基因组监测平台。到目前为止，该平台已经从汉堡的普通人群中产生了1400多个SARS-CoV-2全长序列，并将在2021年6月之前再产生约4500个序列。我们预计，我们的数据将有力地有助于我们目前对变异的出现以及VOC202012/01和501.V2等复杂变异可能构成的威胁的理解。只有在确定了促进潜在关注变种演变的确切机制和患者群体之后，我们才能减少它们的出现和传播，例如通过卫生管理和/或优化的患者治疗方案。

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.