Extensive global sampling and whole genome sequencing of the pandemic virus SARS-CoV-2 have enabled researchers to characterise its spread, and to identify mutations that may increase transmission or enable the virus to escape therapies or vaccines. Two important components of viral spread are how frequently variants arise within individuals, and how likely they are to be transmitted. Here, we characterise the within-host diversity of SARS-CoV-2, and the extent to which genetic diversity is transmitted, by quantifying variant frequencies in 1390 clinical samples from the UK, many from individuals in known epidemiological clusters. We show that SARS-CoV-2 infections are characterised by low levels of within-host diversity across the entire viral genome, with evidence of strong evolutionary constraint in Spike, a key target of vaccines and antibody-based therapies. Although within-host variants can be observed in multiple individuals in the same phylogenetic or epidemiological cluster, highly infectious individuals with high viral load carry only a limited repertoire of viral diversity. Most viral variants are either lost, or occasionally fixed, at the point of transmission, consistent with a narrow transmission bottleneck. These results suggest potential vaccine-escape mutations are likely to be rare in infectious individuals. Nonetheless, we identified Spike variants present in multiple individuals that may affect receptor binding or neutralisation by antibodies. Since the fitness advantage of escape mutations in highly-vaccinated populations is likely to be substantial, resulting in rapid spread if and when they do emerge, these findings underline the need for continued vigilance and monitoring.

中文翻译：

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SARS-CoV-2的宿主内基因组学

大流行性病毒SARS-CoV-2的广泛全球采样和全基因组测序已使研究人员能够表征其传播，并鉴定可能增加传播或使病毒逃脱疗法或疫苗的突变。病毒传播的两个重要组成部分是变异在个体中的出现频率以及传播的可能性。在这里，我们通过量化英国1390个临床样本（许多来自已知流行病学集群中的个体）中的变异频率，来表征SARS-CoV-2的宿主内部多样性以及遗传多样性的传播程度。我们证明了SARS-CoV-2感染的特征在于整个病毒基因组中宿主内部多样性的水平较低，并证明了Spike中强大的进化限制，疫苗和基于抗体的疗法的主要目标。尽管可以在同一系统发育或流行病学集群中的多个个体中观察到宿主内部变异，但具有高病毒载量的高感染性个体仅携带有限的病毒多样性。与狭窄的传播瓶颈相一致，大多数病毒变体在传播点丢失或偶尔固定。这些结果表明，潜在的疫苗逃逸突变可能在传染性个体中很少见。尽管如此，我们还是发现了多个个体中存在的Spike变异体，这些变异体可能会影响抗体的受体结合或中和作用。由于在高度接种疫苗的人群中逃避突变的适应性优势可能非常明显，因此一旦出现就迅速扩散，