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Recurrent emergence and transmission of a SARS-CoV-2 Spike deletion ΔH69/V70

Our take —

This global study, available as a preprint and thus not yet peer reviewed, assessed all publicly available sequence data (as of November 26, 2020) containing a two amino acid deletion in the SARS-CoV-2 spike protein, which is involved in viral entry into human cells. Authors described the primary lineages with this variant and the existing evidence that these lineages may be more infectious, including antibody experiments and the increasing frequency of sequences with these variants being reported in parts of Europe where sequencing is common. The authors conducted in vitro infectivity assays using psuedotyped virus to further corroborate their conclusion that the deletion may increase the ability of the virus to enter human cells, but additional experiments with actual SARS-CoV-2 lineages are needed. This study provided evidence suggesting that SARS-CoV-2 lineages with the H69/V70 deletion may be important for public health because they may be more transmissible. However, additional sequencing and epidemiological analyses from around the globe are needed to determine the true frequency of B.1.1.7 and other deletion-containing variants, as well as the effect of these variants on SARS-CoV-2 transmission.

Study design

Ecological

Study population and setting

This study analyzed all publicly available SARS-CoV-2 sequence data as of November 26, 2020. After removing duplicate and low-quality sequences, a total of 194,265 SARS-CoV-2 sequences from across the globe were analyzed in this study. The aim was to better understand the H69/V70 deletion in the spike protein, including the temporal and geographical distribution of sequences containing this deletion and what other spike protein mutations are observed alongside it. Of particular note are sequences belonging to the widely discussed B.1.1.7 lineage detected in the United Kingdom (which contains this deletion, alongside a number of other spike protein mutations).

Summary of Main Findings

After examining the repeated emergence of the H69/V70 deletion in the SARS-CoV-2 genome, both independently and alongside several other spike protein variants, the authors conclude that this deletion is a fitness-enhancing change that may stabilize other spike protein changes. Specifically, they found that the H69/V70 deletion occurred in many different global lineages (first observed April 2020), suggesting several independent acquisitions. They also note that the proportion of sequences with the N439K mutation (which is in the receptor binding domain of the spike protein) greatly increased after it was observed in combination with the H69/V70 deletion, and that this deletion was also observed in combination with Y453F and other mutations (the lineage associated with mink infections that have been shown to have reduced susceptibility to sera from recovered COVID-19 patients). The authors then address the much-noted B.1.1.7 lineage, in which the H69/V70 deletion occurs alongside N501Y and several other mutations. This lineage was first detected in the UK in September 2020 and is of concern because of its notable divergence from other lineages (which could suggest its evolution in a chronically infected host or emergence in a location with limited sequencing) and association with an increasingly high number of infections. Finally, the authors infected human cell lines with a pseudotyped virus containing the SARS-CoV-2 spike protein with and without the H69/V70 deletion. In these lab experiments, they found that virus with the deletion in the spike protein was better able to enter human cells in culture than virus without the deletion.

Study Strengths

This study analyzed data published through the end of November 2020, which allows the authors to comment on distribution of SARS-CoV-2 around the globe at the time of publication. The authors provided a comprehensive summary of all published genomes with the deletion in question, and described the primary lineages it is observed in.

Limitations

Geographic distribution of published genomes is heavily biased, making it difficult to assess exactly when and where particular lineages were circulating. For example, the B.1.1.7 has only been observed in European countries with extensive sequencing capacity, and the lack of sequencing data from other parts of the world means it is impossible to determine if this lineage is circulating elsewhere. Additionally, the authors did not discuss sampling and epidemiological factors that could contribute to the observed increase in frequency of the observed mutations, i.e., if the increase in frequency of the noted lineages is due to an increase in cases or sequencing in specific regions that already have the variant. Finally, the authors performed lab experiments to test infectivity of SARS-CoV-2 with and without the H69/V70 deletion, but the experiments used only psuedotyped virus, not complete SARS-CoV-2 (due to isolates not being available at the time). They also only used the spike protein with and without the H69/V70 deletion and not any of the other mutations commonly observed alongside the deletion, which limits the conclusions that can be drawn from this experiment.

Value added

This study describes all of the primary global SARS-CoV-2 lineages that contain the H69/V70 deletion in the spike protein and discusses the possible geographic and temporal origins of each. The infectivity assays performed suggest that the H69/V70 deletion increases the ability of the virus to infect human cells in vitro.

This review was posted on: 6 January 2021