SARS-CoV-2 Variant of Concern 202012/01 Has about Twofold Replicative Advantage and Acquires Concerning Mutations

Abstract

The novel SARS-CoV-2 Variant of Concern (VOC)-202012/01 (also known as B.1.1.7), first collected in United Kingdom on 20 September 2020, is a rapidly growing lineage that in January 2021 constituted 86% of all SARS-CoV-2 genomes sequenced in England. The VOC has been detected in 40 out of 46 countries that reported at least 50 genomes in January 2021. We have estimated that the replicative advantage of the VOC is in the range 1.83-2.18 [95% CI: 1.71-2.40] with respect to the 20A.EU1 variant that dominated in England in November 2020, and in range 1.65-1.72 [95% CI: 1.46-2.04] in Wales, Scotland, Denmark, and USA. As the VOC strain will likely spread globally towards fixation, it is important to monitor its molecular evolution. We have estimated growth rates of expanding mutations acquired by the VOC lineage to find that the L18F substitution in spike has initiated a fast growing VOC substrain. The L18F substitution is of significance because it has been found to compromise binding of neutralizing antibodies. Of concern are immune escape mutations acquired by the VOC: E484K, F490S, S494P (in the receptor binding motif of spike) and Q677H, Q675H (in the proximity of the polybasic cleavage site at the S1/S2 boundary). These mutants may hinder efficiency of existing vaccines and expand in response to the increasing after-infection or vaccine-induced seroprevalence.

Keywords: COVID-19 pandemic; SARS-CoV-2; VOC-202012/01; genome sequencing; mutation; spike L18F; spike protein.

Figure 1

Fixation of D614G strain and competition between its substrains: 20A.EU1 and the VOC in England. The proportion of D614G (orange), 20A.EU1 (cyan), VOC (magenta) and D614 strains (black) in weeks 10–53 of 2020 has been determined based on GISAID data available on 12 February 2021 (provided in Supplementary Data File S1).

Figure 2

The replicative advantage of the VOC, 20A.EU1, and the D614G strain. (A) The ratio of the VOC to 20A.EU1 sequences collected in weeks 38–51 of 2020 in England. The trend line is fitted to data points from weeks 43–51 (blue) and from weeks 43–47 (red). The weekly growth rate is 1.88 [95% CI: 1.75–2.01] for weeks 43–51 and 2.24 [95% CI: 2.03–2.48] for weeks 43–47. (B) Stabilization of fits shown in panel A with time-shifting date of the last submission. (C) The ratio of the 20A.EU1 to non-20A.EU1 non-VOC D614G genomes collected in weeks 29–51 of 2020 in England. The trend line is fitted to data points from weeks 34–45. The weekly growth rate is 1.25 [95% CI: 1.23–1.28]. (D) The ratio of the D614G to D614 genomes collected in weeks 11–27 of 2020 in England. The trend line is fitted to data points from weeks 11–24. The weekly growth rate is 1.44 [95% CI: 1.40–1.48]. Data points for selected weeks are labeled with ratios of the counts of genome sequences. Panels A, C and D are based on GISAID data submitted till 12 February 2021 (provided in Supplementary Data File S1).

Figure 3

The replicative advantage of the VOC in (A) Denmark, (B) Scotland, (C) Wales, and (D) USA. (A) The ratio of the VOC to the 20A.EU1 sequences collected in Denmark. The trend line is fitted to data points from week 50 of 2020 to week 4 of 2021. (B) The ratio of the VOC to 20A.EU1 sequences collected in Scotland. The trend line is fitted to data points from weeks 50 of 2020 to week 4 of 2021. (C) The ratio of the VOC to 20A.EU1 sequences collected in Wales. The trend line is fitted to data points from week 50 of 2020 to week 4 of 2021. (D) The ratio of the VOC to non-VOC sequences collected in USA. The trend line is fitted to data points from week 51 of 2020 to week 3 of 2021. Data points are labeled with ratios of the counts of genome sequences. The weekly growth rates and respective confidence intervals are given in each panel. All panels are based on GISAID data submitted till 17 February 2021 (provided in Supplementary Data File S1).

Figure 4

The replicative advantage of the 501Y.V2 strain in South Africa. Shown is the ratio of the 501Y.V2 to the non-501Y.V2 genomes collected in weeks 41–50 of 2020 in South Africa. The trend line is fitted to data points from weeks 43–50. The weekly growth rate is 1.58 [95% CI: 1.45–1.72]. Data points for selected weeks are labeled with ratios of the counts of genome sequences. The figure is based on GISAID data submitted till 12 February 2021 (provided in Supplementary Data File S1).

Figure 5

Mutations in spike protein in the VOC lineage in England in relation to the first VOC genome collected in September 20, 2020 (GISAID sequence accession ID: EPI_ISL_601443): (A) Dots denote genomes collected in a given date (horizontal axis) with a respective number of novel (amino acid-level) mutations in relation to the first VOC genome (vertical axis). The number of the genomes with a given number of novel mutations is provided as gray numbers next to a brace. (B) The average number of novel (amino-acid level) mutations in a VOC lineage sequence (weekly average).

Figure 6

The growth of VOC substrains with respect the whole VOC strain. The figure is based on spike protein sequences from genomes collected in England and submitted to GISAID till 12 February 2021. The growth of the whole VOC strain (red line) in the time span between t and $t_0$ = 12 February 2021 is calculated as VOC($t_0$)/VOC(t), i.e., the ratio of the number of the VOC genomes collected till 12 February 2021 and the number of VOC genomes collected till t (date given on horizontal axis). Disks denote VOC substrains defined by particular mutations (with at least 30 genomes submitted); horizontal axis value for each circle is the date of first collection of a sequence with a given mutation; vertical axis value is the number of genomes collected till 12 February 2021, conferring a given mutation. Red, orange, and green circles denote substrains with leading mutation in respectively in RBD, NTD, and signal peptide; black circles denote mutations in other domains. Selected substrains that may have replicative advantage and all substrains with the leading mutation in RBD are annotated. Detailed data that were analyzed to prepare this figure are provided in Supplementary Data File S1 (sheet ‘Mutations’).

Figure 7

The growth of the spike L18F substrain in relation to the L18 VOC strains. The ratio $v_{\mathrm{L}}$ of the number of VOC genomes conferring spike L18F mutation to the number of non-mutated (L18) VOC genomes collected in the period between week 49 of 2020 and week 3 of 2021 in England. Data aggregated into weeks indicated that $v_{\mathrm{L}}$ changes from 7:2887 = 0.0024 in week 50 of 2020 to 329:8049 = 0.041 in the second week of 2021, i.e., 16.9 times, meaning that $v_{\mathrm{L}}$ increases $16.9^{1/5}$ = 1.76-fold per week. The trend line is fitted to data points shown as filled circles. The weekly growth rate of the ratio is 1.75. The 95% CI calculated as 1.96 × standard error of the slope is [1.66–1.85]; the 95% CrI calculated assuming binomial distribution of substrain genomes is [1.59–2.07]. Data points in week 50 of 2020 and week 2 of 2021 are labeled with ratios of the counts of both types of genome sequences. The figure is based on GISAID data submitted until 12 February 2021 (provided in Supplementary Data File S1).