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Abstract
To the Editor: As scientists, policymakers, and public health officials monitor newly
emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
data regarding the spread of previously identified variants are important in understanding
the mechanisms through which such strains become dominant. Soon after the first case
of infection with the B.1.1.7 (alpha) variant was identified in the United Kingdom
in September 2020, researchers determined that the new variant had several genetic
alterations: a N501Y mutation, which increased the viral binding affinity with angiotensin-converting–enzyme
2 receptor
1
; a H69del/V70del mutation, which was potentially associated with immune evasion and
affected S-gene polymerase-chain-reaction (PCR) assays, resulting in S-gene target
failure; and a P681H mutation, which potentially facilitated epithelial-cell entry.
2
Direct estimates of the potential of a variant for expansion and increased transmission
are limited but have important implications for the global dissemination of these
and future SARS-CoV-2 variants.
To investigate the expansion of the alpha variant in the United Kingdom, we performed
a study using the national Covid-19 Infection Survey, a representative, longitudinal
household sample.
3
Ethics approval for the study was provided by the ethics committee of South Central
Berkshire B.
We analyzed questionnaire data and PCR test results from nose and throat swabs obtained
during the period from September 28, 2020, to January 10, 2021. We used S-gene target
failure as a proxy to identify the alpha variant. (Details regarding the analysis
methods are provided in the Supplementary Appendix, available with the full text of
this letter at NEJM.org.)
A total of 381,773 participants from 189,766 households had a median of 4 results
from nose or throat swabs (interquartile range, 3 to 6; simple range, 1 to 12) (Table
S1 in the Supplementary Appendix). Of 1,690,793 samples, 17,963 (obtained from 14,195
participants from 10,506 households) were positive for SARS-CoV-2 (positivity, 1.06%;
95% confidence interval [CI], 1.05 to 1.08). Of the positive results, 9032 (50.3%)
were triple-gene positive (i.e., indicating detection of all three regions of the
SARS-CoV-2 genome tested: the ORF1ab region, the N [nucleocapsid] gene, and the S
[spike protein] gene), 5258 (29.3%) had S-gene target failure (i.e., were alpha compatible),
and 3673 (20.4%) had other combinations of genes detected. Starting in late November
2020, the samples with S-gene target failure made up an increasing percentage of positive
results in most areas (Fig. S1). The most striking increase in positivity was from
15% to 76% during a 2-month period in London. Corresponding decreases in the cycle
threshold (Ct) from approximately 30 to 20 (with lower values indicating higher viral
loads) among samples with S-gene target failure at least partially reflected the expansion
of the alpha variant in the population. Using finite mixture modeling, we determined
that the infection subgroup with the highest viral load had a mean Ct of 16.1 (95%
CI, 15.1 to 17.1) among samples with S-gene target failure, as compared with a value
of 17.4 (95% CI, 16.9 to 18.0) among samples that were triple-gene positive (Fig.
S2).
Population-level infection rates were consistent with both the expansion and increased
transmissibility of the alpha variant, including during periods of national lockdown,
when triple-gene–positive rates were either stable or decreasing. The timing of increases
in infections with S-gene target failure varied greatly across geographic areas (Figure
1 and Figs. S1 and S3), but the growth rate for S-gene target failure generally exceeded
the corresponding rate for triple-gene–positive infections (relative difference, 6%;
95% CI, 4 to 7) (Fig. S4), which suggests addition and replacement. At the population
level, growth rates for infections with S-gene target failure accelerated as their
prevalence increased, with initial marked increases occurring at a median positivity
rate of 0.21% (simple range, 0.12 to 0.31) (Fig. S5). One explanation for why increases
in rates generally became marked after the 0.21% positivity was exceeded could be
heterogeneity in dispersion and super-spreading events, particularly involving asymptomatic
persons with a high viral load,
4
plus chance variation. Although infections with S-gene target failure replaced triple-gene–positive
infections faster for symptomatic infections (Table S2), absolute increases in positivity
were relatively similar regardless of whether persons reported having symptoms (Fig.
S6), which suggests that asymptomatic infections may have contributed substantially
to the spread of the alpha variant. The growth rate for S-gene target failure was
higher than that for triple-gene–positive infections by 5% (95% CI, 2 to 9) in children
through high school age, as compared with 6% (95% CI, 4 to 7) in older persons, which
suggests that children were not disproportionately affected (Fig. S7).
A limitation of our study is that not all the infections with S-gene target failure
will have been caused by the alpha variant. However, our use of this proxy is supported
by whole-genome sequencing (see the Supplementary Appendix). In addition, misclassification
between the alpha variant and S-gene target failure would generally mean that our
findings underestimate the true growth rates. Our analyses included geographic areas
that had varying social restrictions during the study period. However, mathematical
models that included only changes in behavior or contact patterns had a poor fit with
the observed data, which supports the increased transmissibility of the alpha variant
as the driving force behind the increased rates of infection.
5
Our direct population-level analysis confirmed that the SARS-CoV-2 alpha variant was
associated with a higher infection rate than other variants that were circulating
in the United Kingdom during the study period. Careful monitoring for the emergence
of such variants with enhanced transmissibility is needed.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the capacity to generate variants with major genomic changes. The UK variant B.1.1.7 (also known as VOC 202012/01) has many mutations that alter virus attachment and entry into human cells. Using a variety of statistical and dynamic modeling approaches, Davies et al. characterized the spread of the B.1.1.7 variant in the United Kingdom. The authors found that the variant is 43 to 90% more transmissible than the predecessor lineage but saw no clear evidence for a change in disease severity, although enhanced transmission will lead to higher incidence and more hospital admissions. Large resurgences of the virus are likely to occur after the easing of control measures, and it may be necessary to greatly accelerate vaccine roll-out to control the epidemic. Science , this issue p. eabg3055 The major coronavirus variant that emerged at the end of 2020 in the UK is more transmissible than its predecessors and could spark resurgences. INTRODUCTION Several novel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, emerged in late 2020. One of these, Variant of Concern (VOC) 202012/01 (lineage B.1.1.7), was first detected in southeast England in September 2020 and spread to become the dominant lineage in the United Kingdom in just a few months. B.1.1.7 has since spread to at least 114 countries worldwide. RATIONALE The rapid spread of VOC 202012/01 suggests that it transmits more efficiently from person to person than preexisting variants of SARS-CoV-2. This could lead to global surges in COVID-19 hospitalizations and deaths, so there is an urgent need to estimate how much more quickly VOC 202012/01 spreads, whether it is associated with greater or lesser severity of disease, and what control measures might be effective in mitigating its impact. We used social contact and mobility data, as well as demographic indicators linked to SARS-CoV-2 community testing data in England, to assess whether the spread of the new variant may be an artifact of higher baseline transmission rates in certain geographical areas or among specific demographic subpopulations. We then used a series of complementary statistical analyses and mathematical models to estimate the transmissibility of VOC 202012/01 across multiple datasets from the UK, Denmark, Switzerland, and the United States. Finally, we extended a mathematical model that has been extensively used to forecast COVID-19 dynamics in the UK to consider two competing SARS-CoV-2 lineages: VOC 202012/01 and preexisting variants. By fitting this model to a variety of data sources on infections, hospitalizations, and deaths across seven regions of England, we assessed different hypotheses for why the new variant appears to be spreading more quickly, estimated the severity of disease associated with the new variant, and evaluated control measures including vaccination and nonpharmaceutical interventions. Combining multiple lines of evidence allowed us to draw robust inferences. RESULTS The rapid spread of VOC 202012/01 is not an artifact of geographical differences in contact behavior and does not substantially differ by age, sex, or socioeconomic stratum. We estimate that the new variant has a 43 to 90% higher reproduction number (range of 95% credible intervals, 38 to 130%) than preexisting variants. Similar increases are observed in Denmark, Switzerland, and the United States. The most parsimonious explanation for this increase in the reproduction number is that people infected with VOC 202012/01 are more infectious than people infected with a preexisting variant, although there is also reasonable support for a longer infectious period and multiple mechanisms may be operating. Our estimates of severity are uncertain and are consistent with anything from a moderate decrease to a moderate increase in severity (e.g., 32% lower to 20% higher odds of death given infection). Nonetheless, our mathematical model, fitted to data up to 24 December 2020, predicted a large surge in COVID-19 cases and deaths in 2021, which has been borne out so far by the observed burden in England up to the end of March 2021. In the absence of stringent nonpharmaceutical interventions and an accelerated vaccine rollout, COVID-19 deaths in the first 6 months of 2021 were projected to exceed those in 2020 in England. CONCLUSION More than 98% of positive SARS-CoV-2 infections in England are now due to VOC 202012/01, and the spread of this new variant has led to a surge in COVID-19 cases and deaths. Other countries should prepare for potentially similar outcomes. Impact of SARS-CoV-2 Variant of Concern 202012/01. ( A ) Spread of VOC 202012/01 (lineage B.1.1.7) in England. ( B ) The estimated relative transmissibility of VOC 202012/01 (mean and 95% confidence interval) is similar across the United Kingdom as a whole, England, Denmark, Switzerland, and the United States. ( C ) Projected COVID-19 deaths (median and 95% confidence interval) in England, 15 December 2020 to 30 June 2021. Vaccine rollout and control measures help to mitigate the burden of VOC 202012/01. A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in September 2020 and is rapidly spreading toward fixation. Using a variety of statistical and dynamic modeling approaches, we estimate that this variant has a 43 to 90% (range of 95% credible intervals, 38 to 130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine rollout, COVID-19 hospitalizations and deaths across England in the first 6 months of 2021 were projected to exceed those in 2020. VOC 202012/01 has spread globally and exhibits a similar transmission increase (59 to 74%) in Denmark, Switzerland, and the United States.
Summary The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. Here we experimentally measure how all amino-acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD’s surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.
Summary The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine residues (multibasic) not found in closely related animal coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection is unknown. Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell, but not virus-cell, fusion, suggesting that the corresponding viral variants might exhibit increased cell-cell spread and potentially altered virulence. Our results suggest that acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of humans and identify furin as a potential target for therapeutic intervention.
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Funding
Funded by:
Department of Health and Social Care, FundRef http://dx.doi.org/10.13039/501100000276;
Funded by:
National Institutes of Health Research, FundRef http://dx.doi.org/10.13039/501100000272;
Award ID: NIHR200915
Award ID: Oxford Biomedical Research Centre
Funded by:
Huo Family Foundation, FundRef ;
Funded by:
Medical Research Council UK, FundRef http://dx.doi.org/10.13039/501100000265;
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