A team of researchers led by a group at the Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, has found evidence suggesting that the U.K. variant of the SARS-CoV-2 virus could be 43 to 90% more transmissible than the original virus.
Back in November of last year, medical researchers discovered a new variant of SARS-CoV-2 virus, which subsequently became known as the VOC 202012/01 (U.K.) variant.
The following month, researchers began reporting that they evidence suggested the U.K. variant was more transmissible than the original virus.
These fears appeared to be warranted when subsequent studies found that by the beginning of February, 95% of new infections in England were due to the U.K. variant. The variant has also, to date, been found in 82 other countries.
To learn more about the variant, the researchers sampled 150,000 virus sequences from all across the U.K. In so doing, they found evidence suggesting that the growth rate of the U.K. variant was higher than all 307 other variants they found.
The team then used the model to test certain assumptions that have been made about the variant, such as its ability to cause a higher viral load and how long it persists in infected people. The model showed the reproduction number for the variant to be 43 to 90% higher than for the original virus or other variants.
The researchers also used models to show how effective interventions might be in combating the variant. They found that in order to prevent large increases in infections, the U.K. will have to step up vaccination efforts. Without them, they predict the U.K. will see more hospitalizations and deaths in 2021 than were recorded in 2020.
In mid-December 2020, the United Kingdom reported a SARS-CoV-2 variant termed B.1.1.7 (20I/501Y.V1) that exhibited a rapid increase in its range and incidence following its initial detection in November (Andrew Rambaut, Nick Loman, Oliver Pybus, Wendy Barclay, Jeff Barrett, Alesandro Carabelli, Tom Connor, Tom Peacock, David L Robertson, Erik Volz, COVID-19 Genomics Consortium UK (CoG-UK), 2020; Volz, Mishra, et al., 2021).
Since then, additional “variants of concern” have emerged, namely lineages B.1.351 (20H/501Y.V2) from S Africa (Tegally et al., 2020) and P.1 (20J/501Y.V3) and P.2 from Brazil (Voloch et al., 2020; Faria et al., 2021; Naveca, da Costa, et al., 2021; Sabino et al., 2021).
A key concern is that certain polymorphisms may enhance SARS-CoV-2 infectivity or transmission, akin to what was seen for Spike D614G (Korber et al., 2020; Volz, Hill, et al., 2021), which has overtaken the original D614 form of the virus that dominated at the outset of the pandemic.
In areas where SARS-CoV-2 seroprevalence is high due to elevated rates of transmission during primary waves of the pandemic, selection pressures may have favored the emergence of variants that escape neutralizing antibodies. Such circumstances are thought to have contributed to the emergence of lineages B.1.351 and P.1 (501Y.V2 and 501Y.V3), which in addition to Spike N501Y, harbor at least two other non-synonymous substitutions, K417N/T and E484K, which have been found to confer escape from neutralizing antibodies (Weisblum, Schmidt, Zhang, DaSilva, Poston, J. C. C. Lorenzi, et al., 2020; Cele et al., 2021; Liu et al., 2021; Wang et al., 2021).
Despite accounting for roughly 25% of globally recorded COVID-19 cases, and approximately 20% of the available SARS-CoV-2 genome data, relatively few studies have detailed the introduction and emergence of SARS-CoV-2 lineages in the United States (Rochman et al., 2020; Worobey et al., 2020; Washington et al., 2021; Zeller et al., 2021).
Furthermore, seroprevalence surveys indicate that between 1 in 10 and 1 in 3 people in the USA have already been infected with SARS-CoV-2, potentially high enough that selection for immune evasion may be present (Angulo, Finelli and Swerdlow, 2021; Bubar et al., 2021).
Variants affecting the Spike (S) protein are of great interest due to their potential to impact transmissibility or to escape neutralizing antibodies developed in response to natural infection or vaccines. One early mutation in Spike, D614G, quickly came to dominate the pandemic (currently accounting for >98% of sequences), at least in part because it promotes an S conformation that is more competent for binding to angiotensin-converting enzyme 2 (ACE2) (Yurkovetskiy et al., 2020) and reduces shedding of the S1 subunit that contains the receptor binding domain (Zhang et al., 2020).
Missense mutations at other positions, for example S477N and N439K, have appeared multiple times in large infection clusters in Australia and Europe, and are associated with resistance to certain antibodies and/or increased affinity for ACE2 (Hodcroft et al., 2020; Liu et al., 2020; Weisblum, Schmidt, Zhang, DaSilva, Poston, J. C. Lorenzi, et al., 2020; Gaebler et al., 2021; Thomson et al., 2021).
Here, we describe evidence from two independent SARS-CoV-2 genomic surveillance programs in Louisiana and New Mexico that each detected the rise of S variants affecting position 677 in the later months of 2020.
We further provide phylogenetic analyses that identify six independent Q677H sub-lineages and one Q677P sub-lineage that all appear to have emerged within the United States.
These variants were not detected until mid-August 2020, but as of 03 Feb 2021 already account for over 2,327 of the 102,462 genomes deposited to GISAID from the USA.
Given the broad detection of the lineages across multiple states and the apparent increase in frequency of detection, these novel emergent Q677H and Q677P lineages merit further study for potential differences in transmissibility.
Discussion
Caveats
Selectively neutral mutations can become fixed in a lineage purely by chance and human behaviour. For instance, the 20E (EU1) lineage characterized by an S: A222V polymorphism emerged suddenly in Europe over the summer, but has not been found to show any evidence for increased transmissibility (Hodcroft et al., 2020) and instead is thought to have been spread via holiday travel and relaxing summertime restrictions.
Additional S variants such as N439K and S477N also rapidly increased in frequency in Europe over the summer and into the fall of 2020. Although S477N reportedly increases affinity for the entry receptor, ACE2 (Zahradník et al., 2021), and both mutations may impact antibody neutralization to some degree (Starr et al., 2020; Weisblum, Schmidt, Zhang, DaSilva, Poston, J. C. Lorenzi, et al., 2020; Liu et al., 2021; Thomson et al., 2021), neither shows any signature of increased transmissibility over the S: D614G background from which they emerged, and neither have become prominent in the United States. Therefore, SARS-CoV-2 variants can emerge and increase greatly in number over time in the absence of any clear or sustained selective advantage.
Convergent evolution is a hallmark of positive selection.
The repeated evolution of a trait in independent populations provides strong evidence of adaptation. Between August and November, 2020, seven independent lineages of SARS-CoV-2 with S:Q677H or S:Q677P mutations arose and gained in frequency. This coincidental rise and spread on independent genetic backgrounds is remarkable and suggests some fitness advantage.
Observed frequencies undoubtedly incorporate some sampling biases, which may over-estimate the relative amount of S variants affecting position 677. However, sampling bias cuts both ways. U.S. states with fewer deposited sequences may simply have missed detection of these variants.
To date, all 677H/P mutants collected from the US stem of the S:614G lineage that now predominates worldwide, but alongside varied polymorphisms in S, N, ORF1a, ORF1b, and other genes, suggesting any fitness advantage of S:677 mutations is largely independent of these other mutations (Table 1, FIG. 2–4).
Nonetheless, the relatively slow rise of lineages with S:677 substitutions suggest that any fitness benefits may be modest relative to other circulating variants, which may have also independently gained adaptive mutations. Given their relatively recent emergence, however, Q677P/H lineages may continue to rise as a percentage of total cases. Additional laboratory and genetic surveillance data are needed to define whether S: 677 polymorphisms are biologically and clinically relevant.
Although we focus here on the appearance and expansion of S: 677H/P mutants in the United States, global analyses reveal that 677H mutants have arisen multiple times elsewhere in the world as well, including large clusters of 677H mutants in Egypt and Denmark, and multiple clusters in India (Emma B. Hodcroft, 2021).
Furthermore, a newly designated, emergent PANGO lineage, B.1.525, carries S: Q677H in addition to several mutations seen in B.1.1.7 (501Y.V1), such as S: del 69–70 and S: del 144, and also, S: E484K (Rambaut et al., 2020; Áine O’Toole, 2021). Remarkably, a 19B cluster harboring the ostensibly less fit, ‘ancestral’ D614 Spike, which has been circulating at ≤2% of global frequency since August 2020, recently resurfaced as a newly re-emergent lineage carrying N501Y together with 677H (Wagner, 2021).
N501Y is therefore notably found in all three of the ‘variants of concern’ (Tegally et al., 2020; Faria et al., 2021; Lauring and Hodcroft, 2021; Naveca, Nascimento, et al., 2021; Volz, Mishra, et al., 2021). Acknowledging this observation is circumstantial, it further suggests that the 677H mutation may confer an evolutionary advantage to SARS-CoV-2.
The importance of sequencing for viral surveillance and genetic epidemiology.
Global surveillance of genomic changes in SARS-CoV-2 varies widely, with leading countries such as Australia, New Zealand, the United Kingdom, and Denmark sequencing viruses from 5–50% of all cases and lagging countries such as the United States, France, Spain, and Brazil sequencing less than 1% of all cases.
It is notable that these Q677 variants were detected in the undersampled US population, suggesting that these lineages may actually be more prevalent. The finding of lineages containing 677H mutations in better sampled countries like Denmark indicates that they repeatedly emerge but may be outcompeted by lineages with larger gains in transmission like B.1.1.7 (Davies et al., 2020).
Collectively these findings demonstrate the value of greater genomic sequencing and the importance of tracking the emergence and spread of lineages that combine multiple mutations which could enhance transmissibility or evade immunity from prior infection or vaccines.
At least two emergent lineages of concern, B.1.1.7 (501Y.V1), and a newer variant whose prevalence is on the rise in Uganda both contain amino acid substitutions affecting the first position of the polybasic cleavage site, S:P681H and S:P681R, respectively (Andrew Rambaut, Nick Loman, Oliver Pybus, Wendy Barclay, Jeff Barrett, Alesandro Carabelli, Tom Connor, Tom Peacock, David L Robertson, Erik Volz, COVID-19 Genomics Consortium UK (CoG-UK), 2020; Lule Bugembe et al., 2021). The polybasic site strongly impacts viral replication in culture and as well as pathogenesis in animal models (Hoffmann, Kleine-Weber and Pöhlmann, 2020; Johnson et al., 2021).
Although it is too early to predict whether any particular S: 677 polymorphic lineages will persist, given these observations, the recurrent parallelism affecting S: 677 suggests that this position will continue to surface in variants that show signs of increased transmissibility or fitness. It will thus be critical to not only to continue genomic surveillance of SARS-CoV-2 to monitor the prevalence of such variants over time, but also to formally define any biological characteristics of these polymorphisms in cell culture and small animal model systems.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885944/?utm_source=Chrome&utm_medium=rss&utm_campaign=pubmed-2&utm_content=1DAyVQqGr_VD4Z2pS-nDqKXS_i6lKV9V4e8Cem6Qi8G6wWusuA&fc=20200713154434&ff=20210218114605&v=2.14.2
More information: Nicholas G. Davies et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England, Science (2021). DOI: 10.1126/science.abg3055
