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Variants of SARS-CoV-2
Alpha (lineage B.1.1.7)
Main article: SARS-CoV-2 Alpha variant
First detected in October 2020 during the COVID-19 pandemic in the United Kingdom from a sample taken the previous month in Kent, lineage B.1.1.7, labelled Alpha variant by the WHO, was previously known as the first Variant Under Investigation in December 2020 (VUI – 202012/01) and later notated as VOC-202012/01. It is also known as 20I (V1), 20I/501Y.V1 (formerly 20B/501Y.V1), or 501Y.V1. Since then, its prevalence odds have doubled every 6.5 days, the presumed generational interval. It is correlated with a significant increase in the rate of COVID-19 infection in United Kingdom, associated partly with the N501Y mutation. There had been some evidence that this variant had 40–80% increased transmissibility (with most estimates lying around the middle to higher end of this range), and early analyses suggested an increase in lethality, though more recent work has found no evidence of increased virulence. As of May 2021, the Alpha variant has been detected in some 120 countries.
B.1.1.7 with E484K
Variant of Concern 21FEB-02 (previously written as VOC-202102/02), described by Public Health England (PHE) as "B.1.1.7 with E484K" is of the same lineage in the Pango nomenclature system, but has an additional E484K mutation. As of 17 March 2021, there are 39 confirmed cases of VOC-21FEB-02 in the UK. On 4 March 2021, scientists reported B.1.1.7 with E484K mutations in the state of Oregon. In 13 test samples analysed, one had this combination, which appeared to have arisen spontaneously and locally, rather than being imported. Other names for this variant include B.1.1.7+E484K and B.1.1.7 Lineage with S:E484K.
Beta (lineage B.1.351)
Main article: SARS-CoV-2 Beta variant
On 18 December 2020, the 501.V2 variant, also known as 501.V2, 20H (V2), 20H/501Y.V2 (formerly 20C/501Y.V2), 501Y.V2, VOC-20DEC-02 (formerly VOC-202012/02), or lineage B.1.351, was first detected in South Africa and reported by the country's health department. It has been labelled as Beta variant by WHO. Researchers and officials reported that the prevalence of the variant was higher among young people with no underlying health conditions, and by comparison with other variants it is more frequently resulting in serious illness in those cases. The South African health department also indicated that the variant may be driving the second wave of the COVID-19 epidemic in the country due to the variant spreading at a more rapid pace than other earlier variants of the virus.
Scientists noted that the variant contains several mutations that allow it to attach more easily to human cells because of the following three mutations in the receptor-binding domain (RBD) in the spike glycoprotein of the virus: N501Y, K417N, and E484K. The N501Y mutation has also been detected in the United Kingdom.
Gamma (lineage P.1)
Main article: SARS-CoV-2 Gamma variant
The Gamma variant or lineage P.1, termed Variant of Concern 21JAN-02 (formerly VOC-202101/02) by Public Health England, 20J (V3) or 20J/501Y.V3 by Nextstrain, or just 501Y.V3, was detected in Tokyo on 6 January 2021 by the National Institute of Infectious Diseases (NIID). It has been labelled as Gamma variant by WHO. The new variant was first identified in four people who arrived in Tokyo having travelled from the Brazilian Amazonas state on 2 January 2021. On 12 January 2021, the Brazil-UK CADDE Centre confirmed 13 local cases of the new Gamma variant in the Amazon rainforest. This variant of SARS-CoV-2 has been named lineage P.1 (although it is a descendant of B.1.1.28, the name B.184.108.40.206 is not permitted and thus the resultant name is P.1), and has 17 unique amino acid changes, 10 of which in its spike protein, including the three concerning mutations: N501Y, E484K and K417T.:Figure 5
The N501Y and E484K mutations favour the formation of a stable RBD-hACE2 complex, thus, enhancing the binding affinity of RBD to hACE2. However, the K417T mutation disfavours complex formation between RBD and hACE2, which has been demonstrated to reduce the binding affinity.
The new variant was absent in samples collected from March to November 2020 in Manaus, Amazonas state, but it was detected for the same city in 42% of the samples from 15–23 December 2020, followed by 52.2% during 15–31 December and 85.4% during 1–9 January 2021. A study found that infections by Gamma can produce nearly ten times more viral load compared to persons infected by one of the other lineages identified in Brazil (B.1.1.28 or B.1.195). Gamma also showed 2.2 times higher transmissibility with the same ability to infect both adults and older persons, suggesting P.1 and P.1-like lineages are more successful at infecting younger humans irrespective of sex.
A study of samples collected in Manaus between November 2020 and January 2021, indicated that the Gamma variant is 1.4–2.2 times more transmissible and was shown to be capable of evading 25–61% of inherited immunity from previous coronavirus diseases, leading to the possibility of reinfection after recovery from an earlier COVID-19 infection. As for the fatality ratio, infections by Gamma were also found to be 10–80% more lethal.
A study found that people fully vaccinated with Pfizer or Moderna have significantly decreased neutralisation effect against Gamma, although the actual impact on the course of the disease is uncertain. A pre-print study by the Oswaldo Cruz Foundation published in early April found that the real-world performance of people with the initial dose of the Sinovac's Coronavac Vaccine had approximately 50% efficacy rate. They expected the efficacy to be higher after the 2nd dose. As of July 2021, the study is ongoing.
Preliminary data from two studies indicate that the Oxford–AstraZeneca vaccine is effective against the Gamma variant, although the exact level of efficacy has not yet been released. Preliminary data from a study conducted by Instituto Butantan suggest that CoronaVac is effective against the Gamma variant as well, and as of July 2021 has yet to be expanded to obtain definitive data.
Delta (lineage B.1.617.2)
Main article: SARS-CoV-2 Delta variant
The Delta variant, also known as B.1.617.2, G/452R.V3, 21A or 21A/S:478K, was first discovered in India. Descendant of lineage B.1.617, which also includes the Kappa variant under investigation, it was first discovered in October 2020 and has since spread internationally. On 6 May 2021, British scientists declared B.1.617.2 (which notably lacks mutation at E484Q) as a "variant of concern", labelling it VOC-21APR-02, after they flagged evidence that it spreads more quickly than the original version of the virus and could spread as quickly as Alpha. It carries L452R and P681R mutations in Spike; unlike Kappa it carries T478K but not E484Q.
On 3 June 2021, Public Health England reported that twelve of the 42 deaths from the Delta variant in England were among the fully vaccinated, and that it was spreading almost twice as fast as the Alpha variant. Also on 11 June, Foothills Medical Centre in Calgary, Canada reported that half of their 22 cases of the Delta variant occurred among the fully vaccinated.
In June 2021, reports began to appear of a variant of Delta with the K417N mutation. The mutation, also present in the Beta and Gamma variants, raised concerns about the possibility of reduced effectiveness of vaccines and antibody treatments and increased risk of reinfection. The variant, called "Delta with K417N" by Public Health England, includes two clades corresponding to the Pango lineages AY.1 and AY.2. It has been nicknamed "Delta plus" from "Delta plus K417N". On 22 June, India's Ministry of Health and Family Welfare declared the "Delta plus" variant of COVID-19 a Variant of Concern after 22 cases of the variant were reported in India. After the announcement, leading virologists said there was insufficient data to support labelling the variant as a distinct variant of concern, pointing to the small number of patients studied.
Variants of interest (WHO)
Listed below are the Variants of Interest (VOI) which are, as of July 2021, recognised by the World Health Organization. Other organisations such as the CDC in the United States may at times use a slightly different list.
Eta (lineage B.1.525)
Main article: SARS-CoV-2 Eta variant
The Eta variant or lineage B.1.525, also called VUI-21FEB-03 (previously VUI-202102/03) by Public Health England (PHE) and formerly known as UK1188, 21D or 20A/S:484K, does not carry the same N501Y mutation found in Alpha, Beta and Gamma, but carries the same E484K-mutation as found in the Gamma, Zeta, and Beta variants, and also carries the same ΔH69/ΔV70 deletion (a deletion of the amino acids histidine and valine in positions 69 and 70) as found in Alpha, N439K variant (B.1.141 and B.1.258) and Y453F variant (Cluster 5). Eta differs from all other variants by having both the E484K-mutation and a new F888L mutation (a substitution of phenylalanine (F) with leucine (L) in the S2 domain of the spike protein). As of 5 March, it had been detected in 23 countries. It has also been reported in Mayotte, the overseas department/region of France. The first cases were detected in December 2020 in the UK and Nigeria, and as of 15 February, it had occurred in the highest frequency among samples in the latter country. As of 24 February 56 cases were found in the UK. Denmark, which sequences all its COVID-19 cases, found 113 cases of this variant from 14 January to 21 February, of which seven were directly related to foreign travel to Nigeria.
As of July 2021, UK experts are studying it to ascertain how much of a risk it could be. It is currently regarded as a "variant under investigation", but pending further study, it may become a "variant of concern". Ravi Gupta, from the University of Cambridge said in a BBC interview that lineage B.1.525 appeared to have "significant mutations" already seen in some of the other newer variants, which means their likely effect is to some extent more predictable.
Iota (lineage B.1.526)
Main article: SARS-CoV-2 Iota variant
In November 2020, a mutant variant was discovered in New York City, which was named lineage B.1.526. As of 11 April 2021, the variant has been detected in at least 48 U.S. states and 18 countries. In a pattern mirroring Epsilon, Iota was initially able to reach relatively high levels in some states, but by May 2021 it was outcompeted by the more transmissible Delta and Alpha.
Kappa (lineage B.1.617.1)
Main article: SARS-CoV-2 Kappa variant
The Kappa variant is one of the three sublineages of lineage B.1.617. It is also known as lineage B.1.617.1, 21B or 21A/S:154K, and was first detected in India in December 2020. By the end of March 2021, Kappa accounted for more than half of the sequences being submitted from India. On 1 April 2021, it was designated a variant under investigation (VUI-21APR-01) by Public Health England. It has the notable mutations L452R, E484Q, P681R.
Lambda (lineage C.37)
Main article: SARS-CoV-2 Lambda variant
The Lambda variant, also known as lineage C.37, was first detected in Peru in August 2020 and was designated by the WHO as a variant of interest on 14 June 2021. It spread to at least 30 countries around the world and, as of July 2021, it is unknown whether it is more infectious and resistant to vaccines than other strains.
Former variants of interest
Epsilon (lineages B.1.429, B.1.427, CAL.20C)
Main article: SARS-CoV-2 Epsilon variant
The Epsilon variant or lineage B.1.429, also known as CAL.20C or CA VUI1, 21C or 20C/S:452R, is defined by five distinct mutations (I4205V and D1183Y in the ORF1ab-gene, and S13I, W152C, L452R in the spike protein's S-gene), of which the L452R (previously also detected in other unrelated lineages) was of particular concern. From March 17 to June 29, 2021, the CDC listed B.1.429 and the related B.1.427 as "variants of concern". As of July 2021, Epsilon is no longer considered a variant of interest by the WHO, as it was overtaken by Alpha.
From September 2020 to January 2021, it was 19% to 24% more transmissible than earlier variants in California. Neutralisation against it by antibodies from natural infections and vaccinations was moderately reduced, but it remained detectable in most diagnostic tests.
Epsilon (CAL.20C) was first observed in July 2020 by researchers at the Cedars-Sinai Medical Center, California, in one of 1,230 virus samples collected in Los Angeles County since the start of the COVID-19 epidemic. It was not detected again until September when it reappeared among samples in California, but numbers remained very low until November. In November 2020, the Epsilon variant accounted for 36 per cent of samples collected at Cedars-Sinai Medical Center, and by January 2021, the Epsilon variant accounted for 50 per cent of samples. In a joint press release by University of California, San Francisco, California Department of Public Health, and Santa Clara County Public Health Department, the variant was also detected in multiple counties in Northern California. From November to December 2020, the frequency of the variant in sequenced cases from Northern California rose from 3% to 25%. In a preprint, CAL.20C is described as belonging to clade 20C and contributing approximately 36% of samples, while an emerging variant from the 20G clade accounts for some 24% of the samples in a study focused on Southern California. Note, however, that in the US as a whole, the 20G clade predominates, as of January 2021. Following the increasing numbers of Epsilon in California, the variant has been detected at varying frequencies in most US states. Small numbers have been detected in other countries in North America, and in Europe, Asia and Australia. After an initial increase, its frequency rapidly dropped from February 2021 as it was being outcompeted by the more transmissible Alpha. In April, Epsilon remained relatively frequent in parts of northern California, but it had virtually disappeared from the south of the state and had never been able to establish a foothold elsewhere; only 3.2% of all cases in the United States were Epsilon, whereas more than two-thirds were Alpha.
Zeta (lineage P.2)
Main article: SARS-CoV-2 Zeta variant
Zeta variant or lineage P.2, a sub-lineage of B.1.1.28 like Gamma (P.1), was first detected in circulation in the state of Rio de Janeiro; it harbours the E484K mutation, but not the N501Y and K417T mutations. It evolved independently in Rio de Janeiro without being directly related to the Gamma variant from Manaus. Though previously Zeta was labeled a variant of interest, as of July 2021, it is no longer considered as such by the WHO.
Theta (lineage P.3)
Main article: SARS-CoV-2 Theta variant
On 18 February 2021, the Department of Health of the Philippines confirmed the detection of two mutations of COVID-19 in Central Visayas after samples from patients were sent to undergo genome sequencing. The mutations were later named as E484K and N501Y, which were detected in 37 out of 50 samples, with both mutations co-occurrent in 29 out of these.
On 13 March, the Department of Health confirmed the mutations constitutes a variant which was designated as lineage P.3. On the same day, it also confirmed the first COVID-19 case caused by the Gamma variant in the country. The Philippines had 98 cases of the Theta variant on 13 March. On 12 March it was announced that Theta had also been detected in Japan. On 17 March, the United Kingdom confirmed its first two cases, where PHE termed it VUI-21MAR-02. On 30 April 2021, Malaysia detected 8 cases of the Theta variant in Sarawak.
As of July 2021, Theta is no longer considered a variant of interest by the WHO.
Other notable variants
R.1 is designated as a variant of interest by the National Institute of Infectious Diseases in Japan. It has the E484K mutation on the receptor binding domain and the W152L mutation on the N Terminal Domain, both of which may have implications for immune escape. It has been found in 30 countries with 7,057 cases in Japan, and 1,249 cases in the United States. A small study in the U.S. found that the Pfizer-Biontech vaccine was 94% effective against hospitalisation and death from R.1 during an outbreak. In Japan, cases of R.1 continue to appear.
Lineage B.1.1.207 was first sequenced in August 2020 in Nigeria; the implications for transmission and virulence are unclear but it has been listed as an emerging variant by the US Centers for Disease Control. Sequenced by the African Centre of Excellence for Genomics of Infectious Diseases in Nigeria, this variant has a P681H mutation, shared in common with the Alpha variant. It shares no other mutations with the Alpha variant and as of late December 2020 this variant accounts for around 1% of viral genomes sequenced in Nigeria, though this may rise. As of May 2021, lineage B.1.1.207 has been detected in 10 countries.
In March 2021, Linage B.1.620 was discovered in Lithuania. It was named lineage B.1.620, also known as the 'Lithuanian strain'. It is found in Central Africa as well as North America. Apart from Lithuania, other European countries including France and Belgium have also found presence of this variant. This lineage has 23 mutations and deletions compared to the reference strain, some of which are unique mutations. The lineage contains an E484K mutation. D614G, a mutation present in most circulating strain, is also found in this variant. Other notable mutations include P681H and S477N.
Lineage B.1.618 was first isolated in October 2020. It has the E484K mutation in common with several other variants, and showed significant spread in April 2021 in West Bengal, India. As of 23 April 2021, the PANGOLIN database showed 135 sequences detected in India, with single-figure numbers in each of eight other countries worldwide.
Lineage B.1.1.318 was designated by PHE as a VUI (VUI-21FEB-04, previously VUI-202102/04) on 24 February 2021. 16 cases of it have been detected in the UK. 155 cases were detected in the province of Ontario, Canada between May 30 and June 26, 2021.
Lineage B.1.1.317, while not considered a variant of concern, is noteworthy in that Queensland Health forced 2 people undertaking hotel quarantine in Brisbane, Australia to undergo an additional 5 days' quarantine on top of the mandatory 14 days after it was confirmed they were infected with this variant.
Lineage B.1.621, a new coronavirus variant which was first discovered in Colombia, is also under investigation as of late July 2021. This lineage contains the E484K mutation. It is listed by ECDC as a variant of interest.
Notable missense mutations
There have been a number of missense mutations observed of SARS-CoV-2.
The name of the mutation, N440K, refers to an exchange whereby the asparagine (N) is replaced by lysine (K) at position 440.
This mutation has been observed in cell cultures to be 10 times more infective compared to the previously widespread A2a strain (A97V substitution in RdRP sequence) and 1000 times more in the lesser widespread A3i strain (D614G substitution in Spike and a and P323L substitution in RdRP). It is involved in current rapid surges of Covid cases in India. India has the largest proportion of N440K mutated variants followed by the US and Germany.
The name of the mutation, L452R, refers to an exchange whereby the leucine (L) is replaced by arginine (R) at position 452.
L452R is found in both the Delta and Kappa variants which first circulated in India, but have since spread around the world. L452R is a relevant mutation in this strain that enhances ACE2 receptor binding ability and can reduce vaccine-stimulated antibodies from attaching to this altered spike protein.
L452R, some studies show, could even make the coronavirus resistant to T cells, that are class of cells necessary to target and destroy virus-infected cells. They are different from antibodies that are useful in blocking coronavirus particles and preventing it from proliferating.
A highly flexible region in the receptor binding domain (RBD) of SARS-CoV-2, starting from residue 475 and continuing up to residue 485, was identified using bioinformatics and statistical methods in several studies. The University of Graz and the Biotech Company Innophore have shown in a recent publication that structurally, the position S477 shows the highest flexibility among them.
At the same time, S477 is hitherto the most frequently exchanged amino acid residue in the RBDs of SARS-CoV-2 mutants. By using molecular dynamics simulations of RBD during the binding process to hACE2, it has been shown that both S477G and S477N strengthen the binding of the SARS-COV-2 spike with the hACE2 receptor. The vaccine developer BioNTech referenced this amino acid exchange as relevant regarding future vaccine design in a preprint published in February 2021.
The name of the mutation, E484Q, refers to an exchange whereby the glutamic acid (E) is replaced by glutamine (Q) at position 484.
The Kappa variant circulating in India has E484Q. These variants were initially (but misleadingly) referred to as a "double mutant". E484Q may enhance ACE2 receptor binding ability, and may reduce vaccine-stimulated antibodies' ability to attach to this altered spike protein.
The name of the mutation, E484K, refers to an exchange whereby the glutamic acid (E) is replaced by lysine (K) at position 484. It is nicknamed "Eeek".
E484K has been reported to be an escape mutation (i.e., a mutation that improves a virus's ability to evade the host's immune system) from at least one form of monoclonal antibody against SARS-CoV-2, indicating there may be a "possible change in antigenicity". The Gamma variant (lineage P.1), the Zeta variant (lineage P.2, also known as lineage B.220.127.116.11) and the Beta variant (501.V2) exhibit this mutation. A limited number of lineage B.1.1.7 genomes with E484K mutation have also been detected. Monoclonal and serum-derived antibodies are reported to be from 10 to 60 times less effective in neutralising virus bearing the E484K mutation. On 2 February 2021, medical scientists in the United Kingdom reported the detection of E484K in 11 samples (out of 214,000 samples), a mutation that may compromise current vaccine effectiveness.
N501Y denotes a change from asparagine (N) to tyrosine (Y) in amino-acid position 501. N501Y has been nicknamed "Nelly".
This change is believed by PHE to increase binding affinity because of its position inside the spike glycoprotein's receptor-binding domain, which binds ACE2 in human cells; data also support the hypothesis of increased binding affinity from this change. Molecular interaction modelling and the free energy of binding calculations has demonstrated that the mutation N501Y has the highest binding affinity in variants of concern RBD to hACE2. Variants with N501Y include Gamma, Alpha (VOC 20DEC-01), Beta, and COH.20G/501Y (identified in Columbus, Ohio). This last became the dominant form of the virus in Columbus in late December 2020 and January and appears to have evolved independently of other variants.
Prevalence of mutation D614G across all reported GISAID strains during the course of 2020. Convergence with unity closely matches the upper limb of the logistics curve.
D614G is a missense mutation that affects the spike protein of SARS-CoV-2. From early appearances in Eastern China, the frequency of this mutation in the global viral population has increased during the pandemic. G (glycine) has replaced D (aspartic acid) at position 614 in many countries, especially in Europe though more slowly in China and the rest of East Asia, supporting the hypothesis that G increases the transmission rate, which is consistent with higher viral titres and infectivity in vitro. Researchers with the PANGOLIN tool nicknamed this mutation "Doug".
In July 2020, it was reported that the more infectious D614G SARS-CoV-2 variant had become the dominant form in the pandemic. PHE confirmed that the D614G mutation had a "moderate effect on transmissibility" and was being tracked internationally.
The global prevalence of D614G correlates with the prevalence of loss of smell (anosmia) as a symptom of COVID-19, possibly mediated by higher binding of the RBD to the ACE2 receptor or higher protein stability and hence higher infectivity of the olfactory epithelium.
Variants containing the D614G mutation are found in the G clade by GISAID and the B.1 clade by the PANGOLIN tool.
Logarithmic Prevalence of P681H in 2020 according to sequences in the GISAID database
The name of the mutation, P681H, refers to an exchange whereby the proline (P) is replaced by histidine (H) at position 681.
In January 2021, scientists reported in a preprint that the mutation P681H, a characteristic feature of the Alpha variant and lineage B.1.1.207 (identified in Nigeria), is showing a significant exponential increase in worldwide frequency, thus following a trend to be expected in the lower limb of the logistics curve. This may be compared with the trend of the now globally prevalent D614G.
The name of the mutation, P681R, refers to an exchange whereby the proline (P) is replaced by arginine (R) at position 681.
Indian SARS-CoV-2 Genomics Consortium (INSACOG) found that other than the two mutations E484Q and L452R, there is also a third significant mutation, P681R in lineage B.1.617. All three concerning mutations are on the spike protein, the operative part of the coronavirus that binds to receptor cells of the body.
According to initial media reports, the Malaysian Ministry of Health announced on 23 December 2020 that it had discovered a mutation in the SARS-CoV-2 genome which they designated as A701B(sic), among 60 samples collected from the Benteng Lahad Datu cluster in Sabah. The mutation was characterised as being similar to the one found recently at that time in South Africa, Australia, and the Netherlands, although it was uncertain if this mutation was more infectious or aggressive[clarification needed] than before. The provincial government of Sulu in neighbouring Philippines temporarily suspended travel to Sabah in response to the discovery of 'A701B' due to uncertainty over the nature of the mutation.
On 25 December 2020, the Malaysian Ministry of Health described a mutation A701V as circulating and present in 85% of cases (D614G was present in 100% of cases) in Malaysia. These reports also referred to samples collected from the Benteng Lahad Datu cluster. The text of the announcement was mirrored verbatim on the Facebook page of Noor Hisham Abdullah, Malay Director-General of Health, who was quoted in some of the news articles.
The A701V mutation has the amino acid alanine (A) substituted by valine (V) at position 701 in the spike protein. Globally, South Africa, Australia, Netherlands and England also reported A701V at about the same time as Malaysia. In GISAID, the prevalence of this mutation is found to be about 0.18%. of cases.
On 14 April 2021, the Malaysian Ministry of Health reported that the third wave, which had started in Sabah, has involved the introduction of variants with D614G and A701V mutations.
(Variants of SARS-CoV-2, Wikipedia)