Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has many variants; some are or have been believed to be of particular importance. This article discusses such notable variants of SARS-CoV-2, and also discusses notable missense mutations found in some, or all, of these variants.

The sequence WIV04/2019, belonging to the GISAID S clade / PANGO A lineage / Nextstrain 19B clade, is thought likely to most closely reflect the sequence of the original virus infecting humans known as 'sequence zero', and is widely referred to as such and used as a reference sequence.^[1]

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Overview table

First detection		PANGO Lineages nomenclature system	Other names	Notable mutations	Evidence of clinical changes[note 1]			Spread	Ref.
Location	Date				Transmissibility	Virulence	Antigenicity
Nigeria	Aug 2020	B.1.1.207	P681H	—	—	—	Localized	[2]
United Kingdom	Sep 2020	B.1.1.7	VOC-202012/01, 20I/501Y.V1	N501Y, 69–70del, P681H	Increased ~50% (NERVTAG)	Potentially 30% more lethal (NERVTAG)	Indications of ostensible reduced antigenic activity (ECDC)	Global	[2][3][4][5]
Denmark	Oct 2020	—	Cluster 5, ΔFVI-spike (SSI)	Y453F, 69–70deltaHV	—	—	Moderately decreased sensitivity to neutralising antibodies (WHO)	Likely extinct	[6][7][8]
South Africa	Dec 2020	B.1.351	501.V2, 20H/501Y.V2, VOC-202012/02	N501Y, K417N, E484K	Increased 50% (ECDC)	—	21% reduction in antigenicity, but effective neutralisation (ECDC)	Global	[2][9][10][3][11][12][13]
Japan Brazil	Jan 2021	P.1	Descendant of B.1.1.28, VOC-202101/02	N501Y, E484K, K417T	Likely increased (CDC)	—	Overall reduction in effective neutralisation (ECDC)	Global	[10][14][15][16][13][3]
United Kingdom Nigeria	Dec 2020	B.1.525	VUI-202102/03 (PHE), formerly UK1188	E484K, F888L	—	—	'Modestly' reduced neutralisation (COG-UK)	International	[17][18][19]

Notes

1. ^'—' denotes that no reliable sources could be found to cite.

Nomenclature

SARS-CoV-2 corresponding nomenclatures^[20]

PANGO lineages (cf. Nomenclature proposal, Nature)	Notes to PANGO lineages (cf. Alm et al.)	Nextstrain clades, 2021[21]	GISAID clades	Notable variants
A.1–A.6	19B	S	contains 'reference sequence' WIV04/2019[1]
B.3–B.7, B.9, B.10, B.13–B.16	19A	L
		O[a]
B.2		V
B.1	B.1.5–B.1.72	20A	G	Lineage B.1 in the PANGO Lineages nomenclature system
	B.1.9, B.1.13, B.1.22, B.1.26, B.1.37		GH
	B.1.3–B.1.66	20C		Includes CAL.20C[22]
		20G		Predominant in US generally, Jan '21[22]
		20H		Includes B.1.351 aka 20H/501Y.V2 or 501.V2 lineage
	B.1.1	20B	GR	Includes B.1.1.207
		20D		Includes P.1 and P.2[23]
		20F
		20I		Includes lineage B.1.1.7 aka VOC-202012/01 or 20I/501Y.V1
	B.1.177	20E (EU1)[21]	GV[a]	Derived from 20A[21]

No consistent nomenclature has been established for SARS-CoV-2.^[25] Colloquially, including by governments and news organizations, concerning variants are often referred to by the country in which they were first identified,^[26][27][28] but as of January 2021^[update], the World Health Organization (WHO) is working on 'standard nomenclature for SARS-CoV-2 variants that does not reference a geographical location'.^[29]

While there are many thousands of variants of SARS-CoV-2,^[30] subtypes of the virus can be put into larger groupings such as lineages or clades.^[b] Three main, generally used nomenclatures^[25] have been proposed:

• As of January 2021^[update], GISAID—referring to SARS-CoV-2 as hCoV-19^[31]—had identified eight global clades (S, O, L, V, G, GH, GR, and GV).^[32]
• In 2017, Hadfield et al. announced Nextstrain, intended 'for real-time tracking of pathogen evolution'.^[33] Nextstrain has later been used for tracking SARS-CoV-2, identifying 11 major clades^[c] (19A, 19B, and 20A–20I) as of January 2021^[update].^[34]
• In 2020, Rambaut et al. of the Phylogenetic Assignment of Named Global Outbreak Lineages (PANGOLIN)^[35] software team proposed in an article^[36] 'a dynamic nomenclature for SARS-CoV-2 lineages that focuses on actively circulating virus lineages and those that spread to new locations';^[25] as of February 2021^[update], six major lineages (A, B, B.1, B.1.1, B.1.177, B.1.1.7) had been identified.^[37][38]

Criteria for notability

Viruses generally acquire mutations over time, giving rise to new variants. When a new variant appears to be growing in a population, it can be labeled as an 'emerging variant'.

Some of the potential consequences of emerging variants are the following:^[2][39]

• Increased transmissibility
• Increased morbidity
• Increased mortality
• Ability to evade detection by diagnostic tests
• Decreased susceptibility to antiviral drugs (if and when such drugs are available)
• Decreased susceptibility to neutralizing antibodies, either therapeutic (e.g., convalescent plasma or monoclonal antibodies) or in laboratory experiments
• Ability to evade natural immunity (e.g., causing reinfections)
• Ability to infect vaccinated individuals
• Increased risk of particular conditions such as multisystem inflammatory syndrome or long-haul COVID.
• Increased affinity for particular demographic or clinical groups, such as children or immunocompromised individuals.

Variants that appear to meet one or more of these criteria may be labeled 'variants under investigation' or 'variants of interest' pending verification and validation of these properties. Once validated, a 'variant under investigation/ of interest' may be renamed a 'variant of concern' by monitoring organizations, such as the CDC.^[40][41]

Notable variants

Cluster 5

In early November 2020, Cluster 5, also referred to as ΔFVI-spike by the Danish State Serum Institute (SSI),^[6] was discovered in Northern Jutland, Denmark, and is believed to have been spread from minks to humans via mink farms. On 4 November 2020, it was announced that the mink population in Denmark would be culled to prevent the possible spread of this mutation and reduce the risk of new mutations happening. A lockdown and travel restrictions were introduced in seven municipalities of Northern Jutland to prevent the mutation from spreading, which could compromise national or international responses to the COVID-19 pandemic. By 5 November 2020, some 214 mink-related human cases had been detected.^[42]

The World Health Organization (WHO) has stated that cluster 5 has a 'moderately decreased sensitivity to neutralizing antibodies'.^[7] SSI warned that the mutation could reduce the effect of COVID-19 vaccines under development, although it was unlikely to render them useless. Following the lockdown and mass-testing, SSI announced on 19 November 2020 that cluster 5 in all probability had become extinct.^[8] As of 1 February 2021, authors to a peer-reviewed paper, all of whom were from the SSI, assessed that cluster 5 was not in circulation in the human population.^[43]

Lineage B.1.1.207

First sequenced in August 2020 in Nigeria,^[44] the implications for transmission and virulence are unclear but it has been listed as an emerging variant by the US Centers for Disease Control.^[2] Sequenced by the African Centre of Excellence for Genomics of Infectious Diseases in Nigeria, this variant has a P681H mutation, shared in common with UK's Lineage B.1.1.7. It shares no other mutations with Lineage B.1.1.7 and as of late December 2020 this variant accounts for around 1% of viral genomes sequenced in Nigeria, though this may rise.^[44]

Lineage B.1.1.7 / Variant of Concern 202012/01

First detected in October 2020 during the COVID-19 pandemic in the United Kingdom from a sample taken the previous month,^[45]Lineage B.1.1.7,^[46] was previously known as the first Variant Under Investigation in December 2020 (VUI – 202012/01)^[47] and also as lineage B.1.1.7 or 20I/501Y.V1 (formerly 20B/501Y.V1).^[48][49][2] Since then, its prevalence odds have doubled every 6.5 days, the presumed generational interval.^[50][51] It is correlated with a significant increase in the rate of COVID-19 infection in United Kingdom, associated partly with the N501Y mutation. There is some evidence that this variant has 40%–80% increased transmissibility (with most estimates lying around the middle to higher end of this range),^[52] and early analyses suggest an increase in lethality.^[4][53]

Variant of Concern 202102/02

Variant of Concern 202102/02 (VOC-202102/02), described by Public Health England (PHE) as 'B.1.1.7 with E484K'^[17] is of the same lineage in the Rambaut classification system but has an additional E484K mutation. As of 18 February 2021, there are 26 confirmed cases of VOC-202102/02 in the UK.^[17]

Lineage B.1.1.317

While B.1.1.317 is not considered a Variant of concern, 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.^[54]

Lineage B.1.1.318

Lineage B.1.1.318 was designated by PHE as a VUI (VUI-202102/04) on 24 February 2021. 16 cases of it have been detected in the UK.^[55][56]

Lineage B.1.351

On 18 December 2020, the 501.V2 variant, also known as 501.V2, 20H/501Y.V2 (formerly 20C/501Y.V2), VOC-202012/02 (PHE), or lineage B.1.351,^[2] was first detected in South Africa and reported by the country's health department.^[57] 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.^[58][59] 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.^[57][58]

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,^[57][60] K417N, and E484K.^[9][61] The N501Y mutation has also been detected in the United Kingdom.^[57][62]

Lineage B.1.429 / CAL.20C

CAL.20C, also known as lineage B.1.429, is defined by five distinct mutations (I4205V and D1183Y in the ORF1ab-gene, and S13I, W152C, L452R in the spike proteins S-gene), of which the L452R (previously also detected in other unrelated lineages) was of particular concern.^[22][63] CAL.20C is possibly more transmissible, but further study is necessary to confirm this.^[63] It 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.^[64] It was not detected again until September when it reappeared among samples in California, but numbers remained very low until November.^[65][66] In November 2020, the CAL.20C variant accounted for 36 percent of samples collected at Cedars-Sinai Medical Center, and by January 2021, the CAL.20C variant accounted for 50 percent of samples.^[63] In a joint press release by University of California, San Francisco, California Department of Public Health, and Santa Clara County Public Health Department,^[67] 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%.^[68] 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.^[22] Following the increasing numbers of CAL.20C 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.^[65][66]

Lineage B.1.525

B.1.525, also called VUI-202102/03 by Public Health England (PHE) and formerly known as UK1188,^[17] does not carry the same N501Y mutation found in B.1.1.7, 501.V2 and P.1, but carries the same E484K-mutation as found in the P.1, P.2, and 501.V2 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 B.1.1.7, N439K variant (B.1.141 and B.1.258) and Y453F variant (Cluster 5).^[69] B.1.525 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 March 5, it had been detected in 23 countries, including the UK, Denmark, Finland, Norway, Netherlands, Belgium, France, Spain, Nigeria, Ghana, Jordan, Japan, Singapore, Australia, Canada, Germany, Italy, Slovenia, Austria, Malaysia, Switzerland, the Republic of Ireland and the US.^{[70][71][72][19][73][74][75]} It has also been reported in Mayotte, the overseas department/region of France.^[70] 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.^[19] As of 24 February, 56 cases were found in the UK.^[17] Denmark, which sequence all their COVID-19 cases, found 113 cases of this variant from January 14 to February 21, of which seven were directly related to foreign travels to Nigeria.^[71]

UK experts are studying it to understand 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'. Prof Ravi Gupta, from the University of Cambridge spoke to the BBC and said B.1.525 appeared to have 'significant mutations' already seen in some of the other newer variants, which is partly reassuring as their likely effect is to some extent more predictable.^[18]

Lineage P.1

Lineage P.1, termed Variant of Concern 202101/02 by Public Health England^[17] and 20J/501Y.V3 by Nextstrain,^[76][77] was detected in Tokyo on 6 January 2021 by the National Institute of Infectious Diseases (NIID). The new lineage was first identified in four people who arrived in Tokyo having travelled from the Brazilian Amazonas state on 2 January 2021.^[78] On 12 January 2021, the Brazil-UK CADDE Centre confirmed 13 local cases of the P.1 new lineage in the Amazon rain forest.^[15] This variant of SARS-CoV-2 has been named P.1 lineage (although it is a descendant of B.1.1.28, the name B.1.1.28.1 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 N501Y and E484K.^[15] The new lineage was absent in samples from March to November from Manaus, Amazonas state, but it was identified in 42% of the samples from December 2020 collected in the same city, suggesting a recent increase in frequency.^[15]A separate preprint by Voloch et al. identified another sub-lineage of the B.1.1.28 lineage circulating in the state of Rio de Janeiro, Brazil, now named P.2 lineage^[79] (previously referred to as B.1.1.248^[80]), that harbours the E484K mutation but not the N501Y mutation. The P.2 lineage is not directly related with the P.1 lineage identified in Manaus.^[15][81] Although both lineages harbour the E484K mutation, the mutation was acquired independently through convergent evolution.^{[15][better source needed]} Nevertheless, on 3 March 2021, scientists reported that the Lineage P.1 variant may be associated with Covid-19 disease reinfection after recovery from an earlier Covid-19 infection.^[82][83]

Notable missense mutations

D614G

D614G is a missense mutation that affects the spike protein of SARS-CoV-2. The frequency of this mutation in the 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 titers and infectivity in vitro.^[1] Researchers with PANGOLIN nicknamed this mutation 'Doug'.^[85]

In July 2020, it was reported that the more infectious D614G SARS-CoV-2 variant had become the dominant form in the pandemic.^{[86][87][88][89]} PHE confirmed that the D614G mutation had a 'moderate effect on transmissibility' and was being tracked internationally.^[90]

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.^[91]

Variants containing the D614G mutation are found in the G clade by GISAID^[1] and the B.1 clade by the PANGOLIN tool.^[1]

E484K

The name of the mutation, E484K, refers to an exchange whereby the glutamic acid (E) is replaced by lysine (K) at position 484.^[92] It is nicknamed 'Eeek'.^[85]

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^[93][94]) from at least one form of monoclonal antibody against SARS-CoV-2, indicating there may be a 'possible change in antigenicity'.^[12] The P.1. lineage described in Japan and Manaus,^[15] the P.2 lineage (also known as B.1.1.248 lineage, Brazil)^[81] and 501.V2 (South Africa) exhibit this mutation.^[12] A limited number of B.1.1.7 genomes with E484K mutation have also been detected.^[95] Monoclonal and serum-derived antibodies are reported to be from 10 to 60 times less effective in neutralizing virus bearing the E484K mutation.^[96][13] 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.^[97][98]

N501Y

N501Y denotes a change from asparagine (N) to tyrosine (Y) in amino-acid position 501.^[90] N501Y has been nicknamed 'Nelly'.^[85]

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.^[99] Variants with N501Y include P.1 (Brazil/Japan),^[12][15] Variant of Concern 202012/01 (UK), 501.V2 (South Africa), and COH.20G/501Y (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.^[100][101]

S477G/N

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^[102] and the Biotech Company Innophore^[103] have shown in a recent publication that structurally, the position S477 shows the highest flexibility among them.^[104]

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^[105] referenced this amino acid exchange as relevant regarding future vaccine design in a preprint published in February 2021.^[106]

P681H

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In January 2021, scientists reported in a preprint that the mutation 'P681H', a characteristic feature of the significant novel SARS-CoV-2 variants detected in the U.K. (B.1.1.7) and Nigeria (B.1.1.207), is showing a significant exponential increase in worldwide frequency, similar to the now globally prevalent 'D614G'.^[107][84]

New variant detection and assessment

On 26 January 2021, the British government said it would share its genomic sequencing capabilities with other countries in order to increase the genomic sequencing rate and trace new variants, and announced a 'New Variant Assessment Platform'.^[108] As of January 2021^[update], more than half of all genomic sequencing of COVID-19 was carried out in the UK.^[109]

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Origin of variants

Researchers have suggested that multiple mutations can arise in the course of the persistent infection of an immunocompromised patient, particularly when the virus develops escape mutations under the selection pressure of antibody or convalescent plasma treatment,^[110][111] with the same deletions in surface antigens repeatedly recurring in different patients.^[112]

Differential vaccine effectiveness

A preliminary study by Pfizer, Inc. has indicated that there is, at most, only minor reduction of the company's mRNA vaccine effectiveness against different SARS-CoV-2 variants.^[113] According to the US CDC, most experts believe that, due to the nature of the virus, the emergence of variants that completely escape the immune response (both natural and vaccine induced) is considered unlikely.^[114]

T-cell immunity is under investigation as a potential solution to the problem of reduced effectiveness of vaccines against the relevant variants. This is because T-cells target multiple pieces of the virus.^[115] As the majority of genetic variation is on the spike protein, T-cells that attack other parts of the virus should be able to recognise new variants. Viral vector and mRNA based vaccines are believed to elicit the strongest t-cell response.^[116] This believed to be the reason why the vaccine developed for yellow fever, an RNA virus like SARS-CoV-2, has remained effective for so long; by targeting Antigens within the virus that are unlikely to change, as opposed to those on the surface, it is unaffected by the majority of mutations. Companies including Emergex, Osivax and eTheRNA are targeting these internal antigens in the hope of creating a 'universal' SARS-CoV-2 vaccine.^[117] Biotechnology firm Gritstone is also experimenting to develop a vaccine aimed specifically at creating T-cell immunity.^[118][119]

On 29 January 2021, a deputy of the Moscow City Duma, Darya Besedina, turned to the Russian Minister of Health with a request to fund the study of new strains and conduct research on the effectiveness of Russian vaccines against these strains.

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^[120] On 10 February 2021, the European Medicines Agency made a similar appeal to vaccine manufacturers.^[121] On 15 February, Russian President Vladimir Putin instructed the government to deploy the sequencing of the genomes of Russian SARS-CoV-2 strains within a month, allocate funds for these studies, and also check whether Russian vaccines are effective against new strains.^[122]

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