Variants of SARS-CoV-2

The origin of SARS-CoV-2 has not been identified. However, the emergence of SARS-CoV-2 may have resulted from recombination events between a bat SARS-like coronavirus and a pangolin coronavirus through cross-species transmission. The earliest available SARS-CoV-2 viral genomes were collected from patients in December 2019, and Chinese researchers compared these early genomes with bat and pangolin coronavirus strains to estimate the ancestral human coronavirus type; the identified ancestral genome type was labeled "S", and its dominant derived type was labeled "L" to reflect the mutant amino acid changes. Independently, Western researchers carried out similar analyses but labeled the ancestral type "A" and the derived type "B". The B-type mutated into further types including B.1, which is the ancestor of the major global variants of concern, labeled in 2021 by the WHO as alpha, beta, gamma, delta and omicron variants. Early in the pandemic, the relatively low number of infections (compared with later stages of the pandemic) resulted in fewer opportunities for mutation of the viral genome and, therefore, fewer opportunities for the occurrence of differentiated variants. Since the occurrence of variants was rarer, the observation of S-protein mutations in the receptor-binding domain (RBD) region interacting with ACE2 was also not frequent. As time went on, the evolution of SARS-CoV-2's genome (by means of random mutations) led to mutant specimens of the virus (i.e., genetic variants), observed to be more transmissible, to be naturally selected. Notably, both the Alpha and the Delta variants were observed to be more transmissible than previously identified viral strains. Some SARS-CoV-2 variants are considered to be of concern as they maintain (or even increase) their replication fitness in the face of rising population immunity, either by infection recovery or via vaccination. Some of the variants of concern show mutations in the RBD of the S-protein. == Definitions ==

The term variant of concern (VOC) for SARS-CoV-2, which causes COVID-19, is a category used for variants of the virus where mutations in their spike protein receptor binding domain (RBD) substantially increase binding affinity (e.g., N501Y) in RBD-hACE2 complex (genetic data), while also being linked to rapid spread in human populations (epidemiological data). Before being allocated to this category, an emerging variant may have been labeled a variant of interest (VOI), or in some countries a variant under investigation (VUI). During or after fuller assessment as a variant of concern the variant is typically assigned to a lineage in the Pango nomenclature system Updated definitions, published on 4 October 2023, add variants of interest (VOI) and variants under monitoring (VUM) to the World Health Organization's working definitions for SARS-CoV-2 variants. The updated definition of VUMs includes having a suspected epidemiological growth advantage or community transmission in at least two countries over a 2–4 week period; while the definition of VOIs requires known genetic changes related to greater epidemiological risk and a known growth advantage in at least two WHO regions and increasing prevalence, or other epidemiological evidence "suggest[ing] an emerging risk to global public health". A VOC, under the October 2023 definition, must satisfy the definition of VOIs and satisfy other criteria defining a risk to global health. Greek letter names for the variants are restricted to VOCs since March 2023. The WHO defines a VOI as a variant "with genetic changes that are predicted or known to affect virus characteristics such as transmissibility, virulence, antibody evasion, susceptibility to therapeutics and detectability" and that is circulating more than other variants in over one WHO region to such an extent that a global public health risk can be suggested. Furthermore, the update stated that "VOIs will be referred to using established scientific nomenclature systems such as those used by Nextstrain and Pango". == Notability criteria ==

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 labelled as an "emerging variant". In the case of SARS-CoV-2, new lineages often differ from one another by just a few nucleotides. • 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 neutralising 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 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 labelled "variants under investigation" or "variants of interest" pending verification and validation of these properties. The primary characteristic of a variant of interest is that it shows evidence that demonstrates it is the cause of an increased proportion of cases or unique outbreak clusters; however, it must also have limited prevalence or expansion at national levels, or the classification would be elevated to a "variant of concern". If there is clear evidence that the effectiveness of prevention or intervention measures for a particular variant is substantially reduced, that variant is termed a "variant of high consequence". == Nomenclature ==

SARS-CoV-2 variants are grouped according to their lineage and component mutations. After months of discussions, the World Health Organization announced Greek-letter names for important strains on 31 May 2021, so they could be easily referred to in a simple, easy to say, and non-stigmatising fashion. This decision may have partially been taken because of criticism from governments on using country names to refer to variants of the virus; the WHO mentioned the potential for mentioning country names to cause stigma. After using all the letters from Alpha to Mu (see below), in November 2021 the WHO skipped the next two letters of the Greek alphabet, Nu and Xi, and used Omicron, prompting speculation that Xi was skipped to avoid offending Chinese leader Xi Jinping. In the event that the WHO uses the entirety of the Greek alphabet, the agency considered naming future variants after constellations. Lineages and clades While there are many thousands of variants of SARS-CoV-2, subtypes of the virus can be put into larger groupings such as lineages or clades. Three main, generally used nomenclatures—had identified eight global clades (S, O, L, V, G, GH, GR, and GV). • In 2017, Hadfield et al. announced Nextstrain, intended "for real-time tracking of pathogen evolution". Nextstrain has later been used for tracking SARS-CoV-2, identifying 13 major clades (19A–B, 20A–20J and 21A) . • In 2020, Rambaut et al. of the Phylogenetic Assignment of Named Global Outbreak Lineages (PANGOLIN) software team proposed in an article "a dynamic nomenclature for SARS-CoV-2 lineages that focuses on actively circulating virus lineages and those that spread to new locations"; National public health institutes may also create their own nomenclature system for the purposes of tracking specific variants. For example, Public Health England designated each tracked variant by year, month and number in the format [YYYY] [MM]/[NN] (where YYYY is the year, MM is the month and NN is a sequential number within the month), prefixing 'VUI' or 'VOC' for variant under investigation or variant of concern respectively. This system has been modified and now uses the format [YY] [MMM]-[NN], where the month is written out using a three-letter code. == Reference sequence ==

As it is currently not known when the index case or "patient zero" occurred, the choice of reference sequence for a given study is relatively arbitrary, with different notable research studies' choices varying as follows: • The earliest sequence, Wuhan-1, was collected on 24 December 2019. this sample was collected on 26 December 2019, although they also used the WIV04 GISAID reference genome (ID: EPI_ISL_402124), in their analyses. • According to another source (Zhukova et al.), the sequence WIV04/2019, belonging to the GISAID S clade / PANGO A lineage / Nextstrain 19B clade, is thought to most closely reflect the sequence of the original virus infecting humans—known as "sequence zero". as a reference sequence. Subsequently, many distinct lineages of SARS-CoV-2 have evolved. ==Overview of historical variants of concern or under monitoring==

The following table presents information and relative risk level for currently (as of 2021) and formerly circulating variants of concern (VOC). The intervals assume a 95% confidence or credibility level, unless otherwise stated. As of 2021, all estimates were approximations due to the limited availability of data for studies. For Alpha, Beta, Gamma and Delta, there is no change in test accuracy, PCR tests continue to detect the Omicron variant. == Previously circulating and formerly monitored variants (WHO) ==

The WHO defines a previously circulating variant as a variant that "has demonstrated to no longer pose a major added risk to global public health compared to other circulating SARS-CoV-2 variants", but should still be monitored. 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. or 501Y.V1. From October to December 2020, its prevalence 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. and early analyses suggested an increase in lethality, though later work found no evidence of increased virulence. As of May 2021, the Alpha variant had been detected in some 120 countries. On 16 March 2022, the WHO has de-escalated the Alpha variant and its subvariants to "previously circulating variants of concern". 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" 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) On 18 December 2020, the 501.V2 variant, also known as 501.V2, 20H (V2), VOC-20DEC-02 (formerly VOC-202012/02), or lineage B.1.351, 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. K417N, and E484K. The N501Y mutation has also been detected in the United Kingdom. On 16 March 2022, the WHO has de-escalated the Beta variant and its subvariants to "previously circulating variants of concern". 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.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 the three concerning mutations: N501Y, E484K and K417T. 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. 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. On 16 March 2022, the WHO has de-escalated the Gamma variant and its subvariants to "previously circulating variants of concern". It 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 quicker or as quickly as Alpha. It carries L452R and P681R mutations in Spike; 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". The name of the mutation, K417N, refers to an exchange whereby lysine (K) is replaced by asparagine (N) at position 417. 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. In the UK in July 2021, AY.4.2 was identified. Alongside those previously mentioned it also gained the nickname 'Delta Plus', on the strength of its extra mutations, Y145H and A222V. These are not unique to it, but distinguish it from the original Delta variant. On 7 June 2022, the WHO has de-escalated the Delta variant and its subvariants to "previously circulating variants of concern". Previously circulating variants of interest (VOI) Epsilon (lineages B.1.429, B.1.427, CAL.20C) The Epsilon variant or lineage B.1.429, also known as CAL.20C or CAVUI1, 21C From 17 March to 29 June 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, 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. 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. 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 2021, it had been detected in 23 countries. It has also been reported in Mayotte, the overseas department/region of France. Theta (lineage P.3) 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. As of July 2021, Theta is no longer considered a variant of interest by the WHO. Iota (lineage B.1.526) Kappa (lineage B.1.617.1) Lambda (lineage C.37) Mu (lineage B.1.621) Formerly monitored variants (WHO) The variants listed below were once listed under variants under monitoring, but were reclassified due to either no longer circulating at a significant level, not having had a significant impact on the situation, or scientific evidence of the variant not having concerning properties. ==Omicron==

Lineage B.1.1.529 The Omicron variant, known as lineage B.1.1.529, was declared a variant of concern by the World Health Organization on 26 November 2021. The variant has a large number of mutations, of which some are concerning. Some evidence shows that this variant has an increased risk of reinfection. Studies are underway to evaluate the exact impact on transmissibility, mortality, and other factors. Named Omicron by the WHO, it was identified in November 2021 in Botswana and South Africa; one case had travelled to Hong Kong, one confirmed case was identified in Israel in a traveler returning from Malawi, along with two who returned from South Africa and one from Madagascar. Belgium confirmed the first detected case in Europe on 26 November 2021 in an individual who had returned from Egypt on 11 November. Indian SARS-CoV-2 Genomics Consortium (INSACOG) in its January 2022 bulletin noted that Omicron is in community transmission in India where new cases have been rising exponentially. BA sublineages According to the WHO, BA.1, BA.1.1, and BA.2 were the most common sublineages of Omicron globally . BA.2 contains 28 unique genetic changes, including four in its spike protein, compared to BA.1, which had already acquired 60 mutations since the ancestral Wuhan strain, including 32 in the spike protein. BA.2 is more transmissible than BA.1. It was causing most cases in England by mid-March 2022, and by the end of March, BA.2 became dominant in the US. (with the latter excluding BA.3). XBB sublineages During 2022, a number of further new strains emerged in different localities, including XBB.1.5, which evolved from a recombination of BJ.1 and BM.1.1.1, both descended from Omicron. The first case involving XBB in England was detected from a specimen sample taken on 10 September 2022 and further cases have since been identified in most English regions. By the end of the year, XBB.1.5 accounted for 40.5% of new cases across the US, and was the dominant strain; variant of concern BQ.1 was running at 18.3% and BQ.1.1 represented 26.9% of new cases, while the BA.5 strain was in decline, at 3.7%. At this stage, it was uncommon in many other countries, for example in the UK it was represented about 7% of new cases, according to UKHSA sequencing data. BQ.1 and BQ1.1 became known informally as "cerberus". On 22 December 2022, the European Centre for Disease Control wrote in a summary that XBB strains accounted for circa 6.5% of new cases in five EU countries with sufficient volume of sequencing or genotyping to provide estimates.) emerged in February 2023. On 6August 2023, the UK Health Security Agency reported the EG.5 strain was responsible for one in seven new cases in the UK during the third week of July. Lineage BA.2.86 During 2023, SARS-CoV-2 continued to circulate in the global population and to evolve, with a number of new subvariants. Testing, sequencing and reporting rates reduced. BA.2.86 was first detected in a sample from 24July 2023, and was designated as a variant under monitoring by the World Health Organization on 17 August 2023. JN.1 (sometimes referred to as "Pirola"), a subvariant of BA.2.86, emerged during August 2023 in Luxembourg. By December 2023, it had been detected in 12 countries, including the UK and US. On 19 December, JN.1 was declared by the WHO to be a variant of interest independently of its parent strain BA.2.86, but overall risk for public health was determined as low. With JN.1 accounting for some 60% of cases in Singapore, in December 2023, Singapore and Indonesia recommended wearing masks at airports. The CDC estimated that the variant accounted for 44% of cases in the US on 22 December 2023 and 62% of cases on 5 January 2024. , JN.1 was estimated by the WHO to be the most prevalent variant of SARS-CoV-2 (70–90% prevalence in four out of six global regions; insufficient data in the East Mediterranean and African regions). The general level of population immunity and immunity from XBB.1.5 booster versions of the COVID-19 vaccine was expected to provide some protection (cross-reactivity) to JN.1. Lineage BA.3.2 Sublineages by year 2024 Late in April 2024, CDC data showed KP.2 to be the most common U.S. variant, with a quarter of all cases, just ahead of JN.1. KP1.1 represented 7 percent of U.S. cases. These two are sometimes referred to as the 'FLiRT' variants because they are characterized by a phenylalanine (F) to leucine (L) mutation and an arginine (R) to threonine (T) mutation in the virus's spike protein. By July 2024, a descendant of KP.2 with an extra amino acid change in the spike protein, Q493E, was given the names KP.3 and, informally, 'FLuQE,' and became a major variant in New South Wales during the Australian winter. Initial research suggested that the Q493E change could help KP.3 be more effective at binding to human cells than KP.2. Early in August 2024, XEC was discovered in Germany. XEC is a recombination of two subvariants: KS.1.1 and KP.3.3. In early December 2024, CDC data showed XEC to be the most common U.S. variant, with 45% of all cases, ahead of KP3.1.1, which accounted for 24% of all cases. 2025 Late in January 2025, XFG (sometimes referred to as "Stratus") was discovered in Canada. XFG is a recombination of two subvariants: LF.7 and LP.8.1.2. In late May 2025, WHO reported that XFG was the 2nd most common variant globally, making up 22.7% of all global cases, behind NB.1.8.1 (named "Nimbus", often with extremely sore throat) with 24.9% of global cases, and closely followed by LP.8.1 accounting for 22.6% of global cases. In late June 2025, CDC estimate data shows XFG to be the 3rd most common U.S. variant, with 14% of all cases, behind NB.1.8.1 and LP.8.1, which account for 43% and 31% of all cases respectively. On 14 September 2025, WHO listed JN.1 as a ; and KP.3.1.1, LP.8.1, NB.1.8.1, XEC, and XFG as s. The estimated prevalence for the week ending 7 September 2025 was 68% for XFG (an increase compared to 61% for the week ending 10 August), 20% for NB.1.8.1 (a decrease compared to 24% for the week ending 10 August), and 4% or lower for the other four variants. In late September, the ECDC listed no s, and listed BA.2.86 as a VOI, and NB.1.8.1 and XFG as VUMs. == Omicron variants under monitoring (WHO, 2022/2023) ==

On 25 May 2022, the World Health Organization introduced a new category for potentially concerning sublineages of widespread variants of concern, initially called VOC lineages under monitoring (VOC-LUMs). This decision was made to reflect that in February 2022, over 98% of all GISAID sequenced samples belonged to the Omicron family, within which much of the variants' evolution took place. By 9 February 2023, the category had been renamed as "Omicron variants under monitoring." == Other notable variants ==

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. 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.1.616, being identified in Brittany, Western France in early January 2021 and designated by WHO as "Variant under investigation" in March 2021, was reported to be difficult to detect from nasopharyngeal swab sampling method of coronavirus detection, and detection of the virus needs to rely on samples from lower respiratory tract. 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. In July 2021, scientists reported in a preprint which was published in a journal in February 2022, the detection of anomalous unnamed unknown-host SARS-CoV-2 lineages via wastewater surveillance in New York City. They hypothesized that "these lineages are derived from unsampled human COVID-19 infections or that they indicate the presence of a non-human animal reservoir". Lineage B.1.640.2 (also known as the IHU variant) was detected in October 2021 by researchers at the Institut Hospitalo-Universitaire (IHU) in Marseille. They found the variant in a traveler who returned to France from Cameroon and reportedly infected 12 people. The B.1.640 lineage, which includes B.1.640.2, was designated a variant under monitoring (VUM) by the World Health Organization (WHO) on 22 November 2021. However, the WHO has reported that lineage B.1.640.2 has spread much slower than the Omicron variant, and so is of relatively little concern. According to a preprint study, lineage B.1.640.2 has two already known spike protein mutations – E484K and N501Y – among a total of 46 nucleotide substitutions and 37 deletions. In March 2022, researchers reported SARS-CoV-2 variant recombinant viruses that contain elements of Delta and Omicron – Deltacron (also called "Deltamicron"). Recombination occurs when a virus combines parts from a related virus with its genetic sequence as it assembles copies of itself. It is unclear whether Deltacron – which is not to be confused with "Deltacron" reported in January albeit the first detection was also in January – will be able to compete with Omicron and whether that would be detrimental to health. In July 2023, Professor Lawrence Young, a virologist at Warwick University announced a super mutated Delta variant from a swab of an Indonesian case with 113 unique mutations, with 37 affecting the spike protein. Between November 2023 and July 2024, an extremely mutated cryptic variant was identified in New Jersey. This variant had the strongest ACE2 binding affinity out of any SARS-CoV-2 variant observed by far, had the most divergent spike protein profile observed to date, and it was also highly-resistant to every single antibody that researchers tested against it. The New Jersey cryptic variant had a sequence identity of just 80.6% compared to the ancestral Wuhan wildtype virus, the lowest observed in any COVID variant so far. The cryptic variant most likely originated from a B.1 lineage that predated the Omicron Variant, with the ancestral lineage circulating in 2021 or earlier, and it was unrelated to the B.1.1 lineage. This cryptic variant had 39 mutations in its spike protein's Receptor Binding Domain (RBD) compared to the Wuhan wildtype virus; only four of the spike mutations (R403K, S477N, V483del, and Y505H) were present in other COVID VOCs and VOIs. Notably, 13 of the remaining RBD mutations had been observed in other cryptic COVID variants, as identified by wastewater sequencing. Three of the novel RBD mutations, S477N, Q493L, and G496N, were identified as likely contributing to the cryptic variant's high ACE2 binding affinity, which was 11.4 times stronger than the ancestral Wuhan RBD. Despite the variant's advantages, it had not circulated since mid-2024, and was presumed to be extinct. == Recombinant variants ==

In 2022, the British government reported a number of recombinant variants of SARS-CoV-2. These recombinant lineages have been given the Pango lineage identifiers XD, XE, and XF. XE is a recombinant lineage of Pango lineages BA.1 and BA.2. XE was believed to have a growth rate 9.8% greater than BA.2. == Incubation theory for multiple mutated 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, with the same deletions in surface antigens repeatedly recurring in different patients. == Notable missense mutations ==

There have been a number of missense mutations observed of SARS-CoV-2. del 69-70 The name of the mutation, del 69-70, or 69-70 del, or other similar notations, refers to the deletion of amino acid at position 69 to 70. The mutation is found in the Alpha variant, and could lead to "spike gene target failure" and result in false negative result in PCR virus test. RSYLTPGD246-253N Otherwise referred to as del 246-252, or other various similar expression, refer to the deletion of amino acid from the position of 246 to 252, in the N-terminal domain of spike protein, accompanied with a replacement of the aspartic acid (D) at the position 253 for asparagine (N). The 7 amino acid deletion mutation is currently (September 2021) described as unique in the Lambda variant, and have been attributed to as one of the cause of the strain's increased capability to escape from neutralizing antibodies according to preprint paper. R346T The name of the mutation, R346T, refers to an exchange where the arginine (R) is replaced by threonine (T) at position 346. N440K The name of the mutation, N440K, refers to an exchange whereby the asparagine (N) is replaced by lysine (K) at position 440. It was involved in rapid surges of COVID-19 cases in India in May 2021. India has the largest proportion of N440K mutated variants followed by the US and Germany. G446V The name of the mutation, G446V, refers to an exchange whereby the glycine (G) is replaced by valine (V) at position 446. L452R The name of the mutation, L452R, refers to an exchange whereby the leucine (L) is replaced by arginine (R) at position 452. 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 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 paper published in September 2021. E484Q The name of the mutation, E484Q, refers to an exchange whereby the glutamic acid (E) is replaced by glutamine (Q) at position 484. E484Q may enhance ACE2 receptor binding ability, and may reduce vaccine-stimulated antibodies' ability to attach to this altered spike protein. 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), 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. F490S F490S denotes a change from phenylalanine (F) to serine (S) in amino-acid position 490. It is one of the mutation found in Lambda, and have been associated with reduced susceptibility to antibody generated by those who were infected with other strains, meaning antibody treatment against people infected with strains carrying such mutation would be less effective. N501Y N501Y denotes a change from asparagine (N) to tyrosine (Y) in amino-acid position 501. N501Y has been nicknamed "Nelly". N501S N501S denotes a change from asparagine (N) to serine (S) in amino-acid position 501. As of September 2021, there are 8 cases of patients around the world infected with Delta variant which feature this N501S mutation. As it is considered a mutation similar to N501Y, it is suspected to have similar characteristics as N501Y mutation, which is believed to increase the infectivity of the virus, however the exact effect is unknown yet. D614G . G (glycine) quickly replaced D (aspartic acid) at position 614 in Europe, though more slowly in China and the rest of East Asia, supporting the hypothesis that G increased the transmission rate, which is consistent with higher viral titres and infectivity in vitro. 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. The mutation has been reported in multiple lineages circulating inside the United States as of late 2020 and also some lineages outside the country. 'Pelican' was first detected in Oregon, and as of early 2021 'Robin 1' was found often in the Midwestern United States, while another Q667H sub-lineage, 'Robin 2', was found mostly in the southeastern United States. P681H (P) is replaced by arginine (R) at position 681. 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. 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. == Data and methods ==

Modern DNA sequencing, where available, may permit rapid detection (sometimes known as 'real-time detection') of genetic variants that appear in pathogens during disease outbreaks. Through use of phylogenetic tree visualisation software, records of genome sequences can be clustered into groups of identical genomes all containing the same set of mutations. Each group represents a 'variant', 'clade', or 'lineage', and comparison of the sequences allows the evolutionary path of a virus to be deduced. For SARS-CoV-2, until March 2021, over 330,000 viral genomic sequences had been generated by molecular epidemiology studies across the world. 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". , more than half of all genomic sequencing of COVID-19 was carried out in the UK. Wastewater surveillance was demonstrated to be one technique to detect SARS-CoV-2 variants Testing Whether one or more mutations visible in RT-PCR tests can be used reliably to identify a variant depends on the prevalence of other variants concurrently circulating in the same population. == Cross-species transmission ==

There is a risk that COVID-19 could transfer from humans to other animal populations and could combine with other animal viruses to create yet more variants that are dangerous to humans. Reverse zoonosis spillovers may cause reservoirs for mutating variants that spill back to humans – another possible source for variants of concern, in addition to immunocompromised people. Cluster 5 In early November 2020, Cluster 5, also referred to as ΔFVI-spike by the Danish State Serum Institute (SSI), was discovered in Northern Jutland, Denmark. It 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. The WHO stated that cluster 5 had a "moderately decreased sensitivity to neutralising antibodies". 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. By 1 February 2021, authors of a peer-reviewed paper, all of whom were from the SSI, assessed that cluster 5 was not in circulation in the human population. == Vaccines ==

During the COVID-19 pandemic, a variety of vaccines was developed. The vaccines were rolled out for administering to a broad range of recipients, typically beginning with the most vulnerable demographic groups. Differential vaccine effectiveness The interplay between the SARS-CoV-2 virus and its human hosts was initially natural but then started being altered by the rising availability of vaccines seen in 2021. The potential emergence of a SARS-CoV-2 variant that is moderately or fully resistant to the antibody response elicited by the COVID-19 vaccines may necessitate modification of the vaccines. The emergence of vaccine-resistant variants is more likely in a highly vaccinated population with uncontrolled transmission. As of February 2021, the US Food and Drug Administration believed that all FDA authorized vaccines remained effective in protecting against circulating strains of SARS-CoV-2. Immune evasion by variants Vaccine adjustments == See also ==