What SARS-CoV-2 Mutations Are Raising Serious Concern?

Viruses change and develop as a result of environmental selection forces, creating variations that may have increased virulence. Public health professionals are most worried about the viral transmissibility, reinfection rates, illness severity, and vaccination effectiveness of these novel variations as they continue to appear.

RNA viruses’ methods of mutation
Compared to organisms that have single-stranded deoxyribonucleic acid (ssDNA) and many times more than those with double-stranded DNA, viruses with single-stranded ribonucleic acid (ssRNA) have a substantially greater mutation rate (dsDNA). Not all mutations inevitably lead to an increase in virulence; in fact, most alterations have the potential to be harmful or insignificant.

Therefore, in order to adapt to changing environmental conditions, organisms need to establish a balance between a high mutation rate and a low one that reduces the likelihood of catastrophic mutations. Some RNA viruses also share the ability to detect and correct replication faults, and small DNA viruses have the potential to encode their own DNA repair.

While RNA viruses encode for their own transcription machinery, DNA viruses typically rely on the host cell’s transcriptional machinery. This indicates that RNA viruses are more closely connected to their own genome and are thus subject to the same evolutionary forces in terms of replication and mutation rates.

According to Vignuzzi & Andino (2012), RNA virus offspring typically have genomes between 7 and 12 kilobases (kb) in length and typically have one to two unique mutations per nucleotide site. Since the genome of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is estimated to be between 27 and 31 kb long, more mutations are likely to have been acquired overall without necessarily raising the incidence rate.

Viruses can emerge in new hosts, escape vaccine-induced immunity, and develop increased virulence thanks to their capacity to quickly acquire new genetic traits. Additionally, this capability may have a negative impact on the fitness of the entire genome.

In order to name and track SARS-CoV-2 variants, the World Health Organization (WHO) recently proposed a nomenclature system. This approach will help with ongoing public discussions about variants. The SARS-CoV-2 variations were given this nomenclature system by virological, microbiological, nomenclature, and communication experts from around the world to make sure it is simple to say and steer clear of any potentially derogatory words. To this purpose, the WHO-convened expert committee has suggested giving each new SARS-CoV-2 variation a name based on a letter from the Greek alphabet.
B.1.1.7 ancestry (Alpha variant)
In September 2020, a new strain known as VOC 202012/01 with a disproportionately high number of mutations was discovered for the first time in the United Kingdom (a variant of concern – December 2020). The WHO refers to the B.1.1.7 variant as the Alpha variant, while the Centers for Disease Control and Prevention (CDC) of the United States refer to it as 20B/501Y.V1. This strain, which is now known as the B.1.1.7 variation, possesses 17 amino acid alterations and a total of 23 mutations.

The B.1.1.7 strain has been discovered in more than 90 nations since being discovered in Britain. In fact, the B.1.1.7 variety is the most frequent cause of new SARS-CoV-2 infections in the United States as of April 7, 2021.

The fact that this particular strain is estimated to be 30–50% more contagious and perhaps more deadly than the original SARS-CoV-2 strains is worrying. But the strain is still susceptible to the current vaccinations.

The following crucial mutations are present in the B.1.1.7 strain:

N501Y P681H H69-V70, Y144/145 deletions, and H69-V70
Using its spike protein, SARS-CoV-2 communicates with ACE2 receptors within the body. The receptor-binding domain is located in the first of the two subunits that make up this structure. The N501Y mutation, which affects the receptor-binding domain, is present in the B.1.1.7 lineage and involves the substitution of tyrosine for asparagine at position 501.

The strain also frequently exhibits a loss of amino acids 69 and 70, which have been observed to appear spontaneously in other strains and affect the shape of the spike protein.

A spontaneous change from proline to histidine at position 681 has also been observed in numerous strains and is prevalent in B.1.1.7, as has a chance to open reading frame 8 whose function is now unknown.

This strain may be more contagious, but the evidence does not support a decrease in vaccine effectiveness. Recent research indicates that this strain is more lethal and associated with a higher risk of hospitalization.

B.1.351 ancestry (Beta variant)
The N501Y mutation also exists in strain B.1.351. The 20C/501Y.V2 or Beta variation are other names for the B.1.351 strain. Since its initial discovery in South Africa in October 2020, the Beta SARS-CoV-2 strain has been found in more than 48 other nations.

The following crucial mutations are present in the B.1.351 strain:

N501Y \sK417N \sE484K
In comparison to other variants reported in South Africa, it is thought that this mutation is around 50% more contagious. The Pfizer-BioNTech vaccine is currently 75% effective at preventing infection with this variant. Additionally, 97.4% of people who received the vaccination were protected from developing a serious, life-threatening, or fatal illness brought on by SARS-CoV-2 infection with either this version or the B.1.1.7 variant.

Unfortunately, it has been discovered that the University of Oxford-AstraZeneca vaccine is less effective against the B.1.351 variety, and as a result, South Africa has decided to halt the countrywide roll-out of this particular vaccination.

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P.1 ancestry (Gamma variant)
The National Institute of Infectious Diseases first identified the P.1 lineage of SARS-CoV-2, also known as 20J/501Y.V3 or the Gamma SARS-CoV-2 variation, in Japan. It is believed to have arrived in the nation from Brazil on January 6. The Brazilian city of Manaus is where the variety originated.

The strain of SARS-CoV-2 is thought to be more transmissible than the initial strain but not necessarily more lethal.

These significant mutations are present in the P.1 strain:

N501Y \sK417T \sE484K
Twelve mutations in the spike protein, including the previously noted N501Y and exchange of glutamic acid for lysine at position 484, are present in the P.1 lineage, a subset of the B.1.1.248 lineage (E484K). It is related to the B.1.351 strain closely.

As early as the summer of 2020, the E484K mutation was discovered in a separate lineage that originated in Brazil (B.1.1.28).

Data from clinical trials utilizing the Moderna mRNA vaccine show that in previously immunized patients, a single booster dose of this vaccine successfully boosted neutralizing titers against the virus and the B.1.351 and P.1 variants. Notably, this booster dose used the strain-matched vaccine mRNA-1273.351, which was produced from the original Moderna mRNA vaccination designated as mRNA-1273.
CAL.20C variation of the B.1.427/B.1.429 lineage (Epsilon variants)
It is thought that the CAL.20C variation, which includes the B.1.427 and B.1.429 lineages, first appeared in California in May 2020. Although they do not appear to be spreading as quickly as some variants, such as the B.1.1.7, both of these variants, collectively known as the Epsilon variants, are thought to be 20% more contagious than preexisting variant strains.

Currently, North America, Europe, Asia, and Australia have all reported finding the B.1.427/B.1.429 strains. Neutralizing antibodies discovered from persons who had previously had the Moderna or Novavax vaccinations were found to be slightly less efficient against these variations, but still produced effective protection, according to research. Although the Pfizer vaccine was not examined in this work, experts feel that it would probably have a similar reaction because it makes use of technology that is comparable to that found in the Moderna vaccine.

These significant mutations characterize this strain:

Eta variant and Iota variant L452R B.1.525 and B1.526 lineages
The B.1.525 variation, often known as the Eta variant, was initially discovered to be spreading throughout New York City in December 2020. The B.1.525 variation appears to share the same E484K mutation and the H69-V70 deletion as the B.1.1.7 lineage of SARS-CoV-2 variants. The B.1.525 variant lineage also bears the Q677H mutation in addition to these mutations.

The B.1.526 lineage of variants, commonly referred to as the Iota variants, as well as the B.1.525 lineage, have both been found in New York City. Notably, there are two variants of the B.1.526 lineage; one contains the S477N mutation and the other has the E484K spike mutation.

It indicates that neutralizing antibodies from both convalescent plasma of COVID-19-recovered patients and that produced post-vaccination are less effective against these two variants; however, more research is required to confirm this finding.

The lineage of B.1.617 (Kappa and Delta variants)
Due to two alarming changes it harbors, the B.1.617 strain has been termed the “double mutant virus.” These are the two main mutations:

E484Q \sL452R
Some experts believe that this variety is extremely transmissible based on how quickly it has spread throughout India. This finding is largely attributable to the B.1.617 variant’s apparent higher prevalence when compared to other variants found in India, such as the B.1.618 variant that was first found in West Bengal.

Three distinct subtypes of the B.1.617 variation, including the B.1.617.1, B.1.617.2, and B.1.617.3 variants, have been identified as the B.1.617 variant continues to spread alarmingly quickly in India. Data indicate that the B.1.617.2 or Delta variant has a growth rate advantage over the initial subtype of this variant, also known as the Kappa variant, which has allowed it to become the dominant subtype found across much of India.

It is still unknown exactly why the B.1.617.2 variety is highly contagious or whether it can be prevented by the vaccinations available today. Researchers from the University of Cambridge discovered in one trial that the neutralizing antibodies produced by people who had previously received one dose of the Pfizer vaccine are roughly 80% less effective against some B.1.617 mutations.

Additionally, a group of German researchers discovered that SARS-CoV-2 neutralizing antibodies obtained from individuals who had already contracted the virus were 50% less efficient at eradicating these circulating strains. The data does not necessarily imply that the vaccines are ineffective against these variations, it should be highlighted, though.

B.1.1.529 family tree (Omicron variant)
The WHO identified the new SARS-CoV-2 variant as B.1.1.529, also known as the Omicron variant, and it was discovered by South Africa on November 24, 2021. Samples taken on November 11, 2021, in Botswana and November 14, 2021, in South Africa were the first to contain this variation.

The Omicron variety has been found in numerous other nations since it was first discovered, including Brazil, Australia, Saudi Arabia, England, Spain, France, Denmark, the Netherlands, Germany, Italy, Japan, South Korea, Canada, and the United States. In fact, as of December 6, 2021, cases of COVID-19 that tested positive for the Omicron variety had been found in more than a third of the states in the US. It should be highlighted that the Delta version continues to be the prevalent form, accounting for around 99.9% of new COVID-19 cases, despite its widespread discovery in the United States.

Based on epidemiological evidence that showed an increase in SARS-CoV-2 infections that coincided with the discovery of this variant, the WHO quickly designated the Omicron variant as a VOC. Additionally, the spike protein of the Omicron variant contains a number of protein substitutions, some of which have already been found in other SARS-CoV-2 variants and are linked to a decreased susceptibility to neutralization by monoclonal antibody treatments, convalescent serum, and vaccinee sera.

As was already mentioned, the SARS-CoV-2 spike protein exhibits numerous important amino acid changes in the Omicron version. A67V, del69-70, T951, de142-144, Y145D, del211, L212I, ins214EPE, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, and L981F are a few of these. The following additional mutations are located in the receptor binding domain (RBD) of this variant: G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, and Y505H. Together, the extra alterations to the spike protein found in the Omicron variant—15 of which have been discovered in the RBD—have not been seen in other SARS-CoV-2 variations.

A more hazardous strain of SARS-CoV-2 may not necessarily result from the combination of so many distinct substitutions, even though some of the changes in the Omicron variation had already been described in other SARS-CoV-2 variants. For instance, even though the N501Y and Q498R mutations in the Omicron variant both improve binding affinity to the ACE2 receptor, the presence of other protein substitutions in this variant’s spike protein may actually decrease binding to ACE2.

The lineages and sublineages that make up the Omicron variation are BA.1, BA1.1, BA.2, BA.2.75, BA.3, BA.4, BA.5, and XAK. The three most prevalent lineages, however, are BA.2, BA.4, and BA.5. Regardless of their immunization history and/or the frequency of their symptoms, the CDC noted that people can spread the virus to others. Omicron variants spread at a faster rate than the Delta strain. It’s significant to note that Omicron has been observed to reinfect people who have just recovered from COVID-19.

People infected with the Omicron strain showed symptoms resembling those of earlier versions. Although the majority of these people had minor symptoms, some of them needed to be hospitalized. The extent of the illness was largely influenced by immunization history.

The latest COVID-19 vaccinations offer a defense against fatal infections brought on by the Omicron variant as well as severe sickness. However, there have been reports of breakthrough infection in the immunized group. The best COVID-19 treatment is currently being determined by scientists. Certain monoclonal antibodies have been discovered to be less effective than others in treating specific Omicron strains.

The public is currently advised to continue using all currently available prevention techniques, such as masking, enhanced ventilation systems, social seclusion, handwashing, and routine testing for SARS-CoV-2 infections, to stop the spread of this variety.

P.2 ancestry (Zeta variant)
The spike E484 mutation was independently gained by the P.2 lineage of SARS-CoV-2 variants, also referred to as the Zeta variants, and was first discovered in Brazil in April 2020. Information on whether monoclonal antibody treatments and the antibodies produced after vaccination have diminished efficacy against this type of concern is currently scarce.
variations of worry
The seeming spontaneity with which some of the important changes that have been detailed here developed leads one to hypothesize that the virus may be subject to global convergent selection forces, with the most contagious forms outcompeting its cousins.

The following recent mutations are of concern because they could be promoting coronavirus spread:

The B.1 lineage D614G mutation first surfaced in early 2020. This mutation rapidly propagated throughout the world and took over.

The aspartic acid (single-letter code: D) and glycine (single-letter code: G) in the protein that the mutant gene encodes are swapped out in the D614G mutation, which is a missense mutation.

This mutation can be found in variants of the lineages B.1.345, B.1.17, P.1, and B.1.1.529. The amino acid asparagine (N) is changed to tyrosine (Y) at position 501 in the RBD of the spike protein by this mutation, which may allow SARS-CoV-2 strains carrying this mutation to bind to the ACE2 receptor on host cells more strongly.

“Eek” or E484K
This spike protein mutation, which has been observed in other lineages, may help the virus dodge some types of antibodies. In it, at position 484, glutamic acid is switched out for lysine.

With the exception of the glutamine being used in place of glutamic acid at position 484, this spike protein mutation is also altered at that location. The immune evasion and ACE2 binding are expected to be enhanced by this mutation.

Several lineages, including P.1 and B.1.351, have this spike protein mutation. It is also believed to aid in the virus’s tighter cell binding.


In numerous lineages, the L452R spike protein mutation has been observed. Leucine is changed to arginine at amino acid 452 in this mutation. The mutation is believed to improve ACE2 binding and immune evasion.

Given that it is prominently present in the CAL.20C variety, which has become common in California, particularly in Los Angeles, this mutation was first noticed in the U.S. and Europe in 2020 before becoming more prevalent in January 2021. It is also clearly present in version B.1.617.

It should be noted that laboratory research has revealed that certain monoclonal antibody therapies may not be as successful in treating COVID-19 caused by variations with the L452R or E484K mutations.

Given that the Q677 mutation is situated next to the SARS-CoV-2 spike protein, it is possible that it contributes to the virus’ increased capacity to enter human cells. Several different SARS-CoV-2 variant lineages, including seven in the United States, have the Q777 mutation found to date. It has not yet been established whether the Q677 variation is more contagious than other mutations.

The B.1.1.7 and B.1.1.529 strains carry the P681H mutation, but the B.1.617.2 variant carries a distinct form of the same mutation (P681R). It has been demonstrated that this mutation causes spike cleavage to increase, which would enable affected strains to be more transmissible.

In the SARS-CoV-2 spike protein, the S943P mutation was initially discovered in Belgium. The recombination of several viruses in an infected host is what caused this mutation.

The S1 domain of the spike protein of SARS-CoV-2 included the V483a mutation in the receptor binding motif (RMB). At position 483, this mutation causes hydrophobic valine to be swapped out for hydrophobic alanine.

Changes in the amino acids at position 477 lead to the S477 mutation. The spike protein’s receptor binding domain is where this mutation is primarily present. The main causes of the increased binding affinity for hACE2 are S477G and S477N. The S477G and S477N mutations are present in the Omicron form.

What parts of the SARS-CoV-2 genome are most prone to mutation?
Over 10,000 SARS-CoV-2 genomes from around the world were collected and examined in a sizable meta-study by Koyama, Platt, and Parida (2020) to determine the most prevalent mutations. Nearly 6,000 different variants were found.

ORF1ab, by far the biggest genome region, accounting for almost one-third of the genome, was the most diverged. The transcription of ORF1ab results in the formation of a multiprotein complex that subsequently cleaves into a variety of transcriptionally active nonstructural proteins. Remdesivir and favipiravir, two antiviral medications, are known to target some of these proteins, which raises questions about the possibility of a strain emerging that is resistant to these medications.

The area surrounding the spike protein, which must stay mostly conserved in order to interact with ACE2, is the second most varied section of the SARS-CoV-2 genome. Some alterations, including D364Y, have been shown to improve the spike protein’s structural stability and boost its affinity for the receptor. However, the majority of them are probably going to reduce the virus’ pathogenicity to the point that the lineage quickly disappears.

What SARS-CoV-2 subtypes have been discovered?
The list of SARS-CoV-2 variants, divided into variants of concern (VOC), variants of interest (VOI), variants under monitoring (VUM), and de-escalated variants, was recently released by the European Center for Disease Prevention and Control (ECDC). Based on existing genetic epidemiology and in vitro data, SARS-CoV-2 variants are categorized.

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Variants of the SARS-CoV-2 virus classified as VOC have a substantial impact on the disease’s severity, transmissibility, and immunity evasion. The epidemiological situation in the European Union is profoundly impacted by these mutations. Although VOIs have a high potential to lead to unfavorable epidemiological conditions, the supporting evidence is still in its infancy and contains significant uncertainty.

VUM mutants have several characteristics that are similar to VOCs, according to genomic variant screening and preliminary scientific evidence. However, ECDC hasn’t yet analyzed the evidence or it isn’t strong enough to be assessed. Currently, these variations are being closely watched.

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