COVID-19 Variants of Concern

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Mohamed Riad, M.D.[2] Deekshitha Manney, M. D[3], Arooj Naz, M.B.B.S

Overview

All viruses mutate. Mutations are mistakes that happen in the genetic material of the virus when it replicates. Every single viral replication is an opportunity to mutate. All viruses, including COVID 19 needs a host cell to replicate, because viruses have genetic material but no cytoplasm and cellular proteins to replicate on their own. So the longer a virus replicates and circulates in a population of hosts, the higher chance of a mutation. Not all mutations are significant enough to change the characteristics of virus. However, a sequence of mutations (which is more likely to happen, when the viral load in a community is very high such as in a pandemic), can lead to a change in viral characteristics and can lead to difference either in transmissibility and/or virulence. These mutations can also change the efficiency of vaccines and the viral response to treatment. One of the examples of how viral mutations can affect the efficiency of vaccine is why annual flu vaccines are required. Similar to influenza virus, SARS-CoV-2 (the virus responsible for COVID-19) also can mutate and in a pandemic situation, the likelihood of the mutation and emergence of variants is high. WHO is actively tracking and monitoring the emergence of variants in order to alert the nations and public as part of ongoing response to the current pandemic. Not all variants are of "interest" and/or "concern". The WHO has working definitions for "Variants of Interest (VOI)" and "Variants of Concern (VOC)" as follows:

Variant of Interest or VOI is "A SARS-CoV-2 variant :

• with genetic changes that are predicted or known to affect virus characteristics such as transmissibility, disease severity, immune escape, diagnostic or therapeutic escape; AND
• Identified to cause significant community transmission or multiple COVID-19 clusters, in multiple countries with increasing relative prevalence alongside increasing number of cases over time, or other apparent epidemiological impacts to suggest an emerging risk to global public health."

Variant of Concern or VOC is "A SARS-CoV2 variant that meets the definition of a variant of interest (VOI) and, through a comparative assessment, has been demonstrated to be associated with one or more of the following changes at a degree of global public heath significance:

• Increase in transmissibility or detrimental change in COVID-19 epidemiology; OR
• Increase in virulence or change in clinical disease presentation; OR
• Decrease in effectiveness of public health and social measures or available diagnostics, vaccines, therapeutics."

In the following section, we discuss about all the variants of concern identified by WHO so far, the mutations that were significant, when and where it originated, the impact of the variant on global health.

Variants of Concern

The established nomenclature systems for naming and tracking SARS-CoV-2 variants include Pango, GISIAD and NextStrain. The above mentioned nomenclature is used by the scientific community for research and monitoring purposes. WHO labels them independently and there are total 5 variants of concern. They are Alpha, Beta, Gamma, Delta, and Omicron .

Alpha Variant:

Pango lineage: B.1.1.7

GISIAD clade: GRY

NeXT Strain clade: 20I (V1)

This variant was first detected in the United Kingdom in November 2020 from a sample that was collected in September 2020. WHO announced this as a variant of concern in May 2021 and labelled it "alpha". Some of the key mutations of the alpha variant are N501Y, H69del/V70del, Y144del, A570D. N501Y mutation (a change from amino acid asparagine (N) to amino acid tyrosine (Y) in position 501) lead to increase in the affinity of receptor binding domain on SARS-CoV2's spike protein to ACE2 receptor on human cell enhancing the infectivity of the virus. H69/V70del and Y144del mutation also increases infectivity, decreased response to neutralizing antibodies thus evading preexisting immunity that is acquired via vaccination or previous infection and this mutation lead to increased false negative test results. N501Y and H69/V70del mutations together has increased the transmission of this variant by 75% compared to the wild variant of SARS-CoV2.

As of January 27, 2022, UK reported the highest number of alpha variant cases with a total of 272,340 cases. The first case of alpha variant was reported in November 2020 in USA and has become the major variant of spread by the end of March 2021. USA has reported a total of 241,424 cases as of January 27, 2022. As of early 2023, effective vaccines against this strain include Pfizer, Moderna, and Johnson & Johnson.

Most Common countries:

• United Kingdom 24%
• United States of America 20%
• Germany 9%
• Sweden 6%
• Denmark 6%

Beta Variant:

Pango lineage: B.1.351

GISIAD clade: GH/501Y.V2

NeXT Strain clade: 20H (V2)

This variant was first detected in South Africa in October 2020 and this was designated as a variant of concern in December 2020. Some of the key mutations in this variant include N501Y (a change from amino acid asparagine (N) to amino acid tyrosine (Y) in position 501), E484K (a change from amino acid glutamic acid (E) to amino acid lysine (K) in position 484) and K417N (a change from amino acid lysine (K) to amino acid asparagine (N) in position 417). N501Y, is the same mutation that was found in alpha variant and serves to increase the affinity of receptor binding domain on SARS-CoV2's spike protein to ACE2 receptor on human cell enhancing the infectivity of the virus. E484K mutation is first identified in beta variant, but this mutation also spread to alpha and was identified in a few isolates. This mutation involves receptor binding domain and serves to decrease the efficiency of vaccines by reducing the neutralization of virus by low to moderate levels of IgG post vaccination. K417N also is a mutation involving receptor binding domain on SARS-CoV2's spike protein and leads to immune escape, but decreases the affinity of RBD to ACE2 receptor on human cell. With these 3 major mutations, this variant successfully evades immune response and antibody (Obtained through immunization or previous infection) neutralization while increasing the transmission at the same time. This variant targets younger population leading to severe disease. Overall, worldwide 28,380 cases were reported from this variant as of July 2021. As of early 2023, pharmaceutical companies including Pfizer, Moderna, and Johnson & Johnson stated the vaccine were not as effective against this strain, whereas AstraZeneca was rendered ineffective against strain found in South Africa.

Most Common countries:

• South Africa 19%
• Philippines 9%
• United States of America 9%
• Sweden 8%
• Germany 7%

Gamma Variant:

Pango lineage: P.1

GISIAD clade: GR/501Y.V3

NeXT Strain clade: 20J (V3)

This variant was first detected in Brazil in December of 2020 and first presented in the United States in January of 2021. The variant has 10 mutations in the spike protein, including L18F, T20N, P26S, D138Y, R190S, H655Y, T1027I V1176, K417T, E484K, and N501Y. The Gamma variant has spread to 45 countries.

Most Common countries:

• Brazil 58%
• United States of America 27%
• Chile 3%
• Argentina 2%
• Spain 1%

Delta Variant:

Pango lineage: B.1.617.2

GISIAD clade: GK

NeXT Strain clade: 21A, 21I, 21J

This variant was first detected in India in October 2020 and this was designated as a variant of concern in May 2021. Some of the key mutations in this variant include D614G, T478K, L452R, P681R. D614G mutation increase the transmissibility of the virus by increasing the affinity of the virus to human cell and colonizing mainly the upper respiratory tract. As of early 2023, effective vaccines against this strain include Pfizer, Moderna, and Johnson & Johnson. CDC has also recommended "layered prevention" against this strain, suggesting that staying up to date on vaccines can help reduce infectivity.

Most Common countries:

• United States of America 18%
• India 18%
• Turkey 16%
• United Kingdom 12%
• Germany 5.0%

Omicron Variant:

Pango lineage: B.1.1.529

GISIAD clade: GRA

NeXT Strain clade: 21K, 21L, 21M

This variant was first detected in South Africa in November of 2021. Omicron presented with upwards of 30 mutations affecting the spike protein including T91 in the envelope, G204R in the nucleocapsid protein, A63T in the matrix, and A67V, G339D and D796Y in the spike.Strains of Omicron presented with 13 times increase in infectivity, making it more infective than the Delta variant. In late 2022, Pfizer and Moderna bivalent shots were recommended for all individuals aged 6 months and older. According to WHO’s weekly update on January 25^th, 2023, four descendants of the Omicron lineage are being monitored closely. These include BF.7, BQ.1, BA.2.75 and XBB . In particular, the XBB.1.5 variant, nicknamed “kraken" has become prevalent in certain parts of the United States and has been found to be more common in those aged 70 and above. The strain is thought to be more easily transmissible. Affected regions in the United States include the Midwest, Massachusetts, Connecticut, Virginia and North Carolina while infection rates continue to increase in the states of Texas and California.

Most Common countries:

• South Africa
• Botswana