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SARS-CoV-2 Delta variant mutation sites

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it has undergone several mutations giving rise to different variants of the virus. The current and most notorious variant among them is the Delta variant. It is more contagious and infectious compared to the previous variants of SARS-CoV-2. Therefore, the Delta variant has been classified as one of the variants of concern by the World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (US-CDC).

Study: SARS-CoV-2 Delta (B.1.617.2) Variant: A Unique T478K Mutation in Receptor Binding Motif (RBM) of Spike Gene. Image Credit: MIA Studio/ Shutterstock

Vaccines against coronavirus disease 2019 (COVID-19) started to be distributed worldwide in January 2021 to curb the pandemic.

Currently, there are four major types of the vaccine: whole SARS-CoV-2 virus, adenovirus, mRNA, and subunit recombinant protein. Most of these vaccines are based on the Spike (S) protein presented on the viral envelope except the SARS-CoV-2 viral vaccine. The S protein comprises 16 subdomains, out of which the receptor-binding domain (RBD) is most important as it interacts with the angiotensin-converting enzyme 2 (ACE2) of the host.

Along with vaccines, separate neutralizing antibodies (Abs) were also developed to treat COVID-19 patients. The mode of action of all four vaccines is different. Still, all of them generate neutralizing Abs to protect an individual from SARS-CoV-2 infection and prevent the spread of the virus.

A new review article published in Immune Network dissected the sites of mutation in the RBD of the Delta variant and other variants of concern and variants of alert and interest. This would identify the critical mutation sites in the variants and help to analyze the current crisis of the pandemic.

SARS-CoV-2 Alpha variant

The Alpha variant of SARS-CoV-2 was originally reported in the United Kingdom (UK).  This variant was found to cause 50 percent more infectivity, hospitalization, and fatality than the original strain. The alpha variant has 13 mutations in the S gene, out of which three are E484K, S494P, and N501Y in the RBD, while the rest are in the functionally uncharacterized domain.

SARS-CoV-2 Beta variant

The Beta variant was first reported from South Africa. It was found to have ten mutations in the S gene. Five of these mutations were present at L241del, L242del, and A243del of the N-terminal domain (NTD) of S and E484K, K417N, and N501Y of the RBD. All the nine mutations of the Beta variant are located at the S1 region and C-terminal S2 of the spike protein.

SARS-CoV-2 Gamma variant

The Gamma variant was first reported in Brazil and Japan. It has a total of 11 mutations in the S gene. Most of the mutations are located in the S1 region except T1027I, located in the S2 region. Three mutations in RBD, K417T, E484K, and N501Y are almost identical to the Beta variant except for K417, where T is substituted by N. The gamma variant is different from the Alpha and Beta variants since it does not have any deletions in the NTD domain.

SARS-CoV-2 Delta variant

The SARS-CoV-2 Delta variant was first reported in India, following which it became the most prevalent variant in European countries. Two other variants Kappa and B.1.617.3, were reported in India during the same time and are the closest variants to Delta.

Three common mutation sites, L452R, D614G, and P681R, are shared between the Delta variant and the Kappa and B.1.617.3 variant. However, the D614G variant has been reported in all four variants of concern and all six variants of interest and alert.

The P681 is substituted by H instead of R in the Delta variant compared to the Alpha variant. The L452R mutation site was also found in SARS-CoV-2 ε and ι variants from the US. However, three mutation sites that were unique to Delta were E156del, R158G, and T478K.

SARS-CoV-2 variants of interest and alert

Six SARS-CoV-2 variants of interest and alert were reported along with the four variants of concerts. These variants were ε, ζ, η, ι, κ, and B.1.617.3. SARS-CoV-2 ε and ζ have only four mutation sites, which is the least number of mutations reported in any of the variants. Furthermore, the ζ variant has the common mutation sites E484K and D614G. The D614G mutation is present in all the variants, while the E484K mutation is found in eight of the variants.

The SARS-CoV-2 η (B.1.525) variant of UK and Nigeria consists of eight mutation sites out of which three sites, H69del, V70del, and Y144del, are located in NTD of the S1 region. The η variant has two common mutation sites, E484K and D614G, and three unique sites, A67V, Q677H, and F888L. The ι (B.1.526) variant of New York consists of 14 mutation sites. This variant was found to have mixed mutations in nine mutation sites that are found among several variants, while five mutation sites were unique, L5F, D253G, S477N, T859N, and Q957R.

The SARS-CoV-2 κ (B.1.617.1) and B.1.617.3 variants are very similar to the Delta variant. These three variants share five mutation sites, T19R, G142D, L452R, D614G, and P681R. D950N mutation is common between Delta and B.1.617.3, while Q1071H is unique to the κ variant. The E484Q mutation site of κ and B.1.617.3 variants are also found in the other variants but with the substitution of K instead of Q.

Susceptibility of SARS-CoV-2 variants to monoclonal Ab treatment

The Food and Drug Administration (FDA) has asserted an Emergency Use Authorization (EUA) FDA for the emergency use of unapproved monoclonal Abs against SARS-CoV-2. Currently, there are three monoclonal Abs available for the treatment of COVID-19, bamlanivimab plus etesevimab, sotrovimab, and casirivimab plus imdevimab.

The efficacy of the first vaccine and the treatment of neutralizing Ab was checked on the Alpha and Beta variant of SARS-CoV-2. It was found that the vaccine had protective effects with adenovirus vector and mRNA vaccine, although there is some escape of these variants. The Alpha variant, however, showed little or no susceptibility to the monoclonal Abs. In contrast, the Beta, Gamma, and ι variants showed a reduction in susceptibility when the combination of bamlanivimab and etesevimab was used.

The Delta, κ, B.1.617.3, as well as η variant, showed a reduction in neutralization on the use of monoclonal Abs. Therefore, the distribution of bamlanivimab and etesevimab was paused by the office of the Assistant Secretary for Preparedness and Response as of June 25, 2021.

However, current data revealed that most of the delta variant lineages were sensitive to bamlanivimab and etesevimab. Thus, based on these data, they again gained authorization to be used as of September 15, 2021.

Impact of delta variant across the globe

The spread of the COVID-19 pandemic can be stopped by understanding the characteristics of each of the SARS-CoV-2 variants. The researchers focused on the S gene since it encodes the spike protein that interacts with the ACE-2 receptor of the host and promotes the entry of the virus inside the host cell. All the vaccines and neutralizing Abs are targeted towards the S protein and some treatment to block the replication of the virus inside the host cell.

The SARS-CoV-2 delta variant has been reported in 162 countries across six continents as of September 2021. The best way to curb the pandemic is vaccination and natural infection. Vaccination and a strict lockdown on international borders took place in the US and European Union in early 2021.

However, a new wave of the delta variant spread worldwide despite vaccination. This suggests that the new variant could escape the developed vaccines or neutralizing Abs.

Unique mutation of the delta variant

The two closest variants to delta, SARS-CoV-2 κ and B.1.617.3, did not spread out from India, although they were reported during the same time. Comparison of the S gene mutation sites of the delta variant with the other two variants revealed a single unique mutation site, T478K. This mutation was found within the critical receptor binding motif (RBM) of the S gene. Additionally, the delta variant comprises two other unique mutations in the NTD of the S1 region, E156del and R158G.

The amino acid sequences of the RBM were aligned for the 10 SARS-CoV-2 variants that directly interacted with ACE-2. It was found that only six residues had common interaction sites among the 21 suggested interaction sites. Also, the ACE-2 binding residues in the S gene were directly compared with the mutation sites of the variants.

A minor correlation was found between the ACE-2 interacting residues and the ten variants.

Conclusion

The current review indicates that changes in the mutation sites of the SARS-CoV-2 variants are responsible for the unusual outbreak of COVID-19 throughout the world. A distinct T478K mutation was detected in the delta variant that could be responsible for its increased transmissibility, severity, and vaccine escape.

A vaccine or neutralizing Ab must be developed against the delta variant to prevent future outbreaks.

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