Mutation sites of the Delta SARS-CoV-2 variant

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 famous variant of these is the Delta variant. It is more contagious and infectious than 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 US Centers for Disease Control and Prevention (US-CDC).

Study: Delta SARS-CoV-2 (B.1.617.2) Variant: A unique T478K mutation in the receptor binding motif (RBM) of the Spike gene. Image Credit: MIA / Shutterstock Studio

2019 coronavirus (COVID-19) vaccines began to be distributed around the world in January 2021 to curb the pandemic.

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

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

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

SARS-CoV-2 alpha variant

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

Beta variant of SARS-CoV-2

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 (NTD) domain of S and E484K, K417N, and N501Y of RBD. All nine mutations of the Beta variant are located in the S1 and S2 C-terminal regions 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 mutations are found in the S1 region except T1027I, which is located in the S2 region. Three mutations in RBD, K417T, E484K, and N501Y are nearly identical to the Beta variant with the exception of K417, where T is replaced by N. The gamma variant is different from the Alpha and Beta variants since it has no 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 around 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 variant and B.1.617.3. However, the D614G variant was reported in all four variants of interest and in all six variants of interest and alert.

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

SARS-CoV-2 variants of interest and alert

Six variants of SARS-CoV-2 of interest and alert have been reported along with the four concert variants. 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 fewest 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 variants, while the E484K mutation is found in eight of the variants.

The UK and Nigeria variant SARS-CoV-2 (B.1.525) consists of eight mutation sites of which three sites, H69del, V70del and Y144del, are found in NTDs of the S1 region. The η variant has two common mutation sites, E484K and D614G, and three unique sites, A67V, Q677H, and F888L. The New York variant ι (B.1.526) consists of 14 mutation sites. This variant was found to have mixed mutations in nine mutation sites found between different 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. The D950N mutation is common between Delta and B.1.617.3, while Q1071H is unique to the κ variant. The mutation site E484Q of the variants and B.1.617.3 is also found in the other variants but with the substitution of K instead of Q.

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

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

The efficacy of the first vaccine and treatment of neutralizing Ab was verified on the Alpha and Beta variant of SARS-CoV-2. The vaccine has been found to have protective effects with the adenovirus vector and mRNA vaccine, although there is some leakage of these variants. The Alpha variant, however, showed little or no susceptibility to monoclonal Abs. In contrast, the Beta, Gamma, and variants showed reduced susceptibility when the combination of bamlanivimab and etesevimab was used.

The Delta variant, κ, B.1.617.3, as well as the η variant, showed a reduction in neutralization on the use of monoclonal Abs. Therefore, the distribution of bamlanivimab and etesevimab has been suspended from the Office of the Deputy Secretary for Preparation and Response starting June 25, 2021.

However, current data revealed that most lineages of the delta variant were susceptible to bamlanivimab and etesevimab. Therefore, based on this data, they have again obtained authorization for use starting September 15, 2021.

Impact of the delta variant worldwide

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 as it encodes the spike protein that interacts with the host ACE-2 receptor and promotes virus entry into the host cell. All vaccines and neutralizing Abs are targeted at protein S and some treatments to block replication of the virus within the host cell.

The delta variant SARS-CoV-2 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 rigorous blocking of international borders took place in the United States and the European Union in early 2021.

However, a new wave of the delta variant has spread around the world despite vaccination. This suggests that the new variant could escape developed vaccines or neutralize Abs.

Unique mutation of the delta variant

The two variants closest to the delta, SARS-CoV-2 and B.1.617.3, did not spread from India, although they were reported around the same time. Comparison of the mutation sites of the delta variant S gene 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. Furthermore, the delta variant includes two other unique mutations in the NTD of the S1 region, E156del and R158G.

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

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

Conclusion

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

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

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