Coronaviruses are not known for high rates of mutation. A typical SARS-CoV-2 virus only accumulates ~2 single-letter mutations per month in its genome. This rate of change is about half that of influenza viruses and one-quarter that of the human immunodeficiency virus. Despite the low rate of mutation, SARS-CoV-2 has recently developed 2 concerning mutations: N501Y (B.1.1.7 lineage) and a combination of N501Y and K417N mutations (501Y.V2 lineage).
The N501Y mutation has been mainly observed in the United Kingdom (UK). The variant has a mutation in the receptor binding domain (RBD) of the spike protein, where amino acid asparagine (N) has been replaced by tyrosine (Y). This variant has been associated with increased viral transmissibility (see mechanism later) but not disease severity. The combination N501Y and K417N mutation variant is mainly seen in South African samples. The variant also shows an increased transmissibility, perhaps even more so than the UK variant. Although both variants contain a mutation in the same site, they appear to be completely independent lineages, with the UK variant developing earlier than the South African variant. Both of these mutations have occurred in the spike protein of the virus, an area vital for the binding of ACE-2 receptors in the lungs, immune cells, and neutralising antibodies.
ACE-2 Receptors and Transmission
The spike protein of SARS-CoV-2 is used to direct viral penetration into the host cell. There are 2 main subunits that form the RBD, the S1 and S2 domains (see Figure 1). The S1 domain is vital in recognising carbohydrates that are required for attachment of the virus to the host cell, and the S2 domain is important for ACE-2 binding.
Figure 1: Schematic diagram of the SARS-CoV-2 spike protein
N501Y and K417N therefore have a well-established interaction with the human ACE-2 proteins and surface carbohydrates, which are responsible for the entry of SARS-CoV-2 into cells. N501Y has been demonstrated to produce a decrease of the binding into a change of free energy (ΔG) of -8.92 kcal/mol, ~ 161 times lower than that of the wild type SARS-CoV-2. Less bindings energy (more negative energy) contributes to a higher affinity of the spike protein to the ACE-2 receptor. The mutants’ S1 domain therefore binds spontaneously with human ACE-2 without consuming much energy and this enhances transmission of the virus by more than 70%.
Immune Cells and Antibodies
The K417N mutation in combination with the N501Y mutation has a pronounced effect on the immune system and antibody binding. The S protein is an essential antigenic portion of the SARS-CoV-2 structural proteins and therefore is responsible for triggering the immune system. The combination of the above mutations may result in the lack of immune response and subsequent higher viral loads before diagnosis and treatment, possibly leading to more severe disease, higher transmissibility, and higher infectivity.
In regards to antibodies, the K417N mutation leads to a decrease in the production of an antibody (known as STE90-C11) which usually binds to the virus’s S1 RBD, inhibiting viral entry into human cells. The ΔG for this antibody was, for previous SARS-CoV-2 strains, 5.74 kcal/mol. Due to the combination of mutations it has increased to 8.62 kcal/mol, causing antibody resistance. This is an important issue, as it may decrease susceptibility to therapeutic agents such as monoclonal antibodies, which are used to prevent viral infection. The other problem is that the virus may now be able to evade vaccine-induced immunity. The issue on vaccine efficacy on the variants is still unknown but the Food and Drug Association (FDA) has authorised vaccines that are polyclonal producing antibodies - i.e. they target several parts of the spike protein and therefore more mutations are required in order for there to be vaccine resistance. The ability to eventually evade vaccine-induced immunity by accumulating more mutations is concerning, especially because as more of the population is vaccinated, the higher the immune pressures that favour accelerated emergence of new variants.
Although coronaviruses do not show high rates of mutations, they still accumulate changes that may influence transmissibility, disease severity, treatment, and the effectiveness of vaccines to induce immunity. The rapid growth of these 2 new variants indicates the need for enhanced genomic and epidemiological surveillance as well as research into vaccine efficacy against each new strain.
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