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New mutations capable of reaching a high frequency in SARS-CoV-2 genomes are possible due to the inherent error rate of the SARS-CoV-2 RNA replication process. The rise of these variants may affect the development of vaccines and therapies as they spread through the population.
In addition, to avoid the derailment of promising vaccines or prophylactic or antibody-based treatments, it is essential to understand how and if SARS-CoV-2 can evolve to escape antibody-dependent immunity.
Researchers looked at the immunodominant RBM SARS-CoV-2, a part of the receptor binding domain (RBD) that mediates viral entry and is a major target for neutralizing antibodies in the body. They found it to be a highly variable region of the spike protein in circulating viruses, accounting for the top 10% of entropy (mutation rate). In general, the results suggest that RBM is able to adapt to amino acid changes without disrupting the binding of the human angiotensin 2 converting enzyme (ACE2).
Effect of RBM mutations in SARS-CoV-2
More specifically, the team sought to define the clinical and epidemiological effect, molecular characteristics and immune response to the RBM N439K – cytosine-adenine transversion mutation in the third codon position, resulting in an amino acid change of the asparagine to lysine. The variant was first identified in March 2020 in Scotland and, in January 2021, has two lineages. This mutation has been observed in over 30 countries and is the second most common RBD mutation worldwide and the sixth most common spike mutation.
A position equivalent to N439K in SARS-CoV RBM forms a salt bridge with ACE2 with a positively charged amino acid, according to the team. Therefore, they hypothesized that the N439K SARS-CoV-2 variant can form a salt bridge similar to the RBD-ACE2 interface. They determined the X-ray crystal structure of the N439K RBD complex with ACE2 at 2.8 å resolution and found that the salt bridge is formed. Thus, the N439K mutation can add strength to the interaction at the binding interface.
They then assessed the effect of the mutation on viral fitness by reviewing clinical data and outcomes associated with virus carrying the N439K mutation, as well as in vitro data. The researchers found that the mutation was associated with a similar clinical spectrum of disease and slightly higher viral loads in vivo compared to viruses with the wild-type N439 residue.
“An important finding from this article is the extent of variability found in the immunodominant RBM on the spike protein,” said senior author Gyorgy Snell, PhD, senior director of structural biology at Vir Biotechnology, in a statement. .
Resistance to monoclonal antibodies
Finally, the researchers tested whether the N439K mutation promotes the escape of antibody-mediated immunity. To do this, they evaluated the effectiveness of the monoclonal antibodies and the polyclonal immune serum of 442 individuals recovered, including six donors infected with the SARS-CoV-2 N439K variant, to recognize the N439K RBD. Of these, 6.8% of the sera tested showed a more than two-fold reduction in binding to N439K RBD compared to controls.
To better understand the effect of the mutation on monoclonal antibody binding, the scientists screened a panel of 140 monoclonal antibodies isolated from individuals who recovered from a SARS-CoV-2 infection, which is a sample representative of antibodies targeting RBD generated after infection, as well as therapeutic antibodies in clinical development or already approved for emergency use authorization (REGN10933, REGN10987, LY-CoV555 and S309).
Overall, 16.7% of monoclonal antibodies demonstrated a more than two-fold reduction in RBD binding in response to the N439K mutation. RBD binding competition experiments with ACE2 and three structurally distinct epitopes on RBD revealed that N439K-sensitive monoclonal antibodies were enriched for one of the epitopes (S2H14 / site I) and showed no blockade of the N439K. ACE2. This is consistent with the positioning of the N439K mutation at the edge of RBM.
Importantly, the N439K mutation enabled the pseudoviruses to resist neutralization by a monoclonal antibody approved by the United States Food and Drug Administration (FDA) for emergency use as part of a two antibody cocktail (LY -CoV555). Resistance to an antibody in a cocktail could reduce the overall effectiveness of monotherapy treatment, according to the authors.
To minimize the effect of SARS-CoV-2 monoclonal antibody escape mutations, the authors suggested that researchers should develop monoclonal antibodies with epitopes that are highly resistant to viral leakage, such as epitopes conserved outside of the body. RBM, or screen patients for the presence of resistant variants before drug administration.
An additional challenge for studying SARS-CoV-2, according to Snell, is the limited amount of sequencing. With more than 90 million reported cases of COVID-19, only around 350,000 virus variants have been sequenced.
“It’s only 0.4% – just the tip of the iceberg,” Snell explained. “This highlights the need for broad surveillance, a detailed understanding of the molecular mechanisms of mutations, and the development of therapies with a high barrier to resistance against variants circulating today and those which will emerge in the future.
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