A recent study by US researchers shows how the 501Y.V2 variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is characterized by several mutations, is able to escape neutralization by the current first- wave anti-SARS-CoV-2 antibodies and possibly re-infected COVID-19 repairers. The paper is currently available on the bioRxiv * preprint server.
As many variants of SARS-CoV-2 emerge and displace the first-wave viruses, it is important not only to evaluate their relative transmissibility and virulence in the cause of coronavirus (COVID-19) diseases, but also their propensity to escape antibody neutralization.
Of paramount importance are variants that contain mutations that can affect the interaction of the viral vein receptor-binding domain (S RBD) and the viral receptor on host cells, the angiotensin-converting enzyme 2 (ACE2), which provides an entry point for the coronavirus .
Variants with a greater binding affinity for ACE2 are likely to be more widespread. Furthermore, transmissibility has been linked to mortality, as an inevitable increase in infection rates caused by the new variants will result in higher diseases and mortality rates.
However, these serious consequences of faster and more widespread infections can also be exacerbated by the loss of efficacy of currently available antibody-based treatments and vaccines and a decrease in protective immunity in individuals previously infected with a ‘first wave’ virus.
To improve our understanding of the risks associated with an individual or combined mutations in this ‘second wave’ variant, a research group from the California-based ImmunityBio company conducted a computational analysis of the S RBD’s interactions with human ACE2. .
The K484 substitution in the new South African variant increases the affinity of the peak receptor binding domain (S RBD) for ACE2. (a, b) The positions of the E484K (red), K417N (cyan) and N501K (purple) substitutes at the interface of the 501Y.V2 variant S RBD – hACE2 interface are shown. hACE2 residues closest to the mutated RBD residues are expressed as thin sticks. The E484K mutation is located in a very flexible loop region of the interface, K417N in a region with a lower probability of contact, and N501K at a second point of high affinity contact. (c) The range of motion available to the loop containing residue 484 is shown by PCA of MD simulation of a first-wave series11,13. (d) MD simulation performed in the presence of all three replacements shows that the loop area is strongly associated (black arrow) with hACE2. A key contact ion pair is circled. (e) Compared to K484, when E484 (‘wild type’) occurs only with the Y501 variant, the loop is not so strictly associated (arrow).
In silico simulation methods
In this study, the researchers used MD simulation methods at milliseconds to investigate mutations (E484K, K417N and N501Y) at the S RBD-ACE2 interface in the rapidly spreading South African variant 501Y.V2 – and their effects on RBD binding affinity and spiked glycoprotein formation.
The wild-type ACE2 / RBD complex is constructed from the cryon-electron microscopy structure. In addition, ten specimens of each RBD mutant were minimized, equilibrated, and simulated, and the minimum processing occurred in two phases.
Finally, the main component analysis (PCA) was pursued using the complete set of simulations of the triple mutant, E484K and N501Y systems. Simulation structures were coiled on the eigenvectors for each mutation system.
The great escape from neutralization
The study showed a greater affinity of K484 S RBD for ACE2 compared to E484, as well as the greater probability of altered conformation compared to the original structure. It could actually represent mechanisms by which the new 501Y.V2 viral variant could replace original SARS-CoV-2 strains.
More specifically, both E484K and N501Y mutations showed an increase in affinity of S RBD for human ACE2 receptor, whereas E484K was able to change the charge on the flexible loop region of RBD, leading to the formation of new beneficial contacts.
The above improved affinity is probably the culprit for faster spread of this variant due to greater transmissibility, which is the main reason why it is important to detect these mutations and act in a timely manner.
Furthermore, the induction of conformational changes is responsible for the escape of the 501Y.V2 variant (distinguished from the B.1.1.7 UK variant by the presence of E484K mutation) from neutralization by existing anti-SARS-CoV-2 antibodies and again -infected COVID-19 repairers.
Implications for further vaccine design
“We believe that the MD simulation approach used here is also a tool that can be used in the arsenal against the ongoing pandemic, as it provides insight into the likelihood that mutations alone or in combination may have effects that increase the effectiveness of reduce existing treatments or vaccines “, say the authors of this study.
“We suggest that vaccines whose effectiveness is largely dependent on humoral responses to the S antigen are inherently limited by the emergence of new strains and are dependent on frequent redesign,” they add.
On the other hand, a vaccine that elicits a potent T-cell response is much less subject to change due to sequential mutations and therefore offers a better and more effective approach to protection against this disease.
Finally, the ideal vaccine will also contain a second, conserved antigen (such as the SARS-CoV-2 nucleocapsid protein), which is likely to elicit an effective humoral and cell-mediated immune response – even when confronted with a rapidly changing virus.
* Important notice
bioRxiv publishes preliminary scientific reports that are not judged by peers and therefore should not be considered conclusive, should guide clinical practice / health related behavior, or should be treated as established information.