COVID-19 News: Study Reveals That Combination Of E484K, K417N and N501Y Mutations In New Variants Can Lead To Immune Evasion And Reinfections

COVID-19 News: Scientists from California based biotech company, Immunity Bio Inc have in a new study found that the combination Of E484K, K417N and N501Y mutations found in various new emerging SARS-CoV-2 variants can lead to immune evasion and reinfections even in those with previous immunity. The study findings also indicate that all the current COVID-19 vaccines would most probably be ineffective against these combination of mutations.


 
According to the study team, rapidly spreading SARS-CoV-2 variants present not only an increased threat to human health due to the confirmed greater transmissibility of several of these new strains but conformational changes induced by these mutations that may render first-wave SARS-CoV-2 convalescent sera, vaccine-induced antibodies, or recombinant neutralizing antibodies (nAbs) ineffective.
 
In order to be able to assess the risk of viral escape from neutralization by first-wave antibodies, we leveraged our capability for Molecular Dynamic (MD) simulation of the spike receptor binding domain (S RBD) and its binding to human angiotensin-converting enzyme 2 (hACE2) to predict alterations in molecular interactions resulting from the presence of the E484K, K417N, and N501Y variants found in the South African 501Y.V2 strain, alone and in combination.
 
The study team reports here the combination of E484K, K417N and N501Y results in the highest degree of conformational alterations of S RBD when bound to hACE2, compared to either E484K or N501Y alone. Both E484K and N501Y increase affinity of S RBD for hACE2 and E484K in particular switches the charge on the flexible loop region of RBD which leads to the formation of novel favorable contacts. Enhanced affinity of S RBD for hACE2 very likely underpins the greater transmissibility conferred by the presence of either E484K or N501Y; while the induction of conformational changes may provide an explanation for evidence that the 501Y.V2 variant, distinguished from the B.1.1.7 UK variant by the presence of E484K, is able to escape neutralization by existing first-wave anti-SARS-CoV-2 antibodies and re-infect COVID-19 convalescent individuals.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.01.13.426558v1
 
The study shows how the 501Y.V2 variant of the SARS-CoV-2, characterized by several mutations, is able to escape neutralization by present first-wave anti-SARS-CoV-2 antibodies and potentially re-infect COVID-19 convalescent individuals.
 
While many new variants of SARS-CoV-2 emerge and subsequently displace first-wave viruses, it is pivotal not only to appraise their relative transmissibility and virulence in causing coronavirus disease (COVID-19), but also their propensity to escape antibody neutralization.
 
Most important are variants harboring mutations that can affect the interaction of the viral spike receptor-binding domain (S RBD) with the viral receptor on host cells, angiotensin-converting enzyme 2 (ACE2), which provides an entry point for the coronavirus.
 
New variants with a greater binding affinity for ACE2 are likely to spread more.
 
Also it should be noted that transmissibility is linked to mortality, as an inevitable increase in infection rates caused by the novel variants will result in higher disease and death toll.
 
Moreover these dire repercussions of more rapid and widespread infections can also be compounded by a loss of efficacy of currently available antibody-based treatments and vaccines and a decrease of protective immunity in individuals previously infected with a 'first wave' virus.
 
To improve our understanding of the risks posed by an individual or combined mutations in these 'second wave' variants, the study team from Immunity Bio company in California conducted a computational analysis of interactions of the S RBD with human ACE2.
 
The study team utilized millisecond-scale MD simulation methods 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 spike glycoprotein conformation.
 
For the study, the wild-type ACE2/RBD complex was built from the cryo-electron microscopy structure. Moreover, ten copies of each RBD mutant were minimized, equilibrated and simulated, and the minimization processed occurred in two phases.
 
Principal component analysis (PCA) was pursued by using the full set of simulations of the triple mutant, E484K and N501Y systems. Simulation structures were extrapolated onto the eigenvectors for every mutation system.
 
Interestingly the study revealed greater affinity of K484 S RBD for ACE2 in comparison to E484, as well as the greater probability of modified conformation when compared to the original structure. This may actually represent mechanisms by which the new 501Y.V2 viral variant was able to replace original SARS-CoV-2 strains.
 
Most significantly, both E484K and N501Y mutations were shown an increase affinity of S RBD for human ACE2 receptor, while E484K was able to switch the charge on the flexible loop region of RBD, resulting in the formation of novel favorable contacts.
 
The improved affinity is a likely culprit for more rapid spread of this variant due to greater transmissibility, which is a prime reason why it is important to track these mutations and act in a timely manner.
 
Importantly, 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 re-infect COVID-19 convalescent individuals.
 
Co-researcher Dr Patrick Soon-Shion told Thailand Medical News, "We believe the MD simulation approach used here similarly represents a tool to be used in the arsenal against the continuing pandemic, as it provides insight into the likelihood mutations alone or in combination may have effects that lessen the efficacy of existing therapies or vaccines.”
 
The study team added, "We suggest vaccines whose efficacies are largely dependent upon humoral responses to the S antigen only are inherently limited by the emergence of novel strains and dependent upon frequent re-design. On the other hand, a vaccine that evokes a vigorous T-cell response is much less subject to changes due to accruing mutations and, thus, provides a better and more efficient approach to protection against this disease. Finally, the ideal vaccine would also incorporate a second, conserved antigen (such as the SARS-CoV-2 nucleocapsid protein), which would likely elicit an effective humoral and cell-mediated immune response - even when confronted with a rapidly changing virus.”
 
Though not the subject of the study described here, the team from Imminuty Bio Inc are developing a dual-antigen human adenovirus serotype 5 (Ad5) platform-based vaccine that delivers both a spike protein with a linker to increase cell surface expression and humoral responses (S-Fusion) and the highly antigenic and conserved nucleocapsid (N) protein with a signal sequence (an Enhanced T-cell Stimulation Domain, ETSD) to direct it to subcellular compartments that enhance MHC I and II responses. https://www.medrxiv.org/content/10.1101/2020.11.04.20225417v1
 
It is the study team’s belief that the vaccine, hAd5 S-Fusion + N-ETSD, due to its ability to elicit cell-mediated in addition to humoral immune responses, as shown in both a rodent model and non-human primates , offers hope to those regions such as South Africa wherein dangerous variants of SARS-CoV-2 have swept the country. https://www.biorxiv.org/content/10.1101/2020.07.29.227595v1
https://www.biorxiv.org/content/10.1101/2020.12.08.416297v1
 
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