Triple Mutant Variant Emerges In India And Fast Spreading! SARS-CoV-2 Antibody Escape Variants Emerging As Result Of Deletions In The Spike NTD.
A new triple mutant variant of the SARS-CoV-2 coronavirus
has emerged in India and is fast spreading all over the country. https://www.biorxiv.org/content/10.1101/2021.04.22.440932v1
Parts of india including Delhi (56%), Mumbai (up to 75%) and Hyderabad (54%) have reported high seroprevalence. But in spite of the high prevalence of protective antibodies and previous fall in cases, the number of cases in these cities is once again rising quickly.
Scientists have advanced various explanations, including circulation of the new triple mutant B.1.617 variant
. Phylogenetic analysis revealed that the predominant clade in circulation was a distinct newly identified lineage B.1.617 possessing common signature mutations D111D, G142D, L452R, E484Q, D614G and P681R, in the spike protein including within the receptor binding domain (RBD). Of these, the mutations at residue positions 452, 484 and 681 have been reported in other globally circulating lineages. The structural analysis of RBD mutations L452R and E484Q along with P681R in the furin cleavage site, may possibly result in increased ACE2 binding and rate of S1-S2 cleavage resulting in better transmissibility. The same two RBD mutations indicated decreased binding to selected monoclonal antibodies (mAbs) and may affect their neutralization potential.
The emergence of such local variants through the accumulation of convergent mutations during the COVID-19 pandemic needs to be further investigated for their public health impact in the rest of the country and its possibility of becoming a VOC.
The B.1.617 variant has five mutations in the spike glycoprotein, including L452R and E484Q; Variants with L452R have also been found in California and shown to have high transmissibility. Variants with E484Q or E484K have been found to have decreased neutralization tendency to protective antibodies, i.e. they can escape
the immune system more. Notably, a variant with the E484K mutation was associated with a recent surge in Brazil despite high seroprevalence.
Unfortunately India’s genomic sequencing programme has been slow is low, and researchers are still investigating B.1.617’s increased infectivity and immune escape behavior. But a sudden rise in cases along with a high detection rate of this variant in sequencing, up to 80% in samples from Maharashtra, suggests that it is circulating in the afflicted population.
Interestingly densely populated areas in Mumbai, like Dharavi, showed a high seroprevalence of 75% in October. The area also reported no cases in late December 2020.
However while cases around the country were still in decline in early February, Mumbai once again began reporting a growing number of COVID-19 cases, and continued into March. The city was quickly followed by the state and then the rest of the country. A similar situation has also been reported from Brazil, where cases started to surge again after a decline, even though Brazil had reported a seroprevalence of up to 76%.
One can understand viral evolution better by contemplating the Darwinian law of survival ie ‘the survival o
f the fittest’.
As an example, doctors prescribe multiple antibacterial agents to treat bacterial diseases like tuberculosis. This is done to evade the high risk of emergence of fitter bacteria, with drug resistance, when a single antibacterial agent (suboptimal therapy) is used.
In the same way, neutralizing antibodies to the spike protein, derived from natural infection or a vaccine, and COVID-appropriate behaviour such as use of masks, physical distancing, washing hands are in a sense ‘antiviral’ in that they prevent the spread of disease in a population. So variants of concern may emerge when this ‘antiviral’ response is suboptimal, making the virus resistant (fitter
) to either or both the antibodies (increased rate of reinfections) and COVID-appropriate behavior (increased transmissibility).
It was found that densely populated pockets of the country reported a higher prevalence of protective antibodies and were in line with the rapid fall in cases in these areas.
However the virus was still spreading at much lower levels in the susceptible population. On the other hand, the complete lack of COVID-appropriate behavior across the nation was apparent. This included religious congregations, election rallies and even weddings.
A high prevalence of protective antibodies together with a lack of appropriate behavior would have been a suboptimal ‘antiviral’ response. This would have kept the ‘immune’ population constantly exposed to the virus and created fertile ground for the viruses to select useful mutations under the pressure of protective antibodies.
Experts have observed another well-established suboptimal ‘antiviral’ response in patients with compromised immune systems (such as with HIV or cancer) or those who were transferred convalescent plasma. There have been reports of increased viral evolution in these patients, with some harboring viral particles in the body for months. These conditions have been linked to faster viral evolution. It is important here to highlight the role of vaccines with regard to such patients.
Dr Trevor Bedford, an associate professor of genome sciences at the University of Washington told Thailand Medical News, “The currently observed rate of evolution in S1 (in SARS-CoV-2) is rapid compared to the equivalent domain in influenza virus.”
Dr Bedford has also said that its evolution would depend on whether the virus undergoes convergence in its evolution i.e. mutates until it has a specific set of mutations, and no further. This would suggest, in Dr Bedford’s words, that “SARS-CoV-2 will have arrived at its destination having stacked up all the relevant mutations.” This may mean, then, that we may not observe such waves and that we can easily control the virus’s spread by establishing vaccine-induced herd immunity.
However Dr Bedford warned that the virus could evolve the other way as well ie taking the path of divergence. This is associated with an increased rate of viral evolution and seasonality associated with persistent surges. If this turns out to be true, the virus may continue to evolve and vaccines may need to be modified periodically according to the strain circulating at a given time.
It is being observed that the virus is currently evolving rapidly and new variants will emerge. This in turn means the current surge could persist for longer and that there could be some more surges in future. If we are to curb its spread and evolution without overburdening our healthcare infrastructure, we must wear masks properly, maintain physical distances and wash our hands properly and regularly.
SARS-CoV-2 Antibody Escape Variants Emerging As Result Of Deletions In The Spike N-terminal Domain (NTD)
Another alarming study published in the last 24 hours reveals that the SARS-CoV-2 coronavirus is aggressively mutating via deletions in the Spike N-terminal Domain (NTD) to escape antibodies be it those induced by vaccines, convalescent plasma or by monoclonal or polyclonal therapeutics.
Mutations will still appear as long as the virus continues to replicate within hosts, as a matter of mere probabilities. So far, selective pressures toward the virus might have given rise to variants with a fitness advantage based on infection, replication, or transmission efficiency, although potential evasion from antibodies might result as a by-product or due to immune pressure within an individual during chronic COVID-19. As the population becomes less naive to the virus through natural infection or vaccination, the selective pressure to escape acquired immune responses will be higher and will force the virus to find a way. Variants with antigenic drift would introduce antigenic novelty and enable reinfection, as happens with influenza A, whose hemagglutinin protein requires a very small number of mutations to evade pre-existing immunity.
A recent research paper by Dr Kevin R. McCarthy from the University of Pittsburgh School of Medicine, promptly observed a pattern of recurrent deletions in four discrete regions of the N-terminal Domain (NTD) of the Spike protein, which provide resistance to antibody neutralization, suggesting convergent evolution due to selective pressure and antigenic drift. https://science.sciencemag.org/content/371/6534/1139.abstract
Given that coronaviruses encode an exoribonuclease that provides a proofreading function during the replication, the appearance of variants was at first expected to be marginal. Dr McCarthy’s work anticipated the events, as these deletions were found to be present in some of the lineages causing now a global concern.
These emerging SARS-CoV-2 variants could be distinguished from one another by nucleotide differences and appertained to monophyletic clades, suggesting that within each individual, the repeated pattern of deletions was the result of adaptation and not of onward transmission.
The study team analysed a total of 146,795 sequences in GISAID and identified 1108 with deletions in the S gene with 90% of them occupying four discrete sites within the NTD, which they termed “recurrent deletion regions 1–4” (RDRs).
Though with a degree of variance, RDR1 typically harbored the Δ69–70 deletion, RDR2 the Δ144/145, RDR3 the Δ220, and RDR4 the Δ243–244 deletion. In these RDRs, >97% of the deletions preserved the reading frame, which is largely over the probabilistic rate at which in-frame mutations occur. Besides, the phylogenetic analysis showed independent distinct branches from diverse geographic origins that were followed by onward community transmission, pointing again toward a convergent outcome to evade a common selective pressure.
It is expected that in coming months the COVID-19 pandemic is expected to get far worse and the casualties are expected to rise phenomenally.
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