COVID-19 Alerts: Study By University Of Pittsburgh And Harvard Shows That SARS-Cov-2 Spike Deletion Mutations May Evade Current Vaccine Candidates

COVID-19 Alerts: A new research that is among many that is emerging is indicating that natural deletions in the SARS-CoV-2 spike glycoprotein is driving antibody escape and many of the current vaccine candidates may end up being useless or worse even contribute to the phenomenon of ADE or antibody-dependent enhancement.


 
The new research by scientist from the University of Pittsburg and Harvard Medical School serves as yet another warning of things to come.
 
According to the researchers, Zoonotic pandemics follow the spillover of animal viruses into highly susceptible human populations. Often, pandemics wane, becoming endemic pathogens. Sustained circulation requires evasion of protective immunity elicited by previous infections. The emergence of SARS-CoV-2 has initiated a global pandemic. Since coronaviruses have a lower substitution rate than other RNA viruses this gave hope that spike glycoprotein is an antigenically stable vaccine target.
 
However, the study team describes an evolutionary pattern of recurrent deletions at four antigenic sites in the spike glycoprotein. Deletions abolish binding of a reported neutralizing antibody. Circulating SARS-CoV-2 variants are continually exploring genetic and antigenic space via deletion in individual patients and at global scales. In viruses where substitutions are relatively infrequent, deletions represent a mechanism to drive rapid evolution, potentially promoting antigenic drift.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.11.19.389916v1
 
Already Thailand Medical news had published another study by researchers from multiple institutions about the rise of antibody resistance once antibody protocols and vaccines are introduced into the general populations. https://www.thailandmedical.news/news/experts-warn-that-once-vaccines-and-antibodies-are-used-frequently-in-a-population,-more-antibody-resistant-sars-cov-2-virus-strains-would-emerge
 
The so called claims of early success of several COVID-19 vaccines undergoing clinical trials at present have grabbed the world's attention.
 
This thought-provoking new study however reports that the SARS-CoV-2 spike antibodies elicited by natural infection may not be able to neutralize emerging strains that display deletion mutations in their genomic RNA.
 
The novel SARS-CoV-2 virus is a betacoronavirus, belonging to the coronavirus (CoV) family, including both SARS-CoV and MERS-CoV. These are RNA viruses with very large genomes, about 30 kb in length. The family gets its name from the characteristic 'crown' of spike proteins protruding from the virus's surface.
The spike glycoprotein is the primary viral antigen involved in viral entry into the host target cell. It is also the prime target for most vaccines being developed at present.
 
Should vaccines be unable to induce protective immunity, the COVID-19 pandemic might slowly subside over time to become a n endemic illness, such as influenza but at a high cost of lives. This latter family of viruses has shown the same pattern at least four times over the last 100 years, as have seasonal CoVs like OC43.
 
Often such a  transition is marked by the emergence of mutations in the viral genome, resulting in an altered protein product and therefore disrupts the binding of specific protective antibodies to the viral antigen. Thus, the endemic strain can evade the immune response elicited by earlier strains of the same virus.
 
Such a response was seen with influenza, which has an RNA-dependent RNA polymerase (RdrP) that accumulates numerous errors over the years, finally achieving a very different antigenic profile at the end of this period. However, because of the efficient proofreading apparatus seen with CoV RdRps, the substitution rate of nucleotides is slower relative to other RNA viruses. This has led to the hope that the SARS-CoV-2 spike antigen would remain stable, and that all the currently circulating strains would thus be susceptible to the neutralizing antibodies developed in response to the early vaccines.
 
However, the current study reports that the virus is adapting to the presence of immunity, as signaled by repeated deletion mutations at specific sites of the spike protein, causing the rapid evolution of spike antigenic diversity.
 
To date, these deletions have already been observed both in viral sequences isolated from chronically immunosuppressed patients from all over the world.
 
These specific deletion sites are termed recurrent deletion regions (RDRs), and all four are in the N-terminal domain (NTD) of the spike glycoprotein. All are at defined antigenic sites. One single variant is present in over 2.5% of all isolates from circulating viruses at present.
 
The SARS-CoV-2 coronavirus is therefore finding niches of antigenic variation that enable it to escape neutralization by preventing the binding of the protective antibody to the altered antigen. The escape mutation is also transmitted to other individuals.
 
Interestingly one patient with cancer contracted the virus, and despite treatment with convalescent plasma and remdesivir, was unable to clear the infection. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640888/
 
The virus isolate showed the spike gene had NTD deletions, termed PLTI1. Similar deletions were found in longitudinal samples from eight patients, in the GISAID database, with six being identical or near-identical to PTLI1. Each of these deletion variants stemmed from an early intact spike sequence. Also, among these patients, seven had individually unique patterns of substitutions over the whole period of sample collection, refuting the hypothesis that the deletions came from other individuals at the hospital or from the community.
 
Corresponding author of the study Dr Kevin R. McCarthy from the Center for Vaccine Research, University of Pittsburgh School of Medicine told Thailand Medical News, "The most parsimonious explanation is that each deletion arose independently in response to a common and strong selective pressure."
 
The study team found in GISAID over 1,000 viruses with spike deletions, and 90% of these were in the RDRs. Most of these apparently arose during replication. Over 90% were in-frame deletions, consisting of 3 or sets of 3 nucleotides being deleted. The eventual outcome was an open reading frame rather than a stop codon, in over 97% of deletions in the NTD. In other parts of the spike protein, deletions follow this trend only about a third of the time. In other words, RDRs have an inherent tolerance for deletions and accumulate them.
 
These RDRs may show anywhere from a unique single-virus deletion to those which are found in multiple variants. Of the four RDRs, 1 and 3 typically show a single-site predilection, belong to clade G and GR and are mostly from Europe. This indicates a selection advantage for certain deletions in some clades, which are limited to certain regions. Conversely, at the other two, there are a number of overlapping deletions, found in strains from all over the world.
 
Importantly for each of the RDRs, identical deletions have been found in different patients simultaneously, indicating that these strains spread between humans. This is probably due to bouts of viral transmission from infected individuals to others.
 
The geographic and genetic distributions of some RDR variants suggest human-to-human transmission. The team identified, for each RDR, instances where viruses with identical deletions were isolated from different patients around the same time. Two patients in France (male, age 58, EPI_ISL_582112 and female, age 59, EPI_ISL_582120) were found to have viruses that where 100% identical, including a six-nucleotide deletion in RDR1. The team identified a cluster of four individuals in Senegal that shared a three-nucleotide deletion in RDR2 and a deletion in Orf1ab (1605 to1608). These viruses group together among all Senegalese samples. The RDR2 deletion is identical to those in PLTI1, MSK-4, MSK-6 and MSK-8, demonstrating that this mutation arises independently and transmits between humans. Four patients from Ireland had viruses that share a three-nucleotide deletion in RDR3. These sequences form distinct branches among Irish SARS-CoV-2 sequences. A cluster of sequences from Switzerland, from at minimum two individuals, share a nine nucleotide deletion in RDR4.
 
Significantly and alarmingly, the presence of RDR variants acts as a type of escape mutation, allowing the virus to escape from a strong selection pressure applied commonly to all variants. RDR1 and 3 are on one side of the spike NTD, while 2 and 4 are on the other side. Both form antibody epitopes, or binding sites. The neutralizing antibody 4A8 is found to be within the connecting loops where RDR 2 and 4 are located, but binding is abolished by three deletions, one in 4 and two in RDR2. However, these deletions still allowed binding by a monoclonal anti-RBD antibody.
 
It was found that deletions at RDR 1 and 3 allowed binding to occur with either of these antibodies, thus showing that these are on separate sites from the other two. Thus, whether in single RDRs or between pairs of RDRs, the occurrence of recurrent deletions associated with distinct epitopes, leading to the abolition of binding, but allowing the protein to retain its function, shows the change in antigenicity between natural SARS-CoV-2 variants.
 
The study team points out, "The simplicity of using deletion to drive diversity is biologically compelling. Selection pressure rarely operates during a pandemic, since the infection typically resolves rapidly, even before antibody production is complete.”
 
However, during the endemic stage the situation is different, since the presence of antibodies in already recovered individuals, and in people who receive passive immunity in the form of convalescent plasma, or therapeutic monoclonal antibodies, exerts selection pressure on the virus. This will then cause viral variants with the ability to evade these antibodies to be selected.
 
Importantly in individuals, several different variants of the same virus can emerge over time, giving rise to quasispecies.
 
Hence this explains how the same deletion can repeatedly appear in many different individuals with long-standing infection.
 
The study team explained, "SARS-CoV-2 is continuously exploring sequence and antigenic space in different genetic, environmental and geographical contexts. One variant, called Δ69-70, has rapidly become more frequent, forming 2.5% of all sequences in October 2020, up from 0.01% in July 2020.
The change in binding behavior is concerning since many of these deletions are found in strains circulating across the UK, where Phase III trials of a COVID-19 vaccine is ongoing. Such behavior is bound to continue, say the researchers, leading to the endemicity of SARS-CoV-2 infection.” https://science.sciencemag.org/content/369/6504/650
 
Importantly to counter this by up-to-date vaccine development or other strategies, they conclude, "Efforts to track and monitor these recurrent, rapidly arising, geographically widespread variants are vital."
 
SARS-CoV-2 appears to be on a trajectory to become an endemic human pathogen and antigenic sites will continue evolving to evade preexisting immunity. Deletions that rapidly alter entire stretches of amino acids at specific antigenic sites are already playing an important role. Efforts to track and monitor these recurrent, rapidly arising, geographically widespread variants are vital
 
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