Source: Medical News-SARS-CoV-2 Research  Dec 05, 2021  8 months ago
BREAKING! Harvard Study Reveals That SARS-CoV-2 Is “Shape-Shifter” When It Comes To Evading Vaccines And Portends Omicron Immune Evasiveness!
BREAKING! Harvard Study Reveals That SARS-CoV-2 Is “Shape-Shifter” When It Comes To Evading Vaccines And Portends Omicron Immune Evasiveness!
Source: Medical News-SARS-CoV-2 Research  Dec 05, 2021  8 months ago
A new study by researchers from Harvard Medical School reveals that the SARS-CoV-2 can cause changes to the conformational formats of the receptor binding domain (RBD) structure in order to evade neutralizing effects of antibodies produced as a result of natural immunity or induced by vaccine.

Numerous studies have examined the impact of SARS-CoV-2 variants on neutralizing antibody activity after they have become dominant strains.
The study team evaluated the consequences of further viral evolution. The team demonstrated mechanisms through which the SARS-CoV-2 receptor binding domain (RBD) can tolerate large numbers of simultaneous antibody escape mutations and show that pseudotypes containing up to seven mutations, as opposed to the one to three found in previously studied variants of concern, are more resistant to neutralization by therapeutic antibodies and serum from vaccine recipients.
The study team also identified an antibody that binds the RBD core to neutralize pseudotypes for all tested variants but show that the RBD can acquire an N-linked glycan to escape neutralization.
The study findings portend continued emergence of escape variants as SARS-CoV-2 adapts to humans.
The study findings were published in the peer reviewed journal: Science.

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The study models future SARS-CoV-2 mutations and forecasts their ability to evade immune defenses developed by vaccines and antibody-based treatments.
Interestingly, since the study was completed, several of the predicted mutations appeared in omicron, the most recently identified SARS-CoV-2 variant, offering insight into how omicron might be able to escape immune defense generated by mRNA vaccines and monoclonal antibody treatments for COVID-19.
The study team modeled their predictions of future mutations using a combination of variables, including rare mutations documented in immunocompromised patients, existing SARS-CoV-2 genotypes, and the virus’s current molecular structure and behavior.
Significantly, the study findings highlight the ability of SARS-CoV-2 to shape-shift, underscoring the likelihood of new variants that contain multiple high-risk mutations and are capable of evading antibody-based treatments and vaccines.
The research findings also the urgent need to help curb viral evolution and future mutations through mitigation measures and by ensuring global immunity through mass vaccination.
The study team in an effort to predict the future evolutionary maneuvers of SARS-CoV-2, identified several likely mutations that would allow the virus to evade immune defenses, including natural immunity acquired through infection and developed from vaccination as well as antibody-based treatments.
The study was designed to gauge how SARS-CoV-2 might evolve as it continues to adapt to its human hosts and in doing so to help public health officials and scientists prepare for future mutations.

Structure of intra-host evolved RBD bound to human ACE2.
(A) Key RBD substitutions discussed in the manuscript and the SARS-CoV-2 variants that contain them. (B) Day 146* RBD/ACE2 ectodomain X-ray crystal structure. RBD residues that are mutated in variants discussed in the text are shown. Boxed residues are mutated in the day 146* RBD as compared to the Wuhan-Hu-1 (wild-type) SARS-CoV-2 RBD. RBM: receptor binding motif. *In addition to the mutations that are shown, the Delta +3 variant contains an additional RBD mutation that is not shown in the schematic diagram. (C) Wild-type RBD ACE2 contacts near N501RBD (PDB ID: 6M0J) (2). (D) Day 146* RBD contacts near Y501RBD. (E) Wild-type SARS-CoV-2 RBD ACE2 interactions near Q493RBD. (F) Day 146* RBD interactions near K493RBD. (G) cryo-EM structure of the SARS-CoV-2 RBD bound to the C1C-A3 antibody Fab. RBD residues discussed in the text are labeled.

Most interestingly as the study was nearing publication, a new variant of concern, named omicron, entered the scene and was subsequently found to contain several of the antibody-evading mutations the researchers predicted in the newly published paper.
As of December 5th, omicron has been identified in 30 countries outside the African continent and in another 10 in Africa itself. The list is growing daily and the case loads are increasing by the hour.
The study team however cautions that the study findings are not directly applicable to omicron because how this specific variant behaves will depend on the interplay among its own unique set of mutations ie at least 32 in the viral spike protein and on how it competes against other active strains circulating in populations around the world.
Nonetheless, the study team said, the study gives important clues about particular areas of concern with omicron, and also serves as a primer on other mutations that might appear in future variants.
Senior author Dr Jonathan Abraham, assistant professor of microbiology in the Blavatnik Institute at Harvard Medical School and an infectious disease specialist at Brigham and Women’s Hospital told Thailand Medical News, “Our study findings suggest that great caution is advised with omicron because these mutations have proven quite capable of evading monoclonal antibodies used to treat newly infected patients and antibodies derived from mRNA vaccines.”
It should be noted however that the study team did not study response to antibodies developed from non-mRNA vaccines.
Importantly the longer the virus continues to replicate in humans, Dr Abraham noted, the more likely it is that it will continue to evolve novel mutations that develop new ways to spread in the face of existing natural immunity, vaccines, and treatments.
Hence that means that public health efforts to prevent the spread of the virus, including mass vaccinations worldwide as soon as possible, are crucial both to prevent illness and to reduce opportunities for the virus to evolve.
The study findings also highlight the importance of ongoing anticipatory research into the potential future evolution of not only SARS-CoV-2 but other pathogens as well, the researchers said.
Study co-lead author Katherine Nabel, a fifth-year student in the Harvard/MIT MD-PhD Program added, “To get out of this pandemic, we need to stay ahead of this virus, as opposed to playing catch up. Our approach is unique in that instead of studying individual antibody mutations in isolation, we studied them as part of composite variants that contain many simultaneous mutations at once-we thought this might be where the virus was headed. Unfortunately, this seems to be the case with omicron.”
Numerous studies have looked at the mechanisms developed in newly dominant SARS-CoV-2 strains that enable the virus to resist the protective power of antibodies to prevent infection and serious disease.
Instead of waiting to see what the next new variant might bring, Dr Abraham and his team set out to determine how possible future mutations might impact the virus’s ability to infect cells and to evade immune defenses, work that he did in collaboration with colleagues from HMS, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Pilgrim Health Care Institute, Harvard T.H. Chan School of Public Health, Boston University School of Medicine and National Emerging Infectious Diseases Laboratories (NEIDL), and AbbVie Bioresearch Center.
In order to estimate how the virus might transform itself next, the study team followed clues in the chemical and physical structure of the virus and looked for rare mutations found in immunocompromised individuals and in a global database of virus sequences.
In lab-based studies using non-infectious virus-like particles, the study team found combinations of multiple, complex mutations that would allow the virus to infect human cells while reducing or neutralizing the protective power of antibodies.
The study team focused on a part of the coronavirus’s spike protein called the receptor-binding domain, which the virus uses to latch on to human cells. The spike protein allows the virus to enter human cells, where it initiates self-replication and, eventually, leads to infection.
Most antibodies function by locking on to the same locations on the virus’s spike protein receptor-binding domain to block it from entering cells and causing infection.
Typically, mutations and evolution are a normal part of a virus’s natural history. Every time a new copy of a virus is made, there’s a chance that a copy error ie a genetic typo might be introduced. As a virus encounters selective pressure from the host’s immune system, copy errors that allow the virus to avoid being blocked by existing antibodies have a better chance of surviving and continuing to replicate.
Mutations that allow a virus to evade antibodies in this way are known as escape mutations.
The study team demonstrated that the virus could develop large numbers of simultaneous escape mutations while retaining the ability to connect to the receptors it needs to infect a human cell.
The researchers worked with so-called pseudotype viruses, lab-made stand-ins for a virus constructed by combining harmless, noninfectious virus-like particles with pieces of the SARS-CoV-2 spike protein containing the suspected escape mutations.
Importantly the experiments showed that pseudo-type viruses containing up to seven of these escape mutations are more resistant to neutralization by therapeutic antibodies and serum from mRNA vaccine recipients.
It should be noted that this level of complex evolution had not been seen in widespread strains of the virus at the time the study team began their experiments.
However, with the emergence of the omicron variant, this level of complex mutation in the receptor-binding domain is no longer hypothetical.
It should also be noted that the delta variant had only two mutations in its receptor binding domain, and the pseudotypes Dr Abraham’s team studied had up to seven mutations, omicron appears to have fifteen, including several of the specific mutations that his team analyzed.
The study team in a series of experiments, performed biochemical assays to see how antibodies would bind to spike proteins containing escape mutations.
Significantly several of the mutations, including some of those found in omicron, enabled the pseudotypes to completely evade therapeutic antibodies, including those found in monoclonal antibody cocktail therapies.
The study team also found one antibody that was able to neutralize all of the tested variants effectively.
However, they also noted that the virus would be able to evade that antibody if the spike protein developed a single mutation that adds a sugar molecule at the location where the antibody binds to the virus. That, in essence, would prevent the antibody from doing its job.
The study team noted that in rare instances, circulating strains of SARS-CoV-2 have been found to gain this mutation. When this happens, it is likely the result of selective pressure from the immune system, the study team said.
Comprehending the role of this rare mutation, they added, is critical to being better prepared before it emerges as part of dominant strains.
Although the study team did not directly study the pseudotype virus’s ability to escape immunity from natural infection, findings from the team’s previous work with variants carrying fewer mutations suggest that these newer, highly mutated variants would also adeptly evade antibodies acquired through natural infection.
It was found in another experiment where the pseudotypes were exposed to blood serum from individuals who had received an mRNA vaccine, some of the highly mutated variants caused the serum from single-dose vaccine recipients to completely lose the ability to neutralize the virus.
However, in samples taken from people who had received a second dose of vaccine, the vaccine retained at least some effectiveness against all variants, including some extensively mutated pseudotypes.
The study team notes that their analysis suggests that repeated immunization even with the original spike protein antigen may be critical to countering highly mutated SARS-CoV-2 spike protein variants.
Dr Abraham concluded, “This virus is a shape-shifter. The great structural flexibility we saw in the SARS-CoV-2 spike protein suggests that omicron is not likely to be the end of the story for this virus.”

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