A computational study shows that dozens of mutations help the virus’ spike protein evade antibodies that target SARS-CoV-2.
Credits:Image: CDC; Christine Daniloff, MIT
Creationist mode: 
Scientists at the Massachusetts Institute of Technology (MIT) have discovered how the omicron variant of the SARS-CoV-2 virus, currently causing the largest wave of new and repeat infections yet in the current pandemic, manages to evade the antibodies we produce in response to either vaccinations or earlier infections.
It can do this because of the large number of mutations in the spike proteins that the antibodies would normally bind to, making it difficult for the antibodies to bind to and neutralize the virus particles to prevent them entering the cells.
The article by Anne Trafton of the MIT News Office explains what was discovered and how:
A new study from MIT suggests that the dozens of mutations in the spike protein of the Omicron variant help it to evade all four of the classes of antibodies that can target the SARS-CoV-2 virus that causes Covid-19.As any Intelligent [sic] Design advocate will argue, a combination of just the right mutations arising together is so vastly improbable that it must have been intelligently designed. So the Omicron variant must be the intended outcome of intervention by their divine malevolence for the purpose of giving the spiralling arms race between it and medical science, another twist.
It is important to get a more comprehensive picture of the many mutations seen in Omicron, especially in the context of the spike protein, given that the spike protein is vital for the virus’s function, and all the major vaccines are based on that protein. There is a need for tools or approaches that can rapidly determine the impact of mutations in new virus variants of concern, especially for SARS-CoV-2.This includes antibodies generated by vaccinated or previously infected people, as well as most of the monoclonal antibody treatments that have been developed, says Ram Sasisekharan, the Alfred H. Caspary Professor of Biological Engineering and Health Sciences and Technology (HST) at MIT
Professor Ram Sasisekharan, Senior author
Alfred H. Caspary professor of Biological Engineering and Health Sciences and Technology
Massachusetts Institute of Technology
Cambridge, MA, USA
Using a computational approach that allowed them to determine how mutated amino acids of the viral spike protein influence nearby amino acids, the researchers were able to get a multidimensional view of how the virus evades antibodies. According to Sasisekharan, the traditional approach of only examining changes in the virus’ genetic sequence reduces the complexity of the spike protein’s three-dimensional surface and doesn’t describe the multidimensional complexity of the protein surfaces that antibodies are attempting to bind to.
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What’s good about vaccines is they don’t just generate B cells, which produce the monoclonal [antibody] response, but also T cells, which provide additional forms of protection.Even though Omicron is able to evade most antibodies to some degree, vaccines still offer protection, Sasisekharan says.
With the network approach, you’re looking at that amino acid residue in the context of its neighborhood and environment. When we started to move away from the one-dimensional sequence space toward multidimensional network space, it became evident that critical information about the interaction of an amino acid in its three-dimensional environment in the protein structure is lost when you look at just the one-dimensional sequence space.
Professor Ram Sasisekharan
Antibody escape
After the Omicron variant emerged last November, Sasisekharan and his colleagues began to analyze its trimeric spike protein using a network-based computational modeling method they had originally developed several years ago to study the hemagglutinin spike protein on flu viruses. Their technique allows them to determine how mutations in the genetic sequence are related in the three-dimensional space through a network of inter-amino-acid interactions that critically impact the structure and function of the viral protein.
The researchers’ approach, known as amino acid interaction network analysis, evaluates how one mutated amino acid can influence nearby amino acids depending on how “networked” they are — a measure of how much a given amino acid interacts with its neighbors. This yields richer information than simply examining individual changes in the one-dimensional amino acid sequence space, Sasisekharan says.
[…]
Sasisekharan’s lab has previously used this technique to determine how mutations in the hemagglutinin protein of an avian flu virus could help it to infect people. In that study, he and his laboratory identified mutations that could change the structure of hemagglutinin so that it could bind to receptors in the human respiratory tract.
When Omicron emerged, with about three dozen mutations on the spike protein, the researchers decided to rapidly use their method to study the variant’s ability to evade human antibodies. They focused their analysis on the receptor binding domain (RBD), which is the part of the spike protein targeted by antibodies. The RBD is also the part of the viral protein that attaches to human ACE2 receptors and allows the virus to enter cells.
Using their network modeling approach, the researchers studied how each of the mutations on the RBD changes the protein’s shape and affect its interactions with four classes of human antibodies that target SARS-CoV-2. Class 1 and 2 antibodies target the RBD site that binds to the ACE2 receptor, while class 3 and 4 antibodies bind to other parts of the RBD.
The researchers compared the Omicron variant to the original SARS-CoV-2 virus, as well as the Beta and Delta variants. The Beta and Delta variants have mutations that help them evade class 1 and 2 antibodies, but not class 3 and 4. Omicron, on the other hand, has mutations that affect the binding of all four classes of antibodies.
With Omicron you can see a significant number of sites being perturbed compared to Beta and Delta. From the original strain to the Beta strain, and then the Delta strain, there is a general trend towards a greater ability to escape.Those perturbations allow the virus to evade not only antibodies generated by vaccination or previous SARS-CoV-2 infection, but also many of the monoclonal antibody treatments that pharmaceutical companies have developed.
Our hope is that as we understand the viral evolution, we’re able to hone in on regions where we think that any perturbation would cause instability to the virus, so that they would be the Achilles heels, and more effective sites to target.
Professor Ram Sasisekharan
As patients began to appear with Omicron infections, researchers and pharmaceutical companies sought to guide treatment by predicting which antibodies were most likely to retain their efficacy against the new variant.
Based on their one-dimensional sequence and single point mutation analyses, pharmaceutical companies believed that their monoclonal antibodies were likely to bind Omicron and not lose any potency. However, when experimental data became available, the Omicron variant was found to substantially escape from monoclonal antibodies known as ADG20, AZD8895, and AZD1061, as predicted by the network analyses in this study, while the activity of monoclonal antibody S309 was also reduced by threefold.
Additionally, the study revealed that some of the mutations in the Omicron variant make it more likely that the RBD will exist in a configuration that makes it easier to grab onto the ACE2 receptor, which may contribute to its enhanced transmissibility.
Creationist mode: 
Of course, as with so many Creationists arguments this ignores reality and relies on ignorant incredulity.
The fact is that, in a process that can produce trillions of new viruses from the few hundreds or thousands in the initial viral load, the one-in-a-billion chance of any particular combination of mutations arising happens a thousand times on average. In a population with millions of unvaccinated people, the probability is very high that a novel variant which is better able to spread and infect people, including those with immunity to the earlier variants, will arise frequently. Omicron is just the latest in a sequence of such variants, and there will be others so long as there is a large pool of unvaccinated people for them to evolve in.
The MIT team's findings are published, open access, in Cell Reports Medicine:
HighlightsIf you are a Creationist, then, you have two choices:
Summary
- Network analyses offer distinct insights into RBD–neutralizing Ab interactions
- Omicron mutations broadly and deeply perturb networks across RBD epitope classes
- Networks capture indirect effects of Omicron mutations on Ab escape potential
- Omicron mutations provide plausible structural rationale for enhanced transmission
The Omicron variant features enhanced transmissibility and antibody escape. Here, we describe the Omicron receptor binding domain (RBD) mutational landscape using amino acid interaction (AAI) networks, which are well-suited for interrogating constellations of mutations that function in an epistatic manner. Using AAI, we map Omicron mutations directly and indirectly driving increased escape breadth and depth in class 1-4 antibody epitopes. Further, we present epitope networks for authorized therapeutic antibodies and assess perturbations to each antibody’s epitope. Since our initial modeling following the identification of Omicron, these predictions have been realized by experimental findings of Omicron neutralization escape from therapeutic antibodies ADG20, AZD8895, and AZD1061. Importantly, the AAI predicted escape resulting from indirect epitope perturbations was not captured by previous sequence or point mutation analyses. Finally, for several Omicron RBD mutations we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBDdown-RBDdown interface.
Miller, N.L., Clark, T., Raman, R., Sasisekharan, R.
Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor binding domain
Cell Reports Medicine (2022), doi: 10.1016/j.xcrm.2022.100527.
Copyright: © 2022 The authors. Published by Elsevier Inc.
Open access
Reprinted under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International license (CC BY-NC-ND 4.0)
- You can ascribe this clearly malevolent piece of redesign to your beloved intelligent [sic] designer and continue to argue that the sheer number of ‘right’ mutations needed to get the desired result proves intelligent intervention. This will tell the world your beloved designer is a malevolent deity who is actively working to make people sick and die and has gone into competition with medical science to make sure it's design keeps on doing that, while ignoring the 'fact' that it also designed the immune system that medical science is using against its design and is now stupidly treating its design, which was intended to protect us against its parasites, as a problem to be overcome.
- You can go against the dogmas of your cult and do what people who understand science do - ascribe it to an evolutionary process in which no intelligence or intent was involved - which lets your favourite deity off the hook, explains the appearance of design and explains the uncaring nature of the process and its random victims.
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