Antibody therapeutics and vaccines are among our last resort to end the raging COVID-19 pandemic. They, however, are prone to over 1,800 mutations uncovered by a Mutation Tracker  . It is urgent to understand how  vaccines and antibodies in the development would be impacted by mutations . In this work, we first study the mechanism, frequency, and ratio of mutations on the spike (S ) protein, which is the common target of most COVID-19 vaccines and antibody therapies . Additionally, we build a library of antibody structures and analyze their 2D and 3D characteristics. Moreover, we predict the mutation-induced binding free energy (BFE) changes for the complexes of S protein and antibodies or ACE2. By integrating genetics, biophysics, deep learning, and algebraic topology, we deduce that some of the mutations such as M153I, S254F, and S255F may weaken the binding of S protein and antibodies , and potentially disrupt the efficacy and reliability of antibody therapies and vaccines in the development. We provide a strategy to prioritize the selection of mutations for designing vaccines or antibody cocktails.%DIFDELCMD < \end{abstract} %DIFDELCMD < %%% \\%DIF > existing RBD mutations, including those variants recently found in the United Kingdom (UK) and South Africa, are binding-strengthen mutations, resulting in more infectious COVID-19 variants. We discover the disparity between the extreme values of RBD mutation-induced BFE strengthening and weakening of the bindings with antibodies and ACE2, suggesting that SARS-CoV-2 is at an advanced stage of evolution for human infection, while the human immune system is able to produce optimized antibodies. This discovery implies the vulnerability of current vaccines and antibody drugs to new mutations. Our predictions were validated by comparison with more than 1,400 deep mutations on the S protein RBD. Our results show the urgent need to develop new mutation-resistant vaccines and antibodies and to prepare for seasonal vaccinations.
Antibody therapeutics and vaccines are among our last resort to end the raging COVID-19 pandemic. They, however, are prone to over 5,000 mutations on the spike (S) protein uncovered by a Mutation Tracker based on over 200,000 genome isolates . It is imperative to understand how mutations would impact vaccines and antibodies in the development . In this work, we study the mechanism, frequency, and ratio of mutations on the S protein . Additionally, we use 56 antibody structures and analyze their 2D and 3D characteristics. Moreover, we predict the mutation-induced binding free energy (BFE) changes for the complexes of S protein and antibodies or ACE2. By integrating genetics, biophysics, deep learning, and algebraic topology, we reveal that most of 462 mutations on the receptor-binding domain (RBD) will weaken the binding of S protein and antibodies and disrupt the efficacy and reliability of antibody therapies and vaccines %DIFDELCMD < \end{abstract} %DIFDELCMD < %%% . A list of 31 vaccine escape mutants is identified, while many other disruptive mutations are detailed as well. We also unveil that about 65\\%DIF > existing RBD mutations, including those variants recently found in the United Kingdom (UK) and South Africa, are binding-strengthen mutations, resulting in more infectious COVID-19 variants. We discover the disparity between the extreme values of RBD mutation-induced BFE strengthening and weakening of the bindings with antibodies and ACE2, suggesting that SARS-CoV-2 is at an advanced stage of evolution for human infection, while the human immune system is able to produce optimized antibodies. This discovery implies the vulnerability of current vaccines and antibody drugs to new mutations. Our predictions were validated by comparison with more than 1,400 deep mutations on the S protein RBD. Our results show the urgent need to develop new mutation-resistant vaccines and antibodies and to prepare for seasonal vaccinations.
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1,800 mutations
5,000 mutations on the spike (S) protein
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based on over 200,000 genome isolates
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urgent
imperative
A
mutations would impact
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would be impacted by mutations
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first
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spike (S ) protein, which is the common target of most COVID-19 vaccines and antibody therapies
S protein
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build a library of
use 56
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deduce that some of the mutations such as M153I, S254F, and S255F may
reveal that most of 462 mutations on the receptor-binding domain (RBD) will
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, and potentially
and
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in the development. We provide a strategy to prioritize the selection of mutations for designing vaccines or antibody cocktails.
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. A list of 31 vaccine escape mutants is identified, while many other disruptive mutations are detailed as well. We also unveil that about 65