  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. A list of 31 vaccine escape mutants is identified,
while many other disruptive mutations are detailed as well. We also unveil that
about 65\% 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.
