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1. Prediction and mitigation of mutation threats to COVID-19 vaccines and antibody therapies

   https://doi.org/10.1039/d1sc01203g  

   Chen, Jiahui ; Gao, Kaifu ; Wang, Rui ; Wei, Guo-Wei ( May 2021 , Chemical Science)

   null (Ed.)

   Antibody therapeutics and vaccines are among our last resort to end the raging COVID-19 pandemic. They, however, are prone to over 5000 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 will impact vaccines and antibodies in development. In this work, we first study the mechanism, frequency, and ratio of mutations on the S protein which is the common target of most COVID-19 vaccines and antibody therapies. Additionally, we build a library of 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 the 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 antibody disrupting mutants is identified, while many other disruptive mutations are detailed as well. We also unveil that about 65% of the existing RBD mutations, including those variants recently found in the United Kingdom (UK) and South Africa, will strengthen the binding between the S protein and human angiotensin-converting enzyme 2 (ACE2), 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 angiotensin-converting enzyme 2 (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, unfortunately, implies the vulnerability of current vaccines and antibody drugs to new mutations. Our predictions were validated by comparison with more than 1400 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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2. Binding of human ACE2 and RBD of Omicron enhanced by unique interaction patterns among SARS‐CoV ‐2 variants of concern

   https://doi.org/10.1002/jcc.27025  

   Kim, Seonghan ; Liu, Yi ; Ziarnik, Matthew ; Seo, Sangjae ; Cao, Yiwei ; Zhang, X. Frank ; Im, Wonpil ( November 2022 , Journal of Computational Chemistry)

   Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the virus causing COVID‐19, has continued to mutate and spread worldwide despite global vaccination efforts. In particular, the Omicron variant, first identified in South Africa in late November 2021, has become the dominant strain worldwide. Compared to the original strain identified in Wuhan, Omicron features 50 genetic mutations, with 15 mutations in the receptor‐binding domain (RBD) of the spike protein, which binds to the human angiotensin‐converting enzyme 2 (ACE2) receptor for viral entry. However, it is not completely understood how these mutations alter the interaction and binding strength between the Omicron RBD and ACE2. In this study, we used a combined steered molecular dynamics (SMD) simulation and experimental microscale thermophoresis (MST) approach to quantify the interaction between Omicron RBD and ACE2. We report that the Omicron brings an enhanced RBD‐ACE2 interface through N501Y, Q498R, and T478K mutations; the changes further lead to unique interaction patterns, reminiscing the features of previously dominated variants, Alpha (N501Y) and Delta (L452R and T478K). Among the Q493K and Q493R, we report that Q493R shows stronger binding to ACE2 than Q493K due to increased interactions. Our MST data confirmed that the Omicron mutations in RBD are associated with a five‐fold higher binding affinity to ACE2 compared to the RBD of the original strain. In conclusion, our results could help explain the Omicron variant's prevalence in human populations, as higher interaction forces or affinity for ACE2 likely promote greater viral binding and internalization, leading to increased infectivity.

    

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3. Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1

   https://doi.org/10.1038/s41467-022-34506-z  

   Moulana, Alief ; Dupic, Thomas ; Phillips, Angela M. ; Chang, Jeffrey ; Nieves, Serafina ; Roffler, Anne A. ; Greaney, Allison J. ; Starr, Tyler N. ; Bloom, Jesse D. ; Desai, Michael M. ( November 2022 , Nature Communications)

   The Omicron BA.1 variant emerged in late 2021 and quickly spread across the world. Compared to the earlier SARS-CoV-2 variants, BA.1 has many mutations, some of which are known to enable antibody escape. Many of these antibody-escape mutations individually decrease the spike receptor-binding domain (RBD) affinity for ACE2, but BA.1 still binds ACE2 with high affinity. The fitness and evolution of the BA.1 lineage is therefore driven by the combined effects of numerous mutations. Here, we systematically map the epistatic interactions between the 15 mutations in the RBD of BA.1 relative to the Wuhan Hu-1 strain. Specifically, we measure the ACE2 affinity of all possible combinations of these 15 mutations (2¹⁵ = 32,768 genotypes), spanning all possible evolutionary intermediates from the ancestral Wuhan Hu-1 strain to BA.1. We find that immune escape mutations in BA.1 individually reduce ACE2 affinity but are compensated by epistatic interactions with other affinity-enhancing mutations, including Q498R and N501Y. Thus, the ability of BA.1 to evade immunity while maintaining ACE2 affinity is contingent on acquiring multiple interacting mutations. Our results implicate compensatory epistasis as a key factor driving substantial evolutionary change for SARS-CoV-2 and are consistent with Omicron BA.1 arising from a chronic infection.

    

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4. The landscape of antibody binding affinity in SARS-CoV-2 Omicron BA.1 evolution

   https://doi.org/10.7554/eLife.83442  

   Moulana, Alief ; Dupic, Thomas ; Phillips, Angela M ; Chang, Jeffrey ; Roffler, Anne A ; Greaney, Allison J ; Starr, Tyler N ; Bloom, Jesse D ; Desai, Michael M ( February 2023 , eLife)

   The Omicron BA.1 variant of SARS-CoV-2 escapes convalescent sera and monoclonal antibodies that are effective against earlier strains of the virus. This immune evasion is largely a consequence of mutations in the BA.1 receptor binding domain (RBD), the major antigenic target of SARS-CoV-2. Previous studies have identified several key RBD mutations leading to escape from most antibodies. However, little is known about how these escape mutations interact with each other and with other mutations in the RBD. Here, we systematically map these interactions by measuring the binding affinity of all possible combinations of these 15 RBD mutations (2 15 =32,768 genotypes) to 4 monoclonal antibodies (LY-CoV016, LY-CoV555, REGN10987, and S309) with distinct epitopes. We find that BA.1 can lose affinity to diverse antibodies by acquiring a few large-effect mutations and can reduce affinity to others through several small-effect mutations. However, our results also reveal alternative pathways to antibody escape that does not include every large-effect mutation. Moreover, epistatic interactions are shown to constrain affinity decline in S309 but only modestly shape the affinity landscapes of other antibodies. Together with previous work on the ACE2 affinity landscape, our results suggest that the escape of each antibody is mediated by distinct groups of mutations, whose deleterious effects on ACE2 affinity are compensated by another distinct group of mutations (most notably Q498R and N501Y). 

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5. Neutralizing antibodies targeting the SARS‐CoV‐2 receptor binding domain isolated from a naïve human antibody library

   https://doi.org/10.1002/pro.4044  

   Bell, Benjamin N. ; Powell, Abigail E. ; Rodriguez, Carlos ; Cochran, Jennifer R. ; Kim, Peter S. ( February 2021 , Protein Science)

   Infection with SARS‐CoV‐2 elicits robust antibody responses in some patients, with a majority of the response directed at the receptor binding domain (RBD) of the spike surface glycoprotein. Remarkably, many patient‐derived antibodies that potently inhibit viral infection harbor few to no mutations from the germline, suggesting that naïve antibody libraries are a viable means for discovery of novel SARS‐CoV‐2 neutralizing antibodies. Here, we used a yeast surface‐display library of human naïve antibodies to isolate and characterize three novel neutralizing antibodies that target the RBD: one that blocks interaction with angiotensin‐converting enzyme 2 (ACE2), the human receptor for SARS‐CoV‐2, and two that target other epitopes on the RBD. These three antibodies neutralized SARS‐CoV‐2 spike‐pseudotyped lentivirus with IC₅₀values as low as 60 ng/ml in vitro. Using a biolayer interferometry‐based binding competition assay, we determined that these antibodies have distinct but overlapping epitopes with antibodies elicited during natural COVID‐19 infection. Taken together, these analyses highlight how in vitro selection of naïve antibodies can mimic the humoral response in vivo, yielding neutralizing antibodies and various epitopes that can be effectively targeted on the SARS‐CoV‐2 RBD.

    

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