Immune Escape Mechanisms of SARS-CoV-2 Delta and Omicron Variants against Two Monoclonal Antibodies That Received Emergency Use Authorization

Xiong, Danyang; Zhao, Xiaoyu; Luo, Song; Cong, Yalong; Zhang, John Z. H.; Duan, Lili

doi:10.1021/acs.jpclett.2c00912

Cited by 17 publications

(15 citation statements)

References 39 publications

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“…Omicron BA.2 has 16 mutations in its RBD alone. Such a high number of mutations is unusual and has been predicted to change the antibody epitopes and, therefore, to confer significantly higher immune escape properties than the Delta variant …”

Section: Introductionmentioning

confidence: 99%

When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy

Lacam

Blazhynska

Chen

et al. 2022

J. Chem. Theory Comput.

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Accurate determination of binding free energy is pivotal for the study of many biological processes and has been applied in a number of theoretical investigations to compare the affinity of severe acute respiratory syndrome coronavirus 2 variants toward the host cell. Diversity of these variants challenges the development of effective general therapies, their transmissibility relying either on an increased affinity toward their dedicated human receptor, the angiotensin-converting enzyme 2 (ACE2), or on escaping the immune response. Now that robust structural data are available, we have determined with utmost accuracy the standard binding free energy of the receptor-binding domain to the most widespread variants, namely, Alpha, Beta, Delta, and Omicron BA.2, as well as the wild type (WT) in complex either with ACE2 or with antibodies, namely, S2E12 and H11-D4, using a rigorous theoretical framework that combines molecular dynamics and potential-of-mean-force calculations. Our results show that an appropriate starting structure is crucial to ensure appropriate reproduction of the binding affinity, allowing the variants to be compared. They also emphasize the necessity to apply the relevant methodology, bereft of any shortcut, to account for all the contributions to the standard binding free energy. Our estimates of the binding affinities support the view that while the Alpha and Beta variants lean on an increased affinity toward the host cell, the Delta and Omicron BA.2 variants choose immune escape. Moreover, the S2E12 antibody, already known to be active against the WT (Starr et al., 2021; Mlcochova et al., 2021), proved to be equally effective against the Delta variant. In stark contrast, H11-D4 retains a low affinity toward the WT compared to that of ACE2 for the latter. Assuming robust structural information, the methodology employed herein successfully addresses the challenging protein–protein binding problem in the context of coronavirus disease 2019 while offering promising perspectives for predictive studies of ever-emerging variants.

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Section: Introductionmentioning

confidence: 99%

When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy

Lacam

Blazhynska

Chen

et al. 2022

J. Chem. Theory Comput.

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“…Effects on the protein stability of the spike protein mutations observed in the circulating variants have been investigated by sequence alignments and predictions of differences in free energy due to the amino acid mutations [ 15 ]. Very recently, studies (appeared in literature after the submission of this manuscript and here added during the revision stage) investigated the Omicron variant interaction with a few antibodies active against the reference form of spike protein [ 16 , 17 ]. In this work, we selected several representative ensembles from the available structures of the complexes between spike protein and different antibodies as a starting point to model the amino acid changes affecting the spike protein in the Omicron variant of SARS-CoV-2, with the aim of understanding their impact on these interactions.…”

Section: Introductionmentioning

confidence: 99%

In Silico Analysis of the Effects of Omicron Spike Amino Acid Changes on the Interactions with Human Proteins

et al. 2022

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The SARS-CoV-2 variant Omicron is characterized, among others, by more than 30 amino acid changes occurring on the spike glycoprotein with respect to the original SARS-CoV-2 spike protein. We report a comprehensive analysis of the effects of the Omicron spike amino acid changes in the interaction with human antibodies, obtained by modeling them into selected publicly available resolved 3D structures of spike–antibody complexes and investigating the effects of these mutations at structural level. We predict that the interactions of Omicron spike with human antibodies can be either negatively or positively affected by amino acid changes, with a predicted total loss of interactions only in a few complexes. Moreover, our analysis applied also to the spike-ACE2 interaction predicts that these amino acid changes may increase Omicron transmissibility. Our approach can be used to better understand SARS-CoV-2 transmissibility, detectability, and epidemiology and represents a model to be adopted also in the case of other variants.

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“…One possibility is its decreased virulence to result in the large amount of asymptomatic infection of Omicron variants(130), which affect the overall efficacy of COVID-19 vaccines. Another possibility for the decreased efficiency of COVID-19 vaccines for the Omicron variant is likely due to a combination of extended time interval post-vaccination and the immune escape caused by the mutations in the viral spike proteins(30,31,131). In this study, we found that booster immunization could enhance the effectiveness of COVID-19 vaccines to prevent the infection, symptomatic COVID-19, severe COVID-19, and COVID-19-related death which were about 62%, 65%, 88%, and 94% for Omicron sub-lineage BA.1.1.529, respectively.…”

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confidence: 99%

A comprehensive analysis of the efficacy and effectiveness of COVID-19 vaccines

et al. 2022

Front. Immunol.

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It is urgently needed to update the comprehensive analysis about the efficacy or effectiveness of COVID-19 vaccines especially during the COVID-19 pandemic caused by SARS-CoV-2 Delta and Omicron variants. In general, the current COVID-19 vaccines showed a cumulative efficacy of 66.4%, 79.7%, and 93.6% to prevent SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19, respectively, but could not prevent the asymptomatic infection of SARS-CoV-2. Furthermore, the current COVID-19 vaccines could effectively prevent COVID-19 caused by the Delta variant although the incidence of breakthrough infection of the SARS-CoV-2 Delta variant increased when the intervals post full vaccination extended, suggesting the waning effectiveness of COVID-19 vaccines. In addition, one-dose booster immunization showed an effectiveness of 74.5% to prevent COVID-19 caused by the Delta variant. However, current COVID-19 vaccines could not prevent the infection of Omicron sub-lineage BA.1.1.529 and had about 50% effectiveness to prevent COVID-19 caused by Omicron sub-lineage BA.1.1.529. Furthermore, the effectiveness was 87.6% and 90.1% to prevent severe COVID-19 and COVID-19-related death caused by Omicron sub-lineage BA.2, respectively, while one-dose booster immunization could enhance the effectiveness of COVID-19 vaccines to prevent the infection and COVID-19 caused by Omicron sub-lineage BA.1.1.529 and sub-lineage BA.2. Two-dose booster immunization showed an increased effectiveness of 81.8% against severe COVID-19 caused by the Omicron sub-lineage BA.1.1.529 variant compared with one-dose booster immunization. The effectiveness of the booster immunization with RNA-based vaccine BNT162b2 or mRNA-1273 was over 75% against severe COVID-19 more than 17 weeks after booster immunization whereas the heterogenous booster immunization showed better effectiveness than homologous booster immunization. In summary, the current COVID-19 vaccines could effectively protect COVID-19 caused by Delta and Omicron variants but was less effective against Omicron variant infection. One-dose booster immunization could enhance protection capability, and two-dose booster immunization could provide additional protection against severe COVID-19.

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Immune Escape Mechanisms of SARS-CoV-2 Delta and Omicron Variants against Two Monoclonal Antibodies That Received Emergency Use Authorization

Cited by 17 publications

References 39 publications

When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy

When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy

In Silico Analysis of the Effects of Omicron Spike Amino Acid Changes on the Interactions with Human Proteins

A comprehensive analysis of the efficacy and effectiveness of COVID-19 vaccines

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