Virological characteristics of the SARS-CoV-2 BA.2.86 variant

Tamura, Tomokazu; Mizuma, Keita; Nasser, Hesham; Deguchi, Sayaka; Padilla-Blanco, Miguel; Uriu, Keiya; Tolentino, Jarel Elgin M.; Tsujino, Shuhei; Suzuki, Rigel; Kojima, Isshu; Nao, Naganori; Shimizu, Ryo; Jonathan, Michael; Kosugi, Yusuke; Guo, Ziyi; Hinay, Alfredo A; Putri, Olivia; Kim, Yoonjin; Tanaka, Yuri L; Asakura, Hiroyuki; Nagashima, Mami; Sadamasu, Kenji; Yoshimura, Kazuhisa; ,; Saito, Akatsuki; Ito, Jumpei; Irie, Takashi; Zahradnik, Jiri; Ikeda, Terumasa; Takayama, Kazuo; Matsuno, Keita; Fukuhara, Takasuke; Sato, Kei

doi:10.1101/2023.11.02.565304

Cited by 10 publications

(20 citation statements)

References 70 publications

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“…Our results have mixed correspondence with previous studies and data on XBB.1.5 and BA.2.86 (10,40,41,44,46,47). There are many potential explanations for our lack of statistically significant differences.…”

Section: Resultscontrasting

confidence: 79%

Predicting Antibody and ACE2 Affinity for SARS-CoV-2 BA.2.86 and JN.1 withIn SilicoProtein Modeling and Docking

Yasa,

Guirales-Medrano,

Machado

et al. 2023

Preprint

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The emergence of the Omicron sublineage of SARS-CoV-2 virus BA.2.86 (nicknamed “Pirola”) has raised concerns about its potential impact on public health and personal health as it has many mutations with respect to previous variants. We conducted anin silicoanalysis of neutralizing antibody binding to BA.2.86. Selected antibodies came from patients who were vaccinated and/or infected. We predicted binding affinity between BA.2.86 and antibodies. We also predicted the binding affinity between the same antibodies and several previous SARS-CoV2 variants (Wuhan and Omicron descendants BA.1, BA.2, and XBB.1.5). Additionally, we examined binding affinity between BA.2.86 and human angiotensin converting enzyme 2 (ACE2) receptor, a cell surface protein crucial for viral entry. We found no statistically significant difference in binding affinity between BA.2.86 and other variants, indicating a similar immune response. These findings contradict media reports of BA.2.86’s high immune evasion potential based on its mutations. We discuss the implications of our findings and highlight the need for modeling and docking studies to go above and beyond mutation and basic serological neutralization analysis. Future research in this area will benefit from increased structural analyses of memory B-cell derived antibodies and should emphasize the importance of choosing appropriate samples forin silicostudies to assess protection provided by vaccination and infection. This research contributes to understanding the BA.2.86 variant’s potential impact on public health. Moreover, we introduce new methodologies for predictive medicine in ongoing efforts to combat the evolving SARS-CoV-2 pandemic and prepare for other hazards.

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Section: Resultscontrasting

confidence: 79%

Predicting Antibody and ACE2 Affinity for SARS-CoV-2 BA.2.86 and JN.1 withIn SilicoProtein Modeling and Docking

Yasa,

Guirales-Medrano,

Machado

et al. 2023

Preprint

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“…For example, vaccinated individuals who had breakthrough infection with different variants mount nAb response primarily towards the wildtype spike protein (9,10,14,18,21,26,27). In this study, all JN.1 patients in the infected cohort had received some doses of vaccine containing the WT spike (Table S1).…”

Section: Discussionmentioning

confidence: 94%

“…Interestingly, we discovered that the newly emerged BA.2.87.1 variant possesses an increased sensitivity to neutralization by these sera compared to JN.1, implying that this variant may not be able to outcompete the current JN.1 and become predominant. However, given that a single L455S mutation in the spike of JN.1 can dramatically increase the nAb evasion of BA.2.86 (3,14,21), there is a possibility that additional mutations in BA.2.87.1 could similarly result in new variants that dramatically enhance the nAb escape.…”

Section: Discussionmentioning

confidence: 99%

Distinct Patterns of SARS-CoV-2 BA.2.87.1 and JN.1 Variants in Immune Evasion, Antigenicity and Cell-Cell Fusion

Li,

Liu,

Faraone

et al. 2024

Preprint

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The rapid evolution of SARS-CoV-2 variants presents a constant challenge to the global vaccination effort. In this study, we conducted a comprehensive investigation into two newly emerged variants, BA.2.87.1 and JN.1, focusing on their neutralization resistance, infectivity, antigenicity, cell-cell fusion, and spike processing. Neutralizing antibody (nAb) titers were assessed in diverse cohorts, including individuals who received a bivalent mRNA vaccine booster, patients infected during the BA.2.86/JN.1-wave, and hamsters vaccinated with XBB.1.5-monovalent vaccine. We found that BA.2.87.1 shows much less nAb escape from WT-BA.4/5 bivalent mRNA vaccination and JN.1-wave breakthrough infection sera compared to JN.1 and XBB.1.5. Interestingly. BA.2.87.1 is more resistant to neutralization by XBB.15-monovalent-vaccinated hamster sera than BA.2.86/JN.1 and XBB.1.5, but efficiently neutralized by a class III monoclonal antibody S309, which largely fails to neutralize BA.2.86/JN.1. Importantly, BA.2.87.1 exhibits higher levels of infectivity, cell-cell fusion activity, and furin cleavage efficiency than BA.2.86/JN.1. Antigenically, we found that BA.2.87.1 is closer to the ancestral BA.2 compared to other recently emerged Omicron subvariants including BA.2.86/JN.1 and XBB.1.5. Altogether, these results highlight immune escape properties as well as biology of new variants and underscore the importance of continuous surveillance and informed decision-making in the development of effective vaccines.

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“…Comprehensive multiscale investigations of the virological characteristics of the BA.2.86 variant demonstrated that the ACE2 binding affinity of BA.2.86 S RBD was comparable to that of XBB.1.5 S RBD and significantly higher than those of the ancestral B.1.1, XBB.1, XBB.1.16, EG.5.1 and the parental BA.2 variants. 56 This illuminating study showed that fusogenicity of the S protein of BA.2.86 and BA.2 were comparable, but the intrinsic pathogenicity of BA.2.86 was significantly lower than that of BA.2, suggesting that the attenuated pathogenicity of BA.2.86 may be due to its decreased replication capacity. 56…”

Section: Introductionmentioning

confidence: 83%

Accurate Characterization of Conformational Ensembles and Binding Mechanisms of the SARS-CoV-2 Omicron BA.2 and BA.2.86 Spike Protein with the Host Receptor and Distinct Classes of Antibodies Using AlphaFold2-Augmented Integrative Computational Modeling

Raisinghani,

Alshahrani,

Gupta

et al. 2023

Preprint

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The latest wave SARS-CoV-2 Omicron variants displayed a growth advantage and the increased viral fitness through convergent evolution of functional hotspots that work synchronously to balance fitness requirements for productive receptor binding and efficient immune evasion. In this study, we combined AlphaFold2-based structural modeling approaches with all-atom MD simulations and mutational profiling of binding energetics and stability for prediction and comprehensive analysis of the structure, dynamics, and binding of the SARS-CoV-2 Omicron BA.2.86 spike variant with ACE2 host receptor and distinct classes of antibodies. We adapted several AlphaFold2 approaches to predict both structure and conformational ensembles of the Omicron BA.2.86 spike protein in the complex with the host receptor. The results showed that AlphaFold2-predicted conformational ensemble of the BA.2.86 spike protein complex can accurately capture the main dynamics signatures obtained from microscond molecular dynamics simulations. The ensemble-based dynamic mutational scanning of the receptor binding domain residues in the BA.2 and BA.2.86 spike complexes with ACE2 dissected the role of the BA.2 and BA.2.86 backgrounds in modulating binding free energy changes revealing a group of conserved hydrophobic hotspots and critical variant-specific contributions of the BA.2.86 mutational sites R403K, F486P and R493Q. To examine immune evasion properties of BA.2.86 in atomistic detail, we performed large scale structure-based mutational profiling of the S protein binding interfaces with distinct classes of antibodies that displayed significantly reduced neutralization against BA.2.86 variant. The results quantified specific function of the BA.2.86 mutations to ensure broad resistance against different classes of RBD antibodies. This study revealed the molecular basis of compensatory functional effects of the binding hotspots, showing that BA.2.86 lineage may have primarily evolved to improve immune escape while modulating binding affinity with ACE2 through cooperative effect of R403K, F486P and R493Q mutations. The study supports a hypothesis that the impact of the increased ACE2 binding affinity on viral fitness is more universal and is mediated through cross-talk between convergent mutational hotspots, while the effect of immune evasion could be more variant-dependent.

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Virological characteristics of the SARS-CoV-2 BA.2.86 variant

Cited by 10 publications

References 70 publications

Predicting Antibody and ACE2 Affinity for SARS-CoV-2 BA.2.86 and JN.1 withIn SilicoProtein Modeling and Docking

Predicting Antibody and ACE2 Affinity for SARS-CoV-2 BA.2.86 and JN.1 withIn SilicoProtein Modeling and Docking

Distinct Patterns of SARS-CoV-2 BA.2.87.1 and JN.1 Variants in Immune Evasion, Antigenicity and Cell-Cell Fusion

Accurate Characterization of Conformational Ensembles and Binding Mechanisms of the SARS-CoV-2 Omicron BA.2 and BA.2.86 Spike Protein with the Host Receptor and Distinct Classes of Antibodies Using AlphaFold2-Augmented Integrative Computational Modeling

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