The impact of Spike mutations on SARS-CoV-2 neutralization
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Abstract
Multiple SARS-CoV-2 vaccines have shown protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, Spike. Antibodies from SARS-CoV-2 infection neutralize the virus by focused targeting of Spike and there is limited serum cross-neutralization of the closely-related SARS-CoV. As new SARS-CoV-2 variants are rapidly emerging, exemplified by the B.1.1.7, 501Y.V2 and P.1 lineages, it is critical to understand if antibody responses induced by infection with the original SARS-CoV-2 virus or the current vaccines will remain effective against virus variants. In this study we evaluate neutralization of a series of mutated Spike pseudotypes including a B.1.1.7 Spike pseudotype. The analyses of a panel of Spike-specific monoclonal antibodies revealed that the neutralizing activity of some antibodies was dramatically reduced by Spike mutations. In contrast, polyclonal antibodies in the serum of patients infected in early 2020 remained active against most mutated Spike pseudotypes. The majority of serum samples were equally able to neutralize the B.1.1.7 Spike pseudotype, however potency was reduced in a small number of samples (3 of 36) by 5–10-fold. This work highlights that changes in the SARS-CoV-2 Spike can alter neutralization sensitivity and underlines the need for effective real-time monitoring of emerging mutations and their impact on vaccine efficacy.
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SciScore for 10.1101/2021.01.15.426849: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Ethical oversight was provided by the South-Central Berkshire Research Ethics Committee. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Neutralization assay: HIV-1 particles pseudotyped with SARS-Cov-2 spike were produced in a T75 flask seeded the day before with 3 million HEK293T cells in 10 ml complete DMEM, supplemented with 10% FBS, 100 IU/ml penicillin and 100 μg/ml streptomycin. HEK293Tsuggested: NoneHeLa cells stably expressing ACE-2 (provided by J.E. Voss, Scripps Institute) were … SciScore for 10.1101/2021.01.15.426849: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Ethical oversight was provided by the South-Central Berkshire Research Ethics Committee. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Neutralization assay: HIV-1 particles pseudotyped with SARS-Cov-2 spike were produced in a T75 flask seeded the day before with 3 million HEK293T cells in 10 ml complete DMEM, supplemented with 10% FBS, 100 IU/ml penicillin and 100 μg/ml streptomycin. HEK293Tsuggested: NoneHeLa cells stably expressing ACE-2 (provided by J.E. Voss, Scripps Institute) were then added to the assay (10,000 cells per 100 µl per well). HeLasuggested: NoneSoftware and Algorithms Sentences Resources Measurements were performed in duplicate and used to calculate 50% inhibitory concentrations (IC50) in GraphPad Prism software. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:A caveat to the first part of this study is that only RBD substitutions were considered. Further studies to assess potential mutations before they arise should include those in NTD given the emerging importance of NTD as a site for neutralizing antibodies (Andreano et al., 2020; Rosa et al., 2021). However, it should be noted that one RBD change, TEI470-2NVP, resulted in a 24-fold drop in potency for COVA1-21, which does not bind RBD and remains structurally unmapped (Brouwer et al., 2020). Regardless, that sera likely containing a mixture of RBD-and NTD-specificities are more resilient than individual mAbs in the face of Spike mutations within the RBD is not surprising. This further highlights the importance of a broad polyclonal serum response to maintain neutralizing activity in the event of novel Spike mutations emerging, and the need to consider more than RBD binding in serological evaluations. To understand if the conclusions from studying the impact of the SARS-CoV-2/SARS-CoV substitutions on neutralization parallel those of real-world Spike mutations, we examined the responses to the newly emerged B.1.1.7 variant (S. Kemp et al., 2020; Rambaut et al., 2020). This revealed that the first NTD deletion observed, ΔH69/V70, did not alter RBD-specific mAbs or any sera. Although as previously described (S. A. Kemp et al., 2020) it did result in a drop in potency for non-RBD mAb COVA1-21. The RBD mutation N501Y, shared between B.1.1.7, 501Y.V2 and P.1, did remove almost all n...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
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