SARS-CoV-2 B.1.617.2 Delta variant replication, sensitivity to neutralising antibodies and vaccine breakthrough
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Abstract
The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha). In vitro , B.1.617.2 is 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against B.1.617.2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD), in particular to the clinically approved bamlavinimab and imdevimab monoclonal antibodies. B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems as compared to B.1.1.7, associated with B.1.617.2 spike being in a predominantly cleaved state compared to B.1.1.7. Additionally we observed that B.1.617.2 had higher replication and spike mediated entry as compared to B.1.617.1, potentially explaining B.1.617.2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed substantially reduced ChAdOx-1 vaccine efficacy against B.1.617.2 relative to non-B.1.617.2. Compromised vaccine efficacy against the highly fit and immune evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.
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SciScore for 10.1101/2021.05.08.443253: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Controls with COVID-19 were enrolled to the NIHR BioResource Centre Cambridge under ethics review board (17/EE/0025). Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication Contamination: All cells were regularly tested and are mycoplasma free. Table 2: Resources
Antibodies Sentences Resources Membranes were blocked for 1 hour in 5% non-fat milk in PBS + 0.1% Tween-20 (PBST) at room temperature with agitation, incubated in primary antibody (anti-SARS-CoV-2 Spike, which detects the S2 subunit of SARS-CoV-2 S (Invitrogen, PA1-41165) anti-SARS-CoV-2suggested: NonePA1-41165suggested: (Thermo Fisher Scientific Cat# …SciScore for 10.1101/2021.05.08.443253: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Controls with COVID-19 were enrolled to the NIHR BioResource Centre Cambridge under ethics review board (17/EE/0025). Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication Contamination: All cells were regularly tested and are mycoplasma free. Table 2: Resources
Antibodies Sentences Resources Membranes were blocked for 1 hour in 5% non-fat milk in PBS + 0.1% Tween-20 (PBST) at room temperature with agitation, incubated in primary antibody (anti-SARS-CoV-2 Spike, which detects the S2 subunit of SARS-CoV-2 S (Invitrogen, PA1-41165) anti-SARS-CoV-2suggested: NonePA1-41165suggested: (Thermo Fisher Scientific Cat# PA1-41165, RRID:AB_1087210)anti-GAPDH (proteintech) or anti-p24 (NIBSC)) diluted in 5% non-fat milk in PBST for 2 hours at 4°C with agitation, washed four times in PBST for 5 minutes at room temperature with agitation and incubated in secondary antibodies anti-rabbit HRP (1:10000, Invitrogen 31462), anti-bactin HRP (1:5000; sc-47778) diluted in 5% non-fat milk in PBST for 1 hour with agitation at room temperature. anti-GAPDHsuggested: (LSBio (LifeSpan Cat# LS-C147452-10000, RRID:AB_11130690)anti-p24suggested: Noneanti-rabbit HRPsuggested: (Bioss Cat# bs-5000R-HRP, RRID:AB_11112914)anti-bactin HRPsuggested: NoneExperimental Models: Cell Lines Sentences Resources Cells: HEK 293T CRL-3216 HEK 293Tsuggested: ATCC Cat# CRL-3216, RRID:CVCL_0063), Vero CCL-81 were purchased from ATCC and maintained in Dulbecco”s Modified Eagle Medium (DMEM) supplemented with 10% fetal calf serum (FCS), 100 U/ml penicillin, and 100mg/ml streptomycin. Vero CCL-81suggested: None. 293T cells were transfected with a mixture of 11ul of Fugene HD, 1μg of pCDNAΔ19 spike-HA, 1ug of p8.91 HIV-1 gag-pol expression vector and 1.5μg of pCSFLW (expressing the firefly luciferase reporter gene with the HIV-1 packaging signal). 293Tsuggested: NoneSupernatant containing virus particles was harvested after 48 and 72 hours, 0.45 μm filtered, and used to infect 293T or Vero cells to generate stable cell lines. Verosuggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)Briefly, 293T-GFP1-10 and Vero-GFP11 cells were seeded at 80% confluence in a 24 multiwell plate the day before. Vero-GFP11suggested: None293T-GFP1-10 cells were then detached 5 hours post transfection, mixed together with the Vero-GFP11 cells, and plated in a 12 multiwell plate. 293T-GFP1-10suggested: NoneRecombinant DNA Sentences Resources . 293T cells were transfected with a mixture of 11ul of Fugene HD, 1μg of pCDNAΔ19 spike-HA, 1ug of p8.91 HIV-1 gag-pol expression vector and 1.5μg of pCSFLW (expressing the firefly luciferase reporter gene with the HIV-1 packaging signal). pCDNAΔ19 spike-HAsuggested: NonepCSFLWsuggested: NonePlasmids for split GFP system to measure cell-cell fusion: pQCXIP□BSR□GFP11 and pQCXIP□GFP1□10 were from Yutaka Hata40 Addgene plasmid #68716; http://n2t.net/addgene:68716; RRID:Addgene_68716 and Addgene plasmid #68715; http://n2t.net/addgene:68715; RRID:Addgene_68715) Generation of GFP1□ 10 or GFP11 lentiviral particles: Lentiviral particles were generated by co-transfection of 293T cells with pQCXIP□BSR□GFP11 or pQCXIP□GFP1□10 as previously described 41. detected: RRID:Addgene_68716)detected: RRID:Addgene_68715)pQCXIP□BSR□GFP11suggested: NonepQCXIP□GFP1□10suggested: None293T cells were co-transfected with 1.5 μg of spike expression plasmids in pCDNA3 using Fugene 6 and following the manufacturer”s instructions (Promega). pCDNA3suggested: RRID:Addgene_15475)Software and Algorithms Sentences Resources Phylogenetic Analysis: All sequences excluding low-quality sequences (>5% N regions) with the L452R mutation were downloaded from https://gisaid.org33 on the 4th May 2021 and manually aligned to reference strain MN908947.3 with mafft v4.475 34 using the --keeplength --addfragments option. mafftsuggested: (MAFFT, RRID:SCR_011811)Structural Analyses: The PyMOL Molecular Graphics System v. PyMOLsuggested: (PyMOL, RRID:SCR_000305)Graphs were generated using Prism 8 software. Prismsuggested: (PRISM, RRID:SCR_005375)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
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.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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