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. 2023 Apr;20(4):419-422.
doi: 10.1038/s41423-023-00988-0. Epub 2023 Mar 3.

Profound neutralization evasion and augmented host cell entry are hallmarks of the fast-spreading SARS-CoV-2 lineage XBB.1.5

Markus Hoffmann  1   2 , Prerna Arora  3   4 , Inga Nehlmeier  3 , Amy Kempf  3   4 , Anne Cossmann  5 , Sebastian R Schulz  6 , Gema Morillas Ramos  5   7 , Luis A Manthey  5 , Hans-Martin Jäck  6 , Georg M N Behrens  5   7   8 , Stefan Pöhlmann  3   4
Affiliations

Profound neutralization evasion and augmented host cell entry are hallmarks of the fast-spreading SARS-CoV-2 lineage XBB.1.5

Markus Hoffmann et al. Cell Mol Immunol. 2023 Apr.
No abstract available

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Conflict of interest statement

S.P. and M.H. conducted contract research (testing of vaccine sera for neutralizing activity against SARS-CoV-2) for Valneva unrelated to this work. G.M.N.B. served as an advisor for Moderna and S.P. served as an advisor for BioNTech, unrelated to this work. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Host cell entry and neutralization sensitivity of the SARS-CoV-2 XBB.1.5 lineage. a Relative frequency of SARS-CoV-2 lineages BA.5* (without BQ.1*), BA.2.75*, BQ.1*, XBB* (without XBB.1.5*), and XBB.1.5* in selected countries (graphs are based on data retrieved from https://cov-spectrum.org/). b Mutations in the S proteins of SARS-CoV-2 lineages B.1, BA.4-5, BQ.1.1, XBB.1 and XBB.1.5 compared to the S protein of the Wuhan-Hu-01 isolate. The mutation highlighted in pink indicates the unique S protein mutation of the XBB.1.5 lineage that is not present in the S protein of the parental XBB.1 lineage. S protein mutations that are identical for all Omicron sublineages under study are indicated. NTD N-terminal domain, RBD receptor-binding domain, pre-S1/S2 region between RBD and the border between S1 and S2 subunits. c Cell line tropism and entry efficiency of the SARS-CoV-2 XBB.1.5 lineage. Identical volumes of pseudotype particles (pp) harboring the indicated SARS-CoV-2 S proteins were inoculated onto the indicated cell lines and pseudovirus entry was analyzed at 16–18 h postinoculation by measuring the activity of virus-encoded luciferase in cell lysates. Data represent the mean of six biological replicates (each performed with four technical replicates) and entry was normalized against B.1pp (=1; indicated by dashed line). Error bars indicate the standard error of the mean (SEM). Statistical significance was analyzed by two-tailed Student’s t-tests with Welch correction (not significant [ns], p > 0.05; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001). Please also see Supplementary Fig. S1. d Impact of antibody-mediated ACE2 blockade on host cell entry of the SARS-CoV-2 XBB.1.5 lineage. Pseudotype particles harboring the indicated SARS-CoV-2 S proteins or VSV-G (control) were inoculated onto Vero cells that had been preincubated with ACE2-blocking anti-ACE2 antibody. At 16–18 h postinoculation, pseudovirus entry was analyzed and normalized against samples without antibody (=0% inhibition). Data represent the mean of three biological replicates (performed with four technical replicates). Error bars indicate the SEM. The top graph shows dose-dependent inhibition of pseudovirus entry, while the bottom graph shows area under the curve (AUC) data. Statistical significance was analyzed by two-tailed Student’s t-tests with Welch correction (not significant [ns], p > 0.05; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001). e Sensitivity of the SARS-CoV-2 XBB.1.5 lineage to neutralization by monoclonal antibodies (mAb). Pseudotype particles harboring the indicated SARS-CoV-2 S proteins were preincubated with individual mAb or mAb cocktails, and subsequently inoculated onto Vero cells. At 16–18 h postinoculation, pseudovirus entry was analyzed and normalized against samples without mAb (=0% inhibition). Data represent the mean of three biological replicates (performed with four technical replicates). Error bars indicate the SEM. f Sensitivity of the SARS-CoV-2 XBB.1.5 lineage to neutralization by antibodies induced by vaccination or vaccination plus breakthrough infection (BTI). Pseudotype particles harboring the indicated SARS-CoV-2 S proteins were preincubated with plasma from (i) three-times vaccinated individuals with BTI during the BA.5 wave in Germany (n = 13), (ii) four-times vaccinated individuals that received the monovalent BNT162b2/Comirnaty vaccine booster (n = 10), or (iii) four-times vaccinated individuals that received the bivalent BNT162b2/Comirnaty Original/Omicron BA.4-5 vaccine booster (n = 13). Following incubation, the samples were inoculated onto Vero cells. At 16–18 h postinoculation, pseudovirus entry was analyzed, normalized against samples without plasma (=0% inhibition), and the neutralizing titer 50 (NT50), indicating the plasma dilution resulting in half-maximal inhibition, was calculated. Data represent geometric mean NT50 values (geometric mean titers, GMT) from a single biological replicate (conducted with four technical replicates). Information above the graphs indicates responder rates (=proportion of plasma samples with detectable neutralizing activity), GMT, and the fold change in GMT for BA.4-5pp, BQ.1.1pp, XBB.1pp, or XBB.1.5pp against B.1pp. Statistical significance was assessed by the Wilcoxon matched-pairs signed rank test (ns, p > 0.05; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001). Please also see Supplementary Table S1 and Supplementary Fig. S2
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