Since late 2022, the share of infections caused by the SARS-CoV-2 lineage XBB.1.5 has gradually increased in the United States, resulting in XBB.1.5 becoming the dominating SARS-CoV-2 lineage in the United States and a similar trend is likely to soon take place also in European countries. However, information on the virological properties of XBB.1.5 is scarce. Here, we conducted an initial virological assessment of the SARS-CoV-2 XBB.1.5 lineage.
The SARS-CoV-2 XBB lineage possesses an extraordinarily high capacity for antibody evasion due to its unique set of S protein mutations [1,2,3,4]. However, this trait may have come at the cost of a moderately reduced host cell entry efficiency as suggested by recent in vitro data [1, 5], which may explain why infections caused by XBB sublineages only accounted for a small proportion of total SARS-CoV-2 infections in several countries (except India) so far (Fig. 1a). Recently, this trend has changed for the United States, where the share of infections caused by SARS-CoV-2 sublineage XBB.1.5 has gradually increased since late 2022, and XBB.1.5 now represents the dominating SARS-CoV-2 lineage (Fig. 1a). Moreover, although being presently detected at low frequencies only, a similar increase in the share of XBB.1.5-related infections is also observed for European countries (Fig. 1a). The XBB.1.5 S protein differs by only one mutation (S486P) from the S protein of the parental XBB.1 lineage, and this mutation is located in the receptor-binding domain (RBD) (Fig. 1b). Thus, it may affect transmissibility by modulating cell entry efficiency, and may alter sensitivity to antibody-mediated neutralization.
Here, we performed an assessment on the host cell entry efficiency of the SARS-CoV-2 XBB.1.5 lineage and its sensitivity to antibody-mediated neutralization, using S protein-bearing pseudovirus particles (pp), which are a suitable model system for the analysis of SARS-CoV-2 host cell entry and its neutralization [6]. Particles pseudotyped with the S protein of the ancestral B.1 lineage (B.1pp) or Omicron sublineages BA.4/BA.5 (identical on amino acid level, BA.4-5pp), BQ.1.1 (BQ.1.1pp), or XBB.1 (XBB.1pp) were used for comparison. First, we compared cell line tropism and host cell entry efficiency of the different pseudoviruses. As expected, BA.4-5pp displayed augmented cell entry efficiency compared to B.1pp for most cell lines tested with the exception of TMPRSS2-positive Caco-2 (human, intestine) and Calu-3 (human, lung) cells [7], while cell entry of XBB.1.5pp was significantly reduced compared to BA.5pp [1] (Fig. 1c). Entry of BQ.1.1pp was comparable or moderately increased relative to XBB.1pp, but reduced relative to BA.4-5pp (with the exception of Caco-2 cells) (Fig. 1c). Importantly, XBB.1.5pp showed significantly higher cell entry efficiency compared to XBB.1pp for all cell lines tested (Fig. 1c). In order to investigate whether the increase in cell entry of XBB.1.5pp relative to XBB.1pp is the result of improved ACE2 usage, we limited ACE2 availability for cell entry using an ACE2-blocking antibody. We found that XBB.1.5pp entered cells under conditions of limited ACE2 availability more efficiently than XBB.1pp (Fig. 1d), suggesting that mutation S486P optimizes S protein-ACE2-interactions.
Since mutation S486P may also impact sensitivity to antibody-mediated neutralization, we further investigated whether currently used monoclonal antibody (mAb) therapies effectively neutralize XBB.1.5pp. In agreement with expectations, B.1pp were effectively neutralized by Bebtelovimab, Sotrovimab, and a cocktail of Cilgavimab and Tixagevimab (Evusheld), while BA.4-5pp were moderately resistant against neutralization by Sotrovimab and Cilgavimab/Tixagevimab, and BQ.1.1pp could not be effectively neutralized by any mAb treatment tested (Fig. 1e) [8]. XBB.1pp and XBB.1.5pp displayed identical mAb neutralization profiles and only Sotrovimab showed neutralizing activity, which was moderately reduced compared to B.1pp (Fig. 1e).
Finally, we investigated the neutralization sensitivity of XBB.1.5pp to antibodies induced by vaccination with or without breakthrough infection (BTI). For this, we utilized plasma from triple-vaccinated individuals that experienced a BTI during the BA.5 wave in Germany, and plasma from quadruple-vaccinated individuals that received a monovalent or bivalent mRNA-vaccine booster as fourth vaccination. All tested plasma showed high neutralizing activity against B.1pp, while neutralizing activity against BA.4-5pp and BQ.1.1pp was moderately (BA.4-5pp: 2.3–7.2-fold reduced compared to B.1pp) or strongly (BQ.1.1pp: 6.4–19.9-fold reduced compared to B.1pp) reduced (Fig. 1f), as expected [9]. In line with published results, neutralizing activity against XBB.1pp was even further reduced compared to BA.4-5pp and BQ.1.1pp (XBB.1pp: 22.5–38.2-fold reduced compared to B.1pp) [1,2,3,4], and neutralizing activity against XBB.1.5pp was comparable to that of XBB.1pp (XBB.1pp: 23.7–35.9-fold reduced compared to B.1pp) (Fig. 1f).
In summary, our results indicate that the apparently increased transmissibility of the SARS-CoV-2 XBB.1.5 lineage is (at least in part) the combined result of its profound neutralization resistance and the improved ACE2 usage due to S protein mutation S486P. In fact, a deep mutational scanning study using S proteins of SARS-CoV-2 lineages B.1, BA.1 and BA.2 suggests that mutation S486P enhances ACE2 binding affinity [10]. While Sotrovimab retains neutralizing activity against XBB.1 and XBB.1.5 and thus constitutes a treatment option for patients, novel mAbs need to be developed in order to be prepared for emerging XBB.1.5 sublineages that may harbor mutations that confer resistance against Sotrovimab.
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Acknowledgements
We gratefully acknowledge the originating laboratories responsible for obtaining the specimens, as well as the submitting laboratories where the genome data were generated and shared via GISAID, on which this research is based. We further thank Stephan Ludwig, Andrea Maisner, Thomas Pietschmann and Gert Zimmer for providing reagents. Finally, we thank all study participants for their support and Janine Topal, Noemí Calderón Hampel and Metodi V. Stankov for technical and logistical help. S.P. acknowledges funding by BMBF (01KI2006D, 01KI20328A, 01KX2021), the Ministry for Science and Culture of Lower Saxony (14-76103-184, COFONI Network, including projects 7FF22, 6FF22, 10FF22), EU (project UNDINE) and the German Research Foundation (DFG; PO 716/11-1, PO 716/14-1). H.-M.J. received funding from BMBF (01KI2043, NaFoUniMedCovid19-COVIM: 01KX2021), Bavarian State Ministry for Science and the Arts (Bayerisches Staatsministerium für Wissenschaft und Kunst) and DFG through the research training groups RTG1660 and TRR130, the Bayerische Forschungsstiftung (Project CORAd) and the Kastner Foundation. G.M.N.B. acknowledges funding by the German Center for Infection Research (Deutsches Zentrum für Infektionsforschung, DZIF; grant no 80018019238) and a European Regional Development Fund (Defeat Corona, ZW7-8515131). The funding sources had no role in the design and execution of the study, the writing of the manuscript and the decision to submit the manuscript for publication.
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Conceptualization: M.H. and S.P. Methodology: M.H., P.A. and S.P. Investigation: M.H., P.A., I.N., A.K. Formal analysis: M.H. and S.P. Recruitment and plasma collection: A.C., G.M.R. and G.M.N.B. Resources: A.C., S.R.S., G.M.R., L.A.M., H.-M.J. and G.M.N.B. Funding acquisition: H.-M.J., G.M.N.B. and S.P. Writing—original draft: M.H., P.A. and S.P. Writing—review and editing: all authors.
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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.
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Hoffmann, M., Arora, P., Nehlmeier, I. et al. Profound neutralization evasion and augmented host cell entry are hallmarks of the fast-spreading SARS-CoV-2 lineage XBB.1.5. Cell Mol Immunol 20, 419–422 (2023). https://doi.org/10.1038/s41423-023-00988-0
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DOI: https://doi.org/10.1038/s41423-023-00988-0
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