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

Hoffmann, Markus; Arora, Prerna; Nehlmeier, Inga; Kempf, Amy; Cossmann, Anne; Schulz, Sebastian; Ramos, Gema Morillas; Manthey, Luis A; Jäck, Hans‐Martin; Behrens, Georg M. N.; Pöhlmann, Stefan

doi:10.1038/s41423-023-00988-0

Cited by 52 publications

(58 citation statements)

References 11 publications

(11 reference statements)

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“…The bivalent-BA.1 booster induced similarly high neutralization titers as the bivalent-BA.4/BA.5 booster (Figure 1a), but significant differences were not observed relative to the monovalent vaccine, which is in line with previous studies 6 . XBB.1.5-NT titers were lowest in all groups (Figure 1a), which confirms the strong escape of this variant from current vaccine-and infection-elicited neutralizing antibodies 8,9,16 A comparison of NT titers between sera obtained on the day of booster and those one month later showed that the bivalent-BA.1 vaccine yielded the strongest increase in BA.1-NT titers (Figure 1b).…”

Section: Textsupporting

confidence: 58%

Bivalent COVID-19 mRNA booster vaccination (BA.1 or BA.4/BA.5) increases neutralization of matched Omicron variants

Springer

Bauer

Medits

et al. 2023

Preprint

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We report SARS-CoV-2 neutralizing antibody titers in sera of triple-vaccinated individuals who received a booster dose of an original monovalent or a bivalent BA.1- or BA.4/BA.5-adapted vaccine, or had a breakthrough infection with Omicron variants BA.1, BA.2 or BA.4/BA.5. A bivalent BA.4/BA.5 booster or Omicron-breakthrough infection induced increased Omicron-neutralization titers compared with the monovalent booster. The XBB.1.5 variant effectively evaded neutralizing-antibody responses elicited by current vaccines and/or infection with previous variants.

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Section: Textsupporting

confidence: 58%

Bivalent COVID-19 mRNA booster vaccination (BA.1 or BA.4/BA.5) increases neutralization of matched Omicron variants

Springer

Bauer

Medits

et al. 2023

Preprint

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“…It was also found that BA.2.75.2, BQ.1.1 and XBB.1 variants exhibited the lowest vaccine-elicited neutralization, thus indicating that emerging variants may have evolved to elicit stronger immune evasion without sacrificing ACE2 binding [54]. XBB.1.5, which is a subvariant of the recombinant mutant XBB, has shown a substantial growth advantage compared to both BQ.1.1 and XBB.1 [55][56][57]. The biochemical studies examined the binding affinity of the XBB.1.5 RBD to hACE2 revealing the dissociation constant K D = (which was not certified by peer review) is the author/funder.…”

Section: Introductionmentioning

confidence: 99%

“…XBB.1.5, which is a subvariant of the recombinant mutant XBB, has shown a substantial growth advantage compared to both BQ.1.1 and XBB.1 [55][56][57]. The biochemical studies examined the binding affinity of the XBB.1.5 RBD to hACE2 revealing the dissociation constant K D = K444, V445, G446, N450, L452, N460, F486, F490, R493 and S494 were found mutated in at least five independent Omicron sublineages that exhibited a high growth advantage [62,63].…”

Section: Introductionmentioning

confidence: 99%

“…XBB.1.5, which is a subvariant of the recombinant mutant XBB, has shown a substantial growth advantage compared to both BQ.1.1 and XBB.1 [55-57]. The biochemical studies examined the binding affinity of the XBB.1.5 RBD to hACE2 revealing the dissociation constant K D = 3.4 nM which was similar to that of BA.2.75 (K D =1.8 nM) while significantly stronger than that of XBB.1 (K D =19 nM) and BQ.1.1 (K D =8.1 nM) [56].…”

Section: Introductionmentioning

confidence: 99%

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Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages : Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Verkhivker

Alshahrani

Gupta

2023

Preprint

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The evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, protein stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2 , BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and identified energetic hotspots that can mediate the predicted increased stability and the enhanced binding affinity of the BA.2.75 and XBB.1.5 complexes. The results suggested a mechanism driven by the stability hotspots and a spatially localized group of the Omicron binding affinity centers, while allowing for functionally beneficial neutral Omicron mutations in other binding interface positions. A network-based community model for the analysis of non-additive epistatic contributions in the Omicron complexes is proposed revealing the key role of the binding hotspots R498 and Y501 in mediating community-based epistatic couplings with other Omicron sites and allowing for compensatory dynamics and binding energetic changes. The results also showed that mutations in the convergent evolutionary hotspot F486 can modulate not only local interactions but also rewire the global network of local communities in this region allowing the F486P mutation to restore both the stability and binding affinity of the XBB.1.5 variant which may explain the growth advantages over the XBB.1 variant. The results of this study are consistent with a broad range of functional studies rationalizing functional roles of the Omicron mutation sites that form a coordinated network of hotspots enabling balance of multiple fitness tradeoffs and shaping up a complex functional landscape of virus transmissibility.

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“…Besides, XBB.1.5 is also profoundly immunotolerant to humoral immunity induced by coronavirus disease 2019 (COVID‐19) vaccines (both monovalent and bivalent), commercial monoclonal antibodies, and convalescent plasma treatment. 13 , 15 , 16 , 17 It is the most resistant SARS‐CoV‐2 variant ever. Considering the high transmissibility and remarkable immune evasion, XBB.1.5 would probably become the cause of the next global wave.…”

Section: Introductionmentioning

confidence: 99%

A recombinant spike‐XBB.1.5 protein vaccine induces broad‐spectrum immune responses against XBB.1.5‐included Omicron variants of SARS‐CoV‐2

Alu

Hong

et al. 2023

MedComm

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The XBB.1.5 subvariant has drawn great attention owing to its exceptionality in immune evasion and transmissibility. Therefore, it is essential to develop a universally protective coronavirus disease 2019 vaccine against various strains of Omicron, especially XBB.1.5. In this study, we evaluated and compared the immune responses induced by six different spike protein vaccines targeting the ancestral or various Omicron strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in mice. We found that spike-wild-type immunization induced high titers of neutralizing antibodies (NAbs) against ancestral SARS-CoV-2. However, its activity in neutralizing Omicron subvariants decreased sharply as the number of mutations in receptor-binding domain (RBD) of these viruses increased. Spike-BA.5, spike-BF.7, and spike-BQ.1.1 vaccines induced strong NAbs against BA.5, BF.7, BQ.1, and BQ.1.1 viruses but were poor in protecting against XBB and XBB.1.5, which have more RBD mutations. In sharp contrast, spike-XBB.1.5 vaccination can activate strong and broadly protective immune responses against XBB.1.5 and other common subvariants of Omicron. By performing correlation analysis, we found that the NAbs titers were negatively correlated with the number of RBD mutations in the Omicron subvariants. Vaccines with more RBD mutations can effectively overcome the immune resistance caused by the accumulation of RBD mutations, making spike-XBB.1.5 the most promising vaccine candidate against universal Omicron variants.

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

Cited by 52 publications

References 11 publications

Bivalent COVID-19 mRNA booster vaccination (BA.1 or BA.4/BA.5) increases neutralization of matched Omicron variants

Bivalent COVID-19 mRNA booster vaccination (BA.1 or BA.4/BA.5) increases neutralization of matched Omicron variants

Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages : Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

A recombinant spike‐XBB.1.5 protein vaccine induces broad‐spectrum immune responses against XBB.1.5‐included Omicron variants of SARS‐CoV‐2

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