ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5.

SARS-CoV-2 subvariants BQ.1.1 and XBB.1 have been circulating globally with superior growth advantages over most omicron mutants (appendix p 5). However, XBB.1.5, a subvariant of the recombinant mutant XBB, has shown a substantial growth advantage compared with BQ.1.1 and XBB.1. Because of its enhanced transmissibility, XBB.1.5 has rapidly become the dominant SARS-CoV-2 strain in the USA and is highly likely to cause the next global wave of COVID-19 (appendix p 5).1US Centers for Disewase Control and PreventionCOVID Data Tracker.https://covid.cdc.gov/covid-data-tracker/#variant-proportionsDate: 2023Date accessed: January 6, 2023Google Scholar XBB and XBB.1 has already been shown to be extremely evasive against the neutralisation of plasma and serum from vaccinated or convalescent individuals and monoclonal antibodies (mAbs), with a greater evasive ability than the BQ.1.1 variant.2Cao Y Jian F Wang J et al.Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution.Nature. 2022; (published online Dec 19.)https://doi.org/10.1038/s41586-022-05644-7Crossref Scopus (99) Google Scholar, 3Kurhade C Zou J Xia H et al.Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster.Nat Med. 2022; (published online Dec 6.)https://doi.org/10.1038/s41591-022-02162-xCrossref PubMed Scopus (85) Google Scholar, 4Jiang X-L Zhu KL Wang XJ et al.Omicron BQ.1 and BQ.1.1 escape neutralisation by omicron subvariant breakthrough infection.Lancet Infect Dis. 2023; 23: 28-30Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 5Uraki R Ito M Furusawa Y et al.Humoral immune evasion of the omicron subvariants BQ.1.1 and XBB.Lancet Infect Dis. 2023; 23: 30-32Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar Compared with XBB.1, XBB.1.5 carries a Ser486Pro mutation on the spike protein, a rare two nucleotide substitution compared with the ancestral strain (appendix p 5). The mechanism behind the rapid transmission of XBB.1.5, especially the effect of Ser486Pro, requires immediate investigation. We used vesicular stomatitis virus-based pseudovirus neutralisation assays to evaluate the neutralisation titres against XBB.1.5 of convalescent plasma from individuals who had received three doses of CoronaVac (Sinovac) before BA.1 (n=50), BA.5 (n=36), or BF.7 (n=30)breakthrough infection. A cohort of patients with convalescence from BA.5 breakthrough infection who had received at least two doses of BNT162b2 (Pfizer-BioNtech) or mRNA-1273 (Moderna) is also included in the analysis (n=10). Human ACE2 (hACE2)-binding affinity of XBB.1.5 receptor-binding domain was compared with that of XBB.1, BQ.1.1, and BA.2.75 using surface plasmon resonance. Plasma samples associated with CoronaVac were collected on average 27 days (SD 8) after hospital discharge (appendix pp 7–8). Plasma samples associated with the mRNA vaccine were collected within 2–3 weeks after hospital admission (appendix pp 7–8). The absence of BQ.1.1 breakthrough infection in individuals who were convalescent is a limitation of the ability of this study to estimate the scale of immune evasion of XBB.1.5 for this group. Plasma samples from individuals who had received three doses of CoronaVac and had a BA.1, BA.5, or BF.7 breakthrough infection showed a substantial decrease in plasma 50% neutralisation titre (NT50) against XBB.1 and XBB.1.5 compared with that against B.1 (ASP614Gly) variant (figure A). Plasma from patients who received CoronaVac and had a BA.5 breakthrough infection showed a 44-times lower NT50 against XBB.1 compared with the NT50 after B.1. The decrease was 40-times lower for XBB.1.5. For patients who received CoronaVac and had a BF.7 breakthrough infection, the plasma NT50 against XBB.1 was 31-times lower and XBB.1.5 was 27-times lower compared with the NT50 for B.1. A similar trend was also observed in plasma from patients who received two doses of an mRNA vaccine and had a BA.5 breakthrough infection and patients who received CoronaVac and had a BA.1 breakthrough infection. These findings suggest that Pro486 is also a strong neutralising antibody evading mutation, and that the humoral immune escape ability of XBB.1.5 is similar to that of XBB.1. Compared with XBB.1, XBB.1.5 had similar evasion against therapeutic mAbs (figure B); Evusheld and bebtelovimab did not neutralise XBB.1.5 pseudovirus. Sotrovimab is still active but weak against XBB.1.5. Another BA.5-effective mAb, SA58, is escaped by both XBB.1 and XBB.1.5. However, SA55 remains highly effective against XBB.1.5.2Cao Y Jian F Wang J et al.Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution.Nature. 2022; (published online Dec 19.)https://doi.org/10.1038/s41586-022-05644-7Crossref Scopus (99) Google Scholar, 6Cao Y Jian F Zhang Z et al.Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents.Cell Rep. 2022; 41111845Summary Full Text Full Text PDF Scopus (11) Google Scholar Previous deep mutational scanning studies have shown that Pro486 might enhance the affinity to hACE2 compared with Ser486.7Starr TN Greaney AJ Stewart CM et al.Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains.PLoS Pathog. 2022; 18e1010951Crossref Scopus (22) Google Scholar The binding affinity of the XBB.1.5 receptor-binding domain to hACE2 (dissociation constant [KD] 3·4 nM) was similar to that of BA.2.75 (KD 1·8 nM) and much stronger than that of XBB.1 (KD 19 nM) and BQ.1.1 (KD 8.1 nM; figure C; appendix p 6). These results suggest that the probable reason for the significant growth advantage of XBB.1.5 over XBB.1 is that it gained substantially higher ACE2 binding affinity through the Ser486Pro mutation, while retaining an extremely high immune evasion capability. With stronger immune escape ability but weaker ACE2 binding affinity than BQ.1.1, XBB and XBB.1 have only prevailed in a few countries, such as Singapore and India, since September, 2022. Whereas BQ.1.1 has quickly become the dominant global strain. Because of its enhanced hACE2-binding affinity and similar ability to evade the immune system, the prevalence of XBB.1.5 shows that receptor-binding affinity will substantially affect the transmissibility of the strain. The underlying mechanism needs to be investigated. Also, whether the increased receptor-binding affinity would cause a difference in pathogenicity compared with XBB is unclear and requires immediate research.8Tamura T Ito J Uriu K et al.Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants.bioRxiv. 2022; (Published online Dec 27.) (preprint).https://doi.org/10.1101/2022.12.27.521986Google Scholar Moreover, the strong affinity to hACE2 might allow XBB.1.5 to acquire additional immune-escape mutations, similar to the evolution trend of BA.2.75, when met with substantial immune pressure.9Cao Y Song W Wang L et al.Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75.Cell Host Microbe. 2022; 30 (39.e5): 1527Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar Therefore, the circulation of XBB.1.5 needs to be closely monitored, and the development of effective neutralising antibodies and vaccines against XBB.1.5 is urgently needed. YC is a cofounder of Singlomics Biopharmaceuticals and inventor of provisional patents associated with SARS-CoV-2 neutralising antibodies, including SA55 and SA58. All other authors declare no competing interests. CY and WS contributed equally. Download .pdf (1.34 MB) Help with pdf files Supplementary appendix