Neutralization against XBB.1 and XBB.1.5 after omicron subvariants breakthrough infection or reinfection

Abstract

Dear editor, Currently, the omicron XBB subvariant, which is a recombinant of BJ.1 and BA.2.75, was first identified in India in August 2022 and now its new sublineage XBB.1.5, has been reported from at least 79 countries and has become predominant in the world,1WHOWeekly epidemiological update on COVID-19-8 March 2023.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-march-2023Date accessed: March 15, 2023Google Scholar raising the concern of neutralizing activity elicited by breakthrough infection and reinfection.2Kurhade 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. 2023; 29: 344-347Crossref PubMed Scopus (135) Google Scholar, 3Arora P. Cossmann A. Schulz S.R. et al.Neutralisation sensitivity of the SARS-CoV-2 XBB.1 lineage.Lancet Infect Dis. 2023; 23: 147-148Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 4Wang Q. Iketani S. Li Z. et al.Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants.Cell. 2023; 186: 279-286.e8Summary Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 5Yue C. Song W. Wang L. et al.ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5.Lancet Infect Dis. 2023; 23: 278-280Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar Therefore, we tested neutralization titers of serum samples obtained from participants in six groups who suffered omicron subvariants breakthrough infection (BTI) or reinfection against D614G strain and primary omicron subvariants BA.2, BA.4/5, BA.2.75.2, BF.7, BQ.1.1, XBB.1, and XBB.1.5 using pseudovirus neutralization test (pVNT) (Appendix pp 2, 8–13). In all six groups, neutralization titers were lower against all omicron subvariants than against the D614G strain; the level of neutralizing antibodies was lowest against the XBB.1, followed by XBB.1.5 (Fig. 1 and Appendix p 4). For participants four months after BA.2.2 BTI, the neutralization titers against BA.2, BA.4/5, and BF.7 that were 1.8–4.0 times lower than that against D614G, while neutralization titers against BA.2.75.2, BQ.1.1, XBB.1, and XBB.1.5 that were 21.4–77.5 times lower than that against D614G (Fig. 1A). For participants 8 months after BA.2.2 BTI without reinfection, the neutralization titers against BA.2, BA.4/5, and BF.7 that were 1.5–3.1 times lower than that against D614G and neutralization titers against BA.2.75.2, BQ.1.1, XBB.1, and XBB.1.5 that were 15.8–69.1 times lower than that against D614G (Fig. 1B). The neutralization titers remained stable between 4 and 8 months after BA.2.2 BTI among participants without subsequent BA.5.2 infection, and no significant differences were observed between the two time points (Appendix pp 5–6). However, there were also eight subjects suffered BA.5.2 reinfection 8 months after BA.2.2 BTI, and the neutralization titers against omicron subvariants were 1.1–15.4 times lower than that against D614G, along with obvious reduction of GMT ratios and high percentage of neutralized serum (87.5%) against XBB.1 and XBB.1.5 (Fig. 1C). In addition, significantly enhanced neutralizing activity against all omicron subvariants was observed after BA.5.2 reinfection (Appendix pp 5–6). Further comparison showed that the neutralization titers against BA.4/5 and BF.7 were significant lower in subjects with subsequent BA.5.2 reinfection than those without BA.5.2 reinfection at the stage of 4 months after BA.2.2 BTI (Appendix pp 5–6), indicating that subjects with lower neutralization titers elicited by previous infection were more likely to suffered reinfection. After BA.2.76 BTI, the neutralization titer against BA.2, BA.4/5, and BF.7 were 2.6–6.3 times lower than that against D614G and relatively high reduction of neutralization titers (37.6–91.9 times) against BA.2.75.2, BQ.1.1, XBB.1, and XBB.1.5 than against D614G were observed (Fig. 1D). For the participants after BA.5.2 and BF.7 BTI, the neutralization titer against BA.2, BA.4/5, BF.7 were 1.1–2.6 times and 1.6–2.7 times lower than that against D614G, respectively. Differently, the neutralization titers of two groups against BA.2.75.2, BQ.1.1, XBB.1, and XBB.1.5 were 16.4–60.3 times and 17.0–94.9 times lower than that against D614G, respectively (Fig. 1E and F). Further comparison among BTI groups showed that significant higher neutralization titers were observed against BA.2, BA.4/5, BF.7, BA.2.75.2, BQ.1.1, and XBB.1.5 variants in BF.7 BTI group than in BA.2.76 BTI group. And more resistant to BQ.1.1 and XBB.1.5 variants were also found in BA.2.76 BTI group compared to that in BA.5.2 reinfection group (Appendix p 7). Our study has one limitation. Due to the sample size of participants who suffered breakthrough infection is relatively small, factors of sex, age, and time intervals from symptoms onset to sampling are mismatched among different groups. Therefore, studies with large number of participants are needed to analyse the influence of these factors in the future. Overall, our data suggest that the XBB.1 and XBB.1.5 omicron subvariants extensively escape the serum neutralization elicited by BTI or reinfection. We also concluded that the level of serum neutralizing titers was correlated with reinfection. Continued assessment of neutralization after BTI or reinfection against emerging omicron subvariants is needed. G.-L.W., L.-Q.F., and Y.S. designed and supervised the research. L.-B.L., Y.S., H.-H.P., B.J., C.S., C.Q., and W.-G.J. collected clinical samples and data. G.-L.W., J.-J.C., S.T., M.-C.L., and T.-T.L. performed the laboratory detection and analyzed the data. G.-L.W. and L.-Q.F. drafted the manuscript. All authors reviewed and approved the final manuscript. The authors declare no competing interests. We thank all study participants for providing serum and data in the study. This work was supported by Beijing Natural Science Foundation (L222119 to Guo-Lin Wang), the National Key Research and Development Program of China (2019YFC1200502 to Guo-Lin Wang and 2019YFC1200604 to Li-Qun Fang), the National Natural Science Foundation of China (82103901 to Guo-Lin Wang and 32000087 to Bin Ji), the Wuxi Medical Development Discipline (FZXK2021010 to Yuan Shen), and the Project of Science and Technology Research Program (Basic Research) of Wuxi “Light of Taihu Lake” (Y20212042 to Chao Shi). The funders of the study had no role in study design, data collection, data analysis, interpretation, or writing of the report. Download .docx (1.32 MB) Help with docx files Appendix

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