Omicron neutralisation: RBD-dimer booster versus BF.7 and BA.5.2 breakthrough infection

COVID-19 inactivated vaccines (CoronaVac [Sinovac Biotech, Beijing, China] and BBIBP-CorV [Sinopharm, Beijing, China])1Xu K Fan C Han Y Dai L Gao GF Immunogenicity, efficacy and safety of COVID-19 vaccines: an update of data published by 31 December 2021.Int Immunol. 2022; 34: 595-607Crossref PubMed Scopus (9) Google Scholar and the protein subunit vaccine ZF2001 (Anhui Zhifei Longcom, Hefei, China)2Dai L Gao L Tao L et al.Efficacy and safety of the RBD-dimer-based COVID-19 vaccine ZF2001 in adults.N Engl J Med. 2022; 386: 2097-2111Crossref PubMed Scopus (79) Google Scholar, 3Dai L Zheng T Xu K et al.A universal design of betacoronavirus vaccines against COVID-19, MERS, and SARS.Cell. 2020; 182 (33.e11): 722Summary Full Text Full Text PDF PubMed Scopus (289) Google Scholar—which uses dimeric receptor-binding domain (RBD) homodimer as the antigen—were designed to act against ancestral SARS-CoV-2 and are widely used in China and many other countries. The surge of omicron subvariants BF.7 and BA.5.2 in China in December, 2022 caused nationwide breakthrough infections due to waning immunity and the increased resistance of the omicron subvariants to vaccine-induced immune responses.4Pan Y Wang L Feng Z et al.Characterisation of SARS-CoV-2 variants in Beijing during 2022: an epidemiological and phylogenetic analysis.Lancet. 2023; 401: 664-672Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar Omicron subvariants, including BQ.1, BQ.1.1, XBB, and XBB.1.5 continue to emerge worldwide, with further immune evasion due to their increased mutations in the spike protein (appendix p 6).5Wang Q Iketani S Li Z et al.Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants.Cell. 2023; 186 (86.e8): 279Summary Full Text Full Text PDF PubMed Scopus (123) Google Scholar Bivalent boosters containing omicron immunogen (BA.1 or BA.4–BA.5) have been widely used; however, the real-world effectiveness data are still emerging.6Offit PA Bivalent COVID-19 vaccines—a cautionary tale.N Engl J Med. 2023; 388: 481-483Crossref PubMed Scopus (20) Google Scholar We designed a heterotypic delta (B.1.617.2)–omicron (BA.1) chimeric RBD-dimer vaccine (ZF2202),7Xu K Gao P Liu S et al.Protective prototype-beta and delta-omicron chimeric RBD-dimer vaccines against SARS-CoV-2.Cell. 2022; 185 (78.e14): 2265Summary Full Text Full Text PDF PubMed Scopus (42) Google Scholar which is being tested as a booster in clinical trials (NCT05616754 and NCT05574985). Here we report the results of an analysis of the SARS-CoV-2 neutralisation profile of serum samples from participants after they received a booster of a prototype vaccine (inactivated or ZF2001) or ZF2202, or after having an omicron BF.7 or BA.5.2 subvariant breakthrough infection. We obtained serum samples from 175 participants split into seven groups (25 participants per group) according to whether they had received two or three doses of inactivated vaccine or ZF2001 and then a booster vaccination or had a breakthrough infection during the latest BF.7 and BA.5.2 waves in Beijing, China, in December, 2022 (appendix pp 4–5). Groups 1–3 had received two doses of inactivated vaccine, and were boosted with a third dose of inactivated vaccine (group 1), ZF2001 (group 2), or ZF2202 (group 3). Groups 4–5 had received three doses of inactivated vaccine (group 4) or ZF2001 (group 5), and were boosted with a fourth dose of ZF2202. Groups 6–7 had received three doses of inactivated vaccine (group 6) or ZF2001 (group 7), and had breakthrough infection. Serum sample neutralisation was tested against a panel of SARS-CoV-2 pseudoviruses based on a vesicular stomatitis virus backbone to encode SARS-CoV-2 spike protein as described previously.8Zhao X Zhang R Qiao S et al.Omicron SARS-CoV-2 neutralization from inactivated and ZF2001 vaccines.N Engl J Med. 2022; 387: 277-280Crossref PubMed Scopus (35) Google Scholar Three doses of inactivated vaccine or a heterologous ZF2001 booster after two doses of inactivated vaccine elicited neutralising geometric mean titres (GMTs) that ranged between 203 (95% CI 105–394) and 1247 (614–2530) against ancestral and delta pseudoviruses, and lower titres (GMTs ranging between 13 [95% CI 6–26] and 97 [51–185]) against preceding (BA.1) and circulating (BA.2.75, BA.5 or BA.5.2, and BF.7) omicron subvariants (figure A, B; appendix pp 7, 9–10). The titres were close to the limit of detection when tested against the emerging subvariants BQ.1, BQ.1.1, XBB, and XBB.1.5, with the proportions of neutralisation-positive serum samples per group for each of these variants all less than 50% (ranging between 4% [95% CI 0–20] and 44% [27–63]; appendix p 8). In contrast, the heterodimer booster ZF2202 after two doses of inactivated vaccine induced increased (versus groups 1 and 2) neutralising GMTs against all pseudoviruses tested (figure C, F; appendix p 11). More than 50% of samples were positive for neutralising antibodies against the currently emerging BQ.1 (60%, 95% CI 41–77), BQ.1.1 (52%, 33–70), XBB (60%, 41–77), and XBB.1.5 (52%, 33–70) subvariants (appendix p 8). These data suggest that neutralisation following bivalent vaccine booster is broader than following inactivated vaccine or ZF2001 booster. Participants who had received serial vaccinations of three doses of inactivated vaccine plus the heterodimer booster ZF2202 had higher neutralising antibodies to all pseudoviruses tested, by a factor of 1·3–2·1, than did those who had received two inactivated vaccines plus the heterodimer booster ZF2202 (figure D; appendix pp 12, 16). The proportion of neutralisation-positive serum samples against the currently emerging BQ.1, BQ.1.1, XBB, and XBB.1.5 subvariants ranged between 68% (95% CI 48–83) and 76% (57–89) for group 4 (appendix p 8). For participants who had received three doses of ZF2001 plus the heterodimer booster ZF2202, the neutralising GMTs against all pseudoviruses tested further increased by a factor of 1·1–2·1 versus group 4 (figure E; appendix pp 13, 16). 80–84% of samples were neutralisation positive against the currently emerging BQ.1, BQ.1.1, XBB, and XBB.1.5 subvariants (appendix p 8). These data suggest broad serum sample neutralisation after bivalent vaccine boosting. For participants who had a breakthrough infection after three doses of inactivated vaccine, their neutralising GMTs were lower than the ZF2202 booster group (group 4) against all pseudoviruses tested (figure G; appendix p 14). However, for those who had a breakthrough infection after three doses of ZF2001, the serum sample neutralising GMTs were similar to the ZF2202 booster group (group 5) when tested against ancestral and delta pseudoviruses, but higher when tested against all omicron subvariants (figure H; appendix p 15). The neutralising GMTs against the currently emerging BQ.1, BQ.1.1, XBB, and XBB.1.5 subvariants ranged between 142 (95% CI 91–221) and 251 (155–406), with the proportion of neutralisation-positive serum samples between 96% (80–100) and 100% (87–100; appendix p 8). These data suggest that there is a benefit to using an omicron-containing RBD heterodimer as a booster compared with the prototype vaccine booster to counter both circulating and emerging omicron subvariants. Breakthrough infections caused by the circulating omicron subvariants also elicit substantial serum sample cross-neutralisation against the emerging subvariants, including BQ.1, BQ.1.1, and XBB.1.5. However, the difference in the time interval before the booster or between the last dose and breakthrough infection might be a confounding factor in the present descriptive study due to the sampling limitation. Based on our observations, at least for the protein subunit vaccine, updating vaccine components according to subvariants is crucial for the continued control of the COVID-19 pandemic. LD, HD, XL, and HZ contributed equally to this Correspondence. GFG and LD conceived and designed the study. GFG, LD, and KX designed and coordinated the experiments. HD, XL, MD, and YA performed the experiment. HZ and QW acquired serum samples for the clinical trial. LY organised the investigational products, and XZ assisted in the pseudovirus production. GFG, LD, HD, XL, and KX analysed the data. LD and HD drafted the Correspondence and GFG revised it. All authors reviewed and approved the final Correspondence. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. LD, HD, and XL have verified the data. LD, YA, KX, and GFG are listed in the patent (PCT/CN2020/097775: Antigens of beta-coronaviruses, preparation methods and uses thereof) as the inventors of the RBD-dimer as a betacoronavirus vaccine. This patent has been licensed to Anhui Zhifei Longcom for protein subunit COVID-19 vaccine development. Anhui Zhifei Longcom is the manufacturer of ZF2001 and ZF2202. LY is an employee at Anhui Zhifei Longcom and has owned stock of Zhifei. All other authors declare no competing interests. The individual participant-level data that underlie the results reported in this Correspondence will be shared after de-identification. Researchers who provide a scientifically sound proposal will be allowed to access the de-identified individual participant data. Proposals should be sent to the corresponding author. To gain access, data requesters will need to sign a data access agreement. We thank all participants who provided blood samples for the experiment. We thank Fan Ding and Lifeng Tao from Anhui Zhifei Longcom Biopharmaceutical for their help in providing the serum samples. We thank Shuxin Guo, Dedong Li, and Yanfang Zhang for their technical assistance. This work is supported by the National Key Research and Development Programme of China (2020YFA097100 and 2021YFC2302600), the National Natural Science Foundation of China (81991494 and 82122031), a grant from the Bill & Melinda Gates Foundation (INV-027420), and the Chinese Academy of Sciences (YSBR-010). Download .pdf (2.57 MB) Help with pdf files Supplementary appendix