Heterologous BBIBP-CorV/ZF2001 vaccination augments neutralization against SARS-CoV-2 variants: A preliminary observation

Abstract

Vaccination to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is pivotal for reducing deaths and severe illness from coronavirus disease 2019 (COVID-19).1Dai L. Gao G.F. Viral targets for vaccines against COVID-19.Nat Rev Immunol. 2021; 21: 73-82Crossref PubMed Scopus (474) Google Scholar BBIBP-CorV as an inactivated virus vaccine and ZF2001 as a recombinant tandem-repeat dimeric receptor-binding domain (RBD) protein vaccine are two safe, immunogenic COVID-19 vaccines, used in China and several countries.2Xia S. Zhang Y. Wang Y. et al.Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.Lancet Infect Dis. 2021; 21: 39-51Summary Full Text Full Text PDF PubMed Scopus (624) Google Scholar,3Yang S. Li Y. Dai L. et al.Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials.Lancet Infect Dis. 2021; 21: 1107-1119Summary Full Text Full Text PDF PubMed Scopus (204) Google Scholar Since the beginning of the COVID-19 pandemic, SARS-CoV-2 variants are continually emerging and circulating around the world.4Campbell F. Archer B. Laurenson-Schafer H. et al.Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021.EuroSurveill. 2021; 26: 2100509Crossref Scopus (340) Google Scholar Variants of Concern (VOCs) designated by World Health Organization (WHO) currently include B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) and B.1.1.529 (Omicron) lineages,5Callaway E. Heavily mutated Omicron variant puts scientists on alert.Nature. 2021; 600: 21Crossref PubMed Scopus (206) Google Scholar with more rapid transmission and/or more challenges for the effectiveness of public health intervention and vaccines available. The emergence of SARS-CoV-2 variants is recognized as one of the reasons that led to breakthrough infections in the population of vaccination.6Hoffmann M. Arora P. Groß R. et al.SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies.Cell. 2021; 184 (e12): 2384-2393Summary Full Text Full Text PDF PubMed Scopus (494) Google Scholar Thus, one of the major public concerns is the administration of booster doses against COVID-19 pandemic, including the heterotypic vaccines.7Zhang J. He Q. An C. et al.Boosting with heterologous vaccines effectively improves protective immune responses of the inactivated SARS-CoV-2 vaccine.Emerg Microbes Infect. 2021; 10: 1598-1608Crossref PubMed Scopus (33) Google Scholar,8Ai J. Zhang H. Zhang Q. et al.Recombinant protein subunit vaccine booster following two-dose inactivated vaccines dramatically enhanced anti-RBD responses and neutralizing titers against SARS-CoV-2 and variants of concern.Cell Res. 2022; 32: 103-106Crossref PubMed Scopus (42) Google Scholar In this study, seven volunteers (two males and five females) were recruited and each received two doses of the inactivated SARS-CoV-2 vaccine (BBIBP-CorV) with a 28-days interval. Then, they received a dose of the recombinant ZF2001 at 4-5 months after receiving the second dose of BBIBP-CorV. Sera samples were collected from the volunteers at 1 month after receiving the second dose of BBIBP-CorV, and also at around 2-3 months and at 5-6 months after receiving a dose of ZF2001 (Figure 1A, Supplemental Table 1). The study was approved by the Ethics Committee, and all candidates signed the written informed consent. Given the positive correlation between neutralizing titer and protection efficacy,9Khoury D.S. Cromer D. Reynaldi A. et al.Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.Nat Med. 2021; 27: 1205-1211Crossref PubMed Scopus (1455) Google Scholar we assessed 50% pseudovirus neutralization titer (pVNT50) of all sera from the volunteers before and after receiving heterologous BBIBP-CorV/ZF2001 vaccination (Figs. S1 and S2). The median of pVNT50 of sera from volunteers who received a dose of ZF2001 after 2-3 months showed 51.9 (p = 0.0625, interquartile range (IQR) 35.8–89.7, prototype (WH-01)), 66.5 (*, p = 0.0313, IQR 46.8–626.0, B.1.1.7), 221.3 (*, p = 0.0313, IQR 44.9–564.6, B.1.351), 64.8 (*, p = 0.0313, IQR 38.5–120.5, P.1), 55.4 (p = 0.0625, IQR 25.0–220.2, B.1.617.2) and 79.9 (p = 0.0625, IQR 46.8–566.3, B.1.617.1) fold, respectively, higher compared with the ones that received the second dose of BBIBP-CorV (Figures 1B and D, S3). Although pVNT50 against B.1.1.529 (Omicron) from the volunteers that received the second dose of BBIBP-CorV were below the lower limit, the GMT of pVNT50 was elevated to 234.1 after receiving a dose of ZF2001 was about 116.7 fold change of median (*, p = 0.0313, IQR 42.6–254.1) (Figure 1C, D). This result indicated that the humoral response to SARS-CoV-2 variants has been boosted when most volunteers received a dose of ZF2001 after receiving the two doses of BBIBP-CorV. And our results are concordant with the previous study about that heterologous vaccination of protein subunit vaccine significantly recalled and increased the humoral and cellular immune responses against SARS-CoV-2 and its variants.8Ai J. Zhang H. Zhang Q. et al.Recombinant protein subunit vaccine booster following two-dose inactivated vaccines dramatically enhanced anti-RBD responses and neutralizing titers against SARS-CoV-2 and variants of concern.Cell Res. 2022; 32: 103-106Crossref PubMed Scopus (42) Google Scholar,10Ai J. Zhang H. Zhang Y. et al.Omicron variant showed lower neutralizing sensitivity than other SARS-CoV-2 variants to immune sera elicited by vaccines after boost.Emerg Microbes Infect. 2022; 11: 337-343Crossref PubMed Scopus (142) Google Scholar Moreover, we further evaluated the longevity of neutralizing activity against SARS-CoV-2 variants stimulated by the heterologous BBIBP-CorV/ZF2001 vaccination. Notably, at 5-6 months after the boost dose of ZF2001, the neutralization potency was still higher than after receiving the second dose of BBIBP-CorV, for the median of pVNT50 against all strains, i.e. prototype (20.6 fold, p = 0.125, IQR 14.7–38.6), B.1.1.7 (35.2 fold, p = 0.0625, IQR 28.1–403.2), B.1.351 (36.0 fold, p = 0.0625, IQR 18.1–249.6), P.1 (27.1 fold, p = 0.0625, IQR 9.3–58.2), B.1.617.2 (20.6 fold, p = 0.125, IQR 18.9–129.5), B.1.617.1 (45.9 fold, p = 0.125, IQR 14.1–304.4) and B.1.1.529 (20.4 fold, p = 0.0625, IQR 15.3–64.4), respectively (Figures 1B–D, S3). This result showed that the neutralizing antibody titer against variants was elicited and maintained a long-lasting recall humoral response. Recent research showed that the boosting 3-dose inactivated vaccinees could recall long-lasting humoral responses until 6 months.11Zeng G. Wu Q. Pan H. et al.Immunogenicity and safety of a third dose of CoronaVac, and immune persistence of a two-dose schedule, in healthy adults: interim results from two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trials.Lancet Infect Dis. 2022; 22: 483-495Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar Additionally, we also evaluated the changes in the proportion of the neutralizing titer against the SARS-Cov-2 variants as compared with the prototype (WH-01) after receiving a dose of ZF2001. At 2-3 months and 5-6 months after receiving a dose of ZF2001, the neutralizing titer against B.1.1.7 (Alpha) and B.1.617.2 (Delta) variants retain roughly equivalent as compared with the prototype, and the changes of median were 1.08 folds (p > 0.05, IQR 0.97–1.53) and 1.13 folds (p > 0.05, IQR 1.13–1.35) for Alpha to prototype, and 1.00 folds (p > 0.05, IQR 0.79–1.12) and 1.32 folds (p > 0.05, IQR 1.23–1.62) for Delta to prototype, respectively. However, the B.1.351 (Beta) and B.1.617.1 (Kappa) variants showed more pronounced reduction in sensitivity, and the changes of median were 0.64 folds (p > 0.05, IQR 0.26–0.95) and 0.39 folds (p > 0.05, IQR 0.21–0.70) for Beta to prototype, and 0.67 folds (*, p < 0.05, IQR 0.58–0.83) and 0.72 folds (*, p < 0.05, IQR 0.49–0.60) for Kappa to prototype, respectively (Figure 1B and E). Significantly, the median of pVNT50 against B.1.1.529 (Omicron) strain have 0.2 folds (*, p < 0.05, IQR 0.1–0.2) and 0.1 folds (*, p < 0.05, IQR 0.1-0.2) reduction compared to the prototype. Thus, though neutralizing activity could be boosted against the newly emerging variants, the neutralizing titers against B.1.351 (Beta), B.1.617.1 (Kappa), and B.1.1.529 (Omicron) were significantly lower than the prototype (Figure 1C and E). These results were consistent with our previous findings about the multi-boost strategy with receiving 3-dose of ZF2001 or inactivated vaccine would be beneficial for NAb against SARS-CoV-2 variants.12Zhao X. Zheng A. Li D. et al.Neutralisation of ZF2001-elicited antisera to SARS-CoV-2 variants.Lancet Microbe. 2021; 2: e494Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar,13Zhao X. Li D. Ruan W. et al.Effects of a prolonged booster interval on neutralization of omicron variant.N Engl J Med. 2022; 386: 894-896Crossref PubMed Scopus (32) Google Scholar This preliminary study indicated that the heterologous BBIBP-CorV/ZF2001 vaccination could boost and maintain a long-lasting recall of humoral immune responses against SARS-CoV-2 and its VOCs. In our previous study, we showed the BBIBP-CorV vaccine given three times also have evoked cross-antibody responses to different VOCs, which is concordant to the current results of heterologous BBIBP-CorV/ZF2001 vaccination. In this study, we did not involve the control BBIBP-CorV given three times with the same interval, which may be a limitation for the current findings, and the safety and effectiveness of the strategy of heterologous BBIBP-CorV/ZF2001 vaccination should be further studied through clinical trials in the future. More types of vaccines, e.g live intranasal vaccines, peptide vaccines, etc. may be needed to induce more cross-protective immunity to combat SARS-CoV-2, VOCs and other potential emerging coronaviruses. GFG, WJL, YZ and XZ conceived and designed the study. YZ, XZ and WJL designed, and coordinated the experiments. YZ, RZ, BY, DZ, YG, LL and JT performed experiments. YZ, XY and LL recruited volunteers and coordinated the blood samples. YZ, XZ, YG and WJL analyzed the data. GFG, YZ and WJL drafted and revised the manuscript. All authors reviewed and approved the final manuscript. WJL have accessed and verified the data, and takes responsibility for the decision to submit the manuscript. Data will become publicly available upon request from the corresponding author. G.F.G. are listed in the patent as the inventors of the RBD-dimer as a betacoronavirus vaccine. The patent has been licensed to Anhui Zhifei Longcom for protein subunit COVID-19 vaccine development. All other authors declare no competing interests. We thank all the volunteers for providing blood samples. This work was supported by Project of International Cooperation and Exchanges, National Natural Science Foundation of China (82161148008) and National Natural Science Foundation of China (81971501). W.J.L. is supported by the Excellent Young Scientist Program of the National Natural Science Foundation of China (81822040). Download .pdf (1.45 MB) Help with pdf files Download .docx (.01 MB) Help with docx files