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. 2022 Aug 25:11:e78633.
doi: 10.7554/eLife.78633.

A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants

Jing Zhang #  1   2 , Zi Bo Han #  1   2 , Yu Liang  1   2 , Xue Feng Zhang  1   2 , Yu Qin Jin  1 , Li Fang Du  1   2 , Shuai Shao  1   2 , Hui Wang  3 , Jun Wei Hou  1   2 , Ke Xu  4 , Wenwen Lei  4 , Ze Hua Lei  1   2 , Zhao Ming Liu  1   2 , Jin Zhang  3 , Ya Nan Hou  1   2 , Ning Liu  1   2 , Fu Jie Shen  1   2 , Jin Juan Wu  1   2 , Xiang Zheng  1   2 , Xin Yu Li  1   2 , Xin Li  1   2 , Wei Jin Huang  5 , Gui Zhen Wu  4 , Ji Guo Su  1   2 , Qi Ming Li  1   2
Affiliations

A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants

Jing Zhang et al. Elife. .

Abstract

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody ID50 titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the BIBP inactivated COVID-19 vaccine (BBIBP-CorV). Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

Keywords: COVID-19; SARS-CoV-2; broad-spectrum; immunology; infectious disease; inflammation; microbiology; omicron variant; vaccine; viruses.

Plain language summary

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to pose a serious threat to public health and has so far resulted in over six million deaths worldwide. Mass vaccination programs have reduced the risk of serious illness and death in many people, but the virus continues to persist and circulate in communities across the globe. Furthermore, the current vaccines may be less effective against the new variants of the virus, such as Omicron and Delta, which are continually emerging and evolving. Therefore, it is urgent to develop effective vaccines that can provide broad protection against existing and future forms of SARS-CoV-2. There are several different types of SARS-CoV-2 vaccine, but they all work in a similar way. They contain molecules that induce immune responses in individuals to help the body recognize and more effectively fight SARS-CoV-2 if they happen to encounter it in the future. These immune responses may be so specific that new variants of a virus may not be recognized by them. Therefore, a commonly used strategy for producing vaccines with broad protection is to make multiple vaccines that each targets different variants and then mix them together before administering to patients. Here, Zhang et al. took a different approach by designing a new vaccine candidate against SARS-CoV2 that contained three different versions of part of a SARS-CoV2 protein – the so-called spike protein – all linked together as one molecule. The different versions of the spike protein fragment were designed to include key features of the fragments found in Omicron and several other SARS-CoV-2 variants. The experiments found that this candidate vaccine elicited a much higher immune response against Omicron and other SARS-CoV-2 variants in rats than an existing SARS-CoV-2 vaccine. It was also effective as a booster shot after a first vaccination with the existing SARS-CoV-2 vaccine. These findings demonstrate that the molecule developed by Zhang et al. induces potent and broad immune responses against different variants of SARS-CoV-2 including Omicron in rats. The next steps following on from this work are to evaluate the safety and immunogenicity of this vaccine candidate in clinical trials. In the future, it may be possible to use a similar approach to develop new broad-spectrum vaccines against other viruses.

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Conflict of interest statement

JZ, ZH, YL, XZ, YJ, LD, SS, JH, ZL, ZL, YH, NL, FS, JS, QL is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X), HW, JZ is an employee of Beijing Institute of Biological Products Company Limited, KX, WL, JW, XZ, XL, XL, WH, GW No competing interests declared

Figures

Figure 1.
Figure 1.. Design, expression and characterization of the mosaic-type trimeric form of RBD (mos-tri-RBD).
(A) Schematic illustration of the designed mos-tri-RBD. In mos-tri-RBD, three heterologous RBDs were connected end to end into a single chain and co-assembled into a trimeric structure. For the three RBDs, one was derived from the Omicron (BA.1) variant (green color), and the other two were artificially designed harboring the key immune-evasion-related mutations that emerged in SARS-CoV-2 variants, in which one contained the mutations of K417N, L452R, T478K, F490S, and N501Y (cyan color), and the other one contained K417T, S477N, and E484K (blue color). These mutations are highlighted in the red ball-and-stick model in the figure. Each RBD subunit in mos-tri-RBD was composed of the residues 319–537 from the spike protein. The dotted curves in the figure represent the direct connection between the C-terminus of the former RBD and the N-terminus of the latter RBD. The schematic structure of mos-tri-RBD was drawn by Chimera software (Pettersen et al., 2004) based on the PDB file with accession number 6zgi. (B) SDS-PAGE analysis of the recombinant mos-tri-RBD. (C) Concentration-dependent binding ability of mos-tri-RBD with an RBD-specific monoclonal neutralizing antibody MM117 tested using ELISA. (D) Binding avidity of mos-tri-RBD with the receptor hACE2 measured using SPR assay. In this figure, different curves represent different concentrations of analyte (top to bottom: 263.70 ng/ml, 131.85 ng/ml, 65.93 ng/ml, 32.96 ng/ml, and 16.48 ng/ml). Both the original (color curves) and fitted (black curves) data are displayed.
Figure 2.
Figure 2.. Evaluation of the cross-reactive immunogenicity of mos-tri-RBD against multiple SARS-CoV-2 strains, including prototype, Omicron, Beta and Delta strains, using live-virus neutralization assay.
(A) Timeline of rat immunization and serum collections. A group of Wistar rats (n=10 with half male and half female) were immunized intramuscularly with two doses of mos-tri-RBD with three weeks apart. Another three groups of rats received two doses of homo-tri-RBD, BBIBP-CorV and adjuvant, respectively, were used for comparison (n=10 rats per group with half male and half female). Sera from all the immunized rats were collected on day 7 after the last vaccination. (B) The reciprocal neutralizing ID50 titers in the sera elicited by mos-tri-RBD compared with those elicited by homo-tri-RBD and BBIBP-CorV against the live-viruses of SARS-CoV-2 prototype strain, and Omicron, Beta, and Delta variants. The quantification limit of the live-virus neutralization assay was 20, and the ID50 titers below the limit of quantification (LOQ) were set to 20. Data are presented as mean ± SEM. One-way ANOVA followed by the LSD t-test was used for the comparison of data between different groups. *p<0.05, **p<0.01, ****p<0.0001. GMT values are displayed in the lower part of the figure.
Figure 3.
Figure 3.. Evaluation of the cross-reactive immunogenicity of mos-tri-RBD as a booster shot against SARS-CoV-2 Omicron as well as other VOCs and VOIs using pseudo-virus neutralization assays.
(A) Timeline of rat immunization and serum collections. Three groups of Wistar rats (n=10 rats per group with half male and half female) were primed with a dose of BBIBP-CorV and boosted by mos-tri-RBD, homo-tri-RBD or BBIBP-CorV with three weeks apart. Another group of rats (n=10 with half male and half female) vaccinated with two doses of adjuvant served as control. The sera of all the immunized rats were collected on day 7 post-boosting immunization. (B) The reciprocal neutralizing ID50 titers in the sera elicited by ‘BBIBP-CorV +mos-tri-RBD’ vaccination compared with those elicited by ‘BBIBP-CorV +homo-tri-RBD’ and ‘BBIBP-CorV +BBIBP-Corv’ vaccinations against the pseudo-viruses of SARS-CoV-2 Omicron as well as other VOCs and VOIs. The quantification limit of the pseudo-virus neutralization assay was 40, and the ID50 titers below the LOQ were set to 40. Data are presented as mean ± SEM. One-way ANOVA followed by the LSD t-test was used for the comparison of data between different groups. *p<0.05, **p<0.01, ****p<0.0001. GMT values are displayed in the lower part of the figure.
Figure 4.
Figure 4.. Evaluation of the cross-reactive immunogenicity of mos-tri-RBD as a booster shot against multiple SARS-CoV-2 strains, including prototype, Omicron, Beta, and Delta strains, using live-virus neutralization assay.
The reciprocal neutralizing ID50 titers in the sera elicited by ‘BBIBP-CorV +mos-tri-RBD’ vaccination compared with those elicited by ‘BBIBP-CorV +homo-tri-RBD’ and ‘BBIBP-CorV +BBIBP-Corv’ vaccinations against the live-viruses of SARS-CoV-2 Omicron as well as other immune-evasive variants. The quantification limit of the live-virus neutralization assay was 20, and the ID50 titers below the LOQ were set to 20. Data are presented as mean ± SEM. One-way ANOVA followed by the LSD t-test was used for the comparison of data between different groups. *p<0.05, **p<0.01, ****p<0.0001. GMT values are displayed in the lower part of the figure.
Appendix 1—figure 1.
Appendix 1—figure 1.. The gene sequence of the spike region of the Omicron BA.1.1 virus used in the live virus neutralization assay.
Appendix 1—figure 2.
Appendix 1—figure 2.. The amino acid sequence of the spike region of the Omicron BA.1.1 virus used in the live virus neutralization assay aligned with that of the prototype virus.
The sequence alignment result shows that there are 40 residue mutations, deletions or insertions in the spike region compared to that of the prototype virus, including A67V, del69-70, T95I, G142D, del143-145, N211I, del212, insert EPE, G339D, R346K, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K and L981F.
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References

    1. Amicone M, Borges V, Alves MJ, Isidro J, Zé-Zé L, Duarte S, Vieira L, Guiomar R, Gomes JP, Gordo I. Mutation rate of SARS-cov-2 and emergence of mutators during experimental evolution. Evolution, Medicine, and Public Health. 2022;10:142–155. doi: 10.1093/emph/eoac010. - DOI - PMC - PubMed
    1. Barouch DH, O’Brien KL, Simmons NL, King SL, Abbink P, Maxfield LF, Sun Y-H, La Porte A, Riggs AM, Lynch DM, Clark SL, Backus K, Perry JR, Seaman MS, Carville A, Mansfield KG, Szinger JJ, Fischer W, Muldoon M, Korber B. Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nature Medicine. 2010;16:319–323. doi: 10.1038/nm.2089. - DOI - PMC - PubMed
    1. Callaway E. Omicron likely to weaken COVID vaccine protection. Nature. 2021;600:367–368. doi: 10.1038/d41586-021-03672-3. - DOI - PubMed
    1. Callaway E, Ledford H. How to redesign COVID vaccines so they protect against variants. Nature. 2021;590:15–16. doi: 10.1038/d41586-021-00241-6. - DOI - PubMed
    1. Cao Y, Wang J, Jian F, Xiao T, Song W, Yisimayi A, Huang W, Li Q, Wang P, An R, Wang J, Wang Y, Niu X, Yang S, Liang H, Sun H, Li T, Yu Y, Cui Q, Liu S, Yang X, Du S, Zhang Z, Hao X, Shao F, Jin R, Wang X, Xiao J, Wang Y, Xie XS. Omicron escapes the majority of existing SARS-cov-2 neutralizing antibodies. Nature. 2022;602:657–663. doi: 10.1038/s41586-021-04385-3. - DOI - PMC - PubMed

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