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

  1. Jing Zhang
  2. Zi Bo Han
  3. Yu Liang
  4. Xue Feng Zhang
  5. Yu Qin Jin
  6. Li Fang Du
  7. Shuai Shao
  8. Hui Wang
  9. Jun Wei Hou
  10. Ke Xu
  11. Wenwen Lei
  12. Ze Hua Lei
  13. Zhao Ming Liu
  14. Jin Zhang
  15. Ya Nan Hou
  16. Ning Liu
  17. Fu Jie Shen
  18. Jin Juan Wu
  19. Xiang Zheng
  20. Xin Yu Li
  21. Xin Li
  22. Wei Jin Huang  Is a corresponding author
  23. Gui Zhen Wu  Is a corresponding author
  24. Ji Guo Su  Is a corresponding author
  25. Qi Ming Li  Is a corresponding author
  1. National Vaccine and Serum Institute, China
  2. Beijing Institute of Biological Products Company Limited, China
  3. Chinese Center For Disease Control and Prevention, China
  4. National Institutes for Food and Drug Control, China

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.

Data availability

Figure 1 - Source Data 1, Figure 1 - Source Data 2, Figure 2 - Source Data 1, Figure 3 - Source Data 1 and Figure 4 - Source Data 1 contain the numerical data used to generate the figures. The gene sequence of the spike region of the Omicron BA.1.1 virus used in the live virus neutralization assay is provided in Appendix 1-figure 1, and the residue mutations in the Omicron BA.1.1 spike region compared to that of the prototype virus are provided in Appendix 1-figure 2.

Article and author information

Author details

  1. Jing Zhang

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Jing Zhang, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  2. Zi Bo Han

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Zi Bo Han, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  3. Yu Liang

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Yu Liang, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  4. Xue Feng Zhang

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Xue Feng Zhang, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  5. Yu Qin Jin

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Yu Qin Jin, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  6. Li Fang Du

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Li Fang Du, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  7. Shuai Shao

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Shuai Shao, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  8. Hui Wang

    Beijing Institute of Biological Products Company Limited, Beijing, China
    Competing interests
    Hui Wang, is an employee of Beijing Institute of Biological Products Company Limited..
  9. Jun Wei Hou

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Jun Wei Hou, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  10. Ke Xu

    National Institute for Viral Disease Control and Prevention, Chinese Center For Disease Control and Prevention, Beijing, China
    Competing interests
    No competing interests declared.
  11. Wenwen Lei

    National Institute for Viral Disease Control and Prevention, Chinese Center For Disease Control and Prevention, Beijing, China
    Competing interests
    No competing interests declared.
  12. Ze Hua Lei

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Ze Hua Lei, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  13. Zhao Ming Liu

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Zhao Ming Liu, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  14. Jin Zhang

    Beijing Institute of Biological Products Company Limited, Beijing, China
    Competing interests
    Jin Zhang, is an employee of Beijing Institute of Biological Products Company Limited..
  15. Ya Nan Hou

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Ya Nan Hou, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  16. Ning Liu

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Ning Liu, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  17. Fu Jie Shen

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    Fu Jie Shen, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  18. Jin Juan Wu

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    No competing interests declared.
  19. Xiang Zheng

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    No competing interests declared.
  20. Xin Yu Li

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    No competing interests declared.
  21. Xin Li

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    Competing interests
    No competing interests declared.
  22. Wei Jin Huang

    National Institutes for Food and Drug Control, Beijing, China
    For correspondence
    huangweijin@nifdc.org.cn
    Competing interests
    No competing interests declared.
  23. Gui Zhen Wu

    National Institute for Viral Disease Control and Prevention, Chinese Center For Disease Control and Prevention, Beijing, China
    For correspondence
    wugz@ivdc.chinacdc.cn
    Competing interests
    No competing interests declared.
  24. Ji Guo Su

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    For correspondence
    jiguosu@hotmail.com
    Competing interests
    Ji Guo Su, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
  25. Qi Ming Li

    The Sixth Laboratory, National Vaccine and Serum Institute, Beijing, China
    For correspondence
    liqiming189@163.com
    Competing interests
    Qi Ming Li, is listed as an inventor of the pending patent application for the mos-tri-RBD vaccine (Application number: 202210083654.X)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8284-7106

Funding

National Vaccine and Serum Institute (KTZC1900026C)

  • Jing Zhang

National Vaccine and Serum Institute (KTZC1900026C)

  • Qi Ming Li

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the National Vaccine and Serum Institute (NVSI) (No. NVSI-RCD-JSDW-ER-2021238, NVSI-RCD-JSDW-ER-2022015) and conducted under the regulations for the administration of affairs concerning experimental animals of China (2017).

Copyright

© 2022, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,158
    views
  • 329
    downloads
  • 17
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jing Zhang
  2. Zi Bo Han
  3. Yu Liang
  4. Xue Feng Zhang
  5. Yu Qin Jin
  6. Li Fang Du
  7. Shuai Shao
  8. Hui Wang
  9. Jun Wei Hou
  10. Ke Xu
  11. Wenwen Lei
  12. Ze Hua Lei
  13. Zhao Ming Liu
  14. Jin Zhang
  15. Ya Nan Hou
  16. Ning Liu
  17. Fu Jie Shen
  18. Jin Juan Wu
  19. Xiang Zheng
  20. Xin Yu Li
  21. Xin Li
  22. Wei Jin Huang
  23. Gui Zhen Wu
  24. Ji Guo Su
  25. Qi Ming Li
(2022)
A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants
eLife 11:e78633.
https://doi.org/10.7554/eLife.78633

Share this article

https://doi.org/10.7554/eLife.78633

Further reading

    1. Computational and Systems Biology
    2. Immunology and Inflammation
    Lucia Csepregi, Kenneth Hoehn ... Sai T Reddy
    Research Article

    Diverse antibody repertoires spanning multiple lymphoid organs (i.e., bone marrow, spleen, lymph nodes) form the foundation of protective humoral immunity. Changes in their composition across lymphoid organs are a consequence of B-cell selection and migration events leading to a highly dynamic and unique physiological landscape of antibody repertoires upon antigenic challenge (e.g., vaccination). However, to what extent B cells encoding identical or similar antibody sequences (clones) are distributed across multiple lymphoid organs and how this is shaped by the strength of a humoral response remains largely unexplored. Here, we performed an in-depth systems analysis of antibody repertoires across multiple distinct lymphoid organs of immunized mice and discovered that organ-specific antibody repertoire features (i.e., germline V-gene usage and clonal expansion profiles) equilibrated upon a strong humoral response (multiple immunizations and high serum titers). This resulted in a surprisingly high degree of repertoire consolidation, characterized by highly connected and overlapping B-cell clones across multiple lymphoid organs. Finally, we revealed distinct physiological axes indicating clonal migrations and showed that antibody repertoire consolidation directly correlated with antigen specificity. Our study uncovered how a strong humoral response resulted in a more uniform but redundant physiological landscape of antibody repertoires, indicating that increases in antibody serum titers were a result of synergistic contributions from antigen-specific B-cell clones distributed across multiple lymphoid organs. Our findings provide valuable insights for the assessment and design of vaccine strategies.

    1. Immunology and Inflammation
    Yue Yang, Bin Huang ... Fangfang Zhang
    Research Article Updated

    Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.