Abstract
The primary aim of COVID-19 vaccine development is to induce highly efficient broadly neutralizing antibodies (bNAbs) against circulating and emergent SARS-CoV-2 variants. Rapid and sustained germinal center (GC) responses at an early stage are crucial to produce bNAbs. However, the mechanisms underlying the formation of early GC responses and strategies to effectively promote these responses remain to be further investigated. In this study, we found that the combination of anti-CD25 monoclonal antibodies (mAb) with the COVID-19 subunit vaccine significantly enhances cross-reactive neutralizing antibody responses in mice. Modulation of CD25 at different time points before and after vaccination resulted in varying effects on the GC response, with day 0 being the most effective in assisting the vaccine to induce a stronger GC response. This enhancement is achieved by rapidly inhibiting regulatory T (Treg) cells in draining lymph nodes, an effect observed not only in antigen-specific subsets but also across the bulk lymphocyte population—thereby creating a pro-immune microenvironment that facilitates the induction of an effective early GC response. This leads to the generation of more antigen-recognizing B cells and significantly increases both the potency and breadth of neutralizing antibody responses. Our findings propose a strategy to enhance vaccine efficacy against SARS-CoV-2 and other hypervariable pathogens by effectively promoting the development of early and robust GC responses.
Similar content being viewed by others
Data availability
Source data underlying graphs can be obtained from the Supplementary Data.
References
Barouch, D. H. Covid-19 vaccines - immunity, variants, boosters. N. Engl. J. Med. 387, 1011–1020 (2022).
Chenchula, S., Karunakaran, P., Sharma, S. & Chavan, M. Current evidence on efficacy of COVID-19 booster dose vaccination against the Omicron variant: a systematic review. J. Med. Virol. 94, 2969–2976 (2022).
Laidlaw, B. J. & Ellebedy, A. H. The germinal centre B cell response to SARS-CoV-2. Nat. Rev. Immunol. 22, 7–18 (2022).
Lederer, K. et al. SARS-CoV-2 mRNA vaccines foster potent antigen-specific germinal center responses associated with neutralizing antibody generation. Immunity 53, 1281 (2020).
Liu, X., Liu, B. & Qi, H. Germinal center reaction and output: recent advances. Curr. Opin. Immunol. 82, 102308 (2023).
Aung, A. et al. Low protease activity in B cell follicles promotes retention of intact antigens after immunization. Science 379, 350–35 (2023).
Robert, P. A., Marschall, A. L. J. & Meyer-Hermann, M. Induction of broadly neutralizing antibodies in Germinal Centre simulations. Curr. Opin. Biotechnol. 51, 137–145 (2018).
Lee, J. H. et al. Long-primed germinal centres with enduring affinity maturation and clonal migration. Nature 609, 998 (2022).
Cirelli, K. M. et al. Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance. Cell 177, 1153 (2019).
Wing, J. B., Tekgüç, M. & Sakaguchi, S. Control of germinal center responses by T-follicular regulatory cells. Front. Immunol. 9, 1910 (2018).
Vanderleyden, I., Linterman, M. A. & Smith, K. G. C. Regulatory T cells and control of the germinal centre response. Arthritis Res. Ther. 16, 471 (2014).
Bradley, T. et al. Immune checkpoint modulation enhances HIV-1 antibody induction. Nat. Commun. 11, 948 (2020).
Peng, Y. J. et al. CD25: a potential tumor therapeutic target. Int. J. Cancer 152, 1290–1303 (2023).
Song, D. Y. et al. Two novel human anti-CD25 antibodies with antitumor activity inversely related to their affinity and in vitro activity. Sci. Rep. 11, 22966 (2021).
Fattori, S. et al. Selective depletion of regulatory T cells by ALD2510, a novel IL-2-sparing anti-CD25 antibody, synergizes with PD-1 blockade in breast and gynecologic cancers. Cancer Res. 83, 3239 (2023).
Rech A. J. & Vonderheide R. H. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. in (eds Steinman R., Banchereau J., Finn O. J.) Cancer Vaccines (Blackwell, 2009).
Tan, C. R. et al. Impact of anti-CD25 monoclonal antibody on dendritic cell-tumor fusion vaccine efficacy in a murine melanoma model. J. Transl. Med. 11, 148 (2013).
Gu, S. Q. et al. Transient regulatory T cell manipulation is limited by anti-antibody responses in HIV-1 envelope immunized rhesus macaques. Iscience 28, 113191 (2025).
Spolski, R., Li, P. & Leonard, W. J. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat. Rev. Immunol. 18, 648–659 (2018).
Li, F. S. et al. Periodic mesoporous organosilica as a nanoadjuvant for subunit vaccines elicits potent antigen-specific germinal center responses by activating naive B cells. Acs Nano 17, 15424–15440 (2023).
Solomon, I. et al. CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity. Nat. Cancer 1, 1153–115 (2020).
Onda, M., Kobayashi, K. & Pastan, I. Depletion of regulatory T cells in tumors with an anti-CD25 immunotoxin induces CD8 T cell-mediated systemic antitumor immunity. Proc. Natl. Acad. Sci. USA 116, 4575–4582 (2019).
Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 40, 413–442 (2022).
Sage, P. T. & Sharpe, A. H. T follicular regulatory cells. Immunol. Rev. 271, 246–259 (2016).
Pankhurst, T. E. & Linterman, M. A. Highlight of 2023: advances in germinal centers. Immunol. Cell Biol. 102, 463–466 (2024).
Moyer, T. J. et al. Engineered immunogen binding to alum adjuvant enhances humoral immunity. Nat. Med. 26, 430–43 (2020).
Rosser, E. C. & Mauri, C. Regulatory B cells: origin, phenotype, and function. Immunity 42, 607–612 (2015).
Haynes, B. F. et al. Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies. Nat. Rev. Immunol. 23, 142–158 (2023).
Wang, Q. & Zhang, L. Q. Broadly neutralizing antibodies and vaccine design against HIV-1 infection. Front. Med. 14, 30–42 (2020).
Zheng, C. F. et al. Real-world effectiveness of COVID-19 vaccines: a literature review and meta-analysis. Int. J. Infect. Dis. 114, 252–260 (2022).
Kingsley, T., Phelan, D. & Poland, G. A. A review of 2023 adult immunization schedule updates. Vaccine 41, 2631–2633 (2023).
Excler, J. L., Saville, M., Berkley, S. & Kim, J. H. Vaccine development for emerging infectious diseases. Nat. Med. 27, 591–600 (2021).
Rauch, S., Jasny, E., Schmidt, K. E. & Petsch, B. New vaccine technologies to combat outbreak situations. Front. Immunol. 9, 1963 (2018).
Chalkias, S. et al. A bivalent omicron-containing booster vaccine against Covid-19. N. Engl. J. Med. 387, 1279–1291 (2022).
Pather, S., Muik, A., Rizzi, R. & Mensa, F. Clinical development of variant-adapted BNT162b2 COVID-19 vaccines: the early Omicron era. Expert Rev. Vaccines 22, 650–661 (2023).
Wang, L. M., Fu, Y. & Chu, Y. W. Regulatory B Cells. in (ed Wang J. Y.) B Cells in Immunity and Tolerance (Springer, 2020).
Quast, I. & Tarlinton, D. Time is of the essence for vaccine success. Nat. Immunol. 23, 1517–1519 (2022).
Lotspeich-Cole, L. et al. Sustained antigen delivery improves germinal center reaction and increases antibody responses in neonatal mice. Npj Vaccines 9, 92 (2024).
Tam, H. H. et al. Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination. Proc. Natl. Acad. Sci. USA 113, E6639–E6648 (2016).
Sun, Z. J. et al. The role of cellular immunity in the protective efficacy of the SARS-CoV-2 vaccines. Vaccines 10, 1103 (2022).
Zeng, M., Zhang, W., Li, Y. S. & Yu, L. Harnessing adenovirus in cancer immunotherapy: evoking cellular immunity and targeting delivery in cell-specific manner. Biomark. Res. 12, 36 (2024).
Bian, L. J. et al. Intramuscular inoculation of AS02-adjuvanted respiratory syncytial virus (RSV) F subunit vaccine shows better efficiency and safety than subcutaneous inoculation in BALB/c mice. Front. Immunol. 13, 938598 (2022).
Acknowledgements
This research was funded by the National Key Research and Development Program of China (2021YFC2301500; 2023YFC2307900), the Jilin Province Science and Technology Development Plan (20210402031GH), and the “Medicine + X” Interdisciplinary Innovation Team of Norman Bethune Health Science Center of Jilin University (No. 2022JBGS05). This study was also supported by funding from the National Natural Science Foundation of China (32270142 to P.W.), Shanghai Rising-Star Program (22QA1408800 to P.W.), and the Program of Science and Technology Cooperation with Hong Kong, Macao and Taiwan (23410760500 to P.W.). We also thank Prof. Zhen-An Qiao (State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Jilin University) for providing the PMO nanoadjuvant.
Author information
Authors and Affiliations
Contributions
F.L. conceived the study, designed and performed experiments, analyzed data, and wrote the manuscript. X.Yu assisted with experiment design and data analysis. C.Z. performed specific experiments and contributed to data interpretation. W.L. conducted statistical analyses. H.T. assisted with experimental procedures. X.W. provided critical reagents and technical support. P.W. supervised the project, secured funding, and edited the manuscript. B.Yu supervised experimental design and data interpretation. Xh.Yu conceived and supervised the overall study, secured funding, and finalized the manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Communications Biology thanks Timothy A. Bates, Yongjun Sui and the other anonymous reviewer(s) for their contribution to the peer review of this work. Primary handling editor: Ophelia Bu. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Li, F., Yu, X., Zhang, C. et al. CD25 modulation enhances broadly neutralizing antibody response of SARS-CoV-2 subunit vaccine. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09721-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s42003-026-09721-9
