Vaccines combining slow release and follicle targeting of antigens increase germinal center B cell diversity and clonal expansion
Name
nihms-2092992.pdf
Description
Accepted version
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3.22 MB
Format
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Checksum (MD5)
fe6cbff78c56790f10386841d0c00ffd
Author(s)
Rodrigues, Kristen A
Zhang, Yiming J
Lam, Jonathan
Aung, Aereas
Morgan, Duncan M
Romanov, Anna
Maiorino, Laura
Yousefpour, Parisa
Gibson, Grace
Ozorowski, Gabriel
Date Issued
June 18, 2025
Journal
Science Translational Medicine
Publisher
American Association for the Advancement of Science
Citation
Kristen A. Rodrigues et al. ,Vaccines combining slow release and follicle targeting of antigens increase germinal center B cell diversity and clonal expansion.Sci. Transl. Med.17, eadw7499 (2025).
Version
Author's final manuscript
Abstract
Vaccine adjuvants play important roles in shaping the humoral response to immunization. Here, we analyzed mechanisms of action of a clinically relevant combination adjuvant strategy, where phosphoserine (pSer)–tagged immunogens bound to aluminum hydroxide (alum) adjuvant, promoting prolonged antigen release to draining lymph nodes, are combined with a saponin nanoparticle adjuvant termed SMNP, which alters lymph flow and antigen entry into lymph nodes. When used with a stabilized HIV envelope trimer antigen in mice, this combined adjuvant approach promoted substantial enhancements in germinal center and antibody responses relative to either adjuvant alone. Using single-cell RNA and B cell receptor sequencing, we found that the alum-pSer/SMNP combination augmented the clonal expansion and diversity of the germinal center B cell repertoire, coincident with an increased proportion of S-phase germinal center B cells and expression of positive selection markers. Moreover, we found that the combination adjuvant approach, but not alum-pSer delivery or SMNP alone, promoted accumulation of intact antigen on follicular dendritic cells, reflecting integrated effects of slow antigen delivery and altered lymph node uptake. Genetic ablation of Cr1/2 expression by follicular dendritic cells eliminated antigen accumulation and hampered the antigen-specific germinal center response, supporting antigen delivery to these cells as a key mechanism of the improved response elicited by this combination adjuvant. These results demonstrate how adjuvants with complementary mechanisms of action affecting vaccine biodistribution and kinetics can enhance humoral immunity.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Harvard-MIT Program in Health Sciences and Technology
Ragon Institute of MGH, MIT and Harvard
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
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Creative Commons Attribution-Noncommercial-ShareAlike
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DOI of Published Version
https://doi.org/10.1126/scitranslmed.adw7499
