mRNA prime-boost vaccination promotes clonal continuity in germinal center reactions and broadens SARS-CoV-2 variant coverage
mRNA- and adenovirus-based (rAd) SARS-CoV-2 vaccines have been widely used in various homologous and heterologous prime-boost combinations. It remains unknown, however, which vaccination regimens effectively promote B cell clonal continuity (i.e., the participation of individual B cell clones in durable GC reactions to prime and subsequent boost). Here, we characterize SARS-CoV-2-specific GC B cell dynamics in vaccinated mice. While rAd/mRNA prime-boost elicited SARS-CoV-2-neutralizing antibody (nAb) titers equivalent to those induced by mRNA/mRNA, the latter provided broader nAb coverage of variants of concern. B cell fate-mapping experiments revealed that mRNA/mRNA afforded higher clonal continuity between primary and secondary GC reactions than rAd/mRNA, which was associated with similarly sized but more durable GC responses upon mRNA prime. Homologous rAd/rAd prime-boost resulted in vector backbone-biased antibody responses and limited clonal continuity of SARS-CoV-2-specific B cells. Our study suggests that high clonal continuity as observed during mRNA homologous prime-boost is key for vaccination regimens against rapidly evolving pathogens.
Authors
- Anna Lena Kastner
- Ingrid Wagner (ORCID: https://orcid.org/0000-0003-4437-9799)
- Mirela Dimitrova
- Ilena Vincenti (ORCID: https://orcid.org/0000-0003-1061-6071)
- Maddy L. Newby (ORCID: https://orcid.org/0000-0003-0624-245X)
- Max Crispin (ORCID: https://orcid.org/0000-0002-1072-2694)
- Anneli Peters (ORCID: https://orcid.org/0000-0002-8259-2219)
- Davide Finozzi
- Florian Kreppel (ORCID: https://orcid.org/0000-0002-0213-7815)
- Franziska Jönsson (ORCID: https://orcid.org/0000-0001-7671-653X)
- Daniel D. Pinschewer (ORCID: https://orcid.org/0000-0002-1594-3189)
- Doron Merkler (ORCID: https://orcid.org/0000-0002-0247-2007)
- Denice Weklak
- Jonas Fixemer (ORCID: https://orcid.org/0000-0003-0233-2490)
- Matías Ciancaglini (ORCID: https://orcid.org/0000-0002-1296-5606)
- Cemre Seven
Institutions
- University of Geneva (CH)
- Witten/Herdecke University (DE)
- University of Basel (CH)
- University Hospital of Geneva (CH)
- Department of Biomedicine Basel (CH)
- University of Southampton (GB)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Molecular Therapy
- Published
- 2025-08-08
- DOI
- https://doi.org/10.1016/j.ymthe.2025.08.008
- Citations
- 1
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- University of Southampton
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- H2020 Marie Skłodowska-Curie Actions
- HORIZON EUROPE Marie Sklodowska-Curie Actions