mRNA prime-boost vaccination promotes clonal continuity in germinal center reactions and broadens SARS-CoV-2 variant coverage
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.
SARS-CoV-2, adenovirus vector, clonal selection, germinal centers, mRNA vaccines, neutralizing antibodies, prime-boost immunization, vaccination, variant coverage
Ciancaglini, Matias
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Fixemer, Jonas
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Seven, Cemre
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Dimitrova, Mirela
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Finozzi, Davide
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Weklak, Denice
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Kastner, Anna Lena
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Jönsson, Franziska
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Wagner, Ingrid
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Vincenti, Ilena
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Peters, Anneli
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Newby, Maddy L
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Crispin, Max
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Merkler, Doron
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Kreppel, Florian
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Pinschewer, Daniel D.
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Ciancaglini, Matias
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Fixemer, Jonas
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Seven, Cemre
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Dimitrova, Mirela
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Finozzi, Davide
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Weklak, Denice
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Kastner, Anna Lena
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Jönsson, Franziska
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Wagner, Ingrid
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Vincenti, Ilena
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Peters, Anneli
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Newby, Maddy L
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Crispin, Max
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Merkler, Doron
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Kreppel, Florian
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Pinschewer, Daniel D.
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Ciancaglini, Matias, Fixemer, Jonas, Seven, Cemre, Dimitrova, Mirela, Finozzi, Davide, Weklak, Denice, Kastner, Anna Lena, Jönsson, Franziska, Wagner, Ingrid, Vincenti, Ilena, Peters, Anneli, Newby, Maddy L, Crispin, Max, Merkler, Doron, Kreppel, Florian and Pinschewer, Daniel D.
(2025)
mRNA prime-boost vaccination promotes clonal continuity in germinal center reactions and broadens SARS-CoV-2 variant coverage.
Molecular Therapy, 33 (11).
(doi:10.1016/j.ymthe.2025.08.008).
Abstract
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.
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More information
Accepted/In Press date: 5 August 2025
e-pub ahead of print date: 8 August 2025
Keywords:
SARS-CoV-2, adenovirus vector, clonal selection, germinal centers, mRNA vaccines, neutralizing antibodies, prime-boost immunization, vaccination, variant coverage
Identifiers
Local EPrints ID: 506266
URI: http://eprints.soton.ac.uk/id/eprint/506266
ISSN: 1525-0016
PURE UUID: d8db017f-70d5-420d-9dad-abb547052a31
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Date deposited: 31 Oct 2025 17:46
Last modified: 01 Nov 2025 02:50
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Contributors
Author:
Matias Ciancaglini
Author:
Jonas Fixemer
Author:
Cemre Seven
Author:
Mirela Dimitrova
Author:
Davide Finozzi
Author:
Denice Weklak
Author:
Anna Lena Kastner
Author:
Franziska Jönsson
Author:
Ingrid Wagner
Author:
Ilena Vincenti
Author:
Anneli Peters
Author:
Maddy L Newby
Author:
Doron Merkler
Author:
Florian Kreppel
Author:
Daniel D. Pinschewer
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