SARS-CoV-2 MRNA Vaccines Foster Potent Antigen-Specific Germinal Center Responses Associated with Neutralizing Antibody Generation

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2020 Dec 9

PMID 33296685

Citations 219

Authors

Katlyn Lederer

Diana Castano

Daniela Gomez Atria

Thomas H Oguin 3rd

Sidney Wang

Tomaz B Manzoni

Hiromi Muramatsu

Michael J Hogan

Fatima Amanat

Patrick Cherubin

Kendall A Lundgreen

Ying K Tam

Steven H Y Fan

Laurence C Eisenlohr

Ivan Maillard

Drew Weissman

Paul Bates

Florian Krammer

Gregory D Sempowski

Norbert Pardi

Michela Locci

Affiliations

Soon will be listed here.

Abstract

The deployment of effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical to eradicate the coronavirus disease 2019 (COVID-19) pandemic. Many licensed vaccines confer protection by inducing long-lived plasma cells (LLPCs) and memory B cells (MBCs), cell types canonically generated during germinal center (GC) reactions. Here, we directly compared two vaccine platforms-mRNA vaccines and a recombinant protein formulated with an MF59-like adjuvant-looking for their abilities to quantitatively and qualitatively shape SARS-CoV-2-specific primary GC responses over time. We demonstrated that a single immunization with SARS-CoV-2 mRNA, but not with the recombinant protein vaccine, elicited potent SARS-CoV-2-specific GC B and T follicular helper (Tfh) cell responses as well as LLPCs and MBCs. Importantly, GC responses strongly correlated with neutralizing antibody production. mRNA vaccines more efficiently induced key regulators of the Tfh cell program and influenced the functional properties of Tfh cells. Overall, this study identifies SARS-CoV-2 mRNA vaccines as strong candidates for promoting robust GC-derived immune responses.

Citing Articles

A SARS-CoV-2 vaccine on an NIR-II/SWIR emitting nanoparticle platform.

Jiang Y, Sanyal M, Hussein N, Baghdasaryan A, Zhang M, Wang F Sci Adv. 2025; 11(6):eadp5539.

PMID: 39919189 PMC: 11804919. DOI: 10.1126/sciadv.adp5539.

Regulating Immune Responses Induced by PEGylated Messenger RNA-Lipid Nanoparticle Vaccine.

Jo H, Jeoung J, Kim W, Jeoung D Vaccines (Basel). 2025; 13(1).

PMID: 39852793 PMC: 11768904. DOI: 10.3390/vaccines13010014.

M cells targeted H. pylori antigen SAM-FAdE displayed on bacterium-like particles induce protective immunity.

Zhang F, Chen J, Zhang Z, Wu J, Qu Y, Ni L J Nanobiotechnology. 2025; 23(1):23.

PMID: 39825347 PMC: 11748607. DOI: 10.1186/s12951-025-03111-9.

Expression, purification and immunogenicity analyses of receptor binding domain protein of severe acute respiratory syndrome coronavirus 2 from delta variant.

Liu L, Chen H, Liu P, Ke X, Song J, Fang Y Vet Res Forum. 2025; 15(12):657-663.

PMID: 39816631 PMC: 11729102. DOI: 10.30466/vrf.2024.2013858.4037.

A nucleoside-modified rabies mRNA vaccine induces long-lasting and comprehensive immune responses in mice and non-human primates.

Wang Y, Wang S, Haung L, Huang L, Mao W, Li F Mol Ther. 2025; 33(2):548-559.

PMID: 39741409 PMC: 11853375. DOI: 10.1016/j.ymthe.2024.12.041.

References

Corbett K, Flynn B, Foulds K, Francica J, Boyoglu-Barnum S, Werner A . Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N Engl J Med. 2020; 383(16):1544-1555. PMC: 7449230. DOI: 10.1056/NEJMoa2024671. View

Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke M, Arlehamn C . Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013; 39(4):758-69. PMC: 3996844. DOI: 10.1016/j.immuni.2013.08.031. View

Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M . Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020; 369(6499):77-81. PMC: 7202686. DOI: 10.1126/science.abc1932. View

Vinuesa C, Linterman M, Yu D, MacLennan I . Follicular Helper T Cells. Annu Rev Immunol. 2016; 34:335-68. DOI: 10.1146/annurev-immunol-041015-055605. View

Stadlbauer D, Amanat F, Chromikova V, Jiang K, Strohmeier S, Arunkumar G . SARS-CoV-2 Seroconversion in Humans: A Detailed Protocol for a Serological Assay, Antigen Production, and Test Setup. Curr Protoc Microbiol. 2020; 57(1):e100. PMC: 7235504. DOI: 10.1002/cpmc.100. View

Mulligan M, Lyke K, Kitchin N, Absalon J, Gurtman A, Lockhart S . Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 2020; 586(7830):589-593. DOI: 10.1038/s41586-020-2639-4. View

Laczko D, Hogan M, Toulmin S, Hicks P, Lederer K, Gaudette B . A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice. Immunity. 2020; 53(4):724-732.e7. PMC: 7392193. DOI: 10.1016/j.immuni.2020.07.019. View

Freyn A, Silva J, Rosado V, Bliss C, Pine M, Mui B . A Multi-Targeting, Nucleoside-Modified mRNA Influenza Virus Vaccine Provides Broad Protection in Mice. Mol Ther. 2020; 28(7):1569-1584. PMC: 7335735. DOI: 10.1016/j.ymthe.2020.04.018. View

Crotty S . T Follicular Helper Cell Biology: A Decade of Discovery and Diseases. Immunity. 2019; 50(5):1132-1148. PMC: 6532429. DOI: 10.1016/j.immuni.2019.04.011. View

10.

Yusuf I, Kageyama R, Monticelli L, Johnston R, DiToro D, Hansen K . Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J Immunol. 2010; 185(1):190-202. PMC: 2913439. DOI: 10.4049/jimmunol.0903505. View

11.

Juno J, Tan H, Lee W, Reynaldi A, Kelly H, Wragg K . Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19. Nat Med. 2020; 26(9):1428-1434. DOI: 10.1038/s41591-020-0995-0. View

12.

Schmitt N, Bentebibel S, Ueno H . Phenotype and functions of memory Tfh cells in human blood. Trends Immunol. 2014; 35(9):436-42. PMC: 4152409. DOI: 10.1016/j.it.2014.06.002. View

13.

Nurieva R, Chung Y, Hwang D, Yang X, Kang H, Ma L . Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008; 29(1):138-49. PMC: 2556461. DOI: 10.1016/j.immuni.2008.05.009. View

14.

Morita R, Schmitt N, Bentebibel S, Ranganathan R, Bourdery L, Zurawski G . Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011; 34(1):108-21. PMC: 3046815. DOI: 10.1016/j.immuni.2010.12.012. View

15.

Liu X, Chen X, Zhong B, Wang A, Wang X, Chu F . Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature. 2014; 507(7493):513-8. PMC: 4012617. DOI: 10.1038/nature12910. View

16.

Suan D, Krautler N, Maag J, Butt D, Bourne K, Hermes J . CCR6 Defines Memory B Cell Precursors in Mouse and Human Germinal Centers, Revealing Light-Zone Location and Predominant Low Antigen Affinity. Immunity. 2017; 47(6):1142-1153.e4. DOI: 10.1016/j.immuni.2017.11.022. View

17.

Tam H, Melo M, Kang M, Pelet J, Ruda V, Foley M . Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination. Proc Natl Acad Sci U S A. 2016; 113(43):E6639-E6648. PMC: 5086995. DOI: 10.1073/pnas.1606050113. View

18.

Lofano G, Mancini F, Salvatore G, Cantisani R, Monaci E, Carrisi C . Oil-in-Water Emulsion MF59 Increases Germinal Center B Cell Differentiation and Persistence in Response to Vaccination. J Immunol. 2015; 195(4):1617-27. DOI: 10.4049/jimmunol.1402604. View

19.

Liang F, Lindgren G, Sandgren K, Thompson E, Francica J, Seubert A . Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake. Sci Transl Med. 2017; 9(393). DOI: 10.1126/scitranslmed.aal2094. View

20.

Corbett K, Edwards D, Leist S, Abiona O, Boyoglu-Barnum S, Gillespie R . SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature. 2020; 586(7830):567-571. PMC: 7581537. DOI: 10.1038/s41586-020-2622-0. View