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Vaccines combining slow delivery and follicle targeting of antigens increase germinal center B cell clonal diversity and clonal expansion.

作者信息

Rodrigues Kristen A, Zhang Yiming J, Aung Aereas, Morgan Duncan M, Maiorino Laura, Yousefpour Parisa, Gibson Grace, Ozorowski Gabriel, Gregory Justin R, Amlashi Parastoo, Buckley Maureen, Ward Andrew B, Schief William R, Love J Christopher, Irvine Darrell J

机构信息

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Cambridge, MA 02139 USA.

Harvard-MIT Health Sciences and Technology Program, Institute for Medical Engineering and Science; Massachusetts Institute of Technology, Cambridge, MA 02139 USA.

出版信息

bioRxiv. 2024 Aug 19:2024.08.19.608655. doi: 10.1101/2024.08.19.608655.


DOI:10.1101/2024.08.19.608655
PMID:39229011
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11370361/
Abstract

Vaccines incorporating slow delivery, multivalent antigen display, or immunomodulation through adjuvants have an important role to play in shaping the humoral immune response. 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 delivery to draining lymph nodes) are combined with a potent saponin nanoparticle adjuvant termed SMNP (which alters lymph flow and antigen entry into lymph nodes). When employed with a stabilized HIV Env trimer antigen in mice, this combined adjuvant approach promoted substantial enhancements in germinal center (GC) and antibody responses relative to either adjuvant alone. Using scRNA-seq and scBCR-seq, we found that the alum-pSer/SMNP combination both increased the diversity of GC B cell clones and increased GC B cell clonal expansion, coincident with increases in the expression of and the proportion of S-phase GC B cells. To gain insight into the source of these changes in the GC response, we analyzed antigen biodistribution and structural integrity in draining lymph nodes and found that the combination adjuvant approach, but not alum-pSer delivery or SMNP alone, promoted accumulation of highly intact antigen on follicular dendritic cells, reflecting an integration of the slow antigen delivery and altered lymph node uptake effects of these two adjuvants. These results demonstrate how adjuvants with complementary mechanisms of action impacting vaccine biodistribution and kinetics can synergize to enhance humoral immunity.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/635e3791307a/nihpp-2024.08.19.608655v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/8d298c6bb56a/nihpp-2024.08.19.608655v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/f73865330eab/nihpp-2024.08.19.608655v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/3fab234ab6cd/nihpp-2024.08.19.608655v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/6987153cc734/nihpp-2024.08.19.608655v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/635e3791307a/nihpp-2024.08.19.608655v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/8d298c6bb56a/nihpp-2024.08.19.608655v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/f73865330eab/nihpp-2024.08.19.608655v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/3fab234ab6cd/nihpp-2024.08.19.608655v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/6987153cc734/nihpp-2024.08.19.608655v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57da/11370361/635e3791307a/nihpp-2024.08.19.608655v1-f0005.jpg

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[1]
Vaccines combining slow delivery and follicle targeting of antigens increase germinal center B cell clonal diversity and clonal expansion.

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本文引用的文献

[1]
Full-length single-cell BCR sequencing paired with RNA sequencing reveals convergent responses to pneumococcal vaccination.

Commun Biol. 2024-9-28

[2]
Multivalent antigen display on nanoparticle immunogens increases B cell clonotype diversity and neutralization breadth to pneumoviruses.

Immunity. 2023-10-10

[3]
Optimization of an alum-anchored clinical HIV vaccine candidate.

NPJ Vaccines. 2023-8-12

[4]
CD4 binding site immunogens elicit heterologous anti-HIV-1 neutralizing antibodies in transgenic and wild-type animals.

Sci Immunol. 2023-2-17

[5]
Low protease activity in B cell follicles promotes retention of intact antigens after immunization.

Science. 2023-1-27

[6]
Long-primed germinal centres with enduring affinity maturation and clonal migration.

Nature. 2022-9

[7]
Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies.

Nat Rev Immunol. 2023-3

[8]
Developing pan-β-coronavirus vaccines against emerging SARS-CoV-2 variants of concern.

Trends Immunol. 2022-3

[9]
Unraveling B cell trajectories at single cell resolution.

Trends Immunol. 2022-3

[10]
Mannose-binding lectin and complement mediate follicular localization and enhanced immunogenicity of diverse protein nanoparticle immunogens.

Cell Rep. 2022-1-11

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