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抗原性失误和多次突破性感染推动 COVID-19 中和反应趋同进化。

Antigenic sin and multiple breakthrough infections drive converging evolution of COVID-19 neutralizing responses.

机构信息

Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, Siena, Italy.

Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, Siena, Italy; Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy.

出版信息

Cell Rep. 2024 Sep 24;43(9):114645. doi: 10.1016/j.celrep.2024.114645. Epub 2024 Aug 27.


DOI:10.1016/j.celrep.2024.114645
PMID:39207904
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11422482/
Abstract

Understanding the evolution of the B cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is fundamental to design the next generation of vaccines and therapeutics. We longitudinally analyze at the single-cell level almost 900 neutralizing human monoclonal antibodies (nAbs) isolated from vaccinated people and from individuals with hybrid and super hybrid immunity (SH), developed after three mRNA vaccine doses and two breakthrough infections. The most potent neutralization and Fc functions against highly mutated variants belong to the SH cohort. Repertoire analysis shows that the original Wuhan antigenic sin drives the convergent expansion of the same B cell germlines in vaccinated and SH cohorts. Only Omicron breakthrough infections expand previously unseen germ lines and generate broadly nAbs by restoring IGHV3-53/3-66 germ lines. Our analyses find that B cells initially expanded by the original antigenic sin continue to play a fundamental role in the evolution of the immune response toward an evolving virus.

摘要

了解针对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 变体的 B 细胞反应的演变对于设计下一代疫苗和疗法至关重要。我们在单细胞水平上对近 900 种从接种疫苗的人和具有混合和超级混合免疫 (SH) 的个体中分离出的中和人单克隆抗体 (nAb) 进行了纵向分析,这些个体是在接种了三剂 mRNA 疫苗并发生两次突破性感染后产生的。针对高度突变变体,最有效的中和和 Fc 功能属于 SH 队列。受体库分析表明,最初的武汉抗原决定簇驱动了接种疫苗和 SH 队列中相同 B 细胞胚系的趋同扩张。只有奥密克戎突破性感染通过恢复 IGHV3-53/3-66 胚系,扩展了以前从未见过的胚系,并产生了广泛的 nAb。我们的分析发现,最初由原始抗原决定簇扩张的 B 细胞在针对不断进化的病毒的免疫反应的演变中继续发挥着重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/ad468a58c88a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/24035a5637ef/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/fb4c84c47819/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/363861a13c1f/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/5576c13bbed3/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/82d4d25ce754/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/a6b0c9c0bc36/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/ad468a58c88a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/24035a5637ef/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/fb4c84c47819/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/363861a13c1f/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/5576c13bbed3/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/82d4d25ce754/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/a6b0c9c0bc36/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1940/11422482/ad468a58c88a/gr6.jpg

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引用本文的文献

[1]
Exploring the Use of Viral Vectors Pseudotyped with Viral Glycoproteins as Tools to Study Antibody-Mediated Neutralizing Activity.

Microorganisms. 2025-7-31

[2]
The immunological impact of revaccination in a hybrid-immune world.

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[3]
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[4]
Public antibodies: convergent signatures in human humoral immunity against pathogens.

mBio. 2025-5-14

[5]
Structure and function of an unusual R452-dependent monoclonal antibody against SARS-CoV-2.

J Virol. 2025-5-20

[6]
Development of a two-component recombinant vaccine for COVID-19.

Front Immunol. 2024-12-20

本文引用的文献

[1]
Imprinting of serum neutralizing antibodies by Wuhan-1 mRNA vaccines.

Nature. 2024-6

[2]
Immunological imprinting shapes the specificity of human antibody responses against SARS-CoV-2 variants.

Immunity. 2024-4-9

[3]
Persistent immune imprinting occurs after vaccination with the COVID-19 XBB.1.5 mRNA booster in humans.

Immunity. 2024-4-9

[4]
Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 lineages combining increased fitness and antibody evasion.

Nat Commun. 2024-3-13

[5]
SARS-CoV-2 evolution from the BA.2.86 to JN.1 variants: unexpected consequences.

Trends Immunol. 2024-2

[6]
As COVID-19 Cases Surge, Here's What to Know About JN.1, the Latest SARS-CoV-2 "Variant of Interest".

JAMA. 2024-2-6

[7]
High-resolution map of the Fc functions mediated by COVID-19-neutralizing antibodies.

Proc Natl Acad Sci U S A. 2024-1-16

[8]
Immune evasion, infectivity, and fusogenicity of SARS-CoV-2 BA.2.86 and FLip variants.

Cell. 2024-2-1

[9]
SARS-CoV-2 BA.2.86 enters lung cells and evades neutralizing antibodies with high efficiency.

Cell. 2024-2-1

[10]
Fast evolution of SARS-CoV-2 BA.2.86 to JN.1 under heavy immune pressure.

Lancet Infect Dis. 2024-2

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