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基本情報

登録情報
データベース: PDB / ID: 9cci
タイトルDissecting human monoclonal antibody responses from mRNA and protein-based booster vaccinations against XBB1.5 SARS-CoV-2
要素
  • M39 Fab heavy chain
  • M39 Fab light chain
  • Spike glycoprotein
キーワードVIRAL PROTEIN/IMMUNE SYSTEM / SARS-CoV-2 / Antibody / RBD / Immune SYSTEM / VIRUS LIKE PARTICLE / VIRAL PROTEIN-IMMUNE SYSTEM complex
機能・相同性
機能・相同性情報


symbiont-mediated disruption of host tissue / Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular region / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / positive regulation of viral entry into host cell ...symbiont-mediated disruption of host tissue / Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular region / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / positive regulation of viral entry into host cell / membrane fusion / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / Attachment and Entry / entry receptor-mediated virion attachment to host cell / receptor-mediated virion attachment to host cell / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / endocytosis involved in viral entry into host cell / receptor ligand activity / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / symbiont entry into host cell / virion attachment to host cell / host cell plasma membrane / SARS-CoV-2 activates/modulates innate and adaptive immune responses / virion membrane / membrane / identical protein binding / plasma membrane
類似検索 - 分子機能
Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal ...Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S2 superfamily, coronavirus / Spike glycoprotein S2, coronavirus, heptad repeat 1 / Spike glycoprotein S2, coronavirus, heptad repeat 2 / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 2 (HR2) region profile. / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2
類似検索 - ドメイン・相同性
Spike glycoprotein
類似検索 - 構成要素
生物種Homo sapiens (ヒト)
Severe acute respiratory syndrome coronavirus 2 (ウイルス)
手法電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.65 Å
データ登録者Bajic, G. / Jaiswal, D.
資金援助 米国, 1件
組織認可番号国
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI168178 米国
引用
ジャーナル: Lancet Microbe / 年: 2025
タイトル: Mapping of human monoclonal antibody responses to XBB.1.5 COVID-19 monovalent vaccines: a B cell analysis.
著者: Raianna F Fantin / Jordan J Clark / Hallie Cohn / Deepika Jaiswal / Bailey Bozarth / Vishal Rao / Alesandro Civljak / Igor Lobo / Jessica R Nardulli / Komal Srivastava / Jeremy S Yong / ...著者: Raianna F Fantin / Jordan J Clark / Hallie Cohn / Deepika Jaiswal / Bailey Bozarth / Vishal Rao / Alesandro Civljak / Igor Lobo / Jessica R Nardulli / Komal Srivastava / Jeremy S Yong / Robert Andreata-Santos / Kaitlyn Bushfield / Edward S Lee / Gagandeep Singh / / Steven H Kleinstein / Florian Krammer / Viviana Simon / Goran Bajic / Camila H Coelho /
要旨: BACKGROUND: The rapid emergence of highly transmissible and immune-evasive SARS-CoV-2 variants has required the reformulation of COVID-19 vaccines to target these evolving threats. Although previous ...BACKGROUND: The rapid emergence of highly transmissible and immune-evasive SARS-CoV-2 variants has required the reformulation of COVID-19 vaccines to target these evolving threats. Although previous infections and booster vaccinations can boost variant neutralisation, it remains uncertain whether monovalent vaccines-delivered via mRNA or protein-based platforms-can trigger novel B-cell responses specific to omicron XBB.1.5 variants. We sought to address this uncertainty by characterising the antibody repertoire of individuals receiving a monovalent booster vaccine.
手法: In this observational study, we analysed the genetic antibody repertoire of 603 individual plasmablasts from five individuals (recruited at the Icahn School of Medicine at Mount Sinai, New ...手法: In this observational study, we analysed the genetic antibody repertoire of 603 individual plasmablasts from five individuals (recruited at the Icahn School of Medicine at Mount Sinai, New York, NY, USA, from STUDY-16-01215/IRB-16-00971 and STUDY-20-00442/IRB-20-03374) vaccinated with a monovalent XBB.1.5 vaccine, either through mRNA (Moderna or Pfizer-BioNTech; participants 1, 2, and 3) or adjuvanted protein (Novavax; participants 4 and 5) platforms. Before XBB.1.5 booster vaccination, all participants received mRNA-based priming and booster vaccine with ancestral SARS-CoV-2 and four of the five participants had a breakthrough omicron variant infection. We expressed 100 human monoclonal antibodies (mAbs; 50 from participants 1, 2, and 3, and 50 from participants 4 and 5) and evaluated their binding and neutralisation against various SARS-CoV-2 variants, including JN.1. We then selected four mAbs for in-vivo protection experiments by passive immunisation and viral challenge, and cryo-electron microscopy with two selected mAbs complexed with the XBB.1.5 spike (S) protein to determine their structures and binding interactions.
FINDINGS: Between October and November, 2023, we enrolled three male and two female participants (mean age 46 years) all of whom were White. We identified 21 binding mAbs and tested their ...FINDINGS: Between October and November, 2023, we enrolled three male and two female participants (mean age 46 years) all of whom were White. We identified 21 binding mAbs and tested their neutralisation capacity against ancestral SARS-CoV-2, XBB.1.5, and JN.1. From the six neutralising mAbs we characterised, we selected three (M2, M27, and M39) for in-vivo protection studies, along with one broadly binding antibody (M15), finding that three neutralising mAbs offered full protection against morbidity from XBB.1.5. M27 also displayed robust protection against the ancestral and JN.1 strains, and M39 offered partial protection from JN.1. Among these, we identified two standout antibodies: M2 and M39. M2 was uniquely specific to XBB.1.5, and M39 demonstrated the ability to bind and neutralise both XBB.1.5 and JN.1 strains. Using high-resolution cryo-electron microscopy, we mapped the binding sites of M2 and M39 on the XBB.1.5 S glycoprotein, uncovering the precise molecular interactions that dictate their specificity.
INTERPRETATION: Our findings offer key molecular insights into whether strain-specific boosters elicit sufficient protection against SARS-CoV-2 emerging variants. This knowledge can inform decisions ...INTERPRETATION: Our findings offer key molecular insights into whether strain-specific boosters elicit sufficient protection against SARS-CoV-2 emerging variants. This knowledge can inform decisions on booster design and strategies to enhance preparedness to evolving viral threats.
FUNDING: Icahn School of Medicine at Mount Sinai; National Institutes of Health (NIH) FIRST; Laura and Isaac Perlmutter Cancer Center Support Grant; National Institute of Allergy and Infectious ...FUNDING: Icahn School of Medicine at Mount Sinai; National Institutes of Health (NIH) FIRST; Laura and Isaac Perlmutter Cancer Center Support Grant; National Institute of Allergy and Infectious Diseases; Human Immunology Project Consortium by NIH; the São Paulo Research Foundation; the National Heart, Lung, and Blood Institute of the NIH; Irma T Hirschl and Monique Weill-Caulier Trust; and the Collaborative Influenza Vaccine Innovation Centers.
#1: ジャーナル: bioRxiv / 年: 2024
タイトル: Dissecting human monoclonal antibody responses from mRNA- and protein-based XBB.1.5 COVID-19 monovalent vaccines.
著者: Raianna F Fantin / Jordan J Clark / Hallie Cohn / Deepika Jaiswal / Bailey Bozarth / Alesandro Civljak / Vishal Rao / Igor Lobo / Jessica R Nardulli / Komal Srivastava / Jeremy Yong / Robert ...著者: Raianna F Fantin / Jordan J Clark / Hallie Cohn / Deepika Jaiswal / Bailey Bozarth / Alesandro Civljak / Vishal Rao / Igor Lobo / Jessica R Nardulli / Komal Srivastava / Jeremy Yong / Robert Andreata-Santos / Kaitlyn Bushfield / Edward S Lee / Gagandeep Singh / / Steven H Kleinstein / Florian Krammer / Viviana Simon / Goran Bajic / Camila H Coelho /
要旨: The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines ...The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines to target those new variants specifically. While previous infections and booster vaccinations can enhance variant neutralization, it is unclear whether the monovalent version, administered using either mRNA or protein-based vaccine platforms, can elicit B-cell responses specific for Omicron XBB.1.5 variants. Here, we dissected the genetic antibody repertoire of 603 individual plasmablasts derived from five individuals who received a monovalent XBB.1.5 vaccination either with mRNA (Moderna or Pfizer/BioNtech) or adjuvanted protein (Novavax). From these sequences, we expressed 100 human monoclonal antibodies and determined binding, affinity and protective potential against several SARS-CoV-2 variants, including JN.1. We then select two vaccine-induced XBB.1.5 mAbs, M2 and M39. M2 mAb was a , antibody, i.e., specific for XBB.1.5 but not ancestral SARS-CoV-2. M39 bound and neutralized both XBB.1.5 and JN.1 strains. Our high-resolution cryo-electron microscopy (EM) structures of M2 and M39 in complex with the XBB.1.5 spike glycoprotein defined the epitopes engaged and revealed the molecular determinants for the mAbs' specificity. These data show, at the molecular level, that monovalent, variant-specific vaccines can elicit functional antibodies, and shed light on potential functional and genetic differences of mAbs induced by vaccinations with different vaccine platforms.\.
履歴
登録2024年6月21日登録サイト: RCSB / 処理サイト: RCSB
改定 1.02025年3月12日Provider: repository / タイプ: Initial release
改定 1.02025年3月12日Data content type: EM metadata / Data content type: EM metadata / Provider: repository / タイプ: Initial release
改定 1.02025年3月12日Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / タイプ: Initial release
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改定 1.02025年3月12日Data content type: FSC / Part number: 1 / Data content type: FSC / Provider: repository / タイプ: Initial release
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改定 1.12025年5月28日Group: Data collection / カテゴリ: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
改定 1.12025年5月28日Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / カテゴリ: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name
改定 1.22025年7月30日Group: Data collection / Database references / カテゴリ: citation / citation_author / em_admin / Item: _em_admin.last_update
改定 1.32025年8月20日Group: Data collection / Database references / カテゴリ: citation / em_admin / Item: _citation.journal_volume / _em_admin.last_update

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構造の表示

構造ビューア分子:
MolmilJmol/JSmol

ダウンロードとリンク

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集合体

登録構造単位
B: M39 Fab heavy chain
A: Spike glycoprotein
C: M39 Fab light chain
ヘテロ分子


分子量 (理論値)分子数
合計 (水以外)185,6174
ポリマ－185,3963
非ポリマー2211
水00
1


  • 登録構造と同一
  • 登録者が定義した集合体
  • 根拠: 電子顕微鏡法, not applicable
タイプ名称対称操作数
identity operation1_5551

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要素

#1: 抗体 M39 Fab heavy chain


分子量: 24543.383 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Homo sapiens (ヒト)
#2: タンパク質 Spike glycoprotein / S glycoprotein / E2 / Peplomer protein


分子量: 137862.172 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: variant XBB1.5 on a hexapro background
由来: (組換発現) Severe acute respiratory syndrome coronavirus 2 (ウイルス)
遺伝子: S, 2 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: P0DTC2
#3: 抗体 M39 Fab light chain


分子量: 22990.451 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Homo sapiens (ヒト)
#4: 糖 ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


タイプ: D-saccharide, beta linking / 分子量: 221.208 Da / 分子数: 1 / 由来タイプ: 組換発現 / 式: C8H15NO6 / タイプ: SUBJECT OF INVESTIGATION
識別子タイププログラム
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
研究の焦点であるリガンドがあるかY
Has protein modificationY

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実験情報

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実験

実験手法: 電子顕微鏡法
EM実験試料の集合状態: PARTICLE / ３次元再構成法: 単粒子再構成法

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試料調製

構成要素名称: M39 Fab complex with RBD on XBB1.5 spike / タイプ: COMPLEX / Entity ID: #1-#3 / 由来: MULTIPLE SOURCES
緩衝液pH: 7.5
試料濃度: 2 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES
急速凍結凍結剤: ETHANE

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電子顕微鏡撮影

実験機器
モデル: Titan Krios / 画像提供: FEI Company
顕微鏡モデル: TFS KRIOS
電子銃電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: OTHER
電子レンズモード: BRIGHT FIELD / 最大 デフォーカス（公称値）: 2400 nm / 最小 デフォーカス（公称値）: 600 nm
撮影電子線照射量: 49.883 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k)

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解析

EMソフトウェア名称: PHENIX / カテゴリ: モデル精密化
CTF補正タイプ: PHASE FLIPPING ONLY
3次元再構成解像度: 2.65 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 549696 / 対称性のタイプ: POINT
拘束条件
Refine-IDタイプDev ideal数
ELECTRON MICROSCOPYf_bond_d0.0055056
ELECTRON MICROSCOPYf_angle_d0.9046880
ELECTRON MICROSCOPYf_dihedral_angle_d12.3151803
ELECTRON MICROSCOPYf_chiral_restr0.06748
ELECTRON MICROSCOPYf_plane_restr0.009883

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