Structure-selected RBM immunogens prime polyclonal memory responses that neutralize SARS-CoV-2 variants of concern.
Structure-selected RBM immunogens prime polyclonal memory responses that neutralize SARS-CoV-2 variants of concern.
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结构选择的 RBM 免疫原引发多克隆记忆反应，中和相关的 SARS-CoV-2 变体。
DOI：
10.1371/journal.ppat.1010686
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发表时间：
2022-07
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
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作者：
新冠肺炎疫情的成功控制有赖于防止传播的疫苗。全长Spike蛋白具有高度的免疫原性，但大多数抗体不针对病毒：ACE2界面。为了影响抗体反应的质量，使其聚焦于受体结合基序(RBM)，我们通过将暴露于溶剂中的RBM氨基酸残基插入到免疫球蛋白分子的高变环中，产生了一系列构象受限的免疫原。用编码这些重组Spike蛋白的重组Spike蛋白加强免疫的C57BL/6小鼠产生了快速的记忆反应。免疫血清抗体与纯化的受体结合域(RBD)和Spike蛋白强烈结合。PDNA为与有效中和正宗WA1病毒和三种令人担忧的变种(VOC)的抗体产生一致反应做好准备，B.1.351、B.1.617.2和BA.1。我们证明，建立在结构选择基础上的免疫原可以通过将其集中在野生型病毒和VOCs之间共享的保守易损性部位来影响抗体反应的质量，从而产生跨变异体的中和抗体。下一代SARS-CoV-2疫苗需要解决继续威胁全球健康和复苏的新病毒变异的传播问题。这可能需要在免疫原设计和免疫反应工程方面有新的视角。在这里，我们将这些想法应用于两步概念验证研究。首先，我们设计了在RBM：ACE2界面表达关键残基的构象受限免疫原，以模拟它们在天然Spike蛋白中的立体化学定位。其次，我们通过将质粒DNA注射到脾内来启动B细胞免疫(启动)过程，以开发次级淋巴器官的空间组织。用完整的Spike蛋白进行单次加强免疫的小鼠对RBD和Spike蛋白产生了快速的记忆抗体反应。重要的是，免疫血清中和了真正的WA1病毒和令人担忧的B.1.351/Beta、B.1.617.2/Delta和BA.1/Omicron变种。我们的发现表明，建立在结构选择和淋巴器官靶向基础上的免疫原是将抗体反应集中到野生型病毒和所关注的变种之间共享的脆弱的保守部位的一种强有力的方式。
Successful control of the COVID-19 pandemic depends on vaccines that prevent transmission. The full-length Spike protein is highly immunogenic but the majority of antibodies do not target the virus: ACE2 interface. In an effort to affect the quality of the antibody response focusing it to the receptor-binding motif (RBM) we generated a series of conformationally-constrained immunogens by inserting solvent-exposed RBM amino acid residues into hypervariable loops of an immunoglobulin molecule. Priming C57BL/6 mice with plasmid (p)DNA encoding these constructs yielded a rapid memory response to booster immunization with recombinant Spike protein. Immune sera antibodies bound strongly to the purified receptor-binding domain (RBD) and Spike proteins. pDNA primed for a consistent response with antibodies efficient at neutralizing authentic WA1 virus and three variants of concern (VOC), B.1.351, B.1.617.2, and BA.1. We demonstrate that immunogens built on structure selection can be used to influence the quality of the antibody response by focusing it to a conserved site of vulnerability shared between wildtype virus and VOCs, resulting in neutralizing antibodies across variants. Next generation SARS-CoV-2 vaccines need to address the transmission of new virus variants that continue to threaten global health and recovery. This may require new perspectives in immunogen design as well as immune response engineering. Here we applied these ideas in a two-step proof of concept study. First, we designed conformationally-constrained immunogens expressing key residues at the RBM: ACE2 interface to mimic their stereochemical orientation in the native Spike protein. Second, we initiated the process of B cell immunity (priming) using plasmid DNA injected intra-spleen to exploit the spatial organization of a secondary lymphoid organ. Mice given a single booster immunization with intact Spike protein developed a rapid memory antibody response against RBD and Spike proteins. Importantly, immune sera neutralized authentic WA1 virus and the B.1.351/Beta, B.1.617.2/Delta, and BA.1/Omicron variants of concern. Our findings demonstrate that immunogens built on structure selection and lymphoid organ targeting are a powerful way to focus the antibody response to a conserved site of vulnerability shared between wildtype virus and variants of concern.
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影响因子：
64.8
作者：
Barnes CO;Jette CA;Abernathy ME;Dam KA;Esswein SR;Gristick HB;Malyutin AG;Sharaf NG;Huey-Tubman KE;Lee YE;Robbiani DF;Nussenzweig MC;West AP Jr;Bjorkman PJ
通讯作者：
Bjorkman PJ
危及生命的Covid-19患者中针对I型IFN的自身抗体。
DOI：
10.1126/science.abd4585
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bastard P;Rosen LB;Zhang Q;Michailidis E;Hoffmann HH;Zhang Y;Dorgham K;Philippot Q;Rosain J;Béziat V;Manry J;Shaw E;Haljasmägi L;Peterson P;Lorenzo L;Bizien L;Trouillet-Assant S;Dobbs K;de Jesus AA;Belot A;Kallaste A;Catherinot E;Tandjaoui-Lambiotte Y;Le Pen J;Kerner G;Bigio B;Seeleuthner Y;Yang R;Bolze A;Spaan AN;Delmonte OM;Abers MS;Aiuti A;Casari G;Lampasona V;Piemonti L;Ciceri F;Bilguvar K;Lifton RP;Vasse M;Smadja DM;Migaud M;Hadjadj J;Terrier B;Duffy D;Quintana-Murci L;van de Beek D;Roussel L;Vinh DC;Tangye SG;Haerynck F;Dalmau D;Martinez-Picado J;Brodin P;Nussenzweig MC;Boisson-Dupuis S;Rodríguez-Gallego C;Vogt G;Mogensen TH;Oler AJ;Gu J;Burbelo PD;Cohen JI;Biondi A;Bettini LR;D'Angio M;Bonfanti P;Rossignol P;Mayaux J;Rieux-Laucat F;Husebye ES;Fusco F;Ursini MV;Imberti L;Sottini A;Paghera S;Quiros-Roldan E;Rossi C;Castagnoli R;Montagna D;Licari A;Marseglia GL;Duval X;Ghosn J;HGID Lab;NIAID-USUHS Immune Response to COVID Group;COVID Clinicians;COVID-STORM Clinicians;Imagine COVID Group;French COVID Cohort Study Group;Milieu Intérieur Consortium;CoV-Contact Cohort;Amsterdam UMC Covid-19 Biobank;COVID Human Genetic Effort;Tsang JS;Goldbach-Mansky R;Kisand K;Lionakis MS;Puel A;Zhang SY;Holland SM;Gorochov G;Jouanguy E;Rice CM;Cobat A;Notarangelo LD;Abel L;Su HC;Casanova JL
通讯作者：
Casanova JL
影响因子：
64.5
作者：
Dejnirattisai W;Zhou D;Ginn HM;Duyvesteyn HME;Supasa P;Case JB;Zhao Y;Walter TS;Mentzer AJ;Liu C;Wang B;Paesen GC;Slon-Campos J;López-Camacho C;Kafai NM;Bailey AL;Chen RE;Ying B;Thompson C;Bolton J;Fyfe A;Gupta S;Tan TK;Gilbert-Jaramillo J;James W;Knight M;Carroll MW;Skelly D;Dold C;Peng Y;Levin R;Dong T;Pollard AJ;Knight JC;Klenerman P;Temperton N;Hall DR;Williams MA;Paterson NG;Bertram FKR;Siebert CA;Clare DK;Howe A;Radecke J;Song Y;Townsend AR;Huang KA;Fry EE;Mongkolsapaya J;Diamond MS;Ren J;Stuart DI;Screaton GR
通讯作者：
Screaton GR
DOI：
10.1126/science.abl6251
发表时间：
2022-01-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
通讯作者：
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影响因子：
56.9
作者：
Lv, Zhe;Deng, Yong-Qiang;Wang, Xiangxi
通讯作者：
Wang, Xiangxi