Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines.
Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines.
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DOI：
10.1038/s41467-021-22867-w
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发表时间：
2021-05-11
影响因子：
16.6
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
He L;Chaudhary A;Lin X;Sou C;Alkutkar T;Kumar S;Ngo T;Kosviner E;Ozorowski G;Stanfield RL;Ward AB;Wilson IA;Zhu J
埃博拉病毒（EBOV）糖蛋白（GP）可被中和抗体（NAb）识别，是疫苗设计的主要靶点。在这里，我们首先调查的茎和七重复1-C（HR 1C）地区的GP亚稳定性的贡献。粘蛋白缺失形式的特定茎和HR 1C修饰（GPΔmuc）增加了三聚体产量，而HR 1C的改变对热稳定性产生了更复杂的影响。晶体结构的测定验证了两个合理设计的GPΔ μ c三聚体在其未配体状态。然后，我们在重新工程化的蛋白纳米颗粒上展示了修饰的GPΔmuc三聚体，该纳米颗粒封装了一层锁定结构域（LD）和一簇辅助T细胞表位。在小鼠和兔中，GP三聚体和纳米颗粒引发交叉埃博拉病毒NAb，以及增强假病毒感染的非NAb。库测序揭示了疫苗诱导的B细胞应答的定量特征。这项研究证明了一种基于GP稳定化和纳米颗粒展示的针对丝状病毒（例如EBOV）的有前途的疫苗策略。埃博拉病毒糖蛋白（GP）是疫苗设计的主要目标。在这里，作者确定了提高GP稳定性和产量的突变，设计了两种多层纳米颗粒载体，并在小鼠和兔中证明了修饰的GP在纳米颗粒上的良好免疫原性。
Ebola virus (EBOV) glycoprotein (GP) can be recognized by neutralizing antibodies (NAbs) and is the main target for vaccine design. Here, we first investigate the contribution of the stalk and heptad repeat 1-C (HR1C) regions to GP metastability. Specific stalk and HR1C modifications in a mucin-deleted form (GPΔmuc) increase trimer yield, whereas alterations of HR1C exert a more complex effect on thermostability. Crystal structures are determined to validate two rationally designed GPΔmuc trimers in their unliganded state. We then display a modified GPΔmuc trimer on reengineered protein nanoparticles that encapsulate a layer of locking domains (LD) and a cluster of helper T-cell epitopes. In mice and rabbits, GP trimers and nanoparticles elicit cross-ebolavirus NAbs, as well as non-NAbs that enhance pseudovirus infection. Repertoire sequencing reveals quantitative profiles of vaccine-induced B-cell responses. This study demonstrates a promising vaccine strategy for filoviruses, such as EBOV, based on GP stabilization and nanoparticle display. Ebola virus glycoprotein (GP) is a major target for vaccine design. Here, the authors identify mutations to improve GP stability and yield, design two multilayered nanoparticle carriers, and demonstrate good immunogenicity of the modified GP on nanoparticles in mice and rabbits.
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影响因子：
32.4
作者：
Gilchuk P;Kuzmina N;Ilinykh PA;Huang K;Gunn BM;Bryan A;Davidson E;Doranz BJ;Turner HL;Fusco ML;Bramble MS;Hoff NA;Binshtein E;Kose N;Flyak AI;Flinko R;Orlandi C;Carnahan R;Parrish EH;Sevy AM;Bombardi RG;Singh PK;Mukadi P;Muyembe-Tamfum JJ;Ohi MD;Saphire EO;Lewis GK;Alter G;Ward AB;Rimoin AW;Bukreyev A;Crowe JE Jr
通讯作者：
Crowe JE Jr
影响因子：
64.5
作者：
Flyak AI;Shen X;Murin CD;Turner HL;David JA;Fusco ML;Lampley R;Kose N;Ilinykh PA;Kuzmina N;Branchizio A;King H;Brown L;Bryan C;Davidson E;Doranz BJ;Slaughter JC;Sapparapu G;Klages C;Ksiazek TG;Saphire EO;Ward AB;Bukreyev A;Crowe JE Jr
通讯作者：
Crowe JE Jr
DOI：
10.1056/nejmoa1604330
发表时间：
2016-10-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
PREVAIL II Writing Group;Multi-National PREVAIL II Study Team;Davey RT Jr;Dodd L;Proschan MA;Neaton J;Neuhaus Nordwall J;Koopmeiners JS;Beigel J;Tierney J;Lane HC;Fauci AS;Massaquoi MBF;Sahr F;Malvy D
通讯作者：
Malvy D
影响因子：
6.7
作者：
Fusco ML;Hashiguchi T;Cassan R;Biggins JE;Murin CD;Warfield KL;Li S;Holtsberg FW;Shulenin S;Vu H;Olinger GG;Kim DH;Whaley KJ;Zeitlin L;Ward AB;Nykiforuk C;Aman MJ;Berry JD;Saphire EO
通讯作者：
Saphire EO
影响因子：
17.1
作者：
Bruun TUJ;Andersson AC;Draper SJ;Howarth M
通讯作者：
Howarth M