A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera.
A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera.
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DOI：
10.1016/j.antiviral.2022.105370
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发表时间：
2022-08
影响因子：
7.6
通讯作者：
中科院分区：
文献类型：
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作者：
由于SARS-CoV-2病毒的持续进化以及针对当前疫苗的中和抗体反应的持续时间迅速减弱，下一代COVID-19疫苗至关重要。mRNA疫苗mRNA-1273和BNT 162 b2是使用编码野生型刺突的融合前稳定的三聚体（S-2 P）的线性转录物开发的，其显示出对关注变体B.1.617.2和B.1.1.529的中和活性降低。最近，开发了一种新形式的刺突三聚体，称为VFLIP（五（V）脯氨酸，共价连接的，原聚体间二硫化物）。基于野生型刺突的原始氨基酸序列，通过使用五个脯氨酸取代、柔性切割位点氨基酸接头和原聚体间二硫键对VFLIP进行遗传工程改造。已经表明其具有天然样糖基化，并且与S-2 P相比具有更大的融合前三聚体稳定性。在这里，我们报告的刺突蛋白VFLIP-X，含有6个合理取代的氨基酸，以反映新出现的变体（K417 N，L452 R，T478 K，E484 K，N501 Y和D 614 G），为下一代SARS-CoV-2疫苗提供了一个有希望的候选者。通过产生VFLIP-X的环状mRNA（circRNA）疫苗原型免疫的小鼠在针对关注的SARS-CoV-2变体（VOC）和感兴趣的变体（VOI）的加强后长达7周具有可检测的中和抗体滴度。此外，通过用VFLIP-X免疫实现了TH 1和TH 2应答的平衡。我们的研究结果表明，由circRNA递送的VFLIP-X诱导体液和细胞免疫应答，以及针对SARS-CoV-2变体的广泛中和活性。
Next-generation COVID-19 vaccines are critical due to the ongoing evolution of SARS-CoV-2 virus and rapid waning duration of the neutralizing antibody response against current vaccines. The mRNA vaccines mRNA-1273 and BNT162b2 were developed using linear transcripts encoding the prefusion-stabilized trimers (S-2P) of the wildtype spike, which have shown a reduced neutralizing activity against the variants of concern B.1.617.2 and B.1.1.529. Recently, a new version of spike trimer, termed VFLIP (five (V) prolines, Flexibly-Linked, Inter-Protomer disulfide) was developed. Based on the original amino acid sequence of the wildtype spike, VFLIP was genetically engineered by using five proline substitutions, a flexible cleavage site amino acid linker, and an inter-protomer disulfide bond. It has been suggested to possess native-like glycosylation, and greater pre-fusion trimeric stability as opposed to S-2P. Here, we report that the spike protein VFLIP-X, containing six rationally substituted amino acids to reflect emerging variants (K417N, L452R, T478K, E484K, N501Y and D614G), offers a promising candidate for a next-generation SARS-CoV-2 vaccine. Mice immunized by a circular mRNA (circRNA) vaccine prototype producing VFLIP-X had detectable neutralizing antibody titers for up to 7 weeks post-boost against SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs). In addition, a balance in TH1 and TH2 responses was achieved by immunization with VFLIP-X. Our results indicate that the VFLIP-X delivered by circRNA induces humoral and cellular immune responses, as well as broad neutralizing activity against SARS-CoV-2 variants.
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DOI：
10.1016/j.str.2021.05.014
发表时间：
2021-07-01
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Cerutti G;Rapp M;Guo Y;Bahna F;Bimela J;Reddem ER;Yu J;Wang P;Liu L;Huang Y;Ho DD;Kwong PD;Sheng Z;Shapiro L
通讯作者：
Shapiro L
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
影响因子：
56.9
作者：
Hsieh, Ching-Lin;Goldsmith, Jory A.;McLellan, Jason S.
通讯作者：
McLellan, Jason S.
影响因子：
8.8
作者：
Kimura I;Kosugi Y;Wu J;Zahradnik J;Yamasoba D;Butlertanaka EP;Tanaka YL;Uriu K;Liu Y;Morizako N;Shirakawa K;Kazuma Y;Nomura R;Horisawa Y;Tokunaga K;Ueno T;Takaori-Kondo A;Schreiber G;Arase H;Genotype to Phenotype Japan (G2P-Japan) Consortium;Motozono C;Saito A;Nakagawa S;Sato K
通讯作者：
Sato K
影响因子：
7.8
作者：
Álvarez-Díaz DA;Muñoz AL;Tavera-Rodríguez P;Herrera-Sepúlveda MT;Ruiz-Moreno HA;Laiton-Donato K;Franco-Muñoz C;Pelaez-Carvajal D;Cuellar D;Muñoz-Suarez AM;Galindo M;Arias-Ramírez EJ;Mercado-Reyes M
通讯作者：
Mercado-Reyes M