Engineered SARS-CoV-2 receptor binding domain improves manufacturability in yeast and immunogenicity in mice.
Engineered SARS-CoV-2 receptor binding domain improves manufacturability in yeast and immunogenicity in mice.
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DOI：
10.1073/pnas.2106845118
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发表时间：
2021-09-21
影响因子：
11.1
通讯作者：
Love JC
中科院分区：
文献类型：
--
作者：
Dalvie NC;Rodriguez-Aponte SA;Hartwell BL;Tostanoski LH;Biedermann AM;Crowell LE;Kaur K;Kumru OS;Carter L;Yu J;Chang A;McMahan K;Courant T;Lebas C;Lemnios AA;Rodrigues KA;Silva M;Johnston RS;Naranjo CA;Tracey MK;Brady JR;Whittaker CA;Yun D;Brunette N;Wang JY;Walkey C;Fiala B;Kar S;Porto M;Lok M;Andersen H;Lewis MG;Love KR;Camp DL;Silverman JM;Kleanthous H;Joshi SB;Volkin DB;Dubois PM;Collin N;King NP;Barouch DH;Irvine DJ;Love JC
全球大部分人口居住在低收入和中等收入国家，这些国家目前的COVID-19疫苗在很大程度上仍然不可用。对于COVID-19大流行，世界将需要获得超过100亿剂疫苗，或所有其他疾病疫苗年接种量的两倍以上。许多候选疫苗使用SARS-CoV-2受体结合域（RBD）抗原。在这里，我们提出了一种工程RBD，其在巴斯德毕赤酵母中具有改进的生产滴度，巴斯德毕赤酵母是一种通常用于疫苗制造商大规模，低成本制造的酵母。相对于目前候选物中使用的武汉-胡-1序列，修饰的RBD还在小鼠中引起增强的免疫应答。这些综合特性使其成为解决病毒新变种的下一代疫苗的有希望的候选者。全球遏制COVID-19仍然需要中低收入国家（LMIC）获得负担得起的疫苗。最近批准的疫苗提供了必要的干预措施，尽管价格可能限制其全球供应。基于重组蛋白的亚单位疫苗适合于大批量微生物生产，每年生产数十亿剂，从而最大限度地降低其生产成本。这些类型的疫苗是成熟的、经过验证的干预措施，具有多种安全有效的商业实例。这种类型的SARS-CoV-2的许多候选疫苗依赖于含有受体结合结构域（RBD）的序列，该序列介导病毒通过ACE 2进入细胞。在这里，我们报告了一种RBD的工程序列变体，与目前疫苗中使用的Wuhan-Hu-1变体相比，该变体在小鼠中单次给药后表现出高产率的可制造性，与ACE 2的高亲和力结合以及增强的免疫原性。针对工程蛋白质产生的抗体表现出与来自最近报道的两种关注的SARS-CoV-2变体（501Y.V1/V2）的RBD的异型结合。在设计的病毒样颗粒（VLP）上呈现工程化RBD也减少了病毒攻击后仓鼠的体重减轻。
Most of the global population resides in low- and middle-income countries, where current vaccines for COVID-19 remain largely unavailable. For the COVID-19 pandemic, the world will need access to >10 billion doses of vaccines, or more than double the annual volume of vaccines for all other diseases. Many vaccine candidates use the SARS-CoV-2 receptor-binding domain (RBD) antigen. Here, we present an engineered RBD with improved production titers in Pichia pastoris, a yeast commonly used for large-scale, low-cost manufacturing by vaccine manufacturers. The modified RBD also raises an enhanced immune response in mice relative to the Wuhan-Hu-1 sequence used in current candidates. These combined traits make it a promising candidate for next-generation vaccines addressing emerging variants of the virus. Global containment of COVID-19 still requires accessible and affordable vaccines for low- and middle-income countries (LMICs). Recently approved vaccines provide needed interventions, albeit at prices that may limit their global access. Subunit vaccines based on recombinant proteins are suited for large-volume microbial manufacturing to yield billions of doses annually, minimizing their manufacturing cost. These types of vaccines are well-established, proven interventions with multiple safe and efficacious commercial examples. Many vaccine candidates of this type for SARS-CoV-2 rely on sequences containing the receptor-binding domain (RBD), which mediates viral entry to cells via ACE2. Here we report an engineered sequence variant of RBD that exhibits high-yield manufacturability, high-affinity binding to ACE2, and enhanced immunogenicity after a single dose in mice compared to the Wuhan-Hu-1 variant used in current vaccines. Antibodies raised against the engineered protein exhibited heterotypic binding to the RBD from two recently reported SARS-CoV-2 variants of concern (501Y.V1/V2). Presentation of the engineered RBD on a designed virus-like particle (VLP) also reduced weight loss in hamsters upon viral challenge.
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影响因子：
5.5
作者：
Guebre-Xabier M;Patel N;Tian JH;Zhou B;Maciejewski S;Lam K;Portnoff AD;Massare MJ;Frieman MB;Piedra PA;Ellingsworth L;Glenn G;Smith G
通讯作者：
Smith G
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：
4.8
作者：
Gupta, Gaurav;Glueck, Reinhard;Patel, Pankaj R.
通讯作者：
Patel, Pankaj R.
影响因子：
64.5
作者：
Liu C;Ginn HM;Dejnirattisai W;Supasa P;Wang B;Tuekprakhon A;Nutalai R;Zhou D;Mentzer AJ;Zhao Y;Duyvesteyn HME;López-Camacho C;Slon-Campos J;Walter TS;Skelly D;Johnson SA;Ritter TG;Mason C;Costa Clemens SA;Gomes Naveca F;Nascimento V;Nascimento F;Fernandes da Costa C;Resende PC;Pauvolid-Correa A;Siqueira MM;Dold C;Temperton N;Dong T;Pollard AJ;Knight JC;Crook D;Lambe T;Clutterbuck E;Bibi S;Flaxman A;Bittaye M;Belij-Rammerstorfer S;Gilbert SC;Malik T;Carroll MW;Klenerman P;Barnes E;Dunachie SJ;Baillie V;Serafin N;Ditse Z;Da Silva K;Paterson NG;Williams MA;Hall DR;Madhi S;Nunes MC;Goulder P;Fry EE;Mongkolsapaya J;Ren J;Stuart DI;Screaton GR
通讯作者：
Screaton GR
影响因子：
3.7
作者：
Du, Lanying;Zhao, Guangyu;Chan, Chris C. S.;Sun, Shihui;Chen, Min;Liu, Zhonghua;Guo, Hongxiang;He, Yuxian;Zhou, Yusen;Zheng, Bo-Jian;Jiang, Shibo
通讯作者：
Jiang, Shibo