A Glycosylated RBD Protein Induces Enhanced Neutralizing Antibodies against Omicron and Other Variants with Improved Protection against SARS-CoV-2 Infection.
A Glycosylated RBD Protein Induces Enhanced Neutralizing Antibodies against Omicron and Other Variants with Improved Protection against SARS-CoV-2 Infection.
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DOI：
10.1128/jvi.00118-22
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发表时间：
2022-09-14
影响因子：
5.4
通讯作者：
中科院分区：
文献类型：
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作者：
SARS-CoV-2自2019年首次出现以来，变异频繁。许多变种，包括目前出现的Omicron变种，已经表现出高传播性或疾病严重性增加，对全球公共卫生构成严重威胁。本研究鉴定了SARS-CoV-2受体结合域(RBD)上的一个免疫优势非中和表位。通过用多聚糖探针掩蔽该表位构建的针对该突变RBD的亚单位疫苗对RBD的受体结合亲和力或抗体结合亲和力或诱导抗体产生的能力没有显著影响。然而，该疫苗增强了该RBD的中和活性及其在免疫小鼠中的保护效果。具体地说，该疫苗诱导出的中和抗体效价显著高于原型RBD蛋白，其针对Alpha(B.1.1.7谱系)、Beta(B.1.351谱系)、Gamma(P.1谱系)和Epsilon(B.1.427或B.1.429谱系)变异伪病毒，包含棘突蛋白(S)的单一或联合突变，尽管针对某些变异株的中和抗体效价略低于原始SARS-CoV-2。该疫苗还显著提高了原型RBD对假型和正宗Delta(B.1.617.2谱系)和Omicron(B.1.1.529谱系)变异株的中和活性，尽管中和抗体效价低于原始SARS-CoV-2。与原型RBD相比，突变RBD完全保护了人类ACE2(HACE2)转基因小鼠免受SARS-CoV-2原型毒株和Delta变种的致命攻击，而且没有体重减轻。总体而言，这些发现表明，这种RBD疫苗对多种SARS-CoV-2变种具有广谱活性，并有可能对奥美康和其他大流行变种有效并提高疗效。重要性几种SARS-CoV-2变种已经显示出更高的传播性，需要开发具有广泛中和活性的有效疫苗来对抗多种变种。本研究确定了SARS-CoV-2刺突蛋白受体结合域(RBD)上的一个非中和表位，并用一个糖链探针对其进行了屏蔽。基于该突变体RBD的亚单位疫苗显著增强了原型RBD对多种SARS-CoV-2变种的能力，尽管针对其中一些变种的中和抗体效价低于针对原始SARS-CoV-2的中和抗体效价。该突变疫苗还增强了RBD疫苗原型在免疫动物中对SARS-CoV-2感染的保护效果。总之，这项研究确定了一种针对奥美康和其他SARS-CoV-2变种的工程RBD疫苗，它比原始RBD疫苗产生更强的中和抗体和保护作用。它还强调了需要提高现有新冠肺炎疫苗的有效性，以防止大流行的SARS-CoV-2变种。
SARS-CoV-2 has mutated frequently since its first emergence in 2019. Numerous variants, including the currently emerging Omicron variant, have demonstrated high transmissibility or increased disease severity, posing serious threats to global public health. This study describes the identification of an immunodominant non-neutralizing epitope on SARS-CoV-2 receptor-binding domain (RBD). A subunit vaccine against this mutant RBD, constructed by masking this epitope with a glycan probe, did not significantly affect RBD’s receptor-binding affinity or antibody-binding affinity, or its ability to induce antibody production. However, this vaccine enhanced the neutralizing activity of this RBD and its protective efficacy in immunized mice. Specifically, this vaccine elicited significantly higher-titer neutralizing antibodies than the prototypic RBD protein against Alpha (B.1.1.7 lineage), Beta (B.1.351 lineage), Gamma (P.1 lineage), and Epsilon (B.1.427 or B.1.429 lineage) variant pseudoviruses containing single or combined mutations in the spike (S) protein, albeit the neutralizing antibody titers against some variants were slightly lower than against original SARS-CoV-2. This vaccine also significantly improved the neutralizing activity of the prototypic RBD against pseudotyped and authentic Delta (B.1.617.2 lineage) and Omicron (B.1.1.529 lineage) variants, although the neutralizing antibody titers were lower than against original SARS-CoV-2. In contrast to the prototypic RBD, the mutant RBD completely protected human ACE2 (hACE2)-transgenic mice from lethal challenge with a prototype SARS-CoV-2 strain and a Delta variant without weight loss. Overall, these findings indicate that this RBD vaccine has broad-spectrum activity against multiple SARS-CoV-2 variants, as well as the potential to be effective and have improved efficacy against Omicron and other pandemic variants. IMPORTANCE Several SARS-CoV-2 variants have shown increased transmissibility, calling for a need to develop effective vaccines with broadly neutralizing activity against multiple variants. This study identified a non-neutralizing epitope on the receptor-binding domain (RBD) of SARS-CoV-2 spike protein, and further shielded it with a glycan probe. A subunit vaccine based on this mutant RBD significantly enhanced the ability of prototypic RBD against multiple SARS-CoV-2 variants, including the Delta and Omicron strains, although the neutralizing antibody titers against some of these variants were lower than those against original SARS-CoV-2. This mutant vaccine also enhanced the protective efficacy of the prototypic RBD vaccine against SARS-CoV-2 infection in immunized animals. In conclusion, this study identified an engineered RBD vaccine against Omicron and other SARS-CoV-2 variants that induced stronger neutralizing antibodies and protection than the original RBD vaccine. It also highlights the need to improve the effectiveness of current COVID-19 vaccines to prevent pandemic SARS-CoV-2 variants.
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RBD-MRNA疫苗可诱导针对Omicron和其他多种变体的广泛中和抗体，并保护小鼠免受SARS-COV-2挑战。
DOI：
10.1016/j.trsl.2022.04.007
发表时间：
2022-10
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Shi J;Zheng J;Zhang X;Tai W;Odle AE;Perlman S;Du L
通讯作者：
Du L
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：
64.8
作者：
Mlcochova P;Kemp SA;Dhar MS;Papa G;Meng B;Ferreira IATM;Datir R;Collier DA;Albecka A;Singh S;Pandey R;Brown J;Zhou J;Goonawardane N;Mishra S;Whittaker C;Mellan T;Marwal R;Datta M;Sengupta S;Ponnusamy K;Radhakrishnan VS;Abdullahi A;Charles O;Chattopadhyay P;Devi P;Caputo D;Peacock T;Wattal C;Goel N;Satwik A;Vaishya R;Agarwal M;Indian SARS-CoV-2 Genomics Consortium (INSACOG);Genotype to Phenotype Japan (G2P-Japan) Consortium;CITIID-NIHR BioResource COVID-19 Collaboration;Mavousian A;Lee JH;Bassi J;Silacci-Fegni C;Saliba C;Pinto D;Irie T;Yoshida I;Hamilton WL;Sato K;Bhatt S;Flaxman S;James LC;Corti D;Piccoli L;Barclay WS;Rakshit P;Agrawal A;Gupta RK
通讯作者：
Gupta RK
影响因子：
19
作者：
Espenhain, Laura;Funk, Tjede;Muller, Luise
通讯作者：
Muller, Luise
影响因子：
6.7
作者：
Geng Q;Tai W;Baxter VK;Shi J;Wan Y;Zhang X;Montgomery SA;Taft-Benz SA;Anderson EJ;Knight AC;Dinnon KH 3rd;Leist SR;Baric RS;Shang J;Hong SW;Drelich A;Tseng CK;Jenkins M;Heise M;Du L;Li F
通讯作者：
Li F