三种高致病性冠状病毒(CoV),SARS-CoV-2,SARS-CoV,还有MERS-CoV,属于β-CoV属,引起了疫情或流行病。SARS-CoV-2已经进化成许多变体,对当前疫苗的抗性增加。这些CoV的刺突(S)蛋白及其受体结合域(RBD)片段是重要的疫苗靶标;然而,SARS-CoV-2Omicron变体的RBD高度突变,针对该区域的基于祖先的疫苗引起的中和抗体无效,强调需要对SARS-CoV-2变体和其他具有大流行潜力的CoV具有广谱效力的有效疫苗。这项研究描述了一种泛β-CoV亚单位疫苗,Om-S-MERS-RBD,通过将MERS-CoV的保守且高效的RBD融合到RBD截短的SARS-CoV-2OmicronS蛋白中,并在小鼠模型中评价其中和免疫原性和保护功效。Om-S-MERS-RBD形成构象结构,保持有效的功能和抗原性,并有效结合MERS-CoV受体,人二肽基肽酶4和MERS-CoVRBD或SARS-CoV-2S特异性抗体。用Om-S-MERS-RBD和佐剂(明矾加单磷酰脂质A)免疫小鼠可诱导针对假型MERS-CoV的广泛中和抗体,SARS-CoV,和SARS-CoV-2原始菌株,以及对RBD截短的OmicronS蛋白具有特异性的T细胞应答。此外,用Omicron-S-RBD蛋白引发后,对SARS-CoV-2Omicron亚变体的中和活性得到了有效改善。调节Om-S-MERS-RBD蛋白保护小鼠免受SARS-CoV-2Omicron变体的攻击,MERS-CoV,和SARS-CoV,显着降低肺部病毒滴度。总的来说,这些发现表明Om-S-MERS-RBD蛋白可以作为一种有效的通用亚单位疫苗来预防MERS-CoV感染,SARS-CoV,SARS-CoV-2及其变体。
目标:冠状病毒(CoV),SARS-CoV-2,SARS-CoV,还有MERS-CoV,2019年冠状病毒病、SARS、MERS,不断威胁人类健康。这些CoV的刺突(S)蛋白及其受体结合域(RBD)片段是关键的疫苗靶标。然而,SARS-CoV-2变种的高度突变的RBD,尤其是Omicron,显着降低了当前疫苗对SARS-CoV-2变体的效力。在此,通过将MERS-CoV的有效且保守的RBD融合到RBD截短的OmicronS蛋白中来设计基于蛋白质的泛β-CoV亚单位疫苗。所得疫苗保持了有效的功能性和抗原性,诱导针对所有这些高致病性人类CoV的广泛中和抗体,并引发OmicronS特异性细胞免疫反应,保护免疫小鼠免受SARS-CoV-2Omicron,SARS-CoV,和MERS-CoV感染。一起来看,本研究合理设计了具有广谱功效的泛β-CoV亚单位疫苗,该疫苗具有开发作为针对SARS-CoV-2变体和其他具有大流行潜力的CoV的有效通用疫苗的潜力。
Three highly pathogenic coronaviruses (CoVs), SARS-CoV-2, SARS-CoV, and MERS-CoV, belonging to the genus beta-CoV, have caused outbreaks or pandemics. SARS-CoV-2 has evolved into many variants with increased resistance to the current vaccines. Spike (S) protein and its receptor-binding domain (RBD) fragment of these CoVs are important vaccine targets; however, the RBD of the SARS-CoV-2 Omicron variant is highly mutated, rending neutralizing antibodies elicited by ancestral-based vaccines targeting this region ineffective, emphasizing the need for effective vaccines with broad-spectrum efficacy against SARS-CoV-2 variants and other CoVs with pandemic potential. This study describes a pan-beta-CoV subunit vaccine, Om-S-MERS-RBD, by fusing the conserved and highly potent RBD of MERS-CoV into an RBD-truncated SARS-CoV-2 Omicron S protein, and evaluates its neutralizing immunogenicity and protective efficacy in mouse models. Om-S-MERS-RBD formed a conformational structure, maintained effective functionality and antigenicity, and bind efficiently to MERS-CoV receptor, human dipeptidyl peptidase 4, and MERS-CoV RBD or SARS-CoV-2 S-specific antibodies. Immunization of mice with Om-S-MERS-RBD and adjuvants (Alum plus monophosphoryl lipid A) induced broadly neutralizing antibodies against pseudotyped MERS-CoV, SARS-CoV, and SARS-CoV-2 original strain, as well as T-cell responses specific to RBD-truncated Omicron S protein. Moreover, the neutralizing activity against SARS-CoV-2 Omicron subvariants was effectively improved after priming with an Omicron-S-RBD protein. Adjuvanted Om-S-MERS-RBD protein protected mice against challenge with SARS-CoV-2 Omicron variant, MERS-CoV, and SARS-CoV, significantly reducing viral titers in the lungs. Overall, these findings indicated that Om-S-MERS-RBD protein could develop as an effective universal subunit vaccine to prevent infections with MERS-CoV, SARS-CoV, SARS-CoV-2, and its variants.
OBJECTIVE: Coronaviruses (CoVs), SARS-CoV-2, SARS-CoV, and MERS-CoV, the respective causative agents of coronavirus disease 2019, SARS, and MERS, continually threaten human health. The spike (S) protein and its receptor-binding domain (RBD) fragment of these CoVs are critical vaccine targets. Nevertheless, the highly mutated RBD of SARS-CoV-2 variants, especially Omicron, significantly reduces the efficacy of current vaccines against SARS-CoV-2 variants. Here a protein-based pan-beta-CoV subunit vaccine is designed by fusing the potent and conserved RBD of MERS-CoV into an RBD-truncated Omicron S protein. The resulting vaccine maintained effective functionality and antigenicity, induced broadly neutralizing antibodies against all of these highly pathogenic human CoVs, and elicited Omicron S-specific cellular immune responses, protecting immunized mice from SARS-CoV-2 Omicron, SARS-CoV, and MERS-CoV infections. Taken together, this study rationally designed a pan-beta-CoV subunit vaccine with broad-spectrum efficacy, which has the potential for development as an effective universal vaccine against SARS-CoV-2 variants and other CoVs with pandemic potential.