Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2.
Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2.
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DOI：
10.1101/2020.08.11.247395
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发表时间：
2020-11-25
期刊：
影响因子：
64.5
通讯作者：
King, Neil P
中科院分区：
文献类型：
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作者：
Walls, Alexandra C;Fiala, Brooke;King, Neil P
迫切需要一种安全、有效和可扩展的疫苗来阻止正在进行的SARS-CoV-2大流行。在这里，我们描述了基于结构的自组装蛋白质纳米颗粒免疫原的设计，该免疫原可在小鼠中引发针对SARS-CoV-2的有效和保护性抗体反应。纳米颗粒疫苗在高度免疫原性阵列中显示了SARS-CoV-2尖峰(S)糖蛋白受体结合域（RBD）的60个拷贝，并且诱导的中和抗体滴度比预灌注稳定的S外结构域三聚体高约10倍，尽管剂量低5倍以上。纳米颗粒免疫原引发的抗体靶向RBD上多个不同的表位，表明它们可能不容易受到逃逸突变的影响，并且与恢复期的人血清相比，表现出明显较低的结合中和率，这可能将疫苗相关的增强呼吸道疾病的风险降至最低。蛋白质组分和组装的纳米颗粒的高产率和稳定性，特别是与SARS-CoV-2预压稳定的S三聚体相比，表明纳米颗粒疫苗的制造将具有高度的可扩展性。这些结果强调了强大的抗原展示平台在诱导强效中和抗体反应方面的效用，并启动了cGMP生产工作，以推进RBD纳米颗粒疫苗进入临床。需要一种安全、有效和可扩展的疫苗来阻止正在进行的SARS-CoV-2大流行。我们描述了基于结构的自组装蛋白质纳米颗粒免疫原的设计，该免疫原可在小鼠中引发针对SARS-CoV-2的有效和保护性抗体反应。纳米颗粒疫苗以高度免疫原性阵列显示60个SARS-CoV-2刺突受体结合域（rbd），诱导中和抗体滴度比预灌注稳定刺突高10倍，尽管剂量低5倍。RBD纳米颗粒引发的抗体针对多个不同的表位，表明它们可能不容易受到逃逸突变的影响，并且比恢复期的人血清表现出更低的结合中和率，这可能最大限度地降低疫苗相关的增强呼吸道疾病的风险。组装的纳米颗粒的高产率和稳定性表明，纳米颗粒疫苗的制造将具有高度的可扩展性。这些结果突出了强大的抗原展示平台的实用性，并启动了cGMP生产工作，以推进SARS-CoV-2-RBD纳米颗粒疫苗进入临床。
A safe, effective, and scalable vaccine is urgently needed to halt the ongoing SARS-CoV-2 pandemic. Here, we describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 copies of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain (RBD) in a highly immunogenic array and induce neutralizing antibody titers roughly ten-fold higher than the prefusion-stabilized S ectodomain trimer despite a more than five-fold lower dose. Antibodies elicited by the nanoparticle immunogens target multiple distinct epitopes on the RBD, suggesting that they may not be easily susceptible to escape mutations, and exhibit a significantly lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the protein components and assembled nanoparticles, especially compared to the SARS-CoV-2 prefusion-stabilized S trimer, suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms for inducing potent neutralizing antibody responses and have launched cGMP manufacturing efforts to advance the lead RBD nanoparticle vaccine into the clinic.A safe, effective, and scalable vaccine is needed to halt the ongoing SARS-CoV-2 pandemic. We describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 SARS-CoV-2 spike receptor-binding domains (RBDs) in a highly immunogenic array and induce neutralizing antibody titers 10-fold higher than the prefusion-stabilized spike despite a 5-fold lower dose. Antibodies elicited by the RBD nanoparticles target multiple distinct epitopes, suggesting they may not be easily susceptible to escape mutations, and exhibit a lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the assembled nanoparticles suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms and have launched cGMP manufacturing efforts to advance the SARS-CoV-2-RBD nanoparticle vaccine into the clinic.