In 2020, two mRNA-based vaccines, encoding the full length of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, have been introduced for control of the coronavirus disease (COVID-19) pandemic1,2. However, reactogenicity, such as fever, caused by innate immune responses to the vaccine formulation remains to be improved. Here, we optimized a lipid nanoparticle (LNP)-based mRNA vaccine candidate, encoding the SARS-CoV-2 spike protein receptor-binding domain (LNP-mRNA-RBD), which showed improved immunogenicity by removing reactogenic materials from the vaccine formulation and protective potential against SARS-CoV-2 infection in cynomolgus macaques. LNP-mRNA-RBD induced robust antigen-specific B cells and follicular helper T cells in the BALB/c strain but not in the C57BL/6 strain; the two strains have contrasting abilities to induce type I interferon production by dendritic cells. Removal of reactogenic materials from original synthesized mRNA by HPLC reduced type I interferon (IFN) production by dendritic cells, which improved immunogenicity. Immunization of cynomolgus macaques with an LNP encapsulating HPLC-purified mRNA induced robust anti-RBD IgG in the plasma and in various mucosal areas, including airways, thereby conferring protection against SARS-CoV-2 infection. Therefore, fine-tuning the balance between the immunogenic and reactogenic activity of mRNA-based vaccine formulations may offer safer and more efficacious outcomes.

中文翻译：

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靶向SARS-CoV-2受体结合域的LNP-mRNA候选疫苗的优化

在2020年，已引入了两种基于mRNA的疫苗，它们编码严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）刺突蛋白的全长，用于控制冠状病毒疾病（COVID-19）大流行1,2。然而，由对疫苗制剂的先天免疫反应引起的反应性，例如发烧，仍有待改善。在这里，我们优化了基于脂质纳米颗粒（LNP）的mRNA疫苗候选物，编码SARS-CoV-2穗蛋白受体结合结构域（LNP-mRNA-RBD），该结构通过从疫苗制剂中去除反应原性物质而显示出更高的免疫原性，并且对猕猴猕猴SARS-CoV-2感染的保护潜力。LNP-mRNA-RBD在BALB / c株中诱导了健壮的抗原特异性B细胞和滤泡辅助性T细胞，而在C57BL / 6株中则没有。这两种菌株具有诱导能力，以诱导树突状细胞产生I型干扰素。通过HPLC从原始合成的mRNA中去除反应原性物质，减少了树突状细胞产生的I型干扰素（IFN）的产生，从而提高了免疫原性。用包裹有HPLC纯化的LNP的LNP免疫猕猴，在血浆和包括呼吸道在内的各种粘膜区域诱导了强大的抗RBD IgG，从而赋予了抵抗SARS-CoV-2感染的保护。因此，微调基于mRNA的疫苗制剂的免疫原性和反应原性活性之间的平衡可能会提供更安全，更有效的结果。改善了免疫原性。用包裹有HPLC纯化的LNP的LNP免疫猕猴，在血浆和包括呼吸道在内的各种粘膜区域诱导了强大的抗RBD IgG，从而赋予了抵抗SARS-CoV-2感染的保护。因此，微调基于mRNA的疫苗制剂的免疫原性和反应原性活性之间的平衡可能会提供更安全，更有效的结果。改善了免疫原性。用包裹有HPLC纯化的LNP的LNP免疫猕猴，在血浆和包括呼吸道在内的各种粘膜区域诱导了强大的抗RBD IgG，从而赋予了抵抗SARS-CoV-2感染的保护。因此，微调基于mRNA的疫苗制剂的免疫原性和反应原性活性之间的平衡可能会提供更安全，更有效的结果。