RNA-based vaccines against SARS-CoV-2 have demonstrated promising protective immunity against the global COVID-19 epidemic. Enhancing the intensity and duration of mRNA antigen expression is anticipated to markedly boost antiviral immune responses. Self-amplifying RNA (saRNA) represents a next-generation platform for RNA-based vaccines, amplifying transcripts in situ to augment the expression of encoded immunogens. Here, we develop a saRNA nanovaccine, formulated with a mutated saRNA encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein, encapsulated within a lipid nanoparticle (LNP-saRNA-RBD). This LNP-saRNA vaccine platform enables efficient delivery of saRNA-RBD, inducing enhanced and prolonged expression of the RBD antigen. LNP-saRNA-RBD vaccination stimulated the generation of antigen-specific T cells, promoting their differentiation into a long-lived effector memory phenotype. Immunization with LNP-saRNA-RBD induced a germinal center response in draining lymph nodes, leading to the production of anti-RBD IgG antibodies with the ability to neutralize SARS-CoV-2 pseudovirus. Furthermore, prime-boost immunizations with LNP-saRNA-RBD conferred protection to mice against SARS-CoV-2 challenge by suppressing viral infection and replication, as well as pulmonary inflammatory responses and associated damage. Taken together, these findings provide strong support for advancing the development of LNP-saRNA-RBD as a safe and efficacious vaccine candidate against SARS-CoV-2 infection.

中文翻译：

---

使用自扩增 RNA 脂质纳米颗粒疫苗增强对 SARS-CoV-2 的保护性免疫力


针对 SARS-CoV-2 的基于 RNA 的疫苗已显示出对全球 COVID-19 流行病的有希望的保护性免疫力。预计提高 mRNA 抗原表达的强度和持续时间将显着增强抗病毒免疫反应。自扩增 RNA （saRNA） 代表了基于 RNA 的疫苗的下一代平台，可原位扩增转录本以增强编码免疫原的表达。在这里，我们开发了一种 saRNA 纳米疫苗，该疫苗由编码 SARS-CoV-2 刺突糖蛋白受体结合域 （RBD） 的突变 saRNA 配制而成，封装在脂质纳米颗粒 （LNP-saRNA-RBD） 中。该 LNP-saRNA 疫苗平台能够高效递送 saRNA-RBD，诱导 RBD 抗原的增强和延长表达。LNP-saRNA-RBD 疫苗接种刺激抗原特异性 T 细胞的产生，促进其分化为长寿命效应记忆表型。用 LNP-saRNA-RBD 免疫在引流淋巴结中诱导生发中心反应，导致产生具有中和 SARS-CoV-2 假病毒能力的抗 RBD IgG 抗体。此外，使用 LNP-saRNA-RBD 的初免-加强免疫通过抑制病毒感染和复制以及肺部炎症反应和相关损伤，保护小鼠免受 SARS-CoV-2 攻击。综上所述，这些发现为推进 LNP-saRNA-RBD 作为安全有效的 SARS-CoV-2 感染候选疫苗的开发提供了有力支持。