自扩增 mRNA (saRNA)：下一代疫苗 RNA 平台 

Unlike conventional mRNA vaccines which encodes only for the target antigens, the self-amplifying mRNAs (saRNAs) encodes for non-structural proteins and promotor as well which makes saRNAs replicons capable of transcribing in vivo in the host cells. Early results indicates that their effectiveness, when given in smaller doses, is at par with that of regular doses of conventional 基因. Due to low dose requirements, fewer side effects and longer duration of action, saRNA appears as better RNA platform for vaccines (including for v.2.0 of mRNA COVID vaccines) and newer therapeutics. No saRNA-based vaccine or drug is approved for human use yet. However, significant progress in this area has the potential to usher in a renaissance in prevention and treatment of infections and degenerative disorders.  

毋庸置疑，人类在像 COVID 这样的大流行病面前是脆弱的。 我们都经历过它，并以某种方式受到它的影响； 数百万人无法活到第二天早上。 鉴于中国也有大规模的 COVID-19 免疫接种计划，有关北京及其周边地区病例和死亡率激增的最新媒体报道令人担忧。 不能低估做好准备和不懈追求更有效的疫苗和疗法的必要性。  

The extraordinary situation presented by the COVID-19 pandemic provided an opportunity for the promising RNA technology to come out of age. Clinical trials could be completed at a record pace and 基因 based COVID Vaccines, BNT162b2 (manufactured by Pfizer/BioNTech) and 基因-1273 (by Moderna) received EUA from the regulators and, in due course, played an important role in providing protection against the pandemic to the people especially in Europe and North America¹. 这些 mRNA 疫苗基于合成 RNA 平台。 这允许快速、可扩展和无细胞的工业生产。 但这些并非没有限制，例如高成本、冷供应链、抗体滴度下降等。  

mRNA vaccines currently in use (sometimes referred to as conventional or 1st generation 基因 vaccines) are based on encoding the viral antigen in synthetic RNA. A non-viral delivery system transports the transcript to the host cell cytoplasm where the viral antigen is expressed. The expressed antigen then induces immune response and provide active immunity. Because RNA degrades easily and this mRNA in the vaccine cannot self-transcribe, an appreciable amount of synthetic viral RNA transcripts (mRNA) need to be administered in the vaccine for eliciting desired immune response. But what if the synthetic RNA transcript is incorporated also with non-structural proteins and promotor genes, in addition to the desired viral antigen? Such an RNA transcript will have ability to transcribe or self-amplify itself when transported into the host cell though it will be longer and heavier and its transport to the host cells may be more complex.  

Unlike conventional (or, non-amplifying) 基因 which has codes only for the targeted viral antigen, the self-amplifying 基因 (saRNA), has ability to transcribe itself when in vivo in the host cells by virtue of presence of required codes for non-structural proteins and a promotor. mRNA vaccine candidates based on self-amplifying mRNAs are referred to as second or next generation 基因 vaccines. These offer better opportunities in terms of lower dosage requirements, relatively fewer side effects, and longer duration of action/effects ^（2-5）. RNA 平台的两个版本都为科学界所知有一段时间了。 在大流行应对中，鉴于其简单性和大流行情况的紧迫性，研究人员选择了非复制版本的 mRNA 平台用于疫苗开发，并在谨慎的情况下首先获得非扩增版本的经验。 现在，我们有两种已获批的针对 COVID-19 的 mRNA 疫苗，还有几种候选疫苗和治疗药物正在筹备中，例如 艾滋病毒疫苗 和治疗 Charcot-Marie-Tooth 病。  

针对 COVID-19 的 saRNA 候选疫苗  

对 saRNA 疫苗的兴趣并不是很新鲜。 在大流行开始后的几个月内，即 2020 年年中，McKay 等. 提出了一种基于 saRNA 的候选疫苗，该候选疫苗在小鼠血清中显示出高抗体滴度和良好的病毒中和作用⁶. The phase-1 clinical trial of VLPCOV–01 (a self-amplifying RNA vaccine candidate) on 92 healthy adults whose results were published on preprint last month concluded that low dose administration of this 血清RNA based vaccine candidate induced immune response comparable to conventional mRNA vaccine BNT162b2 and recommends its further development as booster vaccine⁷. In another recently published study conducted as part of the COVAC1 clinical trial to develop booster dose administration strategy, a superior immune response was found in people who had previous COVID-19 and received a novel self-amplifying RNA (saRNA) COVID-19 vaccine plus a UK authorised vaccine⁸. A pre-clinical trial of novel oral vaccine candidate based on self-amplifying RNA on mouse model elicited high antibody titre⁹.  

针对流感的 saRNA 候选疫苗  

目前使用的流感疫苗基于灭活病毒或合成重组体（合成 HA 基因与杆状病毒结合）¹⁰. A self-amplifying 基因-based vaccine candidate may induce immunity against multiple viral antigens. Pre-clinical trial of sa-mRNA bicistronic A/H5N1 vaccine candidate against influenza on mice and ferrets elicited potent antibody and T-cell response warranting evaluation on humans in clinical trials¹¹.  

由于显而易见的原因，针对 COVID-19 的疫苗受到了广泛关注。 一些针对 RNA 平台应用的临床前工作已经针对其他感染和非感染性疾病（例如癌症、阿尔茨海默氏病和遗传性疾病）进行； 然而，目前还没有基于 saRNA 的疫苗或药物被批准用于人类。 需要对基于 saRNA 的疫苗的使用进行更多研究，以便全面了解它们用于人类受试者的安全性和有效性。

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参考文献：  

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