看一下CureVac的设计
The global coronavirus disease 2019 (COVID-19) pandemic has highlighted the ne
ed for novel technologies that allow rapid development and production of human
vaccines against newly emerging infectious pathogens. Following pioneering wo
rk using mRNA formulated with protamine to target tumours1–4, CureVac has est
ablished that mRNA elicits immune responses against target antigens as a proph
ylactic vaccine5–9. CureVac’s proprietary mRNA technology is designed to rap
idly identify, produce and test stable and immunogenic mRNA molecules10. Follo
wing preclinical proof of concept with rabies glycoprotein RABV-G mRNA, formul
ated with protamine7,8, a first-in-human study showed that immune responses ar
e elicited in adult volunteers, although protective titres could only be induc
ed when specialised injection devices were used9. Further research has demonst
rated that RABV-G mRNA encapsulated in lipid nanoparticles (LNP) over- comes t
hese deficiencies and significantly improves vaccine efficacy in animal models
6, and in human volunteers11.
mRNA technology is now the basis for several severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2) vaccine candi- dates12–16. The main antigenic tar
get of SARS-CoV-2 is the glycosylated spike protein (S) that interacts with hu
man angiotensin-converting enzyme 2 (ACE2). Consistent with the mode of action
of SARS-CoV, which first emerged in 2002–200317, ACE2 binding allows cellula
r entry of the virus18–20. S is a trimeric glycoprotein complex located on th
e viral surface and is a critical target for viral neutralising antibodies21.
Each monomer consists of two domains, S1 and S2 that act separately to mediate
viral binding and fusion to the host cell membrane, respectively. The S1 doma
in interacts with cell-surface receptors through a receptor- binding domain (R
BD) and monoclonal antibodies (mAb) against the RBD possess neutralising capac
ity22. Fusion with the membrane through S1 leads to a conformational change in
the spike protein, proteolytic cleavage of the S1 and S2 domains and, ultimat
ely, viral uptake and replication21,23.
CureVac has applied its mRNA technology to the rapid development of CVnCoV, a
SARS-CoV-2 vaccine designed for maximal protein expression and balanced immune
activation. CVnCoV is comprised of LNP-formulated, non-chemically mod- ified,
sequence engineered mRNA encoding full-length S protein with two proline muta
tions (S-2P). These mutations stabilise protein conformation as previously rep
orted for Middle East respiratory syndrome coronavirus (MERS-CoV)24 and SARS-C
oV25. Here we describe the immunogenicity and protective efficacy of CVnCoV in
preclinical studies in rodents. Protective efficacy was assessed in Syrian ha
msters, one of the recognised and accepted models to investigate human-relevan
t immunogenicity and pathogenesis26. Hamsters are susceptible to wild-type SAR
S-CoV- 2 infection, resulting in high levels of virus replication and histopat
hological changes in viral target organs comparable to mild to moderate human
lung disease pathology. Studies shown here enabled the start of CVnCoV clinica
l development27, currently in phase 2b/3 clinical studies.
懒人翻译～
2019 年全球冠状病毒病 (COVID-19) 大流行凸显了对新技术的需求，这些技术可以快速
开发和生产针对新出现的传染性病原体的人类疫苗。在使用与鱼精蛋白配制的 mRNA 靶向
肿瘤 1-4 的开创性工作之后，CureVac 已经确定 mRNA 作为预防性疫苗 5-9 引发针对靶
抗原的免疫反应。 CureVac 的专有 mRNA 技术旨在快速识别、生产和测试稳定且具有免
疫原性的 mRNA 分子10。在使用含有鱼精蛋白 7,8 的狂犬病糖蛋白 RABV-G mRNA 进行概
念的临床前验证后，一项首次人体研究表明，成年志愿者会引发免疫反应，尽管只有在使
用专门的注射装置时才能诱发保护性滴度 9。进一步的研究表明，包裹在脂质纳米颗粒 (
LNP) 中的 RABV-G mRNA 克服了这些缺陷，并显著提高了动物模型 6 和人类志愿者中的
疫苗效力 11。
mRNA 技术现在是几种严重急性呼吸系统综合症冠状病毒-2 (SARS-CoV-2) 疫苗候选者 12
-16 的基础。 SARS-CoV-2 的主要抗原靶点是与人血管紧张素转换酶 2 (ACE2) 相互作用
的糖基化刺突蛋白 (S)。与首次出现于 2002-200317 年的 SARS-CoV 的作用方式一致，A
CE2 结合允许病毒进入细胞 18-20。 S 是位于病毒表面的三聚糖蛋白复合物，是病毒中
和抗体的关键目标。每个单体由两个结构域 S1 和 S2 组成，它们分别作用于介导病毒与
宿主细胞膜的结合和融合。 S1 结构域通过受体结合结构域 (RBD) 与细胞表面受体相互
作用，针对 RBD 的单克隆抗体 (mAb) 具有中和能力22。通过 S1 与膜融合导致刺突蛋白
的构象变化、S1 和 S2 域的蛋白水解切割，并最终导致病毒摄取和复制 21,23。
CureVac 已将其 mRNA 技术应用于 CVnCoV 的快速开发，CVnCoV 是一种 SARS-CoV-2疫苗
，旨在最大限度地表达蛋白质和平衡免疫激活。 CVnCoV 由 LNP 配制的、非化学修饰的
、序列工程化的 mRNA 组成，该 mRNA 编码具有两个脯氨酸突变 (S-2P) 的全长 S 蛋白
。这些突变稳定了蛋白质构象，如先前报导的中东呼吸综合征冠状病毒 (MERS-CoV)24 和
SARS-CoV25。在这里，我们描述了 CVnCoV 在囓齿类动物的临床前研究中的免疫原性和
保护功效。在叙利亚仓鼠中评估了保护功效，这是公认和接受的研究人类相关免疫原性和
发病机制的模型之一。仓鼠易受野生型 SARS-CoV-2 感染，导致病毒复制水平高，病毒靶
器官组织病理学变化与轻至中度人类肺部疾病病理学相当。此处显示的研究启动了 CVnCo
V 临床开发 27，目前处于 2b/3 期临床研究。
人家好像也是用2P抗原欸
又一个抗体数据不错然后三期做VE=47%的例子
那按照某些人的逻辑也用
2P抗原的CVAC也是孪生兄弟吗？
用Nature模型来套 他应该要80趴up的