看一下CureVac的設計
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.
懶人翻譯～
2019 年全球冠狀病毒病 (COVID-19) 大流行凸顯了對新技術的需求，這些技術可以快速
開發和生產針對新出現的傳染性病原體的人類疫苗。在使用與魚精蛋白配製的 mRNA 靶向
腫瘤 1-4 的開創性工作之後，CureVac 已經確定 mRNA 作為預防性疫苗 5-9 引發針對靶
抗原的免疫反應。 CureVac 的專有 mRNA 技術旨在快速識別、生產和測試穩定且具有免
疫原性的 mRNA 分子10。在使用含有魚精蛋白 7,8 的狂犬病糖蛋白 RABV-G mRNA 進行概
念的臨床前驗證後，一項首次人體研究表明，成年志願者會引發免疫反應，儘管只有在使
用專門的注射裝置時才能誘發保護性滴度 9。進一步的研究表明，包裹在脂質納米顆粒 (
LNP) 中的 RABV-G mRNA 克服了這些缺陷，並顯著提高了動物模型 6 和人類誌願者中的
疫苗效力 11。
mRNA 技術現在是幾種嚴重急性呼吸系統綜合症冠狀病毒-2 (SARS-CoV-2) 疫苗候選者 12
-16 的基礎。 SARS-CoV-2 的主要抗原靶點是與人血管緊張素轉換酶 2 (ACE2) 相互作用
的糖基化刺突蛋白 (S)。與首次出現於 2002-200317 年的 SARS-CoV 的作用方式一致，A
CE2 結合允許病毒進入細胞 18-20。 S 是位於病毒表面的三聚醣蛋白複合物，是病毒中
和抗體的關鍵目標。每個單體由兩個結構域 S1 和 S2 組成，它們分別作用於介導病毒與
宿主細胞膜的結合和融合。 S1 結構域通過受體結合結構域 (RBD) 與細胞表面受體相互
作用，針對 RBD 的單克隆抗體 (mAb) 具有中和能力22。通過 S1 與膜融合導致刺突蛋白
的構象變化、S1 和 S2 域的蛋白水解切割，並最終導致病毒攝取和復制 21,23。
CureVac 已將其 mRNA 技術應用於 CVnCoV 的快速開發，CVnCoV 是一種 SARS-CoV-2疫苗
，旨在最大限度地表達蛋白質和平衡免疫激活。 CVnCoV 由 LNP 配製的、非化學修飾的
、序列工程化的 mRNA 組成，該 mRNA 編碼具有兩個脯氨酸突變 (S-2P) 的全長 S 蛋白
。這些突變穩定了蛋白質構象，如先前報導的中東呼吸綜合徵冠狀病毒 (MERS-CoV)24 和
SARS-CoV25。在這裡，我們描述了 CVnCoV 在囓齒類動物的臨床前研究中的免疫原性和
保護功效。在敘利亞倉鼠中評估了保護功效，這是公認和接受的研究人類相關免疫原性和
發病機制的模型之一。倉鼠易受野生型 SARS-CoV-2 感染，導致病毒複製水平高，病毒靶
器官組織病理學變化與輕至中度人類肺部疾病病理學相當。此處顯示的研究啟動了 CVnCo
V 臨床開發 27，目前處於 2b/3 期臨床研究。
人家好像也是用2P抗原欸
又一個抗體數據不錯然後三期做VE=47%的例子
那按照某些人的邏輯也用
2P抗原的CVAC也是孿生兄弟嗎？
用Nature模型來套 他應該要80趴up的