TW202306967A - 經改良之冠狀病毒疫苗 - Google Patents
經改良之冠狀病毒疫苗 Download PDFInfo
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Abstract
本發明提供一種經醣化工程改造之SARS-CoV-2棘蛋白,其相對於SARS-CoV-2及其變異體之天然棘蛋白,能夠引發增強之免疫反應。該經醣化工程改造之棘蛋白暴露醣基化位點且同時保持該棘蛋白之三級結構。因此,本發明提供用於更好地預防及治療新出現之冠狀病毒感染的經改良之免疫原、疫苗及方法。
Description
自2019年12月報導第一個病例以來,Covid-19之爆發已在全世界引起超過三百萬例死亡。當前若干針對SARS-CoV-2感染之COVID-19疫苗正在開發中,處於臨床試驗階段,且已授權一些疫苗供人類使用。儘管許多經批准之疫苗展現出高功效,但SARS-CoV-2之基因變異體已出現且在整個COVID-19大流行中在全世界傳播。
因此,迫切需要經改良之COVID-19疫苗以更好地預防新出現之冠狀病毒感染及/或降低危及生命之冠狀病毒感染的嚴重程度。
SARS-CoV-2之棘蛋白廣泛醣基化。本發明基於如下認識:與SARS-CoV-2或其變異體之天然棘蛋白相比,用經修飾之缺乏聚醣遮蔽或較少地被聚醣遮蔽之SARS-CoV-2棘蛋白進行免疫接種誘發增強之針對SARS-CoV-2及其需要關注之變異體(例如Alpha、Gamma、Delta及Omicron)之免疫反應。依據全球共享流感數據倡議組織(GISAID)之超過六百萬個S蛋白序列的比對,可鑑別位於受體結合域(receptor-binding domain, RBD)及包括七肽重複2域(heptad repeat 2, HR2)之S蛋白質第二次單元(S2)中的12個高度保守抗原決定基(SEQ ID: 41-52)。藉由N-聚醣修整來移除聚醣遮蔽以更好地暴露此等高度保守抗原決定基提供一種研發針對SARS-CoV-2及變異體之廣效保護性疫苗的有效方法。棘蛋白之N-聚醣修整可藉由活體外醣化工程改造來實現。藉此,經醣化工程改造之棘蛋白暴露經聚醣覆蓋之高度保守抗原決定基,且同時保持棘蛋白之三級結構。因此,本發明提供用於更好地預防及治療新出現之冠狀病毒(例如SARS-CoV-2)感染的經改良之免疫原、疫苗及方法。
因此,本發明提供一種免疫原,其包含經醣化工程改造之冠狀病毒棘蛋白,該經醣化工程改造之冠狀病毒棘蛋白包含複數個截短N-聚醣及未經修飾之O-聚醣(例如O連接之寡醣)。在一些實施例中,複數個截短N-聚醣位於受體結合域(RBD)中,藉此暴露具有以下胺基酸序列之複數個高度保守抗原決定基:TESIVRFPNITNL (SEQ ID NO.: 41)、NITNLCPFGEVFNATR (SEQ ID NO: 42)、LYNSASFSTFK (SEQ ID NO: 43)、LDSKVGGNYN (SEQ ID NO: 44)、KSNLKPFERDIST (SEQ ID NO: 45)、KPFERDISTEIYQAG (SEQ ID NO: 46)及/或GPKKSTNLVKNKC (SEQ ID NO: 47)。在一些實施例中,複數個截短N-聚醣位於七肽重複2 (HR2)域中,藉此暴露具有以下胺基酸序列之複數個高度保守抗原決定基:NCDVVIGIVNNTVY (SEQ ID NO: 48)、PELDSFKEELDKYFKNHTS (SEQ ID NO: 49)、VNIQKEIDRLNEVA (SEQ ID NO: 50)、NLNESLIDLQ (SEQ ID NO: 51)及/或LGKYEQYIKWP (SEQ ID NO: 52)。
在一些實施例中,複數個截短N-聚醣位於受體結合域(RBD)及七肽重複2 (HR2)域中,藉此暴露具有以下胺基酸序列之複數個高度保守抗原決定基:TESIVRFPNITNL (SEQ ID NO.: 41)、NITNLCPFGEVFNATR (SEQ ID NO: 42)、LYNSASFSTFK (SEQ ID NO: 43)、LDSKVGGNYN (SEQ ID NO: 44)、KSNLKPFERDIST (SEQ ID NO: 45)、KPFERDISTEIYQAG (SEQ ID NO: 46)、GPKKSTNLVKNKC (SEQ ID NO: 47)、NCDVVIGIVNNTVY (SEQ ID NO: 48)、PELDSFKEELDKYFKNHTS (SEQ ID NO: 49)、VNIQKEIDRLNEVA (SEQ ID NO: 50)、NLNESLIDLQ (SEQ ID NO: 51)及/或LGKYEQYIKWP (SEQ ID NO: 52)。
本文所述之經醣化工程改造之冠狀病毒棘蛋白包含SEQ ID NO: 1之胺基酸序列或與SEQ ID NO: 1之胺基酸序列具有至少90%序列一致性之其變異體或該胺基酸序列或該變異體之免疫活性片段組成。
在一些實施例中,經醣化工程改造之冠狀病毒棘蛋白包含由SEQ ID NO: 1之胺基酸序列組成的多肽,其中該多肽由22個截短N-聚醣組成,各截短N-聚醣具有GlcNAc部分。
在一些實施例中,經醣化工程改造之冠狀病毒棘蛋白包含由SEQ ID NO: 2之胺基酸序列組成的多肽,其中該多肽由21個截短N-聚醣組成,各截短N-聚醣具有GlcNAc部分。
在一些實施例中,截短N-聚醣為單醣、雙醣或三醣。在一些實施例中,截短N-聚醣為單醣。在較佳實施例中,單醣為N-乙醯葡萄糖胺(GlcNAc)。
在較佳實施例中,本文所述之截短N-聚醣實質上為均質的。術語「均質」意指由一種期望之聚醣物種表示之醣化圖譜。本文所用之術語「實質上均質」意指組合物中存在至少80%、至少85%、至少90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%之醣蛋白由一種預期之醣基型式(例如經GlcNAc修飾)表示,並伴隨存在痕量之非預期之醣基型式。「痕量」意指醣蛋白組合物中存在之任何既定非預期醣基型式以小於總醣蛋白之5%、較佳小於4%、小於3%、小於2%、小於1%及甚至小於0.5%或甚至小於0.1%的量存在。
如本文所述,術語「棘蛋白」及「棘狀醣蛋白」及「冠狀病毒棘蛋白」可互換使用。本文所述之經醣化工程改造之棘蛋白可自天然冠狀病毒棘蛋白藉由醣化工程改造(例如:活體外或活體內之醣化工程改造)而產生。在一些實施例中,經醣化工程改造之棘蛋白係使用一或多種化學或酵素方法產生。在一些實施例中,經醣化工程改造之棘蛋白係使用醣苷內切酶H(Endo H)產生。
在一些實施例中,本文所述之天然冠狀病毒棘蛋白為嚴重急性呼吸道症候群冠狀病毒2 (SAR-CoV-2)或其變異體之棘蛋白。本文所述之SARS-CoV-2為SARS-CoV-2之武漢病毒株(hCoV/Wuhan/WH01/2019)。本文所述之SARS-CoV-2之變異體包括但不限於 D614G、Alpha (B.1.1.7及Q譜系)、Beta (B.1.351及後代譜系)、Gamma (P.1及後代譜系)、Epsilon (B.1.427及B.1.429)、Eta (B.1.525)、Iota (B.1.526)、Kappa (B.1.617.1)、1.617.3、Mu (B.1.621、B.1.621.1)、Zeta (P.2)、Delta (B.1.617.2及AY譜系)及Omicron (B.1.1.529及BA譜系)。在一些實施例中,天然冠狀病毒棘蛋白為蝙蝠冠狀病毒RaTG13或其變異體之棘蛋白。
如本文所述,術語「天然冠狀病毒棘蛋白」、「天然冠狀病毒棘狀醣蛋白」、「天然棘狀醣蛋白」及「天然棘蛋白」係可互換的。
在一些實施例中,本文所述之經醣化工程改造之棘蛋白呈三聚體(例如溶液中之三聚體)形式存在。本文所述之經醣化工程改造之棘蛋白可保留與其天然冠狀病毒棘蛋白相同的三級結構。
如本文所述,經醣化工程改造之棘蛋白能夠引發相對於其天然冠狀病毒棘蛋白增強之免疫反應。增強之免疫反應為增加之IgG力價、增加之IgM力價、增加之CD4 T細胞反應、增加之CD8 T細胞反應、增加之中和力價或其組合。
在另一態樣中,本發明提供一種免疫原性組合物,其包含:(a)本發明之免疫原,及(b)視情況選用的佐劑。
如本文所述,佐劑可包括但不限於氫氧化鋁、磷酸鋁、不完全弗氏佐劑(incomplete Freund's adjuvant,IFA)、角鯊烯、明礬、鋁膠、MF59、QS-21、CpG 1018、AS03、AS37、Matrix-M或其組合。
本文所述之冠狀病毒可包括SARS-CoV-2及其變異體,且可包括蝙蝠冠狀病毒RaTG13或其變異體。在較佳實施例中,冠狀病毒感染由SARS-CoV-2及其變異體引起。
如本文所述,相對於使用其天然SAR-CoV-2棘蛋白之疫苗,免疫原性組合物能夠引發增強之免疫反應,藉此用作針對由SAR-CoV-2或其變異體引起之冠狀病毒感染的經改良之COVID-19疫苗。
在另一態樣中,本發明提供一種用於在有需要之個體中引發針對SARS-CoV-2或變異體之免疫反應的方法,其包含向該個體投與有效量之本發明之免疫原性組合物。
在另一態樣中,本發明提供一種用於保護有需要之個體避免感染SARS-CoV-2或變異體的方法,其包含向該個體投與有效量之本發明之免疫原性組合物。
在另一態樣中,本發明提供一種用於預防有需要之個體感染COVID-19疾病的方法,該方法包含向該個體投與有效量之本發明之免疫原性組合物。
在另一態樣中,本發明提供本發明之免疫原性組合物之用途,其用於在有需要之個體中引發針對SARS-CoV-2之免疫反應。
在另一態樣中,本發明提供本發明之免疫原性組合物之用途,其用於保護有需要之個體避免感染SARS-CoV-2。
在另一態樣中,本發明提供本發明之免疫原性組合物之用途,其用於預防有需要之個體感染COVID-19疾病。
此等及其他態樣由以下較佳實施例之描述結合以下附圖而將變得顯而易見,但其中可進行變化及修改而不背離本發明之新穎構思的精神及範疇。
在本發明之實施例的以下詳細描述中,參考附圖,在附圖中相同的元件符號指示相似的元件,且藉助於圖示,展示可實踐本發明之特定實施例。詳細描述此等實施例到足以使熟習此項技術者能夠實踐本發明,且應理解,可利用其他實施例,且可在不脫離本發明之範疇的情況下作出其他改變。因此,不應在限制性意義上看待以下詳細描述。
除非以下另外定義,否則本文中所用之所有技術及科學術語均意欲具有與一般技術者通常所理解相同之含義。對本文中所採用之技術之提及意欲指代如在此項技術中通常理解之技術,包括熟習此項技術者將顯而易見的對彼等技術之變化或等效技術或後來開發之技術的取代。另外,為更清晰且簡明地描述本發明之主題,提供本說明書及所附申請專利範圍中所使用之某些術語的以下定義。
除非上下文另外明確規定,否則如本文中及所附申請專利範圍中所使用,單數形式「一(a)」、「一(an)」及「該」包括複數個提及物。因此,舉例而言,提及「蛋白質」可指一種蛋白質或此類蛋白質之混合物,且提及「該方法」包括提及熟習此項技術者已知之同等步驟及/或方法等等。
如本文所用,術語「突變」係指病毒基因體(遺傳密碼)之單個變化。突變頻繁發生,但僅有時會改變病毒特徵。
如本文所用,術語「譜系」係指一組具有共同祖先之緊密相關病毒。SARS-CoV-2具有許多譜系;均引起COVID-19。
如本文所用,術語「變異體」係指可含有一或多個突變之病毒基因體(遺傳密碼)。在一些情況下,具有相似遺傳變化之一組變異體,諸如譜系或一組譜系,可因可能需要公共衛生行動的共享屬性及特徵而被公共衛生組織稱為高關注變異株(VOC)或需留意變異株(VOI)。
如本文所用,術語「佐劑」係指當與免疫原組合使用時加強或以其他方式改變或調節針對免疫原誘導之免疫反應的化合物。免疫反應之調節可包括加強或拓寬任一種或兩種抗體之特異性及細胞免疫反應。
如本文所用,術語「約」或「大約」在位於數值之前時指示該值加或減10%之範圍。舉例而言,「約100」涵蓋90及110。
如本文所用,「免疫原性組合物」為一種包含抗原之組合物,其中向個體投與該組合物引起個體中對該抗原發展體液及/或細胞免疫反應。
如本文所述,術語「棘蛋白」及「棘狀醣蛋白」及「冠狀病毒棘蛋白」可互換使用。
本文所用之術語「實質上均質」意欲意謂組合物中存在之至少80%、至少85%、至少90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%之醣蛋白由一種期望醣型(例如經單GlcNAc裝飾)表示,組合物中存在痕量非期望醣型。「痕量」意欲醣蛋白組合物中存在之任何既定非期望醣型以小於總醣蛋白之5%、較佳小於4%、小於3%、小於2%、小於1%及甚至小於0.5%或甚至小於0.1%存在。
如本文所用,術語「治療(treat)」、「治療(treatment)」及「治療(reating)」係指一種獲得有益或期望結果,例如臨床結果之方法。出於本發明之目的,有益或期望結果可包括抑制或遏制感染或疾病之起始或進展;改善感染或疾病之症狀或減少其發展;或該等結果之組合。
如本文所用,術語「預防(preventing)」及「預防(prevention)」可與「預防(prophylaxis)」互換使用,且可意謂完全預防感染,或預防感染症狀之發展;延遲感染或其症狀之發作;或降低隨後發展之感染或其症狀的嚴重程度。
如本文所用,「有效量」係指免疫原足以誘導免疫反應,減少病原體感染之至少一種症狀的量。有效劑量或有效量可藉由例如用斑塊中和、補體結合、酶聯結免疫吸附劑(ELISA)或微量中和分析法量測中和分泌抗體及/或血清抗體之量來確定。
如本文所用,術語「疫苗」係指一種免疫原性組合物(有或無佐劑),諸如來源於冠狀病毒之免疫原,其用於誘導針對冠狀病毒之免疫反應,提供保護性免疫(例如保護個體避免感染冠狀病毒及/或降低由感染冠狀病毒所引起之病狀之嚴重程度的免疫性)。保護性免疫反應可包括形成抗體及/或細胞介導之反應。視上下文而定,術語「疫苗」亦可指向個體投與以產生保護性免疫的免疫原之懸浮液或溶液。
如本文所用,術語「個體」包括人類及其他動物。通常,個體為人類。舉例而言,個體可為成人、少年、兒童(2歲至14歲)、嬰兒(出生至2歲)或新生兒(至多2個月)。在特定態樣中,個體至多4月齡或至多6月齡。在一些態樣中,成人為約65歲以上或約60歲以上之老年人。在一些態樣中,個體為孕婦或欲懷孕之女性。在其他態樣中,個體不為人類;例如非人類靈長類動物;例如狒狒、黑猩猩、大猩猩或獼猴。在某些態樣中,個體可為寵物,諸如狗或貓。
如本文所用,術語「醫藥學上可接受」意謂經美國聯邦政府或州政府之監管機構批准或在美國藥典、歐洲藥典或其他公認之藥典中列出用於動物,且更具體用於人類。此等組合物可用作用於在脊椎動物中誘導保護性免疫反應之疫苗及/或抗原組合物。
嚴重急性呼吸道症候群冠狀病毒2 (SARS-CoV-2)係一種引起冠狀病毒疾病2019 (COVID-19)之正單鏈RNA包膜病毒。病毒粒子包括侵入宿主細胞所需之RNA遺傳物質及結構蛋白。一旦在細胞內部,感染RNA用於編碼構成病毒粒子之結構蛋白、引導病毒組裝、轉錄、複製及宿主控制之非結構蛋白及功能尚未確定之輔助蛋白。SARS-CoV-2之結構蛋白包括包膜蛋白(E)、棘蛋白或表面醣蛋白(S)、膜蛋白(M)及核衣殼蛋白(N)。在病毒粒子之外部發現棘狀醣蛋白且其使冠狀病毒呈王冠樣外觀。此醣蛋白介導病毒粒子之附接及進入宿主細胞。
藉由肺上皮細胞產生之S蛋白具有與感染性增加相關聯之醣型。與完全醣基化之S蛋白相比,用N-聚醣修整為單GlcNAc裝飾狀態之S蛋白(S
MG)進行免疫接種引發針對高關注變異株(VOC)之更強免疫反應且更好地保護人類血管收縮素轉化酶2 (hACE2)轉殖基因小鼠。另外,自經S
MG免疫接種之小鼠鑑別廣泛中和單株抗體,其可以低於皮莫耳之效力中和野生型SARS-CoV-2及高關注變異株(VOC)。
本發明之經醣化工程改造之棘蛋白包含具有SEQ ID NO: 1之胺基酸序列或與SEQ ID NO: 1之胺基酸序列具有至少90%序列一致性之其變異體或該胺基酸序列或該變異體之免疫活性片段的多肽。下文展示SEQ ID NO: 1之胺基酸序列。
SEQ ID NO: 1QCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHV SGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVV IKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQG NFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTL LALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSE TKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNR KRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAP GQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDIS TEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCG PKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLE ILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGS NVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTM SLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLL QYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSK PSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDE MIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIAN QFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILS RLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKR VDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFV SNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELD KYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQY |
如本文所述,SARS-CoV-2或其變異體之經醣化工程改造之棘蛋白可包括包含如下胺基酸序列之棘蛋白:(i)與SEQ ID NO: 1中所示之胺基酸序列實質上一致(例如與SEQ ID NO: 1至少90%、95%或97%一致,諸如SEQ ID NO: 2);及(ii)由能夠在至少中度嚴格條件下與編碼本文所闡述之棘蛋白之任何核酸序列雜交或能夠在至少中度嚴格條件下與編碼本文所闡述之棘蛋白之任何核酸序列雜交但使用同義密碼子(例如不具有一致核苷酸序列但編碼一致胺基酸之密碼子)的核酸序列編碼。
對細胞特異性醣型分佈之分析、序列保守、聚醣遮蔽及其相互相關性引起設計上移除實質上所有遮蔽之聚醣的S
MG疫苗。SARS-CoV-2 S蛋白醣基化對病毒感染、蛋白質完整性及免疫反應具有重大影響。來自肺上皮細胞之S蛋白含有更多唾液酸化複合型聚醣以促進受體結合,且醣位點N801及N1194顯示係S蛋白摺疊及病毒感染所不可或缺的。此使得保守抗原決定基更好地暴露於免疫系統,因此可針對病毒及變異體引發更有效且具有廣泛保護性之B細胞及T細胞反應。
本發明之經醣化工程改造之冠狀病毒棘蛋白靶向整個S蛋白胞外域,尤其由聚醣遮蔽之保守域,刺激RBD與非RBD中和抗體及對於交叉保護而言至關重要之CD8 T細胞反應的誘發。
在某些態樣中,本發明提供一種包含如本文所述之免疫原的疫苗或醫藥組合物。本發明亦提供一種用於治療或預防冠狀病毒感染之方法,其中該方法包含向有需要之個體(例如哺乳動物)投與有效量之如本文所述之免疫原、醫藥組合物或疫苗。
在一個實施例中,疫苗可包括佐劑。示例性佐劑包括但不限於氫氧化鋁、磷酸鋁、不完全弗氏佐劑(IFA)、角鯊烯、明礬、鋁膠、MF59、QS-21、CpG 1018、AS03、AS37、Matrix-M或其組合。
疫苗或醫藥組合物可使用任何適合之方法調配。可使用醫藥領域中之常規方法,用標準醫藥學上可接受之載劑及/或賦形劑進行調配。調配物之確切性質將視若干因素而定,包括待投與之疫苗及所需投與途徑。適合類型之調配物充分描述於Remington's Pharmaceutical Sciences, 第19版, Mack Publishing Company, Eastern Pennsylvania, USA中。
如本文所述之疫苗或醫藥組合物可藉由任何途徑投與。此類方法包含例如非經腸,諸如經由注射至皮膚中或穿過皮膚之所有途徑施用:例如肌肉內、靜脈內、腹膜內、皮內、經黏膜、黏膜下層或皮下。此外,其可藉由以液滴、噴霧、凝膠或軟膏形式局部施用至眼部、鼻、口、肛門或陰道之黏膜上皮,或局部施用至身體之任一部分處之外表皮上進行施用。其他可能之施用途徑係經由呼吸道吸入來施用噴霧、氣溶膠或散劑。或者,可經由消化道途徑施用。疫苗組合物之有效量可視許多變數而定,包括(但不限於)物種、品種、體型、身高、體重、年齡、患者之整體健康狀況、調配物之類型或投藥模式或方式。適當有效量通常可由熟習此項技術者使用常規最佳化技術及行醫者之知情判斷及熟習此項技術者顯而易見之其他因素確定。
在一個實施例中,組合物可包含額外治療劑,諸如抗病毒劑。所提供之醫藥組合物適用於治療冠狀病毒感染。額外抗病毒劑之實例包括但不限於利巴韋林(ribavirin)、噴昔洛韋(penciclovir)、硝唑尼特(nitazoxanide)、萘莫司他(nafamostat)、氯奎寧(chloroquine)、瑞德西韋(remdesivir,GS-5734)及法匹拉韋(favipiravir,T-705)、干擾素(interferon)、阿德福韋(adefovir)、替諾福韋(tenofovir)、阿克洛韋(acyclovir)、布立夫定(brivudin)、西多福韋(cidofovir)、福米韋生(fomivirsen)、膦甲酸(foscarnet)、更昔洛韋(ganciclovir)、金剛胺(amantadine)、金剛烷乙胺(rimantadine)、紮那米韋(zanamivir)、瑞德西韋(remdesivir)、莫努拉韋(molnupiravir)及帕克洛維德(paxlovid)。
除非另外定義,否則本文所用之所有技術及科學術語均具有與一般技術者通常理解相同之含義。儘管與本文所述之彼等方法及材料類似或同等之方法及材料可用於實踐或測試本發明,但下文描述適合方法及材料。本文中提及之所有公開案、專利申請案、專利及其他參考文獻均以全文引用的方式併入本文中。在有矛盾的情況下,將以本說明書(包括定義)為準。另外,材料、方法及實例僅為說明性的且並不意欲為限制性的。
實例 實例 1 :基因構築體
基於自GISAID資料庫下載之基因序列設計SARS-CoV-2棘蛋白序列。自全球全球共享流感數據倡議組織(Global Initiative on Sharing Avian Influenza Data,GISAID)資料庫(版本:2021年4月18日)擷取所有可用SARS-CoV-2病毒株之總共1,117,474個S蛋白序列。
來自SARS-CoV-2 Wuhan/WH01/2019及Delta變異體之棘蛋白的DNA序列用針對人類細胞表現最佳化之密碼子合成。弗林蛋白酶裂解位點(furine cleavage site)替換為GSAG(SEQ ID NO: 9)且為蛋白質設計2P替代物以停留在融合前狀態。在棘蛋白C端,跨膜域替換為凝血酶裂解位點(thrombin cleavage site)、摺疊子(foldon)及組胺酸標籤(histidine-tag)。將經修飾之HA序列選殖至pTT載體中以表現蛋白質及純化。
實例 2 : SARS-CoV-2 S 蛋白表現及純化
藉由使用轉染試劑(聚伸乙基亞胺或FectoPRO),將編碼分泌之SARS-CoV-2棘蛋白之質體轉染至HEK293EBNA (ATCC編號CRL-10852)或HEK293S GnTI¯細胞之人類胚胎腎細胞株中,且在補充有0.5%胎牛血清之Freestyle 293表現培養基(Invitrogen)中培養。在轉染之後5天收集上清液且藉由離心清除。接著,棘蛋白用鎳螯合層析法純化且藉由Millipore Amicon超濾器(100 kDa)濃縮溶離部分,且裝載至在基於tris之緩衝液(20 mM tris/HCl、20 mM NaCl、50 mM麩胺酸、50 mM精胺酸)中預平衡的superpose
TM6凝膠過濾管柱(10/300 GL;GE)上,且收集對應三聚體部分。在室溫下將經純化之S
HM用Endo H (NEB)處理隔夜以產生在醣基化位點具有單個GlcNAc之棘蛋白S
MG。對於EndoH移除,藉由緩衝液交換,使用Millipore Amicon超濾器(100 kDa)進一步純化S
MG。自PNAS中公開之實驗室先前研究修改表現及純化方法。
經聚醣工程改造之假病毒(圖1D)之產生遵循先前研究(Y. Watanabe, J. D. Allen, D. Wrapp, J. S. McLellan, M. Crispin, Site-specific glycan analysis of the SARS-CoV-2 spike. Science
369, 330-333 (2020);Q. Yang, T. A. Hughes, A. Kelkar, X. Yu, K. Cheng, S. Park, W.-C. Huang, J. F. Lovell, S. Neelamegham, Inhibition of SARS-CoV-2 viral entry upon blocking N- and O-glycan elaboration. eLife
9, e61552 (2020))。為產生醣位點特異性S突變假病毒(圖1F),將HEK293T細胞用在各醣位點攜帶突變之pVax-nCoV-SΔ19構築體及表現螢光素酶之HIV-1基因體質體(pNL4-3.luc.RE)短暫轉染。
實例 3 : S
MG 蛋白表徵
為表徵S
MG蛋白,使用在基於tris之緩衝液(20mM tris/HCl、20mM NaCl、50mM麩胺酸、50mM精胺酸)中預平衡的ENrich
TMSEC 650 (10×300管柱;Biorad)進行粒徑篩析層析法。接著,為檢驗蛋白質樣品之純度,將樣品與裝載緩衝液組合,藉由7.5% SDS-PAGE分離且藉由考馬斯亮藍-Plus (EBL)染色。
實例 4 :藉由質譜分析進行糖肽分析
使來自兩個生物學重複實驗之兩個20 μg SARS-CoV-2棘蛋白等分試樣在含有10 mM參(2-羧基乙基)膦之50 mM三乙銨碳酸氫鹽緩衝液中在55℃下變性1小時。隨後,還原棘蛋白,且藉由添加18 mM碘乙醯胺(IAA)烷基化,且在黑暗中培育30分鐘。使用比率為1:10 (w/w)之胰凝乳蛋白酶或α溶解蛋白酶或比率為1:20 (w/w)之胰蛋白酶的不同組合,分開消化烷基化Env蛋白。(質譜法級別,Promega)在消化隔夜之後,樣品在SpeedVac濃縮器中乾燥且經加工用於測定LC-MS/MS。根據由Graphpad Prism 9.0.0偵測及目測之組成,遵循先前研究進行聚醣分類。
實例 5 :疫苗接種及攻擊實驗
在第0天及第14天,將雌性6至7週齡金色敍利亞倉鼠(n= 5)在肌肉內用與250 μg氫氧化鋁混合的25 μg經純化之S
FG或S
MG蛋白進行免疫接種。在第一次免疫接種之後28天及42天收集血液,且自各倉鼠收集血清樣品。在第二次免疫接種之後4週,用1×10
4PFU SARS-CoV-2 TCDC#4 (hCoV-19/Taiwan/4/2020,GISAID寄存ID:EPI_ISL_411927)以每隻倉鼠100 µL之體積鼻內攻擊倉鼠。在感染之後每日記錄各倉鼠之體重。在攻擊後第3天,藉由二氧化碳對倉鼠施以安樂死。收集右肺以用於病毒負荷測定(TCID50分析)。將左肺固定於4%三聚甲醛中以用於組織病理學檢驗。所有動物實驗均經中央研究院(Academia Sinica)之實驗動物照護及使用委員會(Institutional Animal Care and Use Committee)評估及批准。
或者,對於利用兩劑時程之小鼠疫苗接種,在第0天及第14天,將雌性6至8週齡BALB/c小鼠(
n= 5)在肌肉內用與氫氧化鋁(50 μg)混合的10 μg經純化之S
FG、S
HM或S
MG進行免疫接種。在第一次疫苗接種之後第28天收集血清,用於評估抗S IgG豐度、IgG亞型及中和力價(補充材料及方法中描述)。在第一次疫苗接種之後第21天收集經S
FG或S
MG免疫接種之小鼠之淋巴結,用於T細胞反應分析(補充材料及方法中描述)。對於B細胞庫分析及針對變異體之血清力價,在第0、14及56天,將雌性6至8週齡BALB/c小鼠(
n= 5)在肌肉內經與氫氧化鋁(20 μg)混合的20 μg經純化之S
FG或S
MG進行免疫接種;在第84天對小鼠施以安樂死以收集全血,用於抗S IgG及中和力價評估,且收集脾,用於分選S蛋白特異性B細胞(補充材料及方法中描述)。
對於倉鼠疫苗接種及病毒攻擊研究,在第0天及第14天將雄性6至7週齡金色敍利亞倉鼠(
n= 5)在肌肉內用與氫氧化鋁(250 μg)混合的25 μg經純化之S
FG或S
MG進行免疫接種。在第二次免疫接種之後四週,用100 μl PBS中1 × 10
4TCID
50SARS-CoV-2 (hCoV-19/Taiwan/4/2020)鼻內攻擊各倉鼠。在感染之後每日記錄體重。在攻擊後第3天,藉由二氧化碳對倉鼠施以安樂死。將左肺上葉固定於10%三聚甲醛中以用於組織病理學檢查,且收集其餘肺以用於病毒負荷測定(TCID
50分析)。
對於轉殖基因小鼠疫苗接種及病毒攻擊研究,在第0及14天將雄性6至8週齡CAG-hACE2轉殖基因小鼠或雄性12週齡K18-hACE2轉殖基因小鼠(購自the Jackson Laboratory)在肌肉內用與氫氧化鋁(50 μg)混合的10 μg經純化之S
FG或S
MG進行免疫接種。在第二次免疫接種之後4週,用1 × 10
3TCID
50WT SARS-CoV-2鼻內攻擊CAG-hACE2轉殖基因小鼠。在第一次試驗(
n= 3)中,在7 dpi對所有小鼠施以安樂死以對左肺上葉進行組織病理學檢查;在第二個試驗(
n= 7)中,在4 dpi對三隻小鼠施以安樂死以獲得肺病毒力價,且保持四隻小鼠直至14 dpi,以進行存活分析。在病毒攻擊之前1天收集血清。
對於使用高關注變異株(VOC)之攻擊研究,用每隻小鼠50 µl PBS中1 × 10
3TCID
50Alpha變異體(hCoV-19/Taiwan/792/2020) (
n= 5)或Gamma變異體(hCoV-19/Taiwan/906/2021) SARS-CoV-2攻擊CAG-hACE2小鼠。另外,在第二次免疫接種之後4週,用每隻小鼠50 µl PBS中1 × 10
4TCID
50Delta SARS-CoV-2 (hCoV-19/Taiwan/1144/2021) (
n= 4)鼻內攻擊K18-hACE2小鼠。對於所有SARS-CoV-2變異體攻擊模型,每日記錄各小鼠之體重直至14 dpi。
對於抗體之預防性保護測試,向雄性8週齡K18-hACE2轉殖基因小鼠(
n= 3)腹膜內注射m31A7 (15 mg/kg)或PBS,1天後用1 × 10
3TCID
50WT SARS-CoV-2 (hCoV-19/Taiwan/4/2020)鼻內攻擊。每日記錄體重及體溫直至5 dpi。所有動物實驗均經中央研究院之實驗動物照護及使用委員會評估及批准(批准編號21-10-1716、18-12-1272及20-10-1522)。
實例 6 :組織學及免疫組織化學 (IHC) 染色
在3 dpi立即收集倉鼠肺且置放於10%中性緩衝福馬林中,固定24小時,隨後轉移至70%乙醇中,保持72小時。將石蠟包埋之肺組織修整至5 mm之厚度。對於組織學染色,將組織用蘇木精及伊紅(H&E)染色。對於免疫組織化學(IHC)染色,用二甲苯將切片之組織去石蠟且用乙醇梯度再水合。藉由在微波烘箱中在10 mM檸檬酸鈉緩衝液(pH 6.0)中將載片加熱至95℃持續10分鐘進行抗原修復。在室溫下冷卻且用PBS洗滌後,施加3% H
2O
2以消除內源過氧化酶活性。將切片之組織用含5%正常山羊血清及1% BSA之1X PBST阻斷1小時,隨後與1:50稀釋之兔抗N及抗S初級抗體(抗SARS-CoV-2多株抗體)在4℃下一起培育隔夜。隨後將組織與1:500稀釋之山羊抗兔HRP二級抗體一起培育1小時且藉由與3,3-二胺基聯苯胺(DAB)受質一起培育且用蘇木精對比染色進行目測。
實例 7 :免疫螢光 (IF) 染色
對於免疫螢光染色,在抗原修復步驟之後,用含Triton X-100之PBS滲透組織。將切片之組織用含5%正常山羊血清及1% BSA之1X PBST阻斷1小時。接著,與自體螢光猝滅劑一起培育5分鐘。隨後將樣品與1:50稀釋之兔抗N及抗S初級抗體(抗SARS-CoV-2多株抗體)在4℃下一起培育隔夜,與二級抗體Alexa Fluor-488 (1:500,Thermo Fisher)在室溫下一起培育1小時,且與核染料4,6-二甲脒基-2-苯基吲哚(DAPI)在室溫下一起培育3分鐘。將蓋玻片安裝在顯微鏡載片上且在具有HC PL APO CS2 10x/1.40鏡片之Leica TCS SP8X共焦顯微鏡(Leica AG, Wetzlar, Germany)下成像。
實例 8 :轉殖基因小鼠疫苗接種及攻擊實驗
在第0天及第14天,將雄性8週齡CAG-hACE2轉殖基因小鼠(n= 3)在肌肉內經與50 μg氫氧化鋁混合的10 μg經純化之S
FG或S
MG蛋白進行免疫接種。
14在第一次免疫接種之後28天及42天收集血液,且自各轉殖基因小鼠收集血清樣品。在第二次免疫接種之後6週,用1×10
3PFU SARS-CoV-2 TCDC#4 (hCoV-19/Taiwan/4/2020,GISAID寄存ID: EPI_ISL_411927)以每隻小鼠100 µL之體積鼻內攻擊倉鼠。感染後每日記錄各轉殖基因小鼠之體重及存活率。在攻擊之後第7天,藉由二氧化碳對所有轉殖基因小鼠施以安樂死。將肺固定於4%三聚甲醛中以用於組織病理學檢驗。所有動物實驗均經中央研究院之實驗動物照護及使用委員會評估及批准。
實例 9 :藉由細胞培養感染分析對肺組織中之病毒力價進行定量 (TCID50)
使用均質器,使倉鼠之中腔、下腔及後腔肺葉於600 µl具有2% FBS及1%青黴素/鏈黴素之DMEM中均質化。以15,000 rpm將組織均質物離心5分鐘且收集上清液以用於活病毒滴定。簡言之,將各樣品之10倍連續稀釋液添加於Vero E6細胞單層上,一式四份,且培育4天。細胞隨後用10%甲醛固定且用0.5%結晶紫染色20分鐘。用自來水洗滌培養盤且對感染進行評分。藉由李-明法(Reed and Muench method)計算50%組織培養物感染劑量(TCID50)/mL。
實例 10 :小鼠疫苗接種研究
在第0天、第14天及第56天,將雌性6至8週齡BALB/c小鼠(n= 5)在肌肉內經與20 μg氫氧化鋁混合的20 μg經純化之S
FG或S
MG蛋白免疫接種。在第三次免疫接種之後14天收集血液,且自各小鼠收集血清樣品。所有動物實驗均經中央研究院之實驗動物照護及使用委員會評估及批准。
實例 11 :血清抗體力價評估
抗S ELISA用於測定血清IgG力價。將培養盤用5%脫脂乳阻斷,且依次添加小鼠多株抗S初級抗體及HRP結合之二級抗體。使用過氧化酶受質溶液(TMB)及1M H
2SO
4終止溶液且藉由微定量盤式讀數器讀取吸光度(OD 450 nm)。測試病毒株包括SARS-CoV-2 (野生型、變異體B.1.1.7及B.1.135)、RnGT13及SARS-CoV-1。
藉由單一B細胞篩選分析分離m31A7抗體且隨後使特徵化。基於先前出版物設計引子(T. Tiller, C. E. Busse, H. Wardemann, Cloning and expression of murine Ig genes from single B cells. J. Immunol. Methods
350, 183-193 (2009))。聚合酶鏈式反應(PCR)在50℃下進行30分鐘,在95℃下進行15分鐘,接著進行94℃下培育30秒、50℃下培育30秒及72℃下培育1分鐘之循環40個,最終延伸在72℃下進行10分鐘。使用KOD One PCR主混合物(TOYOBO)利用1 μl未純化之第一輪PCR產物進行半巢式第二輪PCR,在98℃下2分鐘,接著進行98℃下培育10秒、55℃下培育10秒及68℃下培育10秒之循環45個,最終延伸在68℃下進行1分鐘。隨後藉由電泳及定序分析PCR產物。在國際ImMunoGeneTics資訊系統(http://imgt.org/IMGT_vquest/input)上鑑別Ig V及L基因。接著利用單一基因特異性V及L基因引子,自第二輪PCR產物擴增基因,該等引子含有用於選殖至含有人類IgH或IgL表現主鏈之載體中之限制位點。將嵌合IgH及IgL表現構築體共轉染至Expi293中以產生抗體。在分離m31A7之後,隨後藉由ELISA及螢光活化細胞分選對抗體評估S蛋白結合、假病毒中和效力、結合動力學、抗原決定基定位及結構測定。
實例 12 :假病毒中和分析
為確定假型慢病毒載體之感染單位,在感染前1天,吾人在96孔(每孔100 µL)組織培養盤中以適當密度接種293T-ACE2細胞。在培育隔夜(37℃、5% CO
2)之後,將100 mL三個預混合之假病毒上清液及免疫接種小鼠血清之四倍連續稀釋液添加在塗鋪之細胞中。將細胞在37℃/5% CO
2下培育48小時以允許表現Nano-Luciferase報導基因。藉由ELISA讀數器量測螢光素酶活性。藉由以下等式100×[1-(RLU
樣品/ RLU
模擬處理)]計算抑制百分比。使用Graphpad Prism分析數據且藉由獲取所有樣品之50%抑制濃度值計算pNT
50值。
實例 13 :蝕斑減少分析
在感染前1天,將Vero E6細胞於具有10% FBS及抗生素之DMEM中接種至24孔培養盤中。將SARS-CoV-2與抗體在37℃下一起培育1小時,隨後再添加至細胞單層中,保持一小時。隨後,移除病毒-抗體混合物,且用PBS洗滌細胞單層一次,隨後用含有1%甲基纖維素之培養基覆蓋5-7天。將細胞用10%甲醛固定隔夜。在移除上覆培養基之後,將細胞用0.7%結晶紫染色且計數蝕斑。抑制百分比計算為[1 − (VD/VC)] × 100%,其中VD及VC分別係指在血清存在及不存在下之病毒力價。
對於基於CPE之中和分析,將Vero E6細胞以2×10
5個細胞/孔塗鋪至6孔盤上隔夜,90%細胞覆蓋率。將血清及病毒混合,隨後再添加至細胞單層上,保持一小時。使培養盤在室溫下固化30分鐘,接著在37℃下培育,直至觀測到細胞病變作用(CPE)。
統計分析:所有數據均表示為平均值± 平均值之標準誤差。對於所有分析,除使用t試驗(Student's t-test)(配對,雙尾)進行曲線比較以外,自t試驗(Student's t-test)(未配對,雙尾)獲得
P值。所有圖皆用GraphPad Prism版本9.0.0軟體產生。
實例 14 : 經醣化工程改造之經單 GlcNAc 修飾之棘蛋白 (S
MG ) 疫苗的設計及特徵
具有來自原始SARS-CoV-2武漢病毒株(hCoV/Wuhan/WH01/2019)之序列(胺基酸14-1209)的重組天然蛋白經密碼子最佳化以用於人類細胞表現,其中GSAG(SEQ ID NO: 9)殘基替換原始弗林蛋白酶裂解位點且進行2個脯胺酸突變以將棘蛋白之天然蛋白固定在其融合前狀態,且在其C端處添加摺疊子三聚序列及His標籤,且用人類HEK293S細胞表現(圖1)。首先獲得中間物高甘露醣型棘蛋白重組天然蛋白(S
HM)且純化,其中由分支符號(圖1a)指示之所有N-聚醣均係Man5 N-聚醣。隨後使用內切醣基化酶EndoH移除過量聚醣且產生終產物單醣基化棘蛋白天然蛋白(圖1b)。經純化之S
MG為在溶液中表觀分子量為約520 kDa且具有高純度之三聚體(圖1c及圖1d)。與普通S
FG及中間物S
HM相比,藉由SDS-PAGE分析由N-聚醣之移除所致之尺寸減小(圖1d)。關於S
MG之質譜分析指示,大部分N-醣基化位點具有靠近100%單糖,亦即N-乙醯基葡糖胺(GlcNAc),N603及N1194除外,GlcNAc>90% (圖1f)。相比之下,原始完全醣基化棘蛋白天然蛋白在所有其N-醣基化位點上具有非均質N-聚醣,含有複合型、雜交型及其他類型。
實例 15 : S
MG 疫苗在活體內提供對 SARS-CoV-2 及變異體之優良防護
為評估S
MG疫苗針對SARS-CoV-2之活體內防護功效,首先在經S
MG或S
FG疫苗接種之敍利亞倉鼠中進行WT SARS-CoV-2攻擊(圖2A)。與S
FG及磷酸鹽緩衝鹽水(PBS)組相比,經S
MG疫苗接種之倉鼠(
n= 5)展示體重減少較少(圖2B),而在經S
FG及S
MG疫苗接種之倉鼠之肺中觀測到相似病毒力價減少(圖2C)。另外,根據組織病理學染色及抗核衣殼(N)蛋白質免疫染色數據,在經免疫接種之倉鼠之肺中觀測到較少病變(圖2D)。因為倉鼠在SARS-CoV-2感染之後僅展示輕度至中度噁心,接著使用嚴重疾病模型,高感CAG-hACE2 (
C.-Y. Tsai, C.-Y. Chen, J.-T. Jan, Y.-C. Chou, M.-L. Chang, L. A. Lu, P.-Y. Huang, M. F. C. Chu, T.-T. Hsu, Y.-P. Hsueh, Sex-biased response to and brain cell infection by SARS-CoV-2 in a highly susceptible human ACE2 transgenic model.bioRxiv, 2021)或K18-hACE2 (
E. S. Winkler, A. L. Bailey, N. M. Kafai, S. Nair, B. T. McCune, J. Yu, J. M. Fox, R. E. Chen, J. T. Earnest, S. P. Keeler, J. H. Ritter, L.-I. Kang, S. Dort, A. Robichaud, R. Head, M. J. Holtzman, M. S. Diamond, SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat. Immunol.
21, 1327-1335 (2020
)轉殖基因小鼠(圖2E)。對CAG-hACE2小鼠中抗S IgG結合力價、中和力價、抗S亞型IgG及IgG2c:IgG1比率(圖2,F至I)之分析均展示與BALB/c小鼠相似的結果(圖6,C至G)。在用WT SARS-CoV-2鼻內攻擊之後,在感染後第7天(dpi)藉由抗N染色(圖2J)或在4 dpi藉由中值組織培養物感染劑量(TCID
50)分析(圖2K)在經S
FG及S
MG疫苗接種之CAG-hACE2小鼠(
n= 3)之肺中無法偵測到病毒,而在對照組中觀測到超過1,000 TCID
50之病毒力價(圖2K)。在14 dpi,S
MG組(
n= 4)展現比S
FG(50%)更佳之存活率(75%) (圖2,L及M)。接著評估CAG-hACE2小鼠(
n= 5)中由S
MG疫苗接種賦予的對Alpha變異體攻擊之防護程度。發現S
MG疫苗接種提供100%存活率,直至14 dpi (圖2,N及O)。經S
MG疫苗接種之小鼠亦展示在CAG-hACE2小鼠(
n= 5)中Gamma變異體攻擊中60%存活率(圖22 P及Q)及在K18-hACE2小鼠(
n= 4)中Delta變異體攻擊中75%存活率(圖4,R及S),而在Gamma及Delta變異體攻擊中,少於50%經S
FG疫苗接種之小鼠存活,直至14 dpi (圖2,Q至S)。由S
MG疫苗接種賦予之經改良之活體內防護進一步證明自免疫原移除聚醣遮蔽係引發優良免疫反應之有利策略。
實例 16 : S
MG 疫苗接種在轉殖基因 hACE2 小鼠中提供更好的對致死劑量 SARS-CoV-2 感染之預防
CAG-hACE2轉殖基因小鼠在感染SARS-CoV-2病毒時可能發展嚴重疾病且死亡。在第0及14天在肌肉內給與兩劑S
FG、S
MG疫苗或僅佐劑,在第28及42天收集血清,使用1×10
3TCID50 SARS-CoV-2經鼻內感染各小鼠(圖3a)。經S
MG免疫接種之小鼠的棘蛋白特異性抗體IgG力價比S
FG組高1.9倍(40,000對比20.000),且S
MG之中和力價比S
FG組高2.8倍(圖3b及圖3c)。意外地,在此嚴重疾病模型中,如觀測到體重迅速下降且所有小鼠在病毒感染之後第7天前全部死亡,S
FG疫苗接種未能保護CAG-hACE2轉殖基因小鼠免於嚴重疾病。經S
FG疫苗接種之組之疾病進展僅比僅佐劑組略好(圖3d及圖3e)。相比之下,經S
MG疫苗接種之組展現重量略微減輕,且所有小鼠均經受住SARS-CoV-2感染。此結果證明SARS-CoV-2嚴重疾病轉殖基因小鼠模型中S
MG疫苗接種之優越性。
實例 17 :小鼠中由 S
MG 疫苗誘發之抗體增強針對 SARS-CoV-2 變異體之結合及中和的廣度及效力
接著關於中和新出現之需要關注之SARS-CoV-2變異體的能力,分析由具有來自武漢病毒株之棘蛋白天然序列的S
FG或S
MG之任一疫苗接種引發的抗體反應是否存在差異(圖4)。與S
FG相比,S
MG免疫接種引發更佳的棘蛋白特異性抗體IgG與來自WT之棘蛋白天然蛋白(武漢病毒株)的結合,且亦引發與變異體D614G、B.1.1.7、B.1.351、蝙蝠CoV RnGT13及SARS-CoV-1之結合(圖4b)。使用SARS-CoV-2變異體之假型病毒(pseudotyped viruse)測量中和經疫苗免疫接種之血清中之感染的能力。此外,來自S
MG免疫接種之血清對D614G、B.1.1.7及B.1.351假病毒具有優良的中和能力,且其分別比S
FG誘發之血清優良1.4、2.7及1.5倍(圖4c及圖4d)。最終,在蝕斑中和分析中使用SARS-CoV-2實際病毒D614G及B.1.1.7 (圖4e及圖4f)。與S
FG疫苗接種相比,S
MG疫苗接種對D614G及B.1.1.7變異體引發更佳的中和抗體反應,且其分別優良2.0及1.4倍。
實例 18 :醣基化影響假病毒 S 蛋白與若干細胞類型上之 ACE2 的相互作用
為瞭解醣基化之重要性,自肺上皮細胞(用於感染之初級細胞)表現S蛋白,且發現對受體之較高親合力需要S蛋白之唾液酸化(圖5A)。對HEK293T細胞產生之S蛋白亦觀測到相似模式(圖5B),且對僅具有高甘露糖聚醣或呈所有N-聚醣修整為單一N-乙醯基葡糖胺(GlcNAc)之醣型之S蛋白的親合力亦減少(圖5C)。藉由表現人類血管收縮素轉化酶2 (hACE2)之HEK293T細胞中的假病毒感染進一步測試其醣基化之影響,揭露當施加相同量之病毒時一致之傾向(圖5D)。此使吾人得出結論,複合型聚醣及唾液酸化在功能上對於S蛋白介導之感染性為重要的。亦產生一組完整24種基於慢病毒之假病毒變異體(包含22個N-醣位點及2個
O-醣位點),用於評估五種表現hACE2之細胞株(包括HEK293T、Vero-E6及三種人類肺細胞株A549、Calu-1及Calu-3細胞)中的病毒進入效率(圖5,E至G)。此等假病毒係基於具有C端19個胺基酸缺失之S構築體,其產生最高病毒力價。藉由p24免疫分析定量假病毒產生,且結果相對於各突變病毒株之力價標準化(圖5F)。由於化學相似性,每個N-醣位點之天冬醯胺(Asn)經取代為麩醯胺酸(Gln)以最小化結構影響,且各
O-醣位點之蘇胺酸(Thr)或絲胺酸(Srn)經取代為丙胺酸(Ala)。因為突變誘發改變胺基酸,所以所引起之感染性變化將來自共有的因素,包括影響受體接合的醣基化相關之構形變化,及受蛋白質表現、摺疊及運輸影響之S蛋白表面豐度。結果表明S蛋白醣基化之破壞降低感染性。對於受體結合域(RBD)中之兩個突變N331Q及N343Q以及對於兩個
O-醣位點(T323A及S325A)之突變,觀測到實質性降低,儘管後者的佔有率低(圖5G)。另外,N端域(NTD)中之N122醣基化缺失引起感染性降低及低蛋白質表現(圖5G)。兩個NTD突變N149Q及N165Q分別在Vero-E6及Calu-1細胞中增加感染性,不過在其他細胞中觀測到感染減少(圖5G)。應注意,附接於此N165殘基之聚醣在結構上接近三聚S蛋白中之相鄰RBD,且其突變減少ACE2結合,很可能由於RBD之構形變化至「向下」狀態。鑑別兩種突變體N801Q及N1194Q (圖5F),其在所有五種細胞中普遍消除病毒感染性。醣位點N801位置靠近融合肽近端區(FPPR),且N1194靠近七肽重複2 (HR2)螺旋之中心且為跨膜域前的最後一個N-醣位點(圖5E)。此等突變均引起低產率表現。N801Q突變體更傾向於降解,且N1194Q突變體破壞S蛋白三聚體,此可能部分地解釋了攜帶此等突變體之假病毒感染性之降低。
實例 19 :來自肺上皮細胞之 S 蛋白含有更多唾液酸化複合型聚醣且 S 蛋白中之高度保守抗原決定基主要經聚醣遮蔽
S蛋白之聚醣圖譜分析顯示與人類腎上皮細胞細胞株HEK293T中產生之S蛋白(分別61%及23%) (圖6B)相比,人類肺上皮細胞細胞株BEAS-2B中產生之S蛋白中複合型聚醣豐度較高(78%)且雜交型聚醣較少(小於1%)(圖6A)。在高甘露醣型聚醣中,N連接之甘露糖-5聚醣(man5)係在HEK293T表現之S蛋白中發現的主要類型,儘管僅在來自BEAS-2B細胞之位點N61處看到。另外,在來自BEAS-2B細胞之位點N74、N149、N282及N1194處的複合型聚醣比來自HEK293T細胞之聚醣更多樣地進行加工(多個觸角、半乳醣基化、岩藻醣基化或唾液酸化)。相比之下,在位點N122、N331、N1098及N1134處之聚醣多樣化程度較低。此外,在BEAS-2B中N149及N17無核心岩藻糖。觀測到來自BEAS-2B之所有22個N-醣位點上的唾液酸化程度(53%)總體上高於來自HEK293T (35%)、HEK293E (26%)或先前報導之HEK293F細胞(15%) (Y. Watanabe, J. D. Allen, D. Wrapp, J. S. McLellan, M. Crispin, Site-specific glycan analysis of the SARS-CoV-2 spike. Science
369, 330-333 (2020))。詳言之,BEAS-2B中RBD之兩個N-醣位點(N331及N343) (99%及39%)比HEK293T (49%及15%)更多唾液酸化。儘管有差異,但來自所有細胞類型之S蛋白均含有位於S2域之中間區段周圍的非複合型聚醣帶(圖6C),其中N-醣位點N801對於感染很重要(圖5G),N1074含有多樣化聚醣,且N717係S蛋白表現不可或缺的。
自模型化SARS-CoV-2 S蛋白結構及來自BEAS-2B細胞之聚醣圖譜,對蛋白質表面積上之聚醣覆蓋度進行結構分析,且與使用1,117,474個S蛋白序列的多個比對結果重疊(S. Elbe, G. Buckland-Merrett, Data, disease and diplomacy: GISAID's innovative contribution to global health. Global Chall.
1, 33-46 (2017))。其揭露高度保守但經聚醣遮蔽之若干區域,包括RBD之下側面、具有非複合型聚醣帶之S2莖區及涉及連接域(CD)及HR2之S2 C端部分(圖6,D及E)。在一級序列上,此等區域展示為保守抗原決定基。序列保守分析亦展示,大部分醣位點區域高度保守,且大部分保守醣位點(突變率低於0.02%)包括NTD (N61、N122、N165及N234)、RBD (S325、N331及N343)、亞域1/2 (SD1/2) (N603及N657)、次單元2 (S2)之莖區(N709、N1098、N1134、N1158、N1173及N1194)及靠近FPPR之N801中的彼等醣位點。此等區域中的大部分含有約20%至40%保守表面殘基,且其中一定百分比之殘基經聚醣遮蔽,RBD中36%及其他區域中約50%。儘管不具有N-醣位點,但HR1區69%之保守表面殘基被源於相鄰域之聚醣覆蓋。此等結果突出顯示S蛋白醣基化在結構上及進化上之重要性,從而產生以下想法:暴露經聚醣遮蔽之保守區可能引發針對保守抗原決定基之免疫反應。(將12個保守抗原決定基描述為疫苗設計之目標係更重要的。12個抗原決定基中之10個經聚醣遮蔽;且所遮蔽聚醣之移除暴露保守抗原決定基,從而引起廣泛保護反應)
實例 20 :研發 S
MG 作為疫苗且 S
MG 疫苗使用不同抗體子類引發更好免疫反應
最初嘗試使多個醣位點突變,導致S蛋白之表現明顯減少。然而,當自GnTI HEK293S細胞表現前述之S蛋白時,能夠產生一種具有良好產率及純度之高甘露醣型S蛋白(S
HM)。接著在各N-醣位點處使用醣苷內切酶H (Endo H)將聚醣修整成單一GlcNAc,產生一種可溶性的經單GlcNAc修飾之修整S蛋白,稱為S
MG(圖7A)。藉由質譜分析證實S
MG,所有N-醣位點大部分經單一GlcNAc佔據,且未處理
O-聚醣之佔有率太低而未偵測到。將此經修飾之S
MG及S
HM以及原始完全醣基化S蛋白(S
FG)與作為佐劑之氫氧化鋁(明礬)混合,且隨後用於藉由肌肉內注射對BALB/c小鼠(
n= 5)進行免疫接種(圖7B)。在此研究中用於比較之S
FG由HEK293E細胞表現且含有多樣化聚醣;此類似於許多當前經批准或處於臨床試驗中之COVID-19疫苗中使用的免疫原,包括來自Sanofi及Novavax之昆蟲細胞表現之S蛋白疫苗(P. J. Klasse, D. F. Nixon, J. P. Moore, Immunogenicity of clinically relevant SARS-CoV-2 vaccines in nonhuman primates and humans. Sci. Adv.
7, eabe8065 (2021))、來自Medigen之中國倉鼠卵巢(CHO)細胞表現之重組S疫苗(T.-Y. Kuo, M.-Y. Lin, R. L. Coffman, J. D. Campbell, P. Traquina, Y.-J. Lin, L. T.-C. Liu, J. Cheng, Y.-C. Wu, C.-C. Wu, W.-H. Tang, C.-G. Huang, K.-C. Tsao, C. Chen, Development of CpG-adjuvanted stable prefusion SARS-CoV-2 spike antigen as a subunit vaccine against COVID-19.Sci. Rep.
10, 20085 (2020))、來自AstraZeneca及Johnson&Johnson之基於腺病毒之疫苗及來自Pfizer-BioNTech及Moderna之mRNA疫苗(P. J. Klasse, D. F. Nixon, J. P. Moore, Immunogenicity of clinically relevant SARS-CoV-2 vaccines in nonhuman primates and humans. Sci. Adv.
7, eabe8065 (2021))。藉由陰性染色分析,S
FG與S
MG蛋白展現在溶液中基本上相同之三聚結構。
與S
FG相比,經S
MG免疫接種之小鼠在第二次免疫接種之後誘發優良體液免疫反應,針對S蛋白之免疫球蛋白G (IgG)力價顯著較高,高1.44倍(終點力價:S
FG,39,408 ± 1,619;S
MG,56,957 ± 5,091;P = 0.0079) (圖7C)且基於SARS-CoV-2假病毒感染之抑制,抗體中和效力強3.6倍(半最大中和力價倒數pNT
50:S
FG,1346 ± 285;S
MG,4791 ± 767;P= 0.0159) (圖6D),而經S
HM免疫接種之組展示相似抗S IgG力價(39,086 ± 11,654)且與S
FG組相比pNT
50力價無差異。對IgG亞型力價及T濾泡輔助(Tfh)細胞之干擾素-γ (IFN-γ)或介白素-4 (IL-4)產生的分析揭露,與經S
FG及S
HM疫苗接種之組相比,S
MG疫苗誘導BALB/c小鼠中更多IgG2a (其為T輔助1細胞(TH1)淋巴球之標記物)、更平衡之T
H1/T
H2反應及更多表現IFN-γ之Tfh細胞(圖7,E至J)。此外,S
MG疫苗誘導更高頻率之IL-21
+Tfh細胞(圖7K)及升高頻率之產生顆粒酶B之CD8
+T細胞(圖7L)。此等資料表明,由S
MG引發之體液及細胞適應性免疫反應比由S
FG誘發之體液及細胞適應性免疫反應更有效。接著檢查來自經第三劑S
FG或S
MG免疫接種之小鼠之脾臟的S蛋白特異性B細胞(CD3
−CD19
+S
+)的頻率(圖6A)且發現經S
MG免疫接種之小鼠產生更多S蛋白特異性B細胞(圖6M)。來自經S
FG及S
MG免疫接種之小鼠(
n= 5)之B細胞庫分析表明,與S
FG組中相比,S
MG組中使用更多λ輕鏈基因(S
FG,1.92%;S
MG,9.68%) (圖7N)。另外,與S
FG組中相比,來源於Ig重鏈可變區(
IGHV)之若干特定基因座(圖7O)及Ig κ鏈可變區(
IGKV)基因(圖7P)之抗體在S
MG組中過度表現,尤其
IGHV1-18基因(圖7O)。此發現表明在此兩組中B細胞抗原決定基可以不同方式加工,且仍然進一步探索此差異是否及為何具有免疫益處。另外,針對野生型(WT) S蛋白,三劑S
MG疫苗接種引發之終點力價IgG比兩劑疫苗接種高(終點力價:S
FG,208,911 ± 50,092;S
MG,376,410 ± 80,873)。觀測到藉由酶聯免疫吸附分析(ELISA)針對來自SARS-CoV-2 高關注變異株(VOC)之S蛋白量測的血清IgG結合曲線中S
MG與S
FG組之間的差異(P. R. Krause, T. R. Fleming, I. M. Longini, R. Peto, S. Briand, D. L. Heymann, V. Beral, M. D. Snape, H. Rees, A.-M. Ropero, R. D. Balicer, J. P. Cramer, C. Muñoz-Fontela, M. Gruber, R. Gaspar, J. A. Singh, K. Subbarao, M. D. Van Kerkhove, S. Swaminathan, M. J. Ryan, A.-M. Henao-Restrepo, SARS-CoV-2 variants and vaccines. N. Engl. J. Med
385, 179-186 (2021)),包括Alpha (B.1.1.7;P = 0.0488)、Beta (B.1.351;P = 0.0010)、Gamma (P.1;P = 0.0068)及Delta (B.1.617.2;P = 0.0068),但終點力價分析無統計差異(圖7Q)。藉由假病毒中和曲線,亦觀測到針對高關注變異株(VOC)之中和抗體反應之差異,包括Alpha (
P= 0.0156)、Beta (
P= 0.0156)及Delta (
P= 0.0078),但與S
FG相比,在假病毒或可靠病毒中和之pNT
50力價的值中未觀測到差異(圖7,R及S)。
實例 21 :自經 S
MG 免疫接種之小鼠之 B 細胞分離廣泛中和抗體
自經S
MG免疫接種之小鼠分選之S蛋白特異性B細胞可自
IGHV1-18擴增純系鑑別單株抗體(mAb) m31A7,該等B細胞係經S
MG免疫接種之B細胞庫中特別豐富之子集(圖8O)。此mAb與全長S蛋白、S1及RBD相互作用,但不與S2相互作用(圖8A),且結合於表現來自不同SARS-CoV-2變異株之S蛋白的HEK293T細胞(圖8B)。另外,展示在低於皮莫耳半抑制濃度(IC
50)下m31A7中和各種假病毒變異體(WT、D614G、Alpha、Beta及Delta),比報導之人類mAb EY6A高多達1000倍(圖8C)。預防性研究亦證實在用WT SARS-CoV-2攻擊之K18-hACE2小鼠(
n= 3)中m31A7之良好活體內功效(圖8D)。預防性處理之小鼠維持體重及溫度(圖8,E及F)。生物層干涉術(Biolayer interferometry, BLI)分析用於量測分別在70.9 pM及4.66 nM下m31A7及其Fab結合於S蛋白之解離常數(圖8G)。藉由氫-氘交換質譜法(HDX-MS)之抗原決定基定位揭露其潛在結合區在RBD上(圖8H),與在與m31A7-Fab之複合物中RBD之晶體結構中觀測到之抗原決定基重疊。冷凍電子顯微法(EM)結構進一步闡明m31A7僅與「向上」狀態之RBD結合(圖8I),其中來自相鄰NTD之N165-聚醣在RBD-m31A7界面附近(圖8J)。m31A7在RBD上之佔據面積類似於人類
VH1-58類別mAb (圖8K),但其自不同角度接近RBD,在尖端環上之局部接觸面積變化,繞過高關注變異株(VOC)大部分關鍵突變殘基,諸如E484 K417,但不繞過T478 (圖8L)。此S
MG引發之mAb的詳細RBD-m31A7界面及抑制機制在進一步研究中。
實例 22 : Delta S
MG 疫苗接種引發更多的針對 SARS-CoV-2 變異假病毒之中和抗體SARS-CoV-2 Delta變異體之S
MG蛋白表現構築體
來自A/Brisbane/59/2007 (H1N1))之信號肽:MKVKLLVLLCTFTATYAGT (SEQ ID NO: 4)
凝血酶裂解位點:
LVPRGS(SEQ ID NO: 5)
T4摺疊子:
PGSGYIPEAPRDGQAYVRKDGEWVLLSTFLG(SEQ ID NO: 6)
HRV3C裂解位點:
GSGSLEVLFQGP(SEQ ID NO: 7)
His標籤:
HHHHHH(SEQ ID NO: 8)
在第0週及第2週將BALB/c小鼠(n=5)用Delta S
FG或S
MG疫苗免疫接種兩次。在第6週收集血清且隨後使用假病毒分析測試中和能力(圖9A)。使用SARS-CoV-2 Delta變異體之假型病毒(pseudotyped viruse)測量中和經疫苗免疫接種之血清中之感染的能力。此外,來自S
MG免疫接種之血清對WT、Alpha、Beta、Gamma、Delta及Omicron假病毒具有優良中和能力。Delta S
FG對比S
MG之相應力價(pNT
50,愈高愈好)分別為1018對比3336 (針對野生型WT假病毒)、1396對比2680 (針對Alpha假病毒)、337對比2282 (針對Beta假病毒)、814對比4424 (針對Gamma假病毒)、1138對比6680 (針對Delta假病毒)及144對比2628 (針對Omicron假病毒)。
實例 23 : Delta 或 WT S
MG 疫苗接種引發更多的針對 SARS-CoV-2 Omicron 變異假病毒之中和抗體
在第0週及第2週將BALB/c小鼠(n=5)用Delta/WT S
FG或S
MG疫苗免疫接種兩次。在第6週收集血清且隨後使用假病毒分析測試中和能力(圖10A)。使用SARS-CoV-2 Omicron變異體之假型病毒(pseudotyped viruse)測量中和經WT S
FG/S
MG或Delta S
FG/S
MG疫苗免疫接種之血清中之感染的能力。WT S
FG疫苗接種未引發針對Omicron假病毒之中和,而WT S
MG提供輕微保護。類似地,Delta S
FG疫苗接種引發極少的針對Omicron假病毒感染之中和,然而,Delta S
MG提供極佳中和。
實例 24 : Delta S
MG 蛋白可呈溶液或呈粉末儲存於室溫下
具有兩種胺基酸(pbs-aa)、50 mM L-精胺酸及50 mM L-麩胺酸之磷酸鹽緩衝鹽水添加劑中Delta S
MG蛋白經0.22 μm過濾器過濾且儲存於室溫(RT)或4℃下。在包括3天、7天、14天、21天及3個月之不同時間點收集蛋白質。將所收集之樣品與5X SDS-PAGE裝載染料混合,在100℃下加熱5分鐘且儲存於4℃下,直至跑膠(圖11 A及B)。針對在4℃下儲存Delta S
HM或S
MG(前3個泳道),測試有或無50 mM L-精胺酸及50 mM L-麩胺酸之PBS。測試在有或無賦形劑下凍乾的Delta S
MG且在室溫下儲存超過2週(後2個泳道) (圖11 C)。穩定性測試指示Delta S
MG蛋白可儲存於溶液中且在室溫或4℃下穩定至少21天。此外,Delta S
MG可經凍乾且在室溫下儲存且保持穩定至少3個月。
SARS-CoV-2 Delta變異體之S
MG蛋白表現構築體
A/Brisbane/59/2007(H1N1)經修飾之信號肽
凝血酶裂解位點
T4 摺疊子 HRV3C 裂解位點 His 標籤 替換原始弗林蛋白酶裂解位點的殘基
GSAG (
SEQ ID NO: 9)
高度保守抗原決定基
以下圖式形成本說明書的一部分且包括在內以進一步展示本發明之某些態樣,其中可藉由參考此等圖式中之一或多者且結合本文中呈現之特定實施例的詳細描述更好地理解本發明。
圖 1 (a) 至 (f). 經醣化工程改造之棘蛋白與單 GlcNAc 裝飾 (S
MG)
之蛋白疫苗之設計及表徵。(a)重組SARS-CoV-2棘狀醣蛋白構築體之示意圖。蛋白質結構區域圖示為N端域(NTD)、受體結合域(RBD)、融合肽(FP)、七肽重複1(HR1)、七肽重複2 (HR2)、中心螺旋(CH)及連接域(CD)。可溶性棘蛋白之C端與摺疊子序列及His標籤(His
6)連接。弗林蛋白酶裂解位點經GSAG(SEQ ID NO: 9)殘基取代且兩個脯胺酸突變(K986P及V987P)將棘蛋白固定在融合前狀態。N連接之醣基化序列子(N-X-S/T,其中X ≠ P)之位置展示為分支(N,Asn;X,任何殘基;S,Ser;T,Thr;P,Pro)。井號位點(#)表示凝血酶切割位點。(b)單GlcNAc裝飾之棘蛋白疫苗產生之示意性概述。S
HM,具有高甘露糖類型N-聚醣之棘蛋白;S
MG,在其N-醣基化位點處具有GlcNAc之棘蛋白。(c)經純化之S
MG之粒徑篩析層析法(size-exclusion chromatography)。黑色曲線表示S
MG且灰色曲線展示蛋白質分子量標記物。(d)S
FG(具有典型複合型N-聚醣之棘蛋白)、S
HM及S
MG之SDS-PAGE分析。(e)S
MG之結構模型。藉由使用Wincootm添加聚醣,利用蛋白質資料庫(PDB) ID代碼7CN9建立模型,且用程式ChimeraX顯示。(f)S
FG及S
MG之N-聚醣組合物之質譜分析。
圖 2 (A) 至 (S). S
MG 疫苗接種增強活體內對 SARS-CoV-2 感染之預防。(
A)展示敍利亞倉鼠(Syrian hamster)之免疫接種時程。S
FG(藍色)、S
MG(紅色)及對照(灰色)。(
B)在敍利亞倉鼠中在WT SARS-CoV-2攻擊之後量測體重變化。(
C)展示經攻擊之倉鼠的肺病毒力價。虛線指示偵測下限。(
D)展示來自受感染倉鼠(3 dpi)之肺之病理組織學、免疫組織化學及免疫螢光的代表性圖像。第一列:蘇木精及伊紅(H&E)染色;比例尺,50 μm。第二列:免疫組織化學(IHC)染色;比例尺,50 μm。第三列:免疫螢光(IF)染色;比例尺,100 μm。SARS-CoV-2 N特異性多株抗體用於偵測病毒,在IHC中呈棕色點且在IF染色中呈綠色點。藍色:4,6-二甲脒基-2-苯基吲哚(DAPI)。(
E)展示CAG-hACE2或K18-hACE2轉殖基因小鼠之免疫接種時程。(
F至
I)展示自經免疫接種之CAG-hACE2轉殖基因小鼠(
n= 7)收集之血清樣品的抗S IgG力價(F)、SARS-CoV-2 WT微量中和力價(G)及亞型IgG分析,包括IgG1、IgG2c (H)及IgG2c:IgG1比率(I)。(
J)展示受感染小鼠肺部(7 dpi)之代表性病理組織學、免疫組織化學及免疫螢光。比例尺與(D)中相同。(
K)受感染CAG-hACE2小鼠(
n= 3)之肺病毒力價。虛線指示偵測下限。(
L及
M)展示經WT-SARS-CoV-2攻擊之CAG-hACE2轉殖基因小鼠(
n= 4)之體重變化(L)及存活分析(M)。(
N及
O)展示經SARS-CoV-2 Alpha變異體攻擊之CAG-hACE2轉殖基因小鼠(
n= 5)的體重變化(N)及存活分析(O)。(
P及
Q)展示經SARS-CoV-2 Gamma變異體攻擊之CAG-hACE2轉殖基因小鼠(
n= 5)的體重變化(P)及存活分析(Q)。(
R及
S)展示經SARS-CoV-2 Delta變異體攻擊之K18-hACE2轉殖基因小鼠(
n= 4)的體重變化(R)及存活分析(S)。資料展示為平均值±SEM且藉由雙側曼-惠特尼
U檢驗(two-sided Mann-Whitney
Utest)進行分析以比較兩個實驗組。ns,不顯著;*
P<0.05。
圖 3. S
MG 疫苗接種在轉殖基因 hACE2 小鼠中提供更好的對致死劑量 SARS-CoV-2 感染之預防。(a)轉殖基因小鼠之免疫接種及攻擊時程。(b)對在初始疫苗接種之後28天及42天收集的血清檢查抗棘蛋白特異性IgG。(c)藉由CPE分析對在初始疫苗接種之後42天收集的血清檢查中和抗體力價。(d)在攻擊之後轉殖基因小鼠之體重變化(n = 3)。(e)在攻擊之後的轉殖基因小鼠存活率(n = 3)。資料為平均值 ±SEM(平均值之標準誤差)。比較藉由t試驗(Student's t-test)(未配對,雙尾)進行。條柱上方之數值指示相對於S
FG疫苗由S
MG疫苗引發之抗體之結合及中和的增加倍數。藍色正方形,經S
FG免疫接種之轉殖基因小鼠;紅色三角形,經S
MG免疫接種之轉殖基因小鼠;灰色點,對照組動物(僅明礬組)。
圖 4. 小鼠中由 S
MG 疫苗誘發之抗體增強針對 SARS-CoV-2 變異體之結合及中和的廣度及效力。(a)示出SARS-CoV-2棘蛋白結構之示意性圖示及在此研究中使用之變異體的突變分布圖。RBD,受體結合域。在突變圖中,點(.)指示該位置中與野生型相同之胺基酸且短劃線(-)指示缺失。(b)藉由ELISA來測定SARS-CoV-2特異性IgG抗體力價。條柱上方之數值指示相對於S
FG疫苗由S
MG疫苗引發之抗體之結合的增加倍數。(c)展示SARS-CoV-2變異體假病毒中和曲線。(d)繪製實現SARS-CoV-2變異體50%假病毒中和(pNT
50)之力價。條柱上方之數值指示相對於S
FG疫苗由S
MG疫苗引發之抗體之中和的增加倍數。(e)展示感染性SARS-CoV-2變異體中和曲線,其藉由病毒溶斑抑制中和試驗法(PRNT)測定。(f)繪製實現SARS-CoV-2變異體50%中和(PRNT50)之力價。資料為平均值 ± SEM(平均值之標準誤差)。藉由非線性回歸,使用GraphPrism 9.0擬合曲線,且藉由多重t-試驗(配對,雙尾)進行比較。力價比較藉由t試驗(Student's t-test)(未配對,雙尾)進行。條柱上方之數值指示相對於S
FG疫苗由S
MG疫苗引發之抗體之中和的增加倍數。藍色正方形,經S
FG免疫接種之轉殖基因小鼠;紅色三角形,經S
MG免疫接種之轉殖基因小鼠;灰色點,對照組動物(PBS組)。
圖 5 (A) 至 (G).S蛋白醣基化影響ACE2受體結合及SARS-CoV-2感染。(
A至
C)對來自BEAS-2B細胞(A)、HEK293T細胞(B)及未進行或進行Endo H分解之HEK293S (GnTI¯)細胞(C)的以不同方式醣基化之S蛋白胞外域(S
FG,原始完全醣基化,藍色;deS,未唾液酸化,淡藍色;S
HM,高甘露糖,黃色;及S
MG,單GlcNAc裝飾,紅色)量測ACE2結合親合力。三個技術重複實驗之資料展示為平均值±SD,且針對EC
50值,藉由非線性回歸進行曲線擬合。(
D)對相同輸入量(0.3 μg/ml p24同等物)之攜帶以不同方式醣基化之S蛋白的假病毒量測病毒感染性,著色相應地如(C)中。RLU,相對發光單位。六個技術重複實驗之資料展示為平均值± SD且先後用一般單因子ANOVA檢驗及杜凱氏多重比較檢驗(Tukey's multiple comparisons test)進行分析。ns,不顯著;****
P< 0.0001。(
E)展示SARS-CoV-2 S蛋白[野生型(WT)]之示意圖,按區域著色,包括N端域(NTD;14-306;橙色)、受體結合域(RBD;319-541;紅色)、兩個亞域(SD1/2;542-685;黃色)、融合肽近端區(FPPR;816-856;綠色)、七肽重複1(HR1;912-984;藍綠色)、連接域(CD;1063-1162;藍色)、七肽重複2(HR2;1163-1211;紫色)及跨膜域(TM;1214-1234;白色)。N-聚醣(繪成分支)及
O-聚醣(圓圈)位點用殘基編號標記。上方展示S1及S2域。(
F)展示攜帶野生型(WT)之S蛋白或移除所示各醣位點處之聚醣之突變體的假病毒的病毒力價,藉由p24定量標準化,且著色相應地如(E)中。(
G)在五種表現hACE2之細胞株中測試的如(F)中之相同假病毒組的感染性。以三個獨立實驗之平均值±SD,針對WT值(被定義為100%,深灰色)標準化(F)及(G)中之值。
圖 6 (A) 至 (E).S蛋白聚醣圖譜證明兩種細胞株之差異且與序列保守相關。(
A及
B)展示自BEAS-2B肺上皮細胞(A)及HEK293T腎上皮細胞(B)表現之重組S蛋白之N-醣基化圖譜的比較。將聚醣分組且相應地著色:複合-S (唾液酸化複合型;深藍色)、複合(未唾液酸化複合型;淡藍色)、雜交-S (唾液酸化雜交型;深黃色)及雜交(非唾液酸化雜交型;淡黃色)、高甘露糖(綠色)及未佔據(灰色)。以圓餅圖展示各醣位點之各組百分比,且以長條圖展示各醣型(第1至27號)之比例。條形圖表示三個生物重複實驗之平均值± SD。F雜交指示岩藻醣基化之雜交型聚醣。(
C)在S胞外域之3D結構(自6VSB模型)上映射來自(A)及(B)之聚醣圖譜。如所標記,依據BEAS-2B(左)或HEK293T(右)資料之最高含量組別對聚醣著色(複合型,藍色;雜交型,黃色;及高甘露糖,綠色)。用殘基編號標記非複合型N-醣位點。(
D)展示模型化S結構蛋白上相對表面可及性(relative surface accessibility,RSA)之映射,其中埋入之殘基呈深黃色,遮蔽之聚醣呈黃色,且暴露之部分呈淡黃色。(
E)展示模型化S蛋白結構上序列變異之映射,在熱圖中著色,其中較深紅色表明較高突變率。其中更顯示若干高度保守聚醣遮蔽區。(D)及(E)之更多細節可見於圖S9及資料檔案S1。
圖 7 (A) 至 (S).在BALB/c小鼠中,與S
FG相比,S
MG疫苗接種引發更強體液免疫反應及細胞免疫反應。(
A)展示S
FG及S
MG蛋白疫苗之結構模型(根據
圖 2C)。藍色:聚醣;灰色:蛋白質。S
FG為由HEK293E表現無進一步修飾之棘蛋白。S
MG藉由酶分解以截斷HEK293S GnTI¯表現之S
HM之所有N-聚醣,形成單個GlcNAc來獲得,而
O-聚醣未經修飾。(
B)在BALB/c小鼠(各實驗中
n= 5)中使用如(A)中之蛋白質作為免疫原之免疫接種時程。S
FG(藍色)、S
HM(黃色)、S
MG(紅色)及對照物(灰色)。明礬,氫氧化鋁。(
C)藉由ELISA分析血清樣品之抗S蛋白IgG力價。(
D)使用具有WT S蛋白之假病毒來量測血清樣品之中和力價。(
E至
G)血清之IgG亞型分析,包括IgG1 (E)、IgG2a (F)及IgG2a:IgG1比率(G)。(
H至
K)藉由流動式細胞測量術,BALB/c小鼠之淋巴結(LN)中活化非調節CD4 T細胞中之Tfh百分比(H)及表現IFN-γ (I)、IL-4 (J)及IL-21 (K)之Tfh細胞(CD4
+CD19
−CD44
hiFoxp3
−PD-1
+CXCR5
+)的百分比。(
L)藉由流動式細胞測量術分析的BALB/c小鼠之LN中產生顆粒酶B之CD8
+T細胞(CD3
+B220
−CD8
+CD49b
−)的百分比。(
M)展示脾中相對於螢光扣除對照(FMO)染色(無S蛋白下染色)(百分比)標準化之S蛋白特異性B細胞(CD3
−CD19
+S蛋白
+)(百分比)的比率。(
N)展示κ及λ輕鏈之使用。(
O及
P) B細胞庫分析之重(O)及κ (P)鏈分佈。小於5%之使用以白色展示。(
Q至
S)展示在三劑針對SARS-CoV-2 WT (或D614G)及變異體之所指示疫苗之後自BALB/c小鼠分離之血清的抗S蛋白IgG力價(Q)、假病毒中和力價(R)及可靠病毒中和力價(S) (各條柱上方之數值指示與S
FG組相比S
MG之增加倍數)。pNT
50表示實現50%中和之稀釋倒數。條形圖中之點線表示偵測下限。資料展示為平均值± SEM且藉由雙側曼-惠特尼
U檢驗分析以比較兩個實驗組,(N)除外,其中五種樣品彙集在一起且使用卡方檢驗。
P值展示在各條柱上方。*
P< 0.05;**
P< 0.01。
圖 8 (A) 至 (L).藉由S
MG疫苗接種引發之抗體m31A7的功能、預防性及結構表徵指示交叉中和能力。(
A) m31A7對S1、S2、RBD或整個S胞外域之ELISA結合。(
B) m31A7與表現SARS-CoV-2 WT及變異體之S蛋白之HEK293T細胞的結合之流動式細胞測量術分析。(
C) m31A7針對攜帶WT或變異S蛋白之假病毒的中和活性。(A)、(B)及(C)之三個技術重複實驗之資料展示為平均值± SD,且針對EC
50值,藉由非線性回歸進行曲線擬合。(
D)展示K18-hACE2轉殖基因小鼠(
n= 3)之抗體注射及攻擊時程。(
E及
F)展示用m31A7或PBS處理之小鼠的體重變化(E)及體溫變化(F)。資料呈現為平均值± SEM。(
G)呈現m31A7 IgG及Fab與S蛋白之結合動力學,其中解離常數(
K d)展示在上方。(
H)以時程展示藉由m31A7之HDX-MS進行的抗原決定基定位,揭露兩種候選肽419-433及471-482,其中在15秒ΔHDX大於10%。資料展示為平均值± SD且在各時間點藉由多個t檢驗分析。*
P< 0.05;**
P< 0.01;***
P< 0.001;****
P< 0.0001。(
I)展示符合m31A7-Fab/S蛋白複合物結構之cryo-EM圖。重鏈,深綠色;輕鏈,淡綠色;RBD,紅色;NTD,橙色;S1其餘部分,淡灰色;S2,深灰色;及N-聚醣,藍色。(
J)展示RBD-m31A7界面之放大視圖。星號標記m31A7輕鏈與N165-聚醣之間的附近區域。(
K)先前報導之mAb S2E12 (洋紅色)、COV253 (粉色)及B1-182.1 (淡藍色) (PDB 7BEN、7K4N及7MLZ)重疊至m31A7結合之RBD (灰色)上。已顯示受體結合模體及RBD尖端。(
L) RBD (灰色)上COV253 (粉色)及m31A7 (綠色)之佔據面積比較顯示相似性,其中高關注變異株(VOC)之殘基經標記且繪製為紅色球體。
圖 9 (A) 至 (C).Delta S
MG疫苗接種引發更多的針對SARS-CoV-2變異假病毒之中和抗體。(A)疫苗接種之流程。在第0週及第2週用Delta S
FG或S
MG疫苗對BALB/c小鼠(n=5)進行免疫接種。在第6週收集血清且隨後使用假病毒分析測試中和能力。(B)針對SARS-CoV-2變異假病毒,其中包括野生型(WH01)及高關注變異株(VOC)(包括Alpha、Beta、Gamma、Delta及Omicron之變異株),血清之50%中和力價倒數(50 percent reciprocal neutralization titer, pNT50)。資料展示為平均值(在各條柱上方指示)± SEM且藉由雙側曼-惠特尼
U檢驗分析以比較兩個實驗組。*
P< 0.05。(C)藉由以不同方式稀釋之血清提供的SARS-CoV-2變異假病毒細胞感染之抑制(%)。資料展示為平均值± SEM且曲線藉由非線性回歸使用Graph Prism 9.0擬合。
圖 10 (A) 及 (B).Delta或WT S
MG疫苗接種引發更多的針對SARS-CoV-2 Omicron變異假病毒之中和抗體。(A)疫苗接種之流程。在第0週及第2週用Delta/WT S
FG或S
MG疫苗對BALB/c小鼠(n=5)進行免疫接種。在第6週收集血清且隨後使用假病毒分析測試中和能力。(B)藉由以不同方式稀釋之血清提供的SARS-CoV-2變異假病毒細胞感染之抑制(%)。資料展示為平均值± SEM且曲線藉由非線性回歸使用Graph Prism 9.0擬合。
圖 11 (A) 至 (C). Delta S
MG蛋白可呈溶液或呈粉末儲存於室溫下。(A及B)具有兩種胺基酸(pbs-aa)、50 mM L-精胺酸及50 mM L-麩胺酸之磷酸鹽緩衝鹽水添加劑中Delta S
MG蛋白經0.22 μm過濾器過濾且儲存於室溫(RT)或4℃下。在包括3天、7天、14天、21天及3個月之不同時間點收集蛋白質。將所收集之樣品與5X SDS-PAGE裝載染料混合,在100℃下加熱5分鐘且儲存於4℃下,直至跑膠。(C)在不同緩衝液及凍乾條件中之Delta S
MG蛋白儲存測試。針對在4℃下儲存Delta S
HM或S
MG(前3個泳道),測試有或無50 mM L-精胺酸及50 mM L-麩胺酸之PBS。測試在有或無賦形劑下凍乾的Delta S
MG且在室溫下儲存超過2週(後2個泳道)。
圖 12展示SARS-CoV-2棘蛋白之受體結合域(RBD)中存在之高度保守抗原決定基(E1、E2、E3、E4、E5、E6及E7) (SEQs ID NO: 41-47) 之示意圖,該棘蛋白含有N端域(NTD)、受體結合域(RBD)、融合肽(FP)、七肽重複序列1 (HR1)、七肽重複序列2 (HR2)、跨膜域(TM)、細胞質域(CD)及S2次單元。
圖 13展示SARS-CoV-2棘蛋白之七肽重複序列2 (HR2)中存在之高度保守抗原決定基(E8、E9、E10、E11、E12) (SEQs ID NO: 48-52) 之示意圖。
<![CDATA[<110> 中央研究院(ACADEMIA SINICA)]]> <![CDATA[<120> 經改良之冠狀病毒疫苗]]> <![CDATA[<130> A21893-246717 ]]> <![CDATA[<140> 111113933]]> <![CDATA[<141> 2022-04-12]]> <![CDATA[<150> US 63/173,752]]> <![CDATA[<151> 2021-04-12]]> <![CDATA[<150> US 63/190,199]]> <![CDATA[<151> 2021-05-18]]> <![CDATA[<160> 52 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 1196]]> <![CDATA[<212> PRT]]> <![CDATA[<213> SARS-CoV-2]]> <![CDATA[<400> 1]]> Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr 1 5 10 15 Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser 20 25 30 Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn 35 40 45 Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys 50 55 60 Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala 65 70 75 80 Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr 85 90 95 Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn 100 105 110 Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu 115 120 125 Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe 130 135 140 Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln 145 150 155 160 Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu 165 170 175 Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser 180 185 190 Lys His Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser 195 200 205 Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg 210 215 220 Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp 225 230 235 240 Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr 245 250 255 Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile 260 265 270 Thr Asp Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys 275 280 285 Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn 290 295 300 Phe Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr 305 310 315 320 Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser 325 330 335 Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr 340 345 350 Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly 355 360 365 Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala 370 375 380 Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly 385 390 395 400 Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe 405 410 415 Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val 420 425 430 Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu 435 440 445 Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser 450 455 460 Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln 465 470 475 480 Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg 485 490 495 Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys 500 505 510 Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe 515 520 525 Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys 530 535 540 Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr 545 550 555 560 Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro 565 570 575 Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser 580 585 590 Asn Gln Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro 595 600 605 Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser 610 615 620 Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala 625 630 635 640 Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly 645 650 655 Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg 660 665 670 Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala 675 680 685 Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn 690 695 700 Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys 705 710 715 720 Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys 725 730 735 Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg 740 745 750 Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val 755 760 765 Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe 770 775 780 Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser 785 790 795 800 Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala 805 810 815 Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala 820 825 830 Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu 835 840 845 Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu 850 855 860 Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala 865 870 875 880 Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile 885 890 895 Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn 900 905 910 Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr 915 920 925 Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln 930 935 940 Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile 945 950 955 960 Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala 965 970 975 Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln 980 985 990 Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser 995 1000 1005 Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln 1010 1015 1020 Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser 1025 1030 1035 Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr 1040 1045 1050 Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile 1055 1060 1065 Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val 1070 1075 1080 Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu 1085 1090 1095 Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys 1100 1105 1110 Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu 1115 1120 1125 Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe 1130 1135 1140 Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly 1145 1150 1155 Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu 1160 1165 1170 Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln 1175 1180 1185 Glu Leu Gly Lys Tyr Glu Gln Tyr 1190 1195 <![CDATA[<210> 2]]> <![CDATA[<211> 1193]]> <![CDATA[<212> PRT]]> <![CDATA[<213> SARS-CoV-2]]> <![CDATA[<400> 2]]> Gln Cys Val Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr 1 5 10 15 Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser 20 25 30 Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn 35 40 45 Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys 50 55 60 Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala 65 70 75 80 Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr 85 90 95 Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn 100 105 110 Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu 115 120 125 Asp Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val 130 135 140 Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe 145 150 155 160 Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu 165 170 175 Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His 180 185 190 Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu 195 200 205 Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln 210 215 220 Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser 225 230 235 240 Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln 245 250 255 Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp 260 265 270 Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu 275 280 285 Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg 290 295 300 Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu 305 310 315 320 Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr 325 330 335 Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val 340 345 350 Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser 355 360 365 Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser 370 375 380 Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr 385 390 395 400 Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly 405 410 415 Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly 420 425 430 Asn Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro 435 440 445 Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro 450 455 460 Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr 465 470 475 480 Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val 485 490 495 Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro 500 505 510 Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe 515 520 525 Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe 530 535 540 Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala 545 550 555 560 Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser 565 570 575 Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln 580 585 590 Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala 595 600 605 Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly 610 615 620 Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His 625 630 635 640 Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys 645 650 655 Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg Gly Ser Ala Gly Ser Val 660 665 670 Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn 675 680 685 Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr 690 695 700 Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser 705 710 715 720 Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn 725 730 735 Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu 740 745 750 Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala 755 760 765 Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly 770 775 780 Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg 785 790 795 800 Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala 805 810 815 Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg 820 825 830 Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro 835 840 845 Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala 850 855 860 Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln 865 870 875 880 Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val 885 890 895 Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe 900 905 910 Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser 915 920 925 Ala Leu Gly Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu 930 935 940 Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser 945 950 955 960 Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val 965 970 975 Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr 980 985 990 Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn 995 1000 1005 Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys 1010 1015 1020 Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro 1025 1030 1035 Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val 1040 1045 1050 Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His 1055 1060 1065 Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn 1070 1075 1080 Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln 1085 1090 1095 Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val 1100 1105 1110 Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro 1115 1120 1125 Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn 1130 1135 1140 His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn 1145 1150 1155 Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu 1160 1165 1170 Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu 1175 1180 1185 Gly Lys Tyr Glu Gln 1190 <![CDATA[<210> 3]]> <![CDATA[<211> 1271]]> <![CDATA[<212> PRT]]> <![CDATA[<213> SARS-CoV-2 (δ病毒株)]]> <![CDATA[<400> 3]]> Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr 1 5 10 15 Ala Gly Thr Gln Cys Val Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro 20 25 30 Ala Tyr Thr Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val 35 40 45 Phe Arg Ser Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe 50 55 60 Phe Ser Asn Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn 65 70 75 80 Gly Thr Lys Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val 85 90 95 Tyr Phe Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe 100 105 110 Gly Thr Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn 115 120 125 Ala Thr Asn Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp 130 135 140 Pro Phe Leu Asp Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu 145 150 155 160 Ser Gly Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser 165 170 175 Gln Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn 180 185 190 Leu Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr 195 200 205 Ser Lys His Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe 210 215 220 Ser Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr 225 230 235 240 Arg Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly 245 250 255 Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly 260 265 270 Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr 275 280 285 Ile Thr Asp Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys 290 295 300 Cys Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser 305 310 315 320 Asn Phe Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile 325 330 335 Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala 340 345 350 Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp 355 360 365 Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr 370 375 380 Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr 385 390 395 400 Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro 405 410 415 Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp 420 425 430 Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys 435 440 445 Val Gly Gly Asn Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn 450 455 460 Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly 465 470 475 480 Ser Lys Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu 485 490 495 Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr 500 505 510 Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val 515 520 525 Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn 530 535 540 Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn 545 550 555 560 Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr 565 570 575 Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr 580 585 590 Pro Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr 595 600 605 Ser Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val 610 615 620 Pro Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr 625 630 635 640 Ser Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly 645 650 655 Ala Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala 660 665 670 Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg Gly Ser Ala 675 680 685 Gly Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly 690 695 700 Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr 705 710 715 720 Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr 725 730 735 Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu 740 745 750 Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn 755 760 765 Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu 770 775 780 Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp 785 790 795 800 Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro 805 810 815 Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu 820 825 830 Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile 835 840 845 Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val 850 855 860 Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala 865 870 875 880 Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala 885 890 895 Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly 900 905 910 Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala 915 920 925 Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser 930 935 940 Thr Ala Ser Ala Leu Gly Lys Leu Gln Asn Val Val Asn Gln Asn Ala 945 950 955 960 Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala 965 970 975 Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu 980 985 990 Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu 995 1000 1005 Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg 1010 1015 1020 Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu 1025 1030 1035 Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu 1040 1045 1050 Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His 1055 1060 1065 Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro 1070 1075 1080 Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val 1085 1090 1095 Phe Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe 1100 1105 1110 Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly 1115 1120 1125 Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp 1130 1135 1140 Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys 1145 1150 1155 Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile 1160 1165 1170 Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp 1175 1180 1185 Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp 1190 1195 1200 Leu Gln Glu Leu Gly Lys Tyr Glu Gln Asp Ile Arg Ser Leu Val 1205 1210 1215 Pro Arg Gly Ser Pro Gly Ser Gly Tyr Ile Pro Glu Ala Pro Arg 1220 1225 1230 Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu 1235 1240 1245 Ser Thr Phe Leu Gly Gly Ser Gly Ser Leu Glu Val Leu Phe Gln 1250 1255 1260 Gly Pro His His His His His His 1265 1270 <![CDATA[<210> 4]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 4]]> Met Lys Val Lys Leu Leu Val Leu Leu Cys Thr Phe Thr Ala Thr Tyr 1 5 10 15 Ala Gly Thr <![CDATA[<210> 5]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 5]]> Leu Val Pro Arg Gly Ser 1 5 <![CDATA[<210> 6]]> <![CDATA[<211> 31]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多]]>肽 <![CDATA[<400> 6]]> Pro Gly Ser Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr 1 5 10 15 Val Arg Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu Gly 20 25 30 <![CDATA[<210> 7]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 7]]> Gly Ser Gly Ser Leu Glu Val Leu Phe Gln Gly Pro 1 5 10 <![CDATA[<210> 8]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 8]]> His His His His His His 1 5 <![CDATA[<210> 9]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> SARS-CoV-2]]> <![CDATA[<400> 9]]> Gly Ser Ala Gly 1 <![CDATA[<210> 10]]> <![CDATA[<400> 10]]> 000 <![CDATA[<210> 11]]> <![CDATA[<400> 11]]> 000 <![CDATA[<210> 12]]> <![CDATA[<400> 12]]> 000 <![CDATA[<210> 13]]> <![CDATA[<400> 13]]> 000 <![CDATA[<210> 14]]> <![CDATA[<400> 14]]> 000 <![CDATA[<210> 15]]> <![CDATA[<400> 15]]> 000 <![CDATA[<210> 16]]> <![CDATA[<400> 16]]> 000 <![CDATA[<210> 17]]> <![CDATA[<400> 17]]> 000 <![CDATA[<210> 18]]> <![CDATA[<400> 18]]> 000 <![CDATA[<210> 19]]> <![CDATA[<400> 19]]> 000 <![CDATA[<210> 20]]> <![CDATA[<400> 20]]> 000 <![CDATA[<210> 21]]> <![CDATA[<400> 21]]> 000 <![CDATA[<210> 22]]> <![CDATA[<400> 22]]> 000 <![CDATA[<210> 23]]> <![CDATA[<400> 23]]> 000 <![CDATA[<210> 24]]> <![CDATA[<400> 24]]> 000 <![CDATA[<210> 25]]> <![CDATA[<400> 25]]> 000 <![CDATA[<210> 26]]> <![CDATA[<400> 26]]> 000 <![CDATA[<210> 27]]> <![CDATA[<400> 27]]> 000 <![CDATA[<210> 28]]> <![CDATA[<400> 28]]> 000 <![CDATA[<210> 29]]> <![CDATA[<400> 29]]> 000 <![CDATA[<210> 30]]> <![CDATA[<400> 30]]> 000 <![CDATA[<210> 31]]> <![CDATA[<400> 31]]> 000 <![CDATA[<210> 32]]> <![CDATA[<400> 32]]> 000 <![CDATA[<210> 33]]> <![CDATA[<400> 33]]> 000 <![CDATA[<210> 34]]> <![CDATA[<400> 34]]> 000 <![CDATA[<210> 35]]> <![CDATA[<400> 35]]> 000 <![CDATA[<210> 36]]> <![CDATA[<400> 36]]> 000 <![CDATA[<210> 37]]> <![CDATA[<400> 37]]> 000 <![CDATA[<210> 38]]> <![CDATA[<400> 38]]> 000 <![CDATA[<210> 39]]> <![CDATA[<400> 39]]> 000 <![CDATA[<210> 40]]> <![CDATA[<400> 40]]> 000 <![CDATA[<210> 41]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 41]]> Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu 1 5 10 <![CDATA[<210> 42]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 42]]> Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg 1 5 10 15 <![CDATA[<210> 43]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 43]]> Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys 1 5 10 <![CDATA[<210> 44]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 44]]> Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn 1 5 10 <![CDATA[<210> 45]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 45]]> Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr 1 5 10 <![CDATA[<210> 46]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 46]]> Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly 1 5 10 15 <![CDATA[<210> 47]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 47]]> Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys 1 5 10 <![CDATA[<210> 48]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 48]]> Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr 1 5 10 <![CDATA[<210> 49]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 49]]> Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn 1 5 10 15 His Thr Ser <![CDATA[<210> 50]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 50]]> Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala 1 5 10 <![CDATA[<210> 51]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 51]]> Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln 1 5 10 <![CDATA[<210> 52]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 多肽]]> <![CDATA[<400> 52]]> Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro 1 5 10
Claims (28)
- 一種免疫原,其包含經醣化工程改造之冠狀病毒棘蛋白,該經醣化工程改造之冠狀病毒棘蛋白包含複數個截短N-聚醣及一或多個未經修飾之O-聚醣,其中該經醣化工程改造之冠狀病毒棘蛋白由SEQ ID NO: 1之胺基酸序列或與SEQ ID NO: 1之胺基酸序列具有至少90%序列一致性之其變異體或該胺基酸序列或該變異體之免疫活性片段組成。
- 如請求項1之免疫原,其中該複數個截短N-聚醣為單醣。
- 如請求項2之免疫原,其中該等單醣為N-乙醯葡萄糖胺(GlcNAc)。
- 如請求項1之免疫原,其中該複數個截短N-聚醣位於受體結合域(RBD)中,藉此暴露具有以下胺基酸序列之複數個高度保守抗原決定基:TESIVRFPNITNL (SEQ ID NO.: 41)、NITNLCPFGEVFNATR (SEQ ID NO: 42)、LYNSASFSTFK (SEQ ID NO: 43)、LDSKVGGNYN (SEQ ID NO: 44)、KSNLKPFERDIST (SEQ ID NO: 45)、KPFERDISTEIYQAG (SEQ ID NO: 46)及/或GPKKSTNLVKNKC (SEQ ID NO: 47)。
- 如請求項1之免疫原,其中該複數個截短N-聚醣位於七肽重複2 (HR2)域中,藉此暴露具有以下胺基酸序列之複數個高度保守抗原決定基:NCDVVIGIVNNTVY (SEQ ID NO: 48)、PELDSFKEELDKYFKNHTS (SEQ ID NO: 49)、VNIQKEIDRLNEVA (SEQ ID NO: 50)、NLNESLIDLQ (SEQ ID NO: 51)及/或LGKYEQYIKWP (SEQ ID NO: 52)。
- 如請求項1之免疫原,其中該經醣化工程改造之冠狀病毒棘蛋白藉由活體外醣化工程改造自天然冠狀病毒棘蛋白衍生而來。
- 如請求項6之免疫原,其中該天然冠狀病毒棘蛋白為嚴重急性呼吸道症候群冠狀病毒2 (SAR-CoV-2)或其變異體之棘蛋白。
- 如請求項7之免疫原,其中該變異體係選自由以下組成之群:D614G、Alpha (B.1.1.7及Q譜系)、Beta (B.1.351及後代譜系)、Gamma (P.1及後代譜系)、Epsilon (B.1.427及B.1.429)、Eta (B.1.525)、Iota (B.1.526)、Kappa (B.1.617.1)、1.617.3、Mu (B.1.621、B.1.621.1)、Zeta (P.2)、Delta (B.1.617.2及AY譜系)及Omicron(B.1.1.529及BA譜系)。
- 如請求項1之免疫原,其中該經醣化工程改造之冠狀病毒棘蛋白呈三聚體形式存在。
- 如請求項6之免疫原,其中該經醣化工程改造之冠狀病毒棘蛋白保留與該天然冠狀病毒棘蛋白相同的三級結構。
- 如請求項4之免疫原,其中相對於該天然冠狀病毒棘蛋白,該經醣化工程改造之冠狀病毒棘蛋白能夠引發增強之免疫反應。
- 如請求項11之免疫原,其中該增強之免疫反應為增加之IgG力價、增加之IgM力價、增加之中和力價、增加之CD4 T細胞反應、增加之CD8 T細胞反應或其組合。
- 如請求項6之免疫原,其中該經醣化工程改造之棘蛋白係使用一或多種化學或酵素方法產生。
- 如請求項13之免疫原,其中該經醣化工程改造之棘蛋白係使用醣苷內切酶H (Endo H)產生。
- 如請求項1之免疫原,其中該經醣化工程改造之冠狀病毒棘蛋白包含由SEQ ID NO: 1之胺基酸序列組成的多肽,其中該多肽由22個截短N-聚醣組成,各截短N-聚醣具有GlcNAc部分。
- 如請求項1之免疫原,其中該經醣化工程改造之冠狀病毒棘蛋白包含由SEQ ID NO: 2之胺基酸序列組成的多肽,其中該多肽由21個截短N-聚醣組成,各截短N-聚醣具有GlcNAc部分。
- 一種免疫原性組合物,其包含:(a)如請求項1至16中任一項之免疫原,及(b)視情況選用的佐劑。
- 如請求項17之免疫原性組合物,其中該佐劑為氫氧化鋁、磷酸鋁、不完全弗氏佐劑(incomplete Freund's adjuvant,IFA)、角鯊烯、明礬、鋁膠、MF59、QS-21、CpG 1018、AS03、AS37、Matrix-M或其組合。
- 如請求項17之免疫原性組合物,其中該免疫原性組合物為相對於使用天然冠狀病毒棘蛋白之疫苗,能夠引發增強之免疫反應的經改良之冠狀病毒疫苗。
- 如請求項19之免疫原性組合物,其中該冠狀病毒為SAR-CoV-2或其變異體。
- 一種用於在有需要之個體中引發針對嚴重急性呼吸道症候群冠狀病毒2 (SARS-CoV-2)之免疫反應的方法,其包含向該個體投與有效量之如請求項17或18之免疫原性組合物。
- 如請求項21之方法,其中該免疫反應包含產生針對SARS-CoV-2或其變異體之中和抗體。
- 如請求項22之方法,其中該變異體係選自由以下組成之群:D614G、Alpha (B.1.1.7及Q譜系)、Beta (B.1.351及後代譜系)、Gamma (P.1及後代譜系)、Epsilon (B.1.427及B.1.429)、Eta (B.1.525)、Iota (B.1.526)、Kappa (B.1.617.1)、1.617.3、Mu (B.1.621、B.1.621.1)、Zeta (P.2)、Delta (B.1.617.2及AY譜系)及Omicron (B.1.1.529及BA譜系)。
- 一種如請求項17或18之免疫原性組合物的用途,其用於在有需要之個體中引發針對SARS-CoV-2或其變異體之免疫反應,該方法包含向該有需要之個體投與有效量之該免疫原性組合物。
- 如請求項24之用途,其中該免疫反應包含產生針對SARS-CoV-2或其變異體之中和抗體。
- 如請求項25之用途,其中該變異體係選自由以下組成之群:D614G、Alpha (B.1.1.7及Q譜系)、Beta (B.1.351及後代譜系)、Gamma (P.1及後代譜系)、Epsilon (B.1.427及B.1.429)、Eta (B.1.525)、Iota (B.1.526)、Kappa (B.1.617.1)、1.617.3、Mu (B.1.621、B.1.621.1)、Zeta (P.2)、Delta (B.1.617.2及AY譜系)及Omicron (B.1.1.529及BA譜系)。
- 一種如請求項17或18之免疫原性組合物的用途,其用於保護有需要之個體避免感染SARS-CoV-2或其變異體,該方法包含向該有需要之個體投與有效量之該免疫原性組合物。
- 一種如請求項17或18之免疫原性組合物的用途,其用於預防有需要之個體感染COVID-19疾病,該方法包含向該有需要之個體投與有效量之該免疫原性組合物。
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