TW202144002A - 鼻內的mRNA疫苗 - Google Patents
鼻內的mRNA疫苗 Download PDFInfo
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- TW202144002A TW202144002A TW110105299A TW110105299A TW202144002A TW 202144002 A TW202144002 A TW 202144002A TW 110105299 A TW110105299 A TW 110105299A TW 110105299 A TW110105299 A TW 110105299A TW 202144002 A TW202144002 A TW 202144002A
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Abstract
本發明大體上係關於鼻內mRNA疫苗，更特定言之，包含一或多種免疫刺激分子、一或多種致病性抗原及專門設計的遞送系統。具體而言，該等免疫刺激分子及致病性抗原以編碼此類分子及抗原之mRNA分子形式提供；更特定言之，編碼CD40L、caTLR4及/或CD70之mRNA分子與一或多種編碼細菌、病毒或真菌抗原之mRNA分子組合。具體而言，遞送物為允許保護及儲存疫苗之化合物的混合物且靶向鼻中之抗原呈現細胞。特定言之，本發明非常適合在爆發情況下發展快速反應疫苗。
Description
本發明大體上係關於鼻內mRNA疫苗，更特定言之，包含一或多種免疫刺激分子、一或多種致病性抗原及專門設計的遞送系統。具體而言，該等免疫刺激分子及致病性抗原以編碼此類分子及抗原之mRNA分子形式提供；更特定言之，編碼CD40L、caTLR4及/或CD70之mRNA分子與一或多種編碼細菌、病毒或真菌抗原之mRNA分子組合。具體而言，遞送物為允許保護及儲存疫苗之化合物的混合物且靶向鼻中之抗原呈現細胞。特定言之，本發明非常適合在爆發情況下發展快速反應疫苗。
過去關於如SARS及MERS之爆發感染性疾病之疫苗的努力影響有限，因為疫苗在流行高峰後出現，且所用技術無法在後續爆發中更廣泛的覆蓋及重複使用。目前COVID-19（nCoV-2019）疫苗設計之努力利用誘導高水準全身中和抗體之技術。然而，據報導，自SARS或MERS感染中恢復之患者的抗體反應本質上為短暫的，且針對相關病毒株之交叉反應性有限。相比之下，T細胞對冠狀病毒之反應似乎為長期的且具有顯著的交叉反應性。
黏膜且尤其鼻內T細胞免疫作為預防數種空氣傳播之病毒病原體的下呼吸道感染及疾病之關鍵工具而得以進展。已證明在非常特定的情形下在小鼠鼻內投予mRNA誘導此類強免疫力。使用T細胞免疫作為主要防禦使得該方法更穩健地抵抗體液免疫反應所靶向之病毒蛋白的已知變異性，且為防止病毒株漂變及甚至未來冠狀病毒變異體樹立了希望。鼻內接種mRNA具有誘導此類黏膜T細胞反應之潛力。此外，鼻內遞送為一種經證實之疫苗技術，在市場上有FluMist®。
TriMix為編碼免疫刺激蛋白CD40L、CD70及組成型活性形式之TLR4（caTLR4）之三種mRNA的混合物，已證明在治療性癌症疫苗之背景下，在皮內、靜脈內及結節內mRNA疫苗投予後增強針對共同遞送之mRNA編碼之抗原的T細胞反應的強度及品質。此處，吾等證明TriMix mRNA與編碼抗原的mRNA之共同投予可增強鼻內疫苗接種針對呼吸道病毒之功效。
人類冠狀病毒（HCoV）長期以來一直被視為是無關緊要的病原體，在原本健康的人中引起「普通感冒」。然而，在21世紀，2種高致病性HCoV——嚴重急性呼吸道症候群冠狀病毒（SARS-CoV）、中東呼吸道症候群冠狀病毒（MERS-CoV）自動物保存宿主（animal reservoir）出現，引起發病率及死亡率驚人之全球流行病。
冠狀病毒為一種包膜RNA病毒，其廣泛分佈在人類、其他哺乳動物及鳥類中，且引起呼吸道、腸道、肝臟及神經系統疾病。已知六種冠狀病毒物種引起人類疾病。四種病毒（229E、OC43、NL63及HKU1）為普遍的，典型地引起免疫活性個體之普通感冒症狀。另外兩種病毒株——嚴重急性呼吸道症候群冠狀病毒(SARS-CoV)及中東呼吸道症候群冠狀病毒(MERS-CoV)起源於人畜共患病，有時與致命的疾病有關。SARS-CoV為2002年及2003年在中國廣東省爆發的嚴重急性呼吸道症候群的致病因子。MERS-CoV為2012年在中東地區造成嚴重呼吸道疾病爆發之病原體。
SARS之常見症狀包括發熱、咳嗽、呼吸困難及偶爾水樣腹瀉。在受感染之患者中，20%至30%需要機械通氣且10%死亡，年長患者及患有醫學共生病症之患者的死亡率較高。人與人之間的傳播已有記錄，主要在醫療機構中。此院內擴散可藉由基礎病毒學解釋：SARS S糖蛋白之主要人類受體，亦即人類血管收縮素轉化酶2（ACE2）主要存在於下呼吸道，而非上呼吸道中。受體分佈可解釋上呼吸道症狀稀少及病毒脫落高峰發生在疾病後期(≈10天)，當時個體已住院之發現。SARS護理常常需要氣溶膠生成程序，諸如插管，其亦可能促成顯著的院內擴散。
MERS與SARS具有許多共同的臨床特徵，諸如嚴重的非典型肺炎，但關鍵的差異為明顯的。MERS患者具有顯著的胃腸道症狀且常常患有急性腎衰竭，其原因可能為MERS-CoV S糖蛋白與存在於下呼吸道以及腎臟及胃腸道之二肽基肽酶4（DPP4）結合。MERS使50%至89%之患者需要機械通氣，且病例死亡率為36%。
2019年12月，一群不明原因的肺炎患者與中國武漢之海鮮批發市場有關。經由使用無偏定序在肺炎患者之樣本中發現先前未知的β冠狀病毒。使用人類呼吸道上皮細胞分離出一種新型冠狀病毒，命名為COVID-19，其形成正冠狀病毒亞科（orthocoronavirinae subfamily）沙貝病毒亞屬（subgenus sarbecovirus）內之另一分枝系。不同於MERS-CoV及SARS-CoV，COVID-19為感染人類之冠狀病毒家族的第七個成員。
尚無針對冠狀病毒之人類疫苗註冊或甚至尚未進入I期研發。確實存在許多（減毒的）獸用冠狀病毒疫苗（犬科動物、貓科動物）。
在每次爆發時，均會啟動加速疫苗研發。然而，研發之時長使得當候選疫苗通過I期時，發病率（及因此測試疫苗功效之可能性）已下降至低水準。隨後爆發的為不同的病毒亞型，且因此先前的努力無法使用。
基於SARS爆發，許多US、EU及亞洲疫苗研發人員將候選者轉移至臨床前研發，且少數實際上在I期進行測試。（Roper及Rehm, 2009）截至2003年，所採用之疫苗技術包括若干減毒活病毒、幾種次單位疫苗、一些腺基疫苗及一些DNA疫苗。
數據瞭解到，誘導強烈的全身性抗體反應（例如針對棘蛋白）並不能保證中和。Roper等人, 2009提出鼻內疫苗接種很可能為藉由誘導強烈的IgA反應預防傳播之首選途徑。
為了解決呼吸道疾病爆發時新型疫苗之此等漫長的研發過程，吾等現已研發一種新型疫苗平台，其包含：一或多種編碼選自包含CD40L、caTLR4及CD70之清單之功能性免疫刺激蛋白的mRNA分子；及一或多種編碼細菌、病毒或真菌抗原之mRNA分子；呈鼻內調配物形式。此類平台方法非常適合於在新型或甚至現有呼吸道病原體爆發時快速研發疫苗。
在第一態樣中，本發明提供一種組合，其包含：
- 一或多種編碼功能性免疫刺激蛋白之mRNA分子，該功能性免疫刺激蛋白選自包含CD40L、caTLR4及CD70之清單；及
- 一或多種編碼細菌、病毒或真菌抗原或人工抗原之mRNA分子，該人工抗原經設計以含有T細胞刺激抗原決定基且抑制T調節抗原決定基。
其中該組合呈鼻內調配物形式。
在一特定具體實例中，該一或多種mRNA分子編碼所有該等功能性免疫刺激蛋白CD40L、caTLR4及CD70。
在另一具體實例中，該抗原為來自呼吸道病原體（諸如冠狀病毒）之抗原。
在另一特定具體實例中，該抗原為M（基質）、N（核酸蛋白殼）S（棘）抗原或病毒編碼之非結構蛋白（NSP）；尤其M（基質）、N（核酸蛋白殼）S（棘）抗原。
在另一特定具體實例中，該抗原為由來自病原體基因體之若干抗原決定基構成的人工構成之免疫原。
在本發明之另一具體實例中，該mRNA分子以基於脂質或聚合物之奈米粒子形式調配，包括基於脂質之奈米粒子，或樹枝狀聚合物、聚合複合物（polyplex）、脂質複合物（lipoplex）、混合型脂質聚合複合物（hybrid lipopolyplex）或聚合脂質複合物調配物；諸如基於脂質之奈米粒子或脂質複合物或聚合脂質複合物調配物。
在另一態樣中，本發明亦提供一種疫苗，其包含如本文所定義之組合。
整個發明包含與適當遞送裝置之組合及使向鼻之遞送及暴露達到最大且使肺暴露減至最少的使用方案。
另外，本發明提供如本文所定義之組合或疫苗，其用於人類或獸醫學中，專門用於預防及/或治療感染性疾病。
如上文已詳述，本發明提供一種組合，其包含：
- 一或多種編碼功能性免疫刺激蛋白之mRNA分子，該功能性免疫刺激蛋白選自包含CD40L、caTLR4及CD70之清單；及
- 一或多種編碼細菌、病毒或真菌抗原之mRNA分子，特別是經設計用於誘導抗體反應之mRNA分子；或經設計以含有T細胞刺激抗原決定基及抑制T調節抗原決定基之人工抗原；
其中該組合呈鼻內調配物形式。
在一特定具體實例中，該組合包含TriMix，亦即編碼所有該等CD40L、caTLR4及CD70免疫刺激蛋白之mRNA分子。
在本發明通篇，術語「TriMix」表示編碼CD40L、CD70及caTLR4免疫刺激蛋白之mRNA分子的混合物。使用CD40L及caTLR4之組合生成成熟的分泌細胞介素/趨化介素之DC，如經由添加可溶性CD40L及LPS進行CD40及TLR4連接所示。將CD70引入DC中，藉由抑制活化的T細胞凋亡及支持T細胞增殖而向CD27+
初始T細胞提供共刺激信號。作為caTLR4之替代物，可使用其他Toll樣受體（TLR）。對於各TLR，組成型活性形式為已知的，且可能引入DC中以引發宿主免疫反應。然而，在吾等觀點中，caTLR4為最有效的活化分子且因此為較佳的。
在本說明書通篇使用之術語「目標（target）」不限於可在本文中描述之特定實例。可靶向任何感染物，諸如病毒、細菌或真菌。
在本說明書通篇使用之術語「目標特異性抗原（target-specific antigen）」不限於可在本文中描述之特定實例。所屬技術領域中具有通常知識者應清楚，本發明與APC中免疫刺激之誘導有關，而與所呈現在目標特異性抗原無關。待呈現之抗原將視吾人意欲引發個體免疫反應之目標的類型而定。目標特異性抗原之典型實例為對細菌及真菌細胞或對特定病毒蛋白或病毒結構具有特異性的表現或分泌的標誌物。
目標特異性抗原較佳選自病原體基因體中相當穩定的區域，亦即其中極少觀察到同一病原體物種之不同病毒株之間的變異。對於短期解決方案，亦即為已感染或處於感染高風險下之個體研發疫苗，最佳目標抗原可能為「M」（基質）及/或「N」（核酸蛋白殼）蛋白及非結構蛋白。對於意欲用於防止在高風險地區及密切接觸個體中擴散之圍欄應急疫苗，受關注之組合為鼻內遞送之含有S（棘）及M/N目標之mRNA疫苗。對於長期解決方案，諸如預防性疫苗接種，最佳解決方案為可在下一次事件中迅速部署之「通用」疫苗。棘蛋白之高變異性、所使用之不同受體及對中和潛力之懷疑使得基於抗體之通用疫苗不太可能。在該情況下，針對跨主要致病株之保守區的基於T細胞之疫苗更加可行。在一個特定具體實例中，由來自病原體基因體之強T細胞刺激抗原決定基組成且移除任何T抑制抗原決定基的人工構築之免疫原將賦予此類強且廣泛的保護。或者，抗原可經設計以誘導個體之抗體反應。
在本說明書通篇所用之術語「感染性疾病（infectious disease）」或「感染（infection）」不意欲限於可能已在本文中例示之感染類型。因此，該術語涵蓋疫苗接種將對個體有益之所有感染物。非限制性實例為以下病毒引起之感染或病症：後天免疫缺乏症候群-腺病毒科（Adenoviridae）感染-α病毒感染-蟲媒病毒感染-貝爾麻痹（Bell Palsy）-博爾納病（Borna Disease）-布尼亞病毒科（Bunyaviridae）感染-杯狀病毒科（Caliciviridae）感染-水痘-普通感冒-尖銳濕疣-冠狀病毒科感染-柯沙奇病毒（Coxsackievirus）感染-細胞巨大病毒感染-登革熱（Dengue）-DNA病毒感染-觸染性膿瘡-腦炎-蟲媒病毒腦炎-單純疱疹腦炎-埃-巴二氏病毒（Epstein-Barr Virus）感染-傳染性紅斑-猝發疹-慢性漢坦病毒（Hantavirus）感染疲乏症候群-病毒性出血熱-人類病毒性肝炎-唇疱疹-單純疱疹-帶狀疱疹-耳部帶狀疱疹-疱疹病毒科（Herpesviridae）感染-HIV感染-感染性單核血球病-禽流感-人類流感-拉沙熱（Lassa Fever）-麻疹-病毒性腦膜炎-傳染性軟疣-猴痘-腮腺炎-脊髓炎-乳突狀瘤病毒感染-副黏病毒科（Paramyxoviridae）感染-白蛉熱-脊髓灰白質炎-多瘤病毒感染-脊髓灰白質炎後症候群-狂犬病-呼吸道融合病毒感染-里夫特穀熱（Rift Valley Fever）-RNA病毒感染-風疹-嚴重急性呼吸道症候群-慢病毒病-天花-亞急性硬化性泛腦炎-蜱傳疾病-腫瘤病毒感染-疣-西尼羅河熱（West Nile Fever）-病毒性病-黃熱病-人畜共通傳染病-等。病毒之特異性抗原可為HIV-gag、-tat、-rev或-nef，或肝炎C抗原；尤其較佳的病毒引起之感染或病症為冠狀病毒科感染，諸如由冠狀病毒229E、冠狀病毒OC43、SARS-CoV、HCoV NL63、HKU1、MERS-CoV或COVID-19引起之感染。
其他非限制性實例為以下細菌或真菌引起之感染或病症：膿腫-放線菌病-邊蟲病-炭疽病-反應性關節炎-麴菌病-菌血症-細菌感染及黴菌病-巴爾通體（Bartonella）感染-肉毒桿菌中毒-腦膿腫-布氏桿菌病（Brucellosis）-伯克氏菌（Burkholderia）感染-彎曲桿菌（Campylobacter）感染-念珠菌病-陰道念珠菌病-貓抓病-蜂窩組織炎-中樞神經系統感染-軟下疳-衣原體（Chlamydia）感染-衣原體科（Chlamydiaceae）感染-霍亂-梭菌（Clostridium）感染-球黴菌病-角膜潰瘍-交叉感染-隱球菌病-皮膚真菌病-白喉-艾利希體症（Ehrlichiosis）-膿胸-細菌性心內膜炎-眼內炎-偽膜性小腸結腸炎-丹毒-大腸桿菌感染-壞死性筋膜炎-弗尼爾氏壞疽（Fournier Gangrene）-癤瘡-細梭菌（Fusobacterium）感染-氣性壞疽-淋病-革蘭氏陰性細菌感染-革蘭氏陽性細菌感染-腹股溝肉芽腫-化膿性汗腺炎-組織漿菌病-麥粒腫-膿皰-克雷伯氏菌（Klebsiella）感染-退伍軍人病-麻風-鉤端螺旋體病-李氏菌（Listeria）感染-路德維希氏咽峽炎（Ludwig's Angina）-肺膿腫-萊姆病（Lyme Disease）-性病性淋巴肉芽腫-足分枝菌病-類鼻疽-細菌性腦膜炎-分枝桿菌（Mycobacterium）感染-黴漿菌（Mycoplasma）感染-黴菌病-土壤絲菌（Nocardia）感染-甲癬-骨髓炎-甲溝炎-盆腔炎-瘟疫-肺炎球菌感染-假單胞菌（Pseudomonas）感染-鸚鵡病-產後感染-Q熱-鼠咬熱-回歸熱-呼吸道感染-咽後膿腫-風濕熱-鼻硬結腫-立克次體（Rickettsia）感染-落基山斑點熱（Rocky Mountain Spotted Fever）-沙門氏菌（Salmonella）感染-猩紅熱-叢林性斑疹傷寒-敗血症-細菌性性傳染病-細菌性性傳染病-敗血性休克-細菌性皮膚病-感染性皮膚病-葡萄球菌感染-鏈球菌感染-梅毒-先天梅毒-破傷風-蜱傳疾病-癬-花斑癬-沙眼-肺結核-脊椎結核-兔熱病-傷寒熱-流行性虱傳斑疹傷寒-泌尿道感染-惠普爾病（Whipple Disease）-百日咳-弧菌（Vibrio）感染-莓疹病-耶氏桿菌（Yersinia）感染-人畜共通傳染病-接合菌病-等。
在本發明疫苗之一較佳具體實例中，mRNA或DNA分子編碼CD40L及CD70免疫刺激蛋白。在本發明疫苗之一尤其較佳具體實例中，mRNA或DNA分子編碼CD40L、CD70及caTLR4免疫刺激蛋白。
該等編碼免疫刺激蛋白之mRNA或DNA分子可為單一mRNA或DNA分子之一部分。較佳地，該單一mRNA或DNA分子能夠同時表現兩種或更多種蛋白質。在另一具體實例中，兩種或更多種編碼免疫刺激蛋白之mRNA或DNA分子為單一mRNA或DNA分子之一部分。此單一mRNA或DNA分子較佳能夠獨立地表現兩種或更多種蛋白質。在一較佳具體實例中，兩種或更多種編碼免疫刺激蛋白之mRNA或DNA分子藉由內部核糖體進入位點（IRES）連接在單一mRNA或DNA分子中，使得兩種或更多種mRNA序列中之每一者分別轉譯成胺基酸序列。或者，在不同免疫刺激因子之編碼序列之間併入自裂解2a肽編碼序列。這樣，兩種或更多種因子可由一種單一mRNA或DNA分子編碼。用藉由IRES序列或自裂解2a肽連接之編碼CD40L及CD70之mRNA電穿孔細胞的初步資料展示此方法實際上為可行的。
因此，本發明進一步提供一種編碼兩種或更多種免疫刺激因子之mRNA分子，其中該兩種或更多種免疫刺激因子經由在兩個或更多個編碼序列之間使用IRES而自單一mRNA分子分別轉譯。或者，本發明提供一種編碼由自裂解2a肽編碼序列分開之兩種或更多種免疫刺激因子之mRNA分子，使得兩個蛋白質序列在轉譯後裂解。
在任何具體實例中，該目標特異性抗原係選自由以下組成之群：自目標細胞分離之總mRNA、一或多種特異性目標mRNA分子、目標細胞之蛋白質溶解物、來自目標細胞之特異性蛋白、合成的目標特異性肽或蛋白質及編碼目標特異性肽或其衍生肽之合成mRNA或DNA。該目標可為病毒、細菌或真菌的蛋白質或mRNA，特別是經設計用於誘導抗體反應之mRNA分子。
本文中使用或提及之mRNA或DNA可為裸mRNA或DNA，或受保護之mRNA或DNA。對DNA或mRNA之保護增加其穩定性，但仍保留將mRNA或DNA用於疫苗接種目的之能力。對mRNA及DNA之保護的非限制性實例可為：脂質體囊封、魚精蛋白保護（陽離子）脂質脂質複合、脂質、陽離子或聚陽離子組成物、甘露糖基化脂質複合、氣泡脂質化、聚乙亞胺（PEI）保護、脂質體負載之微泡保護、脂質奈米粒子等。
在一些較佳具體實例中，本發明方法中所用之mRNA具有所謂CAP-1結構之5'帽結構，意味著倒數第二個核苷酸中核糖之2'羥基相對於帽核苷酸發生甲基化。
在另一特定具體實例中，該mRNA分子為自擴增或反擴增mRNA分子。自擴增mRNA分子典型地編碼抗原以及實現細胞內RNA擴增及充足蛋白質表現的病毒複製機構。反擴增mRNA分子使用類似的原理，但抗原及病毒複製機構係由不同mRNA分子編碼。
在另一特定具體實例中，本發明之兩個、三個、四個……或全部所用mRNA分子具有所謂CAP-1結構之5'帽結構。
在另一具體實例中，本發明之mRNA分子中之一或多者可進一步包含至少一個經修飾之核苷。在另一特定具體實例中，本發明之兩個、三個、四個……或全部所用mRNA分子具有至少一個經修飾之核苷。
在本發明之另一特定具體實例中，該等mRNA分子進一步包含至少一個經修飾之核苷，諸如選自包含假尿苷、5-甲氧基-尿苷、5-甲基-胞苷、2-硫代-尿苷及N6-甲基腺苷之清單。
在本發明之一特定具體實例中，該至少一個經修飾之核苷可為假尿苷，諸如選自4-硫代-假尿苷、2-硫代-假尿苷、1-羧甲基-假尿苷、1-丙炔基-假尿苷、1-牛磺酸甲基-假尿苷、N1-甲基-假尿苷、4-硫代-1-甲基-假尿苷、2-硫代-1-甲基-假尿苷、1-甲基-1-去氮-假尿苷、2-硫代-1-甲基-1-去氮-假尿苷、二氫假尿苷、2-硫代-二氫假尿苷、4-甲氧基-假尿苷及4-甲氧基-2-硫代-假尿苷之清單。在一極特定具體實例中，該至少一個經修飾之核苷為N1-甲基-假尿苷。
適用於本發明之上下文內的替代性核苷修飾包括：吡啶-4-酮核糖核苷、5-氮雜-尿苷、2-硫代-5-氮雜-尿苷、4-硫代-假尿苷、2-硫代-假尿苷、5-羥基尿苷、3-甲基尿苷、5-羧甲基-尿苷、1-羧甲基-假尿苷、5-丙炔基-尿苷、1-丙炔基-假尿苷、5-牛磺酸甲基尿苷、1-牛磺酸甲基-假尿苷、、5-牛磺酸甲基-2-硫代-尿苷、1-牛磺基甲基-4-硫代-尿苷、5-甲基-尿苷、1-甲基-假尿苷、4-硫代-1-甲基-假尿苷、2-硫代-1-甲基-假尿苷、1-甲基-1-去氮-假尿苷、2-硫代-1-甲基-1-去氮-假尿苷、二氫尿苷、二氫假尿苷、2-硫代-二氫尿苷、2-硫代-二氫假尿苷、2-甲氧基尿苷、2-甲氧基-4-硫代-尿苷、4-甲氧基-假尿苷及4-甲氧基-2-硫代-假尿苷。在一些具體實例中，mRNA包含至少一個選自由以下組成之群的核苷：5-氮雜-胞苷、假異胞苷、3-甲基-胞苷、N4-乙醯基胞苷、5-甲醯基胞苷、N4-甲基胞苷、5-羥甲基胞苷、1-甲基-假異胞苷、吡咯并-胞苷、吡咯并-假異胞苷、2-硫代-胞苷、2-硫代-5-甲基-胞苷、4-硫代-假異胞苷、4-硫代-1-甲基-假異胞苷、4-硫代-1-甲基-1-去氮-假異胞苷、1-甲基-1-去氮-假異胞苷、澤布拉林（zebularine）、5-氮雜-澤布拉林、5-甲基-澤布拉林、5-氮雜-2-硫代-澤布拉林、2-硫代-澤布拉林、2-甲氧基-胞苷、2-甲氧基-5-甲基-胞苷、4-甲氧基-假異胞苷及4-甲氧基-1-甲基-假異胞苷。在一些具體實例中，mRNA包含至少一個選自由以下組成之群的核苷：2-胺基嘌呤、2,6-二胺基嘌呤、7-去氮-腺嘌呤、7-去氮-8-氮雜-腺嘌呤、7-去氮-2-胺基嘌呤、7-去氮-8-氮雜-2-胺基嘌呤、7-去氮-2,6-二胺基嘌呤、7-去氮-8-氮雜-2,6-二胺基嘌呤、1-甲基腺苷、N6-異戊烯基腺苷、N6-(順羥基異戊烯基)腺苷、2-甲硫基-N6-(順羥基異戊烯基)腺苷、N6-甘胺醯基胺甲醯基腺苷、N6-蘇胺醯基胺甲醯基腺苷、2-甲硫基-N6-蘇胺醯基胺甲醯基腺苷、N6,N6-二甲基腺苷、7-甲基腺嘌呤、2-甲硫基-腺嘌呤及2-甲氧基-腺嘌呤。在一些具體實例中，mRNA包含至少一個選自由以下組成之群的核苷：肌苷、1-甲基-肌苷、懷俄苷（wyosine）、懷俄丁苷（wybutosine）、7-去氮-鳥苷、7-去氮-8-氮雜-鳥苷、6-硫代-鳥苷、6-硫代-7-去氮-鳥苷、6-硫代-7-去氮-8-氮雜-鳥苷、7-甲基-鳥苷、6-硫代-7-甲基-鳥苷、7-甲基肌苷、6-甲氧基-鳥苷、1-甲基鳥苷、N2-甲基鳥苷、N2,N2-二甲基鳥苷、8-側氧基-鳥苷、7-甲基-8-側氧基-鳥苷、l-甲基-6-硫代鳥苷及N2,N2-二甲基-6-硫代-鳥苷。
本發明中所用之mRNA分子可含有一或多個經修飾之核苷酸，在特定具體實例中，至少10%、20%、30%、40%、50%、60%、70%、80%、90%或100%之特定類型的核苷酸可由經修飾之核苷酸置換。亦不排除在相同的mRNA分子內包括不同的核苷酸修飾。在本發明之一極特定具體實例中，該等mRNA分子中約100%之尿苷經N1-甲基-假尿苷置換。
在一特定具體實例中，本發明之該等mRNA分子中之一或多者可進一步含有轉譯強化子及/或核保留元件。適合之轉譯強化子及核保留元件為WO2015071295中所述之彼等者。
本發明之組合及疫苗經特別調配用於鼻內投予。
在本發明之上下文中，術語「經鼻投予（nasal administration）」或「鼻內投予（intranasal administration）」意謂將本發明之組成物/疫苗應用於鼻腔中之投予途徑。鼻黏膜可用於組分之非侵入式局部或全身投予。更具體而言，在本發明之上下文中，使用此類鼻內投予形式，可使本發明之mRNA分子與上呼吸道中之抗原呈現細胞直接接觸，且誘導若干保護性T細胞，如駐留記憶CD8+ T細胞，從而誘導針對呼吸道感染之局部免疫。此亦降低病原體擴散至下呼吸道之風險，且亦減少疾病病變。
任何允許此類鼻內投予之調配物均適合在本發明之上下文內使用。特定言之，下文提供一些特定非限制性實例：
在一極簡易的設置中，本發明之組成物/疫苗可藉由簡單地將包含一或多種mRNA分子之治療上可接受之溶液注射於口鼻咽腔中，諸如以滴管形式來投予。或者，可使用單位劑量/雙劑量系統，尤其在投予需要精確給藥之情況下。此等系統含有準備投予之一或兩個分開的半劑量。
用於鼻內投予之治療上可接受之溶液較佳經選擇以使其不影響其中所包含之mRNA的穩定性。此外，此類溶液較佳增加口鼻咽腔之抗原呈現細胞的RNA攝取。因此，可使用經典的RNA轉染緩衝液/組分，諸如jetPEI®、Lipofectamine®、RiboJuice®或Stemfect®。
jetPEI®轉染劑為線性聚乙亞胺衍生物(尤其聚合複合物)。因此，在一特定具體實例中，鼻內投予可在聚乙亞胺及/或其衍生物存在下進行。
脂染胺（lipofectamine）由DOSPA（2,3‐二油醯氧基-N-[2(精胺甲醯胺基)乙基]‐N,N‐二甲基-1-丙亞胺三氟乙酸鹽）及DOPE（1,2-二油醯基-sn-甘油-3-磷酸乙醇胺）之3:1混合物組成。
或者，本發明之組成物/疫苗可以氣溶膠噴霧、鼻用噴霧、多劑量噴霧泵等形式調配。在多劑量噴霧泵中，組成物/疫苗可填充至由玻璃或塑膠材料製成之瓶子中，其藉由附接包括汲取管之鼻用噴霧泵來封閉。鼻用噴霧泵為排量泵，當藉由朝向瓶子按壓致動器致動泵時，活塞在計量室中向下移動。計量室底部之閥門機構將防止回流至汲取管中。因此，活塞之向下移動將在計量室內產生壓力，迫使空氣或液體經由致動器向外且生成噴霧。當致動壓力移除時，彈簧將迫使活塞及致動器返回至其初始位置。此在計量室中產生負壓，藉由將球自計量室底部汲取管上方的球座向上提昇而將液體自容器中抽出。計量室確保正確的劑量，且致動器尖端之開放式渦漩室將使計量的劑量氣溶膠化。
對於大多數鼻用噴霧泵，每一致動之分配體積設定在50與150 μl之間，且每一鼻孔投予約100 μl之體積對而成人而言為最佳的，因為較大的體積容易滴出。因此，當噴塗兩個鼻孔時，預期劑量較佳適配於大致100-200 μl之體積中。
視預期目的而定，可根據特定投予方案投予鼻內組成物，諸如每日一次、兩次或三次。或者，鼻內投予可每兩天、三天、四天、五天、六天或七天投予一次，諸如每週一次或者每2週一次。對於該等投予中之每一者，劑量亦可不同，諸如在治療開始時的劑量較高，而在治療即將結束時的劑量較低。使用方案含有具體指導以使肺部攝取減至最少，諸如在投予後屏氣或呼氣。
本發明之組成物可用作預防組成物（諸如在症狀表現之前）或用作治療組成物（諸如當症狀已出現時）。
鑒於mRNA分子之不穩定性質，此等mRNA分子較佳呈諸如上文所定義之受保護形式，更具體而言，其可包含在例如脂質奈米粒子中。因此，本發明亦提供如本文所定義之組合或組成物；其中該等mRNA分子中之一或多者包含於奈米粒子中；諸如基於脂質之奈米粒子或聚合複合物、脂質複合物及聚合脂質複合物。
如本文所用，術語「奈米粒子（nanoparticle）」係指任何具有使該粒子適合於全身，尤其靜脈內投予尤其核酸之直徑，典型地具有小於1000奈米（nm）之直徑的粒子。
在本發明之一特定具體實例中，奈米粒子係選自包含以下之清單：脂質奈米粒子及聚合物奈米粒子。
脂質奈米粒子（LNP）一般稱為由不同脂質之組合構成的奈米級粒子。雖然許多不同類型的脂質可包含於此類LNP中，但本發明之LNP可例如由可離子化脂質、磷脂、固醇及PEG脂質之組合構成。
聚合物奈米粒子可典型地為奈米球或奈米膠囊。兩種主要策略用於聚合物奈米粒子之製備，亦即「自上而下」法及「自下而上」法。在自上而下法中，預先形成之聚合物的分散液產生聚合物奈米粒子，而在自下而上法中，單體之聚合導致聚合物奈米粒子之形成。自上而下法及自下而上法均使用合成的聚合物/單體，如聚(d,l-丙交酯-共-乙交酯)、聚(氰基丙烯酸乙酯)、聚(氰基丙烯酸丁酯)、聚(氰基丙烯酸異丁酯)及聚(氰基丙烯酸異己酯)；穩定劑，如聚(乙烯醇)及二癸基二甲基溴化銨；及有機溶劑，如二氯甲烷及乙酸乙酯、苄醇、環己烷、乙腈、丙酮等。最近，科學界一直在嘗試藉由使用天然聚合物及溶劑毒性較小之合成方法來尋找合成聚合物之替代物。
本發明亦提供如本文所定義之組合及疫苗，其用於人類或獸醫學，尤其用於治療病原性感染，更尤其呼吸道感染，諸如病毒感染。
最後，本發明提供一種用於治療病原性感染之方法，其包含向有需要之個體投予本發明之組合或疫苗的步驟。
組成物亦可能在獸醫學領域中具有價值，就本文之目的而言，該領域不僅包括預防及/或治療動物之疾病，且亦包括（對於經濟上重要之動物，諸如牛、豬、羊、雞、魚等）提高動物之生長及/或重量及/或自動物獲得之肉類或其他產品之量及/或品質。
待治療之個體較佳罹患選自包含以下之群法疾病或病症：細菌、病毒或真菌感染。
如本文所用，術語『預防（prevention）』意謂降低感染風險或減少與病原體感染相關之症狀。實施例
實施例1：短期危機
在危機真正演變成全球大流行之（不太可能的）情形下，應急產品之門檻會迅速降低。參考（即將發生的）流感大流行，數種使用全新佐劑技術之疫苗有機會在該背景下進行快速測試。
在此情況下，可遵循以下選項中之任一者：
A)基於「殺手」T細胞之疫苗，用於高污染風險或受感染之個體。最佳目標可能為「M」（基質）及/或「N」（核酸蛋白殼）蛋白。
B)環圍應急疫苗，用於防止在高風險地區及密切接觸個體中擴散。在此情況下，受關注之組合可能為鼻內遞送之含有S（棘）及M/N目標之mRNA疫苗。在小鼠腫瘤模型中，藉由研究人員自Stemgent之Stemfect®轉染套組改編的鼻內遞送方案獲得令人驚訝的良好結果（Phua, Leong及Nair, 2013；Phua, Staats, Leong及Nair, 2014）。
實施例2：長期解決方案
針對所有可能的冠狀病毒或其他類型病原體之大規模預防疫苗接種似乎不太可能。不僅因為病毒株之變異性，且亦因為襲擊之時間及地點無法預測，因此確定誰處於風險下為不可能的任務。
因此，最佳解決方案為可在下一次事件中迅速部署之「通用」疫苗。棘蛋白之高變異性、所使用之不同受體及對廣泛中和潛力之懷疑使得基於抗體之通用疫苗不太可能。針對跨主要致病株之保守區的基於T細胞之疫苗似乎更加可行。對病原體家族之遺傳組成的充分分析及使用抗原決定基預測及融合構築體之智慧型設計產生最佳的可能候選物。
實施例3：研發概述
步驟1：探索性小鼠實驗（生物分佈、概念及安全性）：
• 鼻內Fluc生物分佈研究
• Trimix-模型抗原（例如E7）-鼻內-免疫讀數及鼻/呼吸道組織病理學。
研究級生產M、N及S mRNA以及編碼結構蛋白及非結構蛋白之mRNA
快捷科學建議：sFDA創新辦公室
步驟2：使小鼠免疫及中毒：
• Trimix-M/S-鼻內-nCoV免疫讀數及全毒素組織病理學。
視需要調整StemFect及供應（最低GMP樣品質）
研究級生產用於攻擊研究-M*及S*
GMP級生產M/S mRNA（及Trimix）
臨床試驗提交
步驟3：在健康志願者中進行I期至II期試驗：
• 時程0天（視情況7天）。I期25名個體
• 增至最少250名個體。
• 安全性參數及免疫讀數（若使用S，則包括IgA）。
動物攻擊模型：
• Trimix-M* ( + S*)-鼻內-免疫接種第0天（視情況第7天）用物種特異性冠狀病毒株攻擊-建立保護/免疫相關性（50隻動物）
商業製造及一致性
緊急使用文件提交
實施例4：臨床前產品研發方法
臨床前計劃由4個步驟組成：
1. 呼吸道表現及分佈評定。使用藉由生物發光監測FLUC mRNA活體內表現之獨特可能性，在小鼠中進行之第一個實驗評估吾等2至3個潛在的經鼻遞送系統（裸mRNA、StemFect及內部LNP），且證實在鼻腔中之遞送及表現及肺中不存在表現或低表現。遞送系統係基於其在此分析中之效能及其一般可製造性而加以選擇。
2. 在第二個小鼠實驗中評定T細胞免疫反應之誘導。此處，在2個給藥方案（0、8天及0、-22天）下投予吾等具有內部及公開經驗及免疫學工具的2種模型抗原。對所有T細胞區室（黏膜、肺、淋巴結、全身）之全面評估以及對呼吸道及所選器官之安全性評估證實免疫學假設及平台之預期安全概況。
3. GLP重複劑量毒性研究使疫苗逐步進入臨床使用。基於吾等先前使用mRNA疫苗之經驗，吾等傾向於選擇單一物種。這項研究允許根據疫苗設計期間預測之反應來確認COVID-19目標誘導相關免疫反應。已對用於非經腸投予之TriMix+抗原mRNA進行毒性評估。此評估之關鍵焦點係關於遞送系統。另外，將支持基因毒性及藥理學研究添加至關於遞送系統之所選成分的計劃中。視實驗1之結果而定，將需要特別關注肺中之副作用。可在I期開始時並行進行一些額外研究。
4. 在動物中進行之攻擊及疾病預防研究。建議此步驟與臨床研究並行進行。相關動物物種及病毒株之選擇受制於冠狀病毒疫苗工作貢獻者網路內之合作。此研究表明，疫苗防止用吾等產品進行免疫接種且在免疫接種後用病毒攻擊之動物出現下呼吸道疾病。免疫評定允許將此保護與免疫反應相關，該免疫反應又可隨後與人類個體中觀察到的反應進行比較。使用動物攻擊允許探索疫苗產生防止病毒株漂變或新冠狀病毒家族成員之廣泛反應的潛力。 實施例5：臨床研發方法
吾等之臨床研發方法集中於安全性及免疫原性，且與動物攻擊模型建立關聯，以支持預期的功效。為了滿足用作應急疫苗的需要，自I期至II期的流暢過渡可最快生成所需數據。出於相同原因，吾等選擇短誘導時程。與體液反應之誘導相反，此類短投予時程確實產生良好的T細胞免疫結果。
產品之安全性分3個步驟進行評定：
1. 量測鼻黏膜上之T細胞免疫為相對新的方法且僅在少數論文中發表。如先前所述（Jochems等人, 2018 & 2019），使用微創刮除術縱向收集疫苗接種個體之鼻樣本。已建立的低溫保存方案允許分批分析。此允許吾等並行量測i)藉由表型分型之活體內疫苗接種反應及ii)抗原特異性反應。活體內T細胞（包括組織駐留之記憶T細胞）、B細胞及DC反應係使用質量式細胞測量術與靶向鼻免疫系統之面板進行深度定性。此分析目前在LUMC微型化以分析鼻刮除術樣本。鼻中抗原特異性免疫之建立係藉由共同培養鼻細胞與同一個體之PBMC的經疫苗活化之單核球衍生之樹突狀細胞來評定。內部方案經調適以能夠評定黏膜反應。在上清液中量測細胞介素之產生（IFNγ、TNFα等），而CD40L及CTLA-4對T細胞之誘導係藉由流動式細胞測量術進行表型分型來量測抗原特異性刺激。使用自人類鼻黏膜收集之縱向微創樣本同時定性細胞表型及功能擁有快速預測疫苗成功的巨大潛力。使此等方法適應吾等特定方案係與該計劃之臨床前階段並行進行。
2. 在健康人類志願者中進行之I期多遞增劑量研究。基於臨床前結果，吾等選擇此研究之起始及目標劑量/時程。研究之第一部分為自起始至主要評估安全性之目標方案的快速步升（例如每一步驟3名個體）。此研究之指標為安全性（臨床評估、患者報告及血液分析）、全身（PBMC）及黏膜（鼻取樣）免疫評定。約40名個體納入此研究中，其中最少25名以目標劑量/時程給藥。在疫苗接種之前（第-5天及第-1天）、疫苗接種後早期（第3天及第7天）及較長時間的隨訪（第2週、第3週、第4週及第8週）收集鼻樣本。
3. 此初始I期之後，亦在健康志願者中擴展進入II期免疫原性研究。隨著所選疫苗時程包括之個體數增加（n=100），允許對誘發的免疫反應、其變異性、其長期動態及其與動物模型及保護之相關性進行穩固評定。在相同的設定及網絡內繼續研究，對數據生成之一致性及速度提供明顯的優勢。 實施例6：小鼠活體內鼻內投予 材料及方法小鼠
自Charles River獲得總共48隻小鼠（Mus musculus），且在研究開始前14天進行適應。在環境適應期間，動物基於體重分配至一組且藉由尾部紋身來鑑別。構築體設計
將流感NP蛋白（A/NL/18/94 H3N2流感）之全長編碼序列與信號序列及DC lamp序列同框（in frame）選殖，以使MHC複合物中之處理及呈現最佳化。為了改良表現且減少針對mRNA構築體之免疫原性反應，使用N1甲基假尿苷修飾。
結合TriMix mRNA，以固定的1:1比率使用免疫原性構築體。投予
在第0天、第7天、第14天，根據組別歸屬進行鼻內候選物及對照投予，如下詳述（每組16隻小鼠）
在第42天，對所有來自NP/TriMix mod（活體內jetPEI）（第1組）、NP-mod（活體內jetPEI）（第2組）或PBS（第3組）之動物進行鼻內攻擊（1 LD50，10 μl）。
在終末時間點（第48天），動物在安樂死前5分鐘接受靜脈內注射之CD45.2-BV605抗體（Biolegend，純系104，3 μg）。收集肺部且使用肺部浸潤免疫（左葉）進行病毒滴定。在第 0 天、第 7 天及第 14 天進行免疫接種 ：
在第0天，用微量吸管向所有動物鼻內投予30 μL（每鼻孔15 μL）候選製劑（第1組及第2組）或PBS（第3組）。在第7天及第14天，用微量吸管鼻內投予三十微升（30 μL）（每鼻孔15 μL）候選製劑（第1組及第2組）或PBS（第3組）。動物在麻醉下進行投予。
在第0天、第7天及第14天，用3.75 μg/3.75 μg NP/TriMix mod（活體內jetPEI）（第1組）或7.5 μg NP-mod（活體內jetPEI）（第2組）進行鼻內免疫接種（每鼻孔15 μL）。病毒感染 ：
用NP/TriMix mod（活體內jetPEI）（第1組）、NP-mod（活體內jetPEI）（第2組）或媒劑（第3組）處理之各組的所有動物在第42天用A型流感PR8進行鼻內攻擊（1 LD50，10 μl）。
肺分離：
在終末時間（第48天），動物藉由二氧化碳窒息安樂死，且在器官收集前進行肉眼屍檢。
無菌收集肺（左葉），稱重且在4℃下置於Precellys管中之0.5 mL收集培養基（（49% DMEM（Gibco，目錄號11965-084）及49% Medium 199（Gibco，目錄號11150-059），補充有0.1% FBS（Gibco，目錄號26140-079））中。將Precellys管中之肺均質化，等分且冷凍以進行病毒滴定。肺組織樣本中之流感病毒負荷估計 ：（ TCID50 ）
收集用於病毒負荷估計之肺樣本（第48天）以5000 rpm之兩個20秒循環破碎，兩次循環之間停頓5秒。在將0.5 ml DMEM/Medium-199、0.1% FBS添加至管中之前及之後，將組織均質物渦旋數秒。藉由在3200×g及4℃下離心10分鐘清除組織均質物中之組織片段。收集經清除之上清液，等分且冷凍以進行病毒滴定。
使用Spin-X管（Corning，目錄號8160）對肺樣本進行過濾滅菌（在14000×g及4℃下5分鐘）。在無菌微量滴定聚丙烯管中，以1/2之起始稀釋度，在滴定培養基（49% DMEM（Gibco，目錄號11965-084）及49% Medium 199（Gibco，目錄號11150-059），補充有0.1% FBS（Gibco，目錄號26140-079）、1×GlutaMax（Gibco，目錄號35050-061）及0.1%正大黴素（Gibco，目錄號15750-060））中製備經過濾之肺樣本的十倍稀釋液。將MDCK細胞用胰蛋白酶處理，彙集且以2.4×105個細胞/mL再懸浮於滴定培養基中。將50 μL樣本連續稀釋液添加至96孔盤之適當孔中（一式八份），且將2.4×104個MDCK細胞（100 μL）添加至所有孔中。將總體積為200 μL之樣本在37℃及5% CO2下培育7天以允許病毒複製。
TCID50係藉由血凝法評估，該方法藉由在V型底96孔盤中混合50 μL病毒上清液與50 μL 0.5%雞紅血球來實現。將盤在室溫下培育1小時且讀取血凝現象。
結果
肺樣本中之病毒負荷估計：
藉由肺部TCID50之流感病毒定量顯示，NP/Trimix mod（活體內jetPEI）（第1組）之16隻動物中有10隻動物的病毒力價低於定量限制，而用NP mod（活體內jetPEI）（第2組）處理及未處理（第3組）中組中僅4隻動物（圖1）。
因此，本發明之組成物在鼻內投予時能夠降低經攻擊之小鼠的病毒負荷。參考文獻
Jochems SP, de Ruiter K, Solórzano C, Voskamp A, Mitsi E, Nikolaou E, Carniel BF, Pojar S, German EL, Reiné J, Soares-Schanoski A, Hill H, Robinson R, Hyder-Wright AD, Weight CM, Durrenberger PF, Heyderman RS, Gordon SB, Smits HH, Urban BC, Rylance J, Collins AM, Wilkie MD, Lazarova L, Leong SC, Yazdanbakhsh M, Ferreira DM. Innate and adaptive nasal mucosal immune responses following experimental human pneumococcal colonization. J Clin Invest. 2019 Jul 30;130:4523-4538
Jochems SP, Marcon F, Carniel BF, Holloway M, Mitsi E, Smith E, Gritzfeld JF, Solórzano C, Reiné J, Pojar S, Nikolaou E, German EL, Hyder-Wright A, Hill H, Hales C, de Steenhuijsen Piters WAA, Bogaert D, Adler H, Zaidi S, Connor V, Gordon SB, Rylance J, Nakaya HI, Ferreira DM. Inflammation induced by influenza virus impairs human innate immune control of pneumococcus. Nat Immunol. 2018 Dec;19(12):1299-1308
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Claims (14)
- 一種組合，其包含： - 一或多種編碼功能性免疫刺激蛋白之mRNA分子，該功能性免疫刺激蛋白選自包含CD40L、caTLR4及CD70之清單；及 - 一或多種編碼細菌、病毒或真菌抗原之mRNA分子； 其中該組合呈鼻內調配物形式。
- 如請求項1之組合，其中該一或多種mRNA分子編碼所有該等功能性免疫刺激蛋白CD40L、caTLR4及CD70。
- 如請求項1或2中任一項所定義之組合；其中該抗原為來自呼吸道病原體之抗原。
- 如請求項1至3中任一項所定義之組合；其中該抗原為M（基質）、N（核酸蛋白殼）或S（棘）抗原、經設計以含有T細胞刺激抗原決定基且抑制T調節抗原決定基之人工抗原或經設計以引發抗體反應之表面抗原。
- 如請求項3所定義之組合；其中該呼吸道病原體為冠狀病毒。
- 如請求項1至5中任一項所定義之組合，其中該等mRNA分子經調配為奈米粒子形式，諸如基於脂質之奈米粒子。
- 如請求項1至5中任一項所定義之組合；其中該等mRNA分子經調配為脂質複合物、樹枝狀聚合物、聚合複合物或混合型脂質聚合複合物形式。
- 如請求項7所定義之組合，其中該等mRNA分子使用聚乙亞胺調配為聚合複合物形式。
- 如請求項1至8中任一項所定義之組合，其中該等mRNA分子中之一或多者包含5' CAP-1結構。
- 如請求項1至9中任一項所定義之組合；其中該等mRNA分子中之一或多者包含一或多個經修飾之核苷，尤其是N1-甲基-假尿苷。
- 一種疫苗，其包含如請求項1至10中任一項之組合。
- 一種如請求項1至10中任一項所定義之組合或如請求項11所定義之疫苗，其用於人類或獸醫學。
- 一種如請求項1至10中任一項所定義之組合或如請求項11所定義之疫苗，其用於預防及/或治療感染性疾病。
- 一種用於預防或治療感染性疾病之方法，該方法包含向有需要之個體投予如請求項1至10中任一項所定義之組合或如請求項11所定義之疫苗。
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