TWI771546B - 針對亨德拉(hendra)及尼帕(nipah)病毒感染之疫苗 - Google Patents
針對亨德拉(hendra)及尼帕(nipah)病毒感染之疫苗 Download PDFInfo
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- TWI771546B TWI771546B TW107146014A TW107146014A TWI771546B TW I771546 B TWI771546 B TW I771546B TW 107146014 A TW107146014 A TW 107146014A TW 107146014 A TW107146014 A TW 107146014A TW I771546 B TWI771546 B TW I771546B
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Abstract
本發明揭示一種保護有需要之動物免受亨德拉(Hendra)或尼帕(Nipah)病毒感染之方法，其包括向該動物投與單次劑量之疫苗，該疫苗包含：抗原組分，其包含亨德拉抗原或尼帕抗原；及佐劑，其包含油、聚陽離子載劑及含CpG之免疫刺激寡核苷酸，其中該疫苗為W/O乳劑。
Description
本發明大體上屬於針對亨德拉病毒(HeV)及尼帕病毒(NiV)感染之動物疫苗領域。
副黏液病毒，諸如HeV及NiV，在病毒顆粒之外膜中具有兩種主要膜錨定糖蛋白。一種糖蛋白為病毒體附接至宿主細胞上之受體所需要且命名為血球凝集素-神經胺糖酸酶蛋白(HN)或血球凝集素蛋白(H)，而另一種為既不具有血球凝集作用亦不具有神經胺糖酸酶活性之糖蛋白(G)。附接糖蛋白為II型膜蛋白，其中該分子之胺基(N)末端朝向細胞質且該蛋白質之羧基(C)末端在細胞外。另一種主要糖蛋白為融合(F)糖蛋白，其為含有兩個七肽重複(HR)區及疏水性融合肽之三聚I類促融合外膜糖蛋白。HeV及NiV在受體結合後藉由其附接G糖蛋白及F糖蛋白協同作用藉由非pH值依賴性膜融合過程進入受體宿主細胞中而感染細胞。HeV及NiV附接G糖蛋白之主要功能在於嚙合宿主細胞表面上之適當受體，對於大多數充分表徵之副黏液病毒而言，其為唾液酸部分。HeV及NiV G糖蛋白利用宿主細胞蛋白受體ephrin B2及/或ephrin B3，並且已開發阻斷藉由G糖蛋白進行之病毒附接的抗體(WO2006137931；Bishop (2008) J. Virol. 82: 11398-11409)。此外，已開發亦使用G糖蛋白作為產生針對HeV及NiV感染之免疫保護反應之手段的疫苗(WO2009117035)。
目前有一種批准用於馬類以預防由亨德拉病毒所致之感染或疾病的許可疫苗(Equivac® HeV；Zoetis)，但不存在用於預防尼帕病毒感染之許可疫苗。尼帕病毒及亨德拉病毒皆為具有生物防禦意義之美國國家過敏與感染疾病研究所C類優先級病原。此外，由於此等病毒為人畜共通性4級生物安全病原(BSL-4)，故安全地生產疫苗及/或診斷劑成本極高而且困難。美國農業部將尼帕病毒及亨德拉病毒二者皆分類為高度嚴重後果外來動物疾病。
在第一態樣中，本發明提供一種保護有需要之動物免受亨德拉病毒或尼帕病毒感染之方法，其包括向該動物投與單次劑量之疫苗，該疫苗包含：抗原組分，其包含亨德拉抗原或尼帕抗原；及佐劑，其包含油、聚陽離子載劑及含CpG之免疫刺激寡核苷酸，其中該疫苗為W/O乳劑。
在某些實施例中，該動物為豬科動物，且該尼帕抗原包含與SEQ ID NO: 11或與其胺基酸71-602具有至少95% (例如，至少98%)一致性之胺基酸序列。
在某些實施例中，其中該動物為馬科動物，且該亨德拉抗原包含與SEQ ID NO: 12或與其胺基酸73-604具有至少95% (例如，至少98%)一致性之胺基酸序列。
在可與以上描述之實施例中之任一者組合的其他實施例中，該油為非代謝性油。
在可與以上描述之實施例中之任一者組合的其他實施例中，該聚陽離子載劑為DEAE聚葡萄糖。
在可與以上描述之實施例中之任一者組合的其他實施例中，該單次劑量之疫苗具有約0.125 ml至約2 ml之體積。
定義
「約」或「大致」當結合可量測數值變數加以使用時係指該變數之指示值及該變數之處於該指示值之實驗誤差內(例如，處於平均值之95%信賴區間內)或處於該指示值之10%內(取較大者)的所有值，除非約係關於以週計之時間間隔加以使用，其中「約3週」為17至25天，且約2至約4週為10至40天。
「抗原」或「免疫原」係指由動物之免疫系統識別且產生免疫反應之任何物質。該術語包括殺死、滅活、減毒或經修飾之活細菌、病毒或寄生物。術語「抗原」亦包括聚核苷酸、多肽、重組蛋白質、合成肽、蛋白質提取物、細胞(包括腫瘤細胞)、組織、多醣或脂質或其片段，單獨或呈其任何組合形式。術語抗原亦包括諸如抗個體基因型抗體或其片段之抗體及可模擬抗原或抗原決定子(抗原決定基)之合成肽模擬抗原決定基。
「緩衝液」意謂防止另一化學物質之濃度變化的化學系統，例如，質子供體及受體系統充當防止氫離子濃度(pH值)顯著變化之緩衝液。緩衝液之另一實例為含有弱酸及其鹽(共軛鹼)或弱鹼及其鹽(共軛酸)之混合物的溶液。
該方法「包括向個體投與單次劑量之疫苗X」不包括投與超過一劑量疫苗X之治療方案。
「基本上由……組成」在應用於佐劑調配物時係指調配物不含一定量之未敍述之額外輔助或免疫調節劑，在該等量下，該等劑發揮可量測之輔助或免疫調節作用。
提及組合物或疫苗為「有效單次劑量疫苗」係指尼帕或亨德拉疫苗在單次投與未對尼帕或亨德拉免疫之動物後分別提供至少五個月，例如六個月、七個月、八個月、九個月、十個月、十一個月、十二個月、十三個月或十四個月之對尼帕或亨德拉攻擊免疫之持續時間。
術語「乳化劑」在本發明中係以廣義使用。其包括一般視為乳化劑之物質，例如，TWEEN®或SPAN®生產線之不同的產品(分別為聚乙氧基化山梨醇及經脂肪酸取代之去水山梨醇表面活性劑之脂肪酸酯)及不同的溶解度增強劑，諸如PEG-40蓖麻油或另一聚乙二醇化氫化油。
抗原之「免疫保護量」或「免疫有效量」或「產生免疫反應之有效量」為在受體中有效誘導免疫原性反應之量。免疫原性反應可能足以用於診斷目的或其他檢驗，或者可能足以預防由感染病原所致之疾病徵象或症狀，包括不利健康影響或其併發症。可誘導體液免疫抑或細胞免疫或二者。動物對免疫原性組合物之免疫原性反應可例如藉由抗體效價量測、淋巴球增殖分析而間接地或者藉由在用野生型病毒株攻擊之後監測徵象及症狀而直接地加以評估，而由疫苗賦予之保護性免疫可藉由量測例如該個體之臨床徵象，諸如死亡率、發病率、體溫數值、總體身體狀態以及總體健康及表現)之減低加以評估。免疫反應可包括但不限於細胞及/或體液免疫之誘導。
「免疫原性」意謂激起免疫或抗原反應。因而，免疫原性組合物將為誘導免疫反應之任何組合物。
「脂質」係指正常情況下被視為不溶(或微溶)於水但可溶於非極性有機溶劑、觸摸呈油性且與碳水化合物及蛋白質一起構成活細胞之主要結構物質的有機化合物群組中的任一種，包括脂肪、油、蠟、固醇及三酸甘油酯。
「醫藥學上可接受」係指在合理醫學判斷之範疇內適用於與個體之組織接觸而無過度毒性、刺激、過敏反應及其類似問題、與合理效益:風險比相稱且對其預定用途有效的物質。
本發明提供一種給有需要之動物接種疫苗以免受亨德拉及/或尼帕感染的方法，該方法係藉由向該動物投與單次劑量之本文中描述之疫苗。簡而言之，該疫苗含有亨德拉或尼帕抗原佐以如以下更詳細描述之佐劑TXO。抗原
關於可用於實施本發明之亨德拉病毒G糖蛋白多肽及其重組表現，參考公開國際專利申請案WO 2012/158643及WO2006/085979之全部揭示內容，其中清楚地闡述了此種資訊。可用於本文中之特定亨德拉病毒G蛋白多肽之較佳實例揭示於WO 2012/158643中，且包括例如：全長G蛋白(SEQ ID NO: 12)；其可溶性片段(SEQ ID NO: 12之編碼胺基酸73-604)；及其中揭示之具有Ig(κ)前導序列之另一片段。參見例如WO 2012/158643之SEQ ID NO: 15。一般而言，亨德拉病毒G糖蛋白之可溶性形式包含胞外域之全部或一部分，並且係由使G糖蛋白之跨膜結構域之全部或一部分及胞質尾之全部或一部分缺失而產生。編碼基因序列較佳為針對表現進行最佳化之密碼子。
在一些實施例中，該亨德拉G糖蛋白可呈二聚及/或四聚形式。此種二聚體依賴於G糖蛋白中之半胱胺酸殘基之間形成的二硫鍵之形成。此種二硫鍵可對應於天然G糖蛋白中形成之彼等二硫鍵，或可形成不同的二硫鍵，從而獲得不同的二聚及/或四聚形式之G糖蛋白，由此增強抗原性。另外，根據本發明之實踐，再考慮到G糖蛋白提供眾多構形依賴性抗原決定基(亦即，由三級三維結構產生)以及保留眾多此種天然抗原決定基從而賦予中和抗體反應因此高度較佳，非二聚及四聚形式亦為可用的。
一般而言，亨德拉G蛋白之表現載體之構建可如WO 2012/158643之實例1中所描述，其中由CHO細胞表現所得蛋白質如其實例2中所描述，或替代地，使用牛痘系統(參見其實例3)或293細胞(參見其實例4)。在一特定較佳實例中，該可溶性G蛋白提供為天然亨德拉病毒G糖蛋白(參見WO 2012/158643中之SEQ ID NO: 2，其與SEQ ID NO: 12一致)之胺基酸73-604。其二聚自發發生，伴隨由CHO細胞表現，且所得G蛋白大致為50%二聚體及50%四聚體，存在極少剩餘單體。在293F細胞中表現獲得約70%二聚體。
亦已描述尼帕G蛋白之表現載體之構建。參見例如WO 2012/158643中之實例1及實例2。可用於本文中之特定尼帕病毒G蛋白多肽之較佳實例揭示於WO 2012/158643中，且包括例如：全長G蛋白(SEQ ID NO: 11)；其可溶性片段(SEQ ID NO:11之編碼胺基酸71-602)；及其中揭示之具有Ig(κ)前導序列之另一片段。一般而言，亨德拉病毒G糖蛋白之可溶性形式包含胞外域之全部或一部分，並且係由使G糖蛋白之跨膜結構域之全部或一部分及胞質尾之全部或一部分缺失而產生。編碼基因序列較佳為針對表現進行最佳化之密碼子。
可與亨德拉G抗原類似地產生尼帕G抗原，例如，如WO 2012/158643之實例3中所描述。
抗原用於大型動物時之較佳劑量處於約50至約200微克/劑量之範圍內，其中約100微克為最佳劑量。對於較小之動物，諸如狗，需要較少量，諸如5-50微克，例如約10微克、約15微克、約20微克、約25微克、約30微克、約35微克、約40微克、約45微克。
在某些實施例中，尼帕抗原及/或亨德拉抗原分別與SEQ ID NO 11及12有至多5%胺基酸不同。改變之胺基酸較佳經保守取代。以下八個群組各自含有用於對彼此進行保守取代之胺基酸：1)丙胺酸(A)、甘胺酸(G)；2)天冬胺酸(D)、麩胺酸(E)；3)天冬醯胺酸(N)、麩醯胺酸(Q)；4)精胺酸(R)、離胺酸(K)；5)異白胺酸(I)、白胺酸(L)、甲硫胺酸(M)、纈胺酸(V)；6)苯丙胺酸(F)、酪胺酸(Y)、色胺酸(W)；7)絲胺酸(S)、蘇胺酸(T)；及8)半胱胺酸(C)、甲硫胺酸(M) (參見例如Creighton, Proteins, W. H. Freeman and Co., N. Y. (1984))。
在諸多實施例中，其中亨德拉或尼帕抗原包含額外的片段(例如，純化標籤或Ig(κ)前導序列)，以便確定該抗原是否與SEQ ID NO 11或12具有至少95%一致性，比較時不包括此種額外的片段。
在其他實施例中，該抗原組分可包含載體，該載體包含編碼以上描述之胺基酸序列中之任一者的核酸序列。適合之載體包括痘病毒載體(例如，牛痘載體或金絲雀痘載體，諸如ALVAC)、腺病毒載體、SIRNAVAXSM
平台及其類似物。佐劑
本發明之疫苗為油包水(W/O)乳劑。多種油及其組合適用於本發明。此等油包括但不限於動物油、植物油以及非代謝性油。適合本發明之植物油之非限制性實例為玉米油、花生油、大豆油、椰子油及橄欖油。動物油之非限制性實例為鯊烷。非代謝性油之適合非限制性實例包括輕質礦物油、直鏈或分支鏈飽和油及其類似物。
在一組實施例中，用於本發明之佐劑調配物中之油為輕質礦物油。如本文中所使用，術語「礦物油」係指經由蒸餾技術獲自礦脂之液體烴的混合物。該術語與「液化石蠟」、「液體礦脂」及「白礦油」同義。該術語亦意欲包括「輕質礦物油」，亦即，類似地藉由蒸餾礦脂而獲得但具有比白礦油稍低之比重的油。參見例如Remington's Pharmaceutical Sciences, 第18版(Easton, Pa.: Mack Publishing Company, 1990, 第788及1323頁)。礦物油可獲自不同的商業來源，例如J. T. Baker (Phillipsburg, Pa.)、USB Corporation (Cleveland, Ohio)。較佳礦物油為可根據名稱DRAKEOL®獲自市面之輕質礦物油。
典型地，油相係以疫苗組合物之50%至95% (以體積計)之量、較佳以大於50%至85%之量、更佳以大於50%至60%之量且更佳以大於50%至52% v/v之量存在。該油相包括油及乳化劑(例如，SPAN® 80、TWEEN® 80等) (若存在任何此種乳化劑)。油相之體積計算為油之體積與乳化劑之體積的總和。因而，舉例而言，若油之體積為組合物之40%且乳化劑之體積為12%，則油相將以該組合物之52% v/v存在。類似地，若油係以約45%之量存在且乳化劑係以組合物之約6%之量存在，則該油相係以該組合物之約51% v/v存在。
在實施例之適用於本發明之所有佐劑/疫苗之子集中，油及油溶性乳化劑之體積百分比共為疫苗組合物之至少50%，例如50%至95% (以體積計)；較佳以大於50%至85%之量；更佳以50%至60%之量，且更佳以50-52% v/v之量。因而，舉例而言且不具限制性，該油可能以45%之量存在且該脂質可溶性乳化劑將以大於5% v/v之量存在。因而，油及油溶性乳化劑之體積百分比將共為至少50%。
在適用於本發明之所有疫苗之另一子集中，油之體積百分比為疫苗組合物之超過40%，例如40%至90% (以體積計)、40%至85%、43%至60%、44-50% v/v。
適用於本發明乳劑之乳化劑包括天然生物相容乳化劑及非天然合成表面活性劑。生物相容乳化劑包括磷脂化合物或磷脂混合物。較佳磷脂為磷脂醯膽鹼(卵磷脂)，諸如大豆卵磷酯或卵磷酯。可藉由對粗植物油進行水洗且分離並乾燥所得水合膠來獲得呈磷脂與三酸甘油酯之混合物形式的卵磷脂。可藉由針對利用丙酮洗滌來移除三酸甘油酯及植物油之後剩餘的丙酮不溶性磷脂及糖脂對混合物進行分餾來獲得精製產品。替代地，卵磷脂可獲自多個商業來源。其他適合之磷脂包括磷脂醯甘油、磷脂醯肌醇、磷脂醯絲胺酸、磷脂酸、心磷脂及磷脂醯乙醇胺。磷脂可自天然來源分離或用習知方式合成。
在其他實施例中，本文中使用之乳化劑不包括卵磷脂，或以不具免疫有效性之量使用卵磷脂。
適用於本發明之佐劑調配物中之非天然合成乳化劑包括基於去水山梨醇之非離子表面活性劑，例如經脂肪酸取代之去水山梨醇表面活性劑(可根據名稱SPAN®或ARLACEL®購自市面)、聚乙氧基化山梨醇脂肪酸酯(TWEEN®)、來自諸如蓖麻油之來源的聚乙二醇脂肪酸酯(EMULFOR®)；聚乙氧基化脂肪酸(例如，可根據名稱SIMULSOL® M-53獲得之硬脂酸)、聚乙氧基化異辛基酚/甲醛聚合物(TYLOXAPOL®)、聚氧乙烯脂肪醇醚(BRIJ®)；聚氧乙烯壬苯基醚(TRITON® N)、聚氧乙烯異辛基苯基醚(TRITON® X)。較佳合成表面活性劑為可根據名稱SPAN®及TWEEN®獲得之表面活性劑，諸如TWEEN®-80 (聚氧乙烯(20)去水山梨醇單油酸酯)及SPAN®-80 (去水山梨醇單油酸酯)。
一般而言，乳化劑可以0.01%至40% (以體積計)、較佳0.1%至15%、更佳2%至10%之量存在於疫苗組合物中。
本發明之佐劑調配物中存在之其他成分包括陽離子載劑及含CpG之免疫刺激寡核苷酸。此種佐劑形成包含免疫刺激寡核苷酸之W/O疫苗組合物，且聚陽離子載劑稱為「TXO」。
適合之陽離子載劑包括但不限於聚葡萄糖、DEAE (二乙基-胺基乙基)聚葡萄糖(及其衍生物)、PEG、瓜爾膠、殼聚糖衍生物、聚纖維素衍生物如羥乙基纖維素(HEC)、聚乙烯亞胺、聚胺基如聚離胺酸，及其類似物。
CpG寡核苷酸為一類醫藥治療劑，其特徵為在特定鹼基序列情況下存在未甲基化之CG二核苷酸(CpG基元)。(Hansel TT, Barnes PJ (編): New Drugs for Asthma, Allergy and COPD. Prog Respir Res. Basel, Karger, 2001, 第31卷, 第229-232頁，其係以引用之方式併入本文中)。此等CpG基元未見於真核生物DNA中(在真核生物DNA中，CG二核苷酸受到抑制並且當存在時通常經甲基化)，但存在於其賦予免疫刺激性質之細菌DNA中。
在所選實施例中，本發明之佐劑利用所謂的P類免疫刺激寡核苷酸，更佳為經修飾之P類免疫刺激寡核苷酸，甚至更佳為經E修飾之P類寡核苷酸。P類免疫刺激寡核苷酸為CpG寡核苷酸，其特徵為存在一般6-20個核苷酸長之回文序列。P類寡核苷酸能夠在活體外及/或活體內自發自組裝成串聯體。此等寡核苷酸在嚴格意義上為單鏈的，但回文序列之存在允許形成串聯體或可能形成莖-環結構，以及二級及三級結構。P類免疫刺激寡核苷酸之總體長度介於19與100個核苷酸之間，例如19-30個核苷酸、30-40個核苷酸、40-50個核苷酸、50-60個核苷酸、60-70個核苷酸、70-80個核苷酸、80-90個核苷酸、90-100個核苷酸。
在本發明之一個態樣中，該免疫刺激寡核苷酸含有5' TLR活化結構域及至少兩個回文區，一個回文區為至少6個核苷酸長之5'回文區且直接或經由間隔子與至少8個核苷酸長之3'回文區連接。
可根據此項技術中已知的技術對P類免疫刺激寡核苷酸進行修飾。舉例而言，J修飾係指經碘基修飾之核苷酸。E修飾係指經乙基修飾之核苷酸。因而，經E修飾之P類免疫刺激寡核苷酸為P類免疫刺激寡核苷酸，其中至少一個核苷酸(較佳為5'核苷酸)經乙基化。其他修飾包括附接6-硝基-苯并咪唑、O-甲基化、用丙炔基-dU修飾、肌苷修飾、2-溴乙烯基附接(較佳至尿苷)。
P類免疫刺激寡核苷酸亦可含有經修飾之核苷酸間鍵聯，包括但不限於磷酸二酯鍵聯及硫代磷酸酯鍵聯。本發明之寡核苷酸可合成或獲自商業來源。
P類寡核苷酸及經修飾之P類寡核苷酸進一步揭示於2008年6月12日公開之公開PCT申請案第WO2008/068638號中。以下提供經修飾之P類免疫刺激寡核苷酸之適合非限制性實例(在SEQ ID NO 1-10中，「*」係指硫代磷酸酯鍵且「_」係指磷酸二酯鍵)。
在TXO佐劑中，該免疫刺激寡核苷酸(較佳為ODN，較佳含有回文序列，且視情況具有經修飾之主鏈)可能以每劑量0.5-400 μg之量存在，且該聚陽離子載劑可能以每劑量0.5-400 mg之量存在。劑量視標的物質而變化。
舉例而言，在某些更適合成豬之實施例中，一劑量之TXO將包含約50與400 μg之間(例如，對於成豬，50-300或100-250 μg，或者約50至約100 μg)免疫刺激寡核苷酸，且聚陽離子載劑可能以介於每劑量約5與約500 mg之間(例如，每劑量10-500 mg或10-300 mg或50-200 mg)的量存在。在更適合仔豬之實施例中，一劑量之TXO將包含介於約5與100 μg之間(例如，10-80 μg或20-50 μg)的免疫刺激寡核苷酸，而聚陽離子載劑可能以每劑量1-50 mg (例如，每劑量1-25 mg，或每劑量10-25 mg)之量存在。
可如下製備TXO佐劑：
a) 將去水山梨醇單油酸酯溶解於輕質礦物油中。對所得油溶液進行無菌過濾；
b) 將免疫刺激寡核苷酸、DEAE聚葡萄糖及聚氧乙烯(20)去水山梨醇單油酸酯溶解於水相中，因而形成水溶液；及
c) 在連續均質化作用下將水溶液添加至油溶液，因而形成佐劑調配物TXO。
可在製備水相之步驟將抗原添加至免疫刺激寡核苷酸與聚陽離子載劑之混合物中。
該疫苗可進一步包含其他免疫調節分子，包括但不限於皂苷(例如，Quil A或其經純化之級分)；糖脂，例如BAY®R1005 (無論是呈鹽形式或是鹼形式)、MPLA、固醇(例如膽固醇)、陽離子化固醇(例如，3β-[N-(N',N'-二甲基胺基乙烷)-胺甲醯基]膽固醇，亦稱為DC-膽固醇)、磷脂(例如，卵磷脂)；明礬；四級胺，例如DDA (二甲基二(十八烷基)銨)；及其類似物。
該疫苗可進一步包含不同的醫藥學上可接受之賦形劑，例如緩衝劑、pH值及/或滲透壓調節劑及/或防腐劑。舉例而言，氯甲酚可用作防腐劑，其量為每劑量0.01%至0.5% w/v，更佳為0.05%至0.2%，最佳為約0.1%。其他適合之賦形劑包括：乙酸及鹽(1-2% w/v)；檸檬酸及鹽(1-3% w/v)；硼酸及鹽(0.5-2.5% w/v)；以及磷酸及鹽(0.8-2% w/v)。適合之防腐劑包括苯紮氯銨(0.003-0.03% w/v)；氯丁醇(0.3-0.9% w/v)；對羥苯甲酸酯(0.01-0.25% w/v)及硫柳汞(0.004-0.02% w/v)及其組合。
非經腸調配物典型地為水溶液，其可含有賦形劑，諸如鹽、碳水化合物及緩衝劑(較佳達至約3至約9或約4至約8或約5至約7.5或約6至約7.5或約7至約7.5之pH值)，但對於一些應用，其可經更適當調配而呈無菌非水溶液或呈乾燥形式以便與諸如無菌無熱原水之適合媒劑聯合使用。
可使用熟習此項技術者熟知的標準醫藥技術容易地實現在無菌條件下製備非經腸調配物，例如藉由凍乾。
疫苗之體積可變化。一般而言，用於豬隻之標準劑量為每次投與約2 ml疫苗。在不同的實施例中，該體積可變化，例如0.125 ml至約5 ml，例如2 ml、1 ml、0.5 ml、0.25 ml等。減小之體積將仍為油包水乳劑，較佳含有50%或更多油相。抗原、聚陽離子載劑及含CpG之免疫刺激寡核苷酸之量較佳將與標準2 ml劑量中相同。在至少兩個態樣中，此種微劑量給藥為有利的。首先，減輕動物之疼痛；其次，對於家畜尤其重要，減少量之油將代謝得更快且因而減少屠宰停藥期(亦即，疫苗接種與管制機關允許屠宰之間的時間)。
目前，市場上不存在含有尼帕抗原之疫苗，且僅有一種含有亨德拉抗原之疫苗。EQUIVAC® Hendra (Zoetis)含有來源於亨德拉G蛋白質之抗原且佐以ISCOM (免疫刺激複合物)。EQUIVAC® Hendra係經肌肉內投與。適當處理方案需要初次投與及加強投與兩者(其中加強投與在初次投與之後約三週)以及每年再接種。相比之下，本文中描述之疫苗僅投與一次(與初次投與及加強投與相反)與每年再接種。
本說明書中所引用之所有出版物(專利出版物與非專利出版物兩者)均指示熟習本發明所屬領域之技術者的技術水平。所有此等出版物係以引用之方式完全併入本文中，其程度如同明確地且個別地指示各個別出版物係以引用之方式併入。
儘管本文中已參考特定實施例描述本發明，但應理解，此等實施例僅說明本發明之原理及應用。因此，應理解，可在不背離如以下申請專利範圍所定義之本發明之精神及範疇的情況下對該等說明性實施例進行眾多修改並且可計劃其他安排。
圖1及圖2說明SEQ ID NO: 11及12，其分別為尼帕病毒及亨德拉病毒之G糖蛋白。
<110> 美商碩騰服務有限責任公司(Zoetis Services LLC)
<120> 針對亨德拉(HENDRA)及尼帕(NIPAH)病毒感染之疫苗
<140> TW107146014
<141> 2018-12-19
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Claims (9)
- 一種單次劑量疫苗之用途，其係用於製備保護動物免受亨德拉(Hendra)或尼帕(Nipah)病毒感染之藥物，該疫苗包含：a)抗原組分，其包含亨德拉抗原或尼帕抗原；及b)佐劑，其包含非代謝性油、DEAE聚葡萄糖及含CpG之免疫刺激寡核苷酸，其中該疫苗為W/O乳劑。
- 如請求項1之用途，其中該動物為豬科動物，且該尼帕抗原包含與SEQ ID NO：11或與其胺基酸71-602具有至少95%一致性之胺基酸序列。
- 如請求項2之用途，其中該胺基酸序列與SEQ ID NO：11或其胺基酸71-602具有至少98%一致性。
- 如請求項1之用途，其中該動物為馬科動物，且該亨德拉抗原包含與SEQ ID NO：12或其胺基酸73-604具有至少95%一致性之胺基酸序列。
- 如請求項4之用途，其中該胺基酸序列與SEQ ID NO：12或其胺基酸73-604具有至少98%一致性。
- 如請求項1之用途，其中該非代謝性油為輕質礦物油。
- 如請求項1至6中任一項之用途，其中該動物先前未接種針對亨德拉或尼帕病毒之疫苗。
- 如請求項1至6中任一項之用途，其中該單次劑量之疫苗具有約0.125ml至約2ml之體積。
- 如請求項8之用途，其中該單次劑量之疫苗具有約0.25ml至約1ml之體積。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762608092P | 2017-12-20 | 2017-12-20 | |
| US62/608,092 | 2017-12-20 |
Publications (2)
| Publication Number | Publication Date |
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| TW201929658A TW201929658A (zh) | 2019-08-01 |
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| AU2005327194B2 (en) | 2004-07-09 | 2010-09-09 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Soluble forms of Hendra and Nipah virus G glycoprotein |
| EP1861424B1 (en) | 2005-03-14 | 2011-03-30 | The Government of the United States of America as represented by The Secretary of the Department of Health and Human Services | Human monoclonal antibodies against hendra and nipah viruses |
| CN101208104B (zh) * | 2005-04-25 | 2012-10-31 | 梅瑞尔有限公司 | Nipah病毒疫苗 |
| SI1957528T1 (sl) * | 2005-11-30 | 2013-02-28 | University Of Copenhagen | Nukleotidno cepivo |
| NZ575437A (en) | 2006-09-27 | 2012-02-24 | Coley Pharm Gmbh | Cpg oligonucleotide analogs containing hydrophobic t analogs with enhanced immunostimulatory activity |
| WO2009117035A1 (en) | 2007-12-19 | 2009-09-24 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Soluble forms of hendra and nipah virus f glycoprotein and uses thereof |
| JP6073031B2 (ja) * | 2009-12-28 | 2017-02-01 | タケダ ヴァクシーンズ， インコーポレイテッド | インフルエンザ抗原のエンベロープウイルスベースのウイルス様粒子溶液を安定化させる方法 |
| WO2012149536A1 (en) * | 2011-04-28 | 2012-11-01 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Neutralizing antibodies to nipah and hendra virus |
| PT2707025T (pt) * | 2011-05-13 | 2017-08-31 | Zoetis Services Llc | Composições imunogénicas contra a glicoproteína g de vírus hendra e nipah |
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| EP3082856A1 (en) * | 2013-12-16 | 2016-10-26 | Zoetis Services LLC | Hendra and nipah virus g glycoprotein immunogenic compositions |
| CN114699518A (zh) * | 2015-01-16 | 2022-07-05 | 硕腾服务有限责任公司 | 口蹄疫疫苗 |
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| TW201929658A (zh) | 2019-08-01 |
| CN111511398A (zh) | 2020-08-07 |
| BR112020011962A2 (pt) | 2020-11-17 |
| JP7370983B2 (ja) | 2023-10-30 |
| AU2018390817A1 (en) | 2020-06-25 |
| PH12020550948A1 (en) | 2021-05-17 |
| EP3727443A1 (en) | 2020-10-28 |
| KR20200090836A (ko) | 2020-07-29 |
| KR20230039766A (ko) | 2023-03-21 |
| JP2021506911A (ja) | 2021-02-22 |
| US20210008195A1 (en) | 2021-01-14 |
| WO2019126110A1 (en) | 2019-06-27 |
| CN117323424A (zh) | 2024-01-02 |
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