呼吸道合胞病毒RSV疫苗

呼吸道合胞病毒RSV背景資料1.1呼吸道合胞病毒肺炎呼吸道合胞病毒肺炎（respiratorysyncytialviruspneumonia）簡稱合胞病毒肺炎，臨床表現(xiàn)為咳嗽、流鼻涕、發(fā)燒、有時喘息，與流感癥狀相似，是一種小兒常見的間質(zhì)性肺炎，多發(fā)生于嬰幼兒。由于母傳抗體不能預(yù)防感染的發(fā)生，出生不久的小嬰兒即可發(fā)病，但新生兒較少見。國外偶有院內(nèi)感染導(dǎo)致產(chǎn)科醫(yī)院新生兒病房爆發(fā)流行的報道。在北京，48%的病毒性肺炎和58%的毛細(xì)支氣管炎系由合胞病毒引起（1980～1984）；在廣州，小兒肺炎及毛細(xì)支氣管炎的31.4%由合胞病毒引起（1973～1986）；在美國，20%～25%的嬰幼兒肺炎和50%～75%的毛細(xì)支氣管炎由合胞病毒引起。1.2人類呼吸道合胞病毒人類呼吸道合胞病毒（HumanRespiratorySyncytialVirus，簡稱HRSV或RSV）是引起小兒病毒性肺炎最常見的病原，可引起間質(zhì)性肺炎，及毛細(xì)支氣管炎。RSV為中型單股反鏈RNA病毒，屬于副粘液病毒科，肺病毒屬，只有一個血清型。RSV在電鏡下所見與副流感病毒類似，病毒顆粒大小約為150nm，較副流感病毒稍小，對乙醚敏感，無血球凝集性，在人上皮組織培養(yǎng)形成特有的合胞（syncytium），病毒在胞漿內(nèi)增殖，可見胞漿內(nèi)包涵體。1.3RSV分子生物學(xué)信息RSV基因組為長約15.2kb的單股負(fù)鏈RNA，編碼11種蛋白，包括3種跨膜包膜糖蛋白(F,G和小疏水蛋白SH)，1種基質(zhì)蛋白(M)，4種核衣殼蛋白(N,P,L和M2-1)，2種非結(jié)構(gòu)蛋白(NS1和NS2)為I型干擾素拮抗劑，1種RNA調(diào)節(jié)因子(M2-2)。其中G和F為主要中和抗原，能刺激機(jī)體產(chǎn)生血清中和抗體和呼吸道粘膜的分泌型sIgA，根據(jù)G蛋白抗原性差異分為A和B兩個亞型。N，F(xiàn)，P，NS2和M等蛋白可誘導(dǎo)機(jī)體產(chǎn)生CD8+細(xì)胞毒性T細(xì)胞(CTLs)。RSV疫苗2.1RSV疫苗研究背景由于呼吸道合胞病毒是引起嬰幼兒支氣管炎和肺炎的主要原因，也可導(dǎo)致免疫缺陷病人和老年人群發(fā)病和死亡。所以被世界衛(wèi)生組織WHO列為全球最優(yōu)先發(fā)展的疫苗之一。經(jīng)過多年研究RSV疫苗取得一些進(jìn)展，但尚未有疫苗上市。目前主要集中在亞單位疫苗和活疫苗的研究上，其中減毒活疫苗和活病毒載體疫苗最有可能用于預(yù)防嬰幼兒RSV感染而受到關(guān)注。20世紀(jì)60年代研制的福爾馬林滅活疫苗(FI-RSV)不僅不能防止嬰幼兒感染，而且接種后支氣管炎和肺炎發(fā)生率及嚴(yán)重程度大大增加，現(xiàn)在認(rèn)為至少2個原因?qū)е略摻Y(jié)果(1)FI-RSV未能誘導(dǎo)產(chǎn)生高親和力、有中和活性抗體，也未能產(chǎn)生保護(hù)性CD8+T細(xì)胞應(yīng)答，使得FI-RSV誘導(dǎo)產(chǎn)生的免疫力不足以控制RSV感染；(2)FI-RSV誘導(dǎo)產(chǎn)生了Th2偏向的CD4+T細(xì)胞應(yīng)答，介導(dǎo)的炎癥反應(yīng)導(dǎo)致疾病增強(qiáng)作用(ERD)發(fā)生。RSV天然感染不能產(chǎn)生持久免疫力,反復(fù)感染常見，作為疫苗主要目標(biāo)人群的新生兒免疫系統(tǒng)發(fā)育不成熟，難以產(chǎn)生高效價及高親和力的抗體,同時體內(nèi)存在的母傳抗體能介導(dǎo)免疫干擾或抑制作用。RSV存在兩種抗原亞型(A和B)的RSV,在同一個流行季節(jié)，不同亞型的RSV可引起再次感染等，這些因素對疫苗的安全性及免疫原性均提出了很高要求。因此,一個成功的RSV疫苗應(yīng)該具備以下特性:(1)在新生兒，甚至在母傳抗體存在的情況下，應(yīng)具有較好的免疫原性；(2)能有效預(yù)防由野生型RSV(wtRSV)初次感染引起的LRI；(3)能同時為預(yù)防兩種亞型RSV感染提供保護(hù)作用；(4)在隨后的自然感染中,不會導(dǎo)致ERD。應(yīng)用分子生物學(xué)技術(shù)，主要評估兩類候選RSV疫苗的有效性，活的減毒疫苗和亞單位疫苗。RSV免疫計劃需要包含不同疫苗用于不同目標(biāo)群體如不滿一周歲嬰兒，孕婦和高危人群。用于預(yù)防不滿2周歲兒童感染RSV的產(chǎn)品Palivizumab——一種人源化鼠單克隆抗體，直接作用于RSV表面融合蛋白，可用于預(yù)防感染。2.2國內(nèi)外研究現(xiàn)狀國內(nèi)外早期主要集中于減毒疫苗和滅活疫苗的研究，最近幾年關(guān)于亞單位疫苗和病毒載體疫苗研究較多。國內(nèi)現(xiàn)在主要集中研究RSV基因工程疫苗，包括亞單位疫苗、病毒載體疫苗、減毒沙門氏菌載體疫苗等方面，但沒有進(jìn)入臨床研究階段的疫苗。國外多家公司對RSV疫苗進(jìn)行了研究，主要研究疫苗類型包括：減毒活疫苗、全病毒滅活疫苗、病毒樣顆粒、亞單位疫苗、核酸疫苗、基因載體疫苗、組合疫苗等，其中減毒活疫苗和病毒樣顆粒進(jìn)入臨床二期。國外各公司具體研究階段如下：嬰幼兒主動免疫用減毒活疫苗包括兩類：副粘病毒載體疫苗(嵌合B/HPIV3:MEDI534帶RSVF的仙臺病毒載體)和減毒活RSV疫苗(MEDI559，RSVMEDIΔM2-2)。RSV融合糖蛋白(F)是主要的亞單位疫苗來源，大多數(shù)中和抗體目標(biāo)蛋白為RSVF，但以前的RSVF疫苗(PFP-1，2，3；RSVF/G/M)不能誘導(dǎo)產(chǎn)生高滴度中和抗體，并且難以實現(xiàn)工業(yè)化生產(chǎn)。最近研究清楚了RSVF蛋白結(jié)構(gòu)，對生產(chǎn)疫苗有指導(dǎo)意義，RSVF蛋白存在融合前和融合后狀態(tài)，融合前F不是天然狀態(tài)，來自諾華、NIAID和NIH最新研究數(shù)據(jù)表明，融合后RSVF具有某些中和抗原決定簇，包括帕利珠單抗決定簇。另有研究表明，人血清中的大部分中和抗體(RSVIg)作用于融合后RSVF蛋白。諾瓦瓦克斯Novavax研制的RSVF納米顆粒疫苗已經(jīng)進(jìn)入臨床實驗評估階段，2013年4月2日做出臨床2期報告。RSV的F蛋白進(jìn)行點突變P102A，I379V，M447V，弗林蛋白酶切位點突變：R133Q，R135Q，R136Q，137-146aa缺失，F(xiàn)2的隱含多聚A位點包含一個修飾。通過構(gòu)建桿狀病毒載體在昆蟲細(xì)胞Sf9中表達(dá)形成納米顆粒三聚體。通過對蛋白點突變和修飾減少RSVF蛋白的細(xì)胞毒性，經(jīng)修飾的蛋白表現(xiàn)為融合后“棒棒糖”形態(tài)而非融合前“桿狀”形態(tài)，并且表達(dá)量增加，免疫原性增強(qiáng)。臨床實驗驗證RSV候選疫苗用于育齡婦女，結(jié)果支持進(jìn)入下期臨床實驗。驗證了疫苗用于產(chǎn)婦的安全性和免疫原性。免疫接種的婦女將自然將抗體轉(zhuǎn)移給胎兒，可以早期被動保護(hù)嬰兒免受RSV感染。諾華的融合后RSVF三聚物疫苗臨床前實驗表明可誘導(dǎo)產(chǎn)生高滴度RSV中和抗體，保護(hù)抵御病毒感染。葛蘭素史克GlaxoSmithKline的RSV疫苗進(jìn)入一期臨床，該疫苗為真核CHO細(xì)胞表達(dá)的可溶性RSVF多肽，包含N端信號肽，F(xiàn)2域(26-105aa)，去掉弗林蛋白酶識別位點pep27域(105-109aa,133-136aa)，添加的融合肽，F(xiàn)1域(137-516aa)，添加的卷曲螺旋(異源穩(wěn)定化域如異亮氨酸拉鏈域，促進(jìn)多個具有此類域的多肽三聚化)，G蛋白多肽(149-229aaor184-198aa)。另外通過L512K增加穩(wěn)定性，多肽之間的接頭可選GG或更長接頭GGSGGSGGS。2013年5月29日葛蘭素史克合并OkairosAG公司，Okairos基于黑猩猩腺病毒(ChAd)和MVA載體(攜帶RSV的F、N和M抗原基因)構(gòu)建了RSV基因疫苗，能夠誘導(dǎo)機(jī)體產(chǎn)生中和抗體和CD8+T細(xì)胞，在嚙齒動物和靈長類中具有安全性和高免疫原性，具有保護(hù)線鼠不被RSV感染的能力。知識產(chǎn)權(quán)分析3.1國內(nèi)相關(guān)專利以“呼吸道合胞病毒疫苗”為檢索詞，檢索結(jié)果10篇，5篇失效，結(jié)果如下：專利號名稱和申請單位申請日期或優(yōu)先權(quán)內(nèi)容CN200610121540.0從克隆的核苷酸序列制備減毒呼吸道合胞病毒疫苗的方法美國政府健康及人類服務(wù)部19960715一種分離的感染性重組RSV，突變株的多個減毒突變的重組修飾。CN201080042586.8抗RSV免疫原和免疫方法美國政府疾病控制和預(yù)防中心20090804一種呼吸道合胞病毒疫苗，包含引起保護(hù)性免疫響應(yīng)的免疫原，所述免疫原包含如下的氨基酸序列：(i)NO：1的第164~176aa；(ii)NO：1的163~190aa、NO：7的163~190aa、NO：8的163~190aa或其類似物；或(iii)NO：1的155~206aa或其類似物。CN201180064939.9呼吸道合胞病毒疫苗佛蘭芒綜合大學(xué)生物技術(shù)研究所/國立比利時根特大學(xué)20101115疫苗包含RSV編碼的小疏水(SH)蛋白的胞外域SHe的重組亞單位疫苗。該胞外域作為寡聚體呈遞、甚至作為五聚體呈遞。還涉及抗該胞外域或?qū)υ摪庥蛱禺惖目贵w，及其在保護(hù)個體免受RSV感染和/或治療受感染的個體中的用途。CN201010589346.1一種呼吸道合胞病毒體疫苗及其制備方法軍事醫(yī)學(xué)科學(xué)院微生物流行病研究所20101208該疫苗含有RSV的完整病毒表面所組成的病毒體(Virosome)，即RSVirosome，具有和活病毒完全一致的表面結(jié)構(gòu)和功能；還攜帶有RSV天然病毒的表面G、F、SH糖蛋白及脂質(zhì)雙脂層有效抗原成分，其中，所述Virosome包括A和B亞型CN201110458973.6一種呼吸道合胞病毒疫苗及其制備方法上海澤潤生物科技有限公司20111230包括下列步驟：a.在培養(yǎng)基吸附培養(yǎng)Vero細(xì)胞；b.人呼吸道合胞病毒的分離，接種，培養(yǎng)；c.獲得病毒-細(xì)胞培養(yǎng)懸液；d.純化病毒制備疫苗。以“呼吸道合胞病毒AND疫苗”為檢索詞，檢索結(jié)果43篇，失效23篇，實質(zhì)審查10篇，有效專利9篇，公開發(fā)明1篇，與本研究有關(guān)專利如下：專利號名稱和申請單位申請日期和優(yōu)先權(quán)內(nèi)容CN201310090044.3呼吸道合胞病毒F蛋白與Fc的融合蛋白及其用途中科院武漢病毒所2013-03-20一種融合蛋白F-Fc，融合蛋白含有RSV的F蛋白與人IgG1恒定區(qū)Fc片段。CN201080036364.5納米乳劑疫苗密執(zhí)安大學(xué)2010-06-1620090616一種免疫原性組合物，其包含納米乳劑滅活的呼吸道合胞病毒(RSV)。CN201080037430.0疫苗魁北克益得/葛蘭素2010-06-2420090624免疫原性組合物，其包含至少兩種選自人間質(zhì)肺炎病毒(hMPV)、副流感病毒3(PIV-3)和呼吸道合胞病毒(RSV)的副粘病毒F蛋白抗原。CN200880127407.3重組RSV抗原魁北克益得/葛蘭素2008-12-2320071224一種重組RSV抗原，包含可溶性F蛋白多肽，包含至少一處穩(wěn)定所述F蛋白的融合前構(gòu)象的修飾。CN201080037770.3重組RSV抗原魁北克益得/葛蘭素2010-06-2420090624重組RSV抗原，含有RSV-F蛋白多肽的F2和F1結(jié)構(gòu)域的可溶性F蛋白多肽，包含至少一個使糖基化改變修飾。CN200980156344.9修飾的RSVF蛋白及其使用方法。諾瓦瓦克斯股份2009-12-0920081209一種RSV融合F蛋白，其包含至少一種增加所述RSVF蛋白在宿主細(xì)胞中的表達(dá)的修飾或突變。3.2國外相關(guān)專利以“RSVvaccine”為檢索詞，檢索美國專利共6個，具體如下：專利號名稱申請日期內(nèi)容17,846,455Attenuatedchimericrespiratorysyncytialvirus20031125感染型RSV含N,P,L,M2,RSVa基因組含RSVb的F和G,刪除SH,NS1/2,M2,Ggene27,709,007Productionofattenuatedrespiratorysyncytialvirusvaccinesfromclonednucleotidesequences20040902RSV含N,P,L,M2,刪除SH,NS1,NS2,Ggene37,485,440ProductionofattenuatedrespiratorysyncytialvirusvaccinesinvolvingmodificationofM2ORF246,713,066ProductionofattenuatedrespiratorysyncytialvirusvaccinesinvolvingmodificationofM2ORF220000707RSV含N,P,L,M2(ORF1),插入終止子刪除M2(ORF2)56,689,367Productionofattenuatedchimericrespiratorysyncytialvirusvaccinesfromclonednucleotidesequences19990413RSV含N,P,L,M2(ORF1)65,993,824Productionofattenuatedrespiratorysyncytialvirusvaccinesfromclonednucleotidesequences19970715以“respiratorysyncytialvirusvaccine”為檢索詞，檢索歐洲專利共118個，如下：名稱申請日期優(yōu)先號HUMANRESPIRATORYSYNCYTIALVIRUSVACCINE20120706US201161504989P20110706VaccineagainstRSV20130322EP2012016068220120322VaccineagainstRSV20130322EP2012001606820120322IMMUNOSTIMULATORYCOMPOSITIONSCOMPRISINGLIPOSOME-ENCAPSULATEDOLIGONUCLEOTIDESANDEPITOPES20100616KR2009006549520090717RESPIRATORYSYNCYTIALVIRUSVACCINE20111115US20100458012P20101115COMBINEDANTIGENANDDNAVACCINEFORPREVENTINGANDTREATINGRSVINFECTION20120806CN201213032520120210FusionproteinofRSV(respiratorysyncytialvirus)proteinFandFc,andapplicationthereof20130320CN201319004420130320Respiratorysyncytialvirusvaccineandpreparationmethodthereof20111230CN2011145897320111230Shark-derivedsqualenecontaininglowlevelsofpolychlorinatedbiphenylcontaminantsforuseinvaccineadjuvants20120104NZ2012059740520120104CATTLEREPRODUCTIVEDISEASEVACCINES20121228US20020405969P20020826RECOMBINANTNANOPARTICLERSVFVACCINEFORRESPIRATORYSYNCYTIALVIRUS20120927US201161542040P20110930GENETICALLYSTABLELIVEATTENUATEDRESPIRATORYSYNCYTIALVIRUSVACCINEANDITSPRODUCTION20130313US201261624010P20120413RECOMBINANTMODIFIEDVACCINIAVIRUSANKARA(MVA)RESPIRATORYSYNCYTIALVIRUS(RSV)VACCINE20130315US201261678367P20120801NANOEMULSIONRESPIRATORYSYNCYTIALVIRUS(RSV)SUBUNITVACCINE20120910US201161533062P20110909HUMANRESPIRATORYSYNCYTIALVIRUSVACCINE20120706US20121354349320120706

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