呼吸道合胞病毒RSV疫苗

呼吸道合胞病毒RSV
一、背景资料
1.1 呼吸道合胞病毒肺炎
呼吸道合胞病毒肺炎（respiratory syncytial virus pneumonia）简称合胞病毒肺炎，临床表现为咳嗽、流鼻涕、发烧、有时喘息，与流感症状相似，是一种小儿常见的间质性肺炎，多发生于婴幼儿。

由于母传抗体不能预防感染的发生，出生不久的小婴儿即可发病，但新生儿较少见。

国外偶有院内感染导致产科医院新生儿病房爆发流行的报道。

在北京，48%的病毒性肺炎和58%的毛细支气管炎系由合胞病毒引起（1980～1984）；在广州，小儿肺炎及毛细支气管炎的31.4%由合胞病毒引起（1973～1986）；在美国，20%～25%的婴幼儿肺炎和50%～75%的毛细支气管炎由合胞病毒引起。

1.2 人类呼吸道合胞病毒
人类呼吸道合胞病毒（Human Respiratory Syncytial Virus，简称HRSV或RSV）是引起小儿病毒性肺炎最常见的病原，可引起间质性肺炎，及毛细支气管炎。

RSV为中型单股反链RNA病毒，属于副粘液病毒科，肺病毒属，只有一个血清型。

RSV在电镜下所见与副流感病毒类似，病毒颗粒大小约为150nm，较副流感病毒稍小，对乙醚敏感，无血球凝集性，在人上皮组织培养形成特有的合胞（syncytium），病毒在胞浆内增殖，可见胞浆内包涵体。

1.3 RSV分子生物学信息
RSV基因组为长约15.2kb的单股负链RNA，编码11种蛋白，包括3种跨膜包膜糖蛋白(F,G和小疏水蛋白SH)，1种基质蛋白(M)，4种核衣壳蛋白(N,P,L 和M2-1)，2种非结构蛋白(NS1和NS2)为I型干扰素拮抗剂，1种RNA调节因子(M2-2)。

其中G和F为主要中和抗原，能刺激机体产生血清中和抗体和呼吸道粘膜的分泌型sIgA，根据G蛋白抗原性差异分为A和B两个亚型。

N，F，P，NS2和M等蛋白可诱导机体产生CD8+细胞毒性T细胞(CTLs)。

二、RSV疫苗
2.1 RSV疫苗研究背景
由于呼吸道合胞病毒是引起婴幼儿支气管炎和肺炎的主要原因，也可导致免疫缺陷病人和老年人群发病和死亡。

所以被世界卫生组织WHO列为全球最优先发展的疫苗之一。

经过多年研究RSV疫苗取得一些进展，但尚未有疫苗上市。

目前主要集中在亚单位疫苗和活疫苗的研究上，其中减毒活疫苗和活病毒载体疫苗最有可能用于预防婴幼儿RSV感染而受到关注。

20世纪60年代研制的福尔马林灭活疫苗(FI-RSV)不仅不能防止婴幼儿感染，而且接种后支气管炎和肺炎发生率及严重程度大大增加，现在认为至少2个原因导致该结果(1)FI-RSV未能诱导产生高亲和力、有中和活性抗体，也未能产生保护性CD8+T细胞应答，使得FI-RSV诱导产生的免疫力不足以控制RSV感染；
(2)FI-RSV诱导产生了Th2偏向的CD4+T细胞应答，介导的炎症反应导致疾病增强作用(ERD)发生。

RSV 天然感染不能产生持久免疫力, 反复感染常见，作为疫苗主要目标人群的新生儿免疫系统发育不成熟，难以产生高效价及高亲和力的抗体, 同时体内存在的母传抗体能介导免疫干扰或抑制作用。

RSV存在两种抗原亚型(A和B)的RSV, 在同一个流行季节，不同亚型的RSV可引起再次感染等，这些因素对疫苗的安全性及免疫原性均提出了很高要求。

因此, 一个成功的
RSV 疫苗应该具备以下特性: (1)在新生儿，甚至在母传抗体存在的情况下，应具有较好的免疫原性；(2)能有效预防由野生型RSV(wt RSV)初次感染引起的LRI；
(3)能同时为预防两种亚型RSV感染提供保护作用；(4)在随后的自然感染中, 不会导致ERD。

应用分子生物学技术，主要评估两类候选RSV疫苗的有效性，活的减毒疫苗和亚单位疫苗。

RSV免疫计划需要包含不同疫苗用于不同目标群体如不满一周岁婴儿，孕妇和高危人群。

用于预防不满2周岁儿童感染RSV的产品Palivizumab——一种人源化鼠单克隆抗体，直接作用于RSV表面融合蛋白，可用于预防感染。

2.2 国内外研究现状
国内外早期主要集中于减毒疫苗和灭活疫苗的研究，最近几年关于亚单位疫苗和病毒载体疫苗研究较多。

国内现在主要集中研究RSV基因工程疫苗，包括亚单位疫苗、病毒载体疫苗、减毒沙门氏菌载体疫苗等方面，但没有进入临床研究阶段的疫苗。

国外多家公司对RSV疫苗进行了研究，主要研究疫苗类型包括：减毒活疫苗、全病毒灭活疫苗、病毒样颗粒、亚单位疫苗、核酸疫苗、基因载体疫苗、组合疫苗等，其中减毒活疫苗和病毒样颗粒进入临床二期。

国外各公司具体研究阶段如下：
1)婴幼儿主动免疫用减毒活疫苗包括两类：副粘病毒载体疫苗(嵌合
B/HPIV3:MEDI534带RSV F的仙台病毒载体)和减毒活RSV疫苗(MEDI559，RSV MEDIΔM2-2)。

2)RSV融合糖蛋白(F)是主要的亚单位疫苗来源，大多数中和抗体目标蛋白为
RSV F，但以前的RSV F疫苗(PFP-1，2，3；RSV F/G/M)不能诱导产生高滴
度中和抗体，并且难以实现工业化生产。

最近研究清楚了RSV F蛋白结构，对生产疫苗有指导意义，RSV F蛋白存在融合前和融合后状态，融合前F不是天然状态，来自诺华、NIAID和NIH最新研究数据表明，融合后RSV F 具有某些中和抗原决定簇，包括帕利珠单抗决定簇。

另有研究表明，人血清中的大部分中和抗体(RSVIg)作用于融合后RSV F蛋白。

3)诺瓦瓦克斯Novavax研制的RSV F纳米颗粒疫苗已经进入临床实验评估阶段，
2013年4月2日做出临床2期报告。

RSV的F蛋白进行点突变P102A，I379V，M447V，弗林蛋白酶切位点突变：R133Q，R135Q，R136Q，137-146aa缺失，F2的隐含多聚A位点包含一个修饰。

通过构建杆状病毒载体在昆虫细胞Sf9中表达形成纳米颗粒三聚体。

通过对蛋白点突变和修饰减少RSV F蛋白的细胞毒性，经修饰的蛋白表现为融合后“棒棒糖”形态而非融合前“杆状”形态，并且表达量增加，免疫原性增强。

临床实验验证RSV候选疫苗用于育龄妇女，结果支持进入下期临床实验。

验证了疫苗用于产妇的安全性和免疫原性。

免疫接种的妇女将自然将抗体转移给胎儿，可以早期被动保护婴儿免受RSV感染。

4)诺华的融合后RSV F三聚物疫苗临床前实验表明可诱导产生高滴度RSV中
和抗体，保护抵御病毒感染。

5)葛兰素史克GlaxoSmithKline的RSV疫苗进入一期临床，该疫苗为真核CHO
细胞表达的可溶性RSV F多肽，包含N端信号肽，F2域(26-105aa)，去掉弗林蛋白酶识别位点pep27域(105-109aa,133-136aa)，添加的融合肽，F1域(137-516aa)，添加的卷曲螺旋(异源稳定化域如异亮氨酸拉链域，促进多个具有此类域的多肽三聚化)，G蛋白多肽(149-229aa or 184-198aa)。

另外通过L512K增加稳定性，多肽之间的接头可选GG或更长接头GGSGGSGGS。

2013年5月29日葛兰素史克合并Okairos AG公司，Okairos基于黑猩猩腺病毒(ChAd)和MV A载体(携带RSV的F、N和M抗原基因)构建了RSV基因疫苗，能够诱导机体产生中和抗体和CD8+T细胞，在啮齿动物和灵长类中具有安全性和高免疫原性，具有保护线鼠不被RSV感染的能力。

三、知识产权分析
3.1 国内相关专利
3.2 国外相关专利
以“RSV vaccine”为检索词，检索美国专利共6个，具体如下：
专利号名称申请日期内容
17,846,455Attenuated chimeric respiratory syncytial virus 20031125感染型RSV含N,P,L, M2,RSVa
基因组含RSVb的F和G, 删
除SH,NS1/2,M2,G gene
27,709,007Production of attenuated respiratory syncytial virus vaccines from cloned nucleotide
sequences 20040902RSV含N,P,L,M2,删除SH,NS1,
NS2,G gene
37,485,440Production of attenuated respiratory syncytial virus vaccines involving modification of M2
ORF2
46,713,066Production of attenuated respiratory syncytial virus vaccines involving modification of M2
ORF2 20000707RSV含N,P,L,M2(ORF1),插入
终止子删除M2(ORF2)
56,689,367Production of attenuated chimeric respiratory
syncytial virus vaccines from cloned
nucleotide sequences
19990413RSV含N,P,L,M2(ORF1)
65,993,824Production of attenuated respiratory syncytial
virus vaccines from cloned nucleotide
sequences
19970715
以“respiratory syncytial virus vaccine”为检索词，检索欧洲专利共118个，如下：
名称申请日期优先号
HUMAN RESPIRATORY SYNCYTIAL VIRUS VACCINE 20120706US201161504989P
20110706 Vaccine against RSV 20130322EP20120160682
20120322 Vaccine against RSV 20130322EP20120016068
20120322
IMMUNOSTIMULATORY COMPOSITIONS COMPRISING LIPOSOME-ENCAPSULATED OLIGONUCLEOTIDES AND EPITOPES 20100616KR20090065495
20090717
RESPIRATORY SYNCYTIAL VIRUS VACCINE 20111115US20100458012P
20101115
COMBINED ANTIGEN AND DNA VACCINE FOR PREVENTING AND TREATING RSV INFECTION 20120806CN2012130325
20120210
Fusion protein of RSV (respiratory syncytial virus) protein F and Fc, and application thereof 20130320CN2013190044
20130320
Respiratory syncytial virus vaccine and preparation method thereof 20111230CN20111458973
20111230
Shark-derived squalene containing low levels of polychlorinated biphenyl contaminants for use in vaccine adjuvants 20120104NZ20120597405
20120104
CATTLE REPRODUCTIVE DISEASE VACCINES 20121228US20020405969P
20020826
RECOMBINANT NANOPARTICLE RSV F VACCINE FOR RESPIRATORY SYNCYTIAL VIRUS 20120927US201161542040P
20110930
GENETICALLY STABLE LIVE ATTENUATED RESPIRATORY SYNCYTIAL VIRUS VACCINE AND ITS PRODUCTION 20130313US201261624010P
20120413
RECOMBINANT MODIFIED VACCINIA VIRUS ANKARA (MVA) RESPIRATORY SYNCYTIAL VIRUS (RSV) VACCINE 20130315US201261678367P
20120801
NANOEMULSION RESPIRATORY SYNCYTIAL VIRUS (RSV) SUBUNIT VACCINE 20120910US201161533062P
20110909
HUMAN RESPIRATORY SYNCYTIAL VIRUS VACCINE 20120706US201213543493
20120706
US201161504989P
PARAMYXOVIRUS IMMUNOGENS AND RELATED MATERIALS AND METHODS 20120611US201161495119P
20110609
ADENOVIRAL VECTOR-BASED RESPIRATORY SYNCYTIAL VIRUS (RSV) VACCINE 20121005US201161543495P
20111005
US201161543506P
20111005
US201161543520P
20111005
Vaccine 20100624US20090219958P
20090624
WO2010EP59006
20100624
F-PROTEIN OF RESPIRATORY SYNCYTIAL VIRUS AND ITS USE 20071218DE20061060799
20061221
VACCINE COMPOSITION FOR RESPIRATORY SYNCYTIAL VIRUS AND MANUFACTURING METHOD THEREOF 20111021KR20100102976
20101021
ENGINEERED RESPIRATORY SYNCYTIAL VIRUSES WITH CONTROL OF CELL-TO-CELL VIRUS TRANSMISSION FOR ENHANCED SAFETY OF LIVE VIRUS VACCINES 20120601US201161492261P
20110601
Replication-Defective Flavivirus Vaccine Vectors Against Respiratory Syncytial Virus 20100316US201013256565
20100316
US20090210305P
20090316
WO2010US27552
20100316
RECOMBINANT PARAINFLUENZA VIRUS VACCINE COMPRISING HETEROLOGOUS ANTIGENS DERIVED FROM RESPIRATORY SYNCYTIAL VIRUS 20101020US20030466181P
20030425
ANTIBODY AGAINST AND METHOD FOR PRODUCING VACCINE FOR RESPIRATORY SYNCYTIAL VIRUS 20110822US20040611313P
20040921
RECOMBINANT PARAINFLUENZA VIRUS EXPRESSION SYSTEMS AND VACCINES COMPRISING HETEROLOGOUS ANTIGENS DERIVED FROM METAPNEUMOVIRUS 20030221US20020358934P
20020221
CA20032477235
20030221
PLANT-DERIVED VACCINES AGAINST RESPIRATORY SYNCYTIAL VIRUS 20110729US201113194194
20110729
US20100847401
20100730
US20040947211
20040923
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20000510
US199********P
Novel vaccine composition for the treatment of respiratory infectious diseases 20080313EP20070290319
20070314 Human respiratory syncytial virus (RSV) vaccine 20090720TW20090124475
20090720
Mycobacterium tuberculosis TB10.4-F1 fusion protein vaccine and preparation method thereof 20110531CN20111144443
20110531
Mycobacterium tuberculosis ESAT-6-F2 fusion protein subunit vaccine and preparation method thereof 20110531CN20111144002
20110531
RESPIRATORY SYNCYTIAL VIRUS (RSV) VACCINE 20110811US20100372725P
20100811 Respiratory syncytial virosome vaccine and preparation method thereof 20101208CN20101589346
20101208
INACTIVATED COMBINED VACCINE AGAINST INFECTIOUS RHINOTRACHEITIS, PARAFLU-3, RESPIRATORY SYNCYTIAL DISEASE, VIRAL DIARRHEA AND PASTEURELLOSIS OF CATTLE 20090629RU20090124616
20090629
Respiratory syncytial virus-like particle vaccine and preparation method thereof 20101208CN20101589315
20101208
HUMAN RESPIRATORY SYNCYTIAL VIRUS (RSV) VACCINE 20090720US20090505998
20090720
Recombinant parainfluenza virus expression systems and vaccines comprising heterologous antigens derived from metapneumovirus 20081222US20080317496
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EP20010200213
20010119
EP20010203985
20011018
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20030221
WO2002NL00040
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20020221
RESPIRATORY SYNCYTIAL VIRUS VACCINE BASED ON CHIMERIC PAPILLOMAVIRUS VIRUS-LIKE PARTICLES OR CAPSOMERES 20081022WO2008US80822
20081022
US20080738991
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US20070981719P
20071022
INACTIVATED COMBINED VACCINE AGAINST CATTLE INFECTIOUS RHINOTRACHEITIS, PARAINFLUENZA-3, VIRUS DIARRHOEA, RESPIRATORY SYNCYTIAL ROTA- AND CORONAVIRAL DISEASE 20090331RU20090111453
20090331
Antisense Respiratory Syncytial Virus Vaccine and Therapy 20081027US20080259155
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US20070983040P 20071026
VENEZUELAN EQUINE ENCEPHALITIS REPLICONS EXPRESSING PARAMYXOVIRUS GLYCOPROTEINS AS VACCINE 20080925US20070975431P
20070926
WO2008US77721
20080925
RESPIRATORY SYNCYTIAL VIRUS (RSV) SEQUENCES FOR PROTEIN EXPRESSION AND VACCINES 20090930US20080101340P
20080930
Cracking method of human respiratory syncytial virus 20090915CN2009194973
20090915 Subunit vaccine against respiratory syncytial virus infection 20040714US20040567586P
20040503
EP20040761567
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20030715
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20040709 VACCINE DELIVERY SYSTEM 20060412WO2006AU00491
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20070921
Production of attenuated respiratory syncytial virus vaccines from cloned nucleotide sequences 19970715US199********P
19970523
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19970509
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19960715
EP199********
19970715
IMMUNOGENIC COMPLEXES, PREPARATION METHOD THEREOF AND USE OF SAME IN PHARMACEUTICAL COMPOSITIONS. 20070122FR20040008175
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20050805 Respiratory syncytial virus sub-units vaccine, preparation and application 20071219CN2007166476
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Production of attenuated, human-bovine chimeric respiratory syncytial virus vaccines 20000623US199********P
19990709
Multivalent immunogenic composition containing RSV subunit compostion and influenza virus preparation 20080521US20080153540
20080521
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19981217
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20030917
Combination vaccine against streptococcus pneumoniae and respiratory syncytial virus (RSV). 20011019GB199********
19990420
Attenuated respiratory syncytial virus vaccine compositions 19930420US199********
19920421 PARTICLES FOR TREATMENT OF PULMONARY INFECTION 20051019US20040623738P
20041029
Immunogenic complexes, preparation method thereof and use of same in pharmaceutical compositions 20071019US20070976085
20071019
WO2005FR01913
20050725
FR20040008175
20040723
Production of recombinant respiratory syncytial viruses expressing immune modulatory molecules 20040811US20040917984
20040811
US20020031095
20020618
WO2000US19042
20000712
US199********P
19990713
Subunit respiratory syncytial virus vaccine preparation 20040729US199********
19960712
US199********
19990503
US20040901147 20040729
Respiratory syncytial virus vaccines expressing protective antigens from promoter-proximal genes 20010622US20000213708P
20000623
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19970509
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19970523
US20010887469
20010622
US199********
19970715
US199********P
19950927
US199********P
19960715
US20010847173
20010503
US199********
19960927
US199********
19990413
Epitope-based vaccine for respiratory syncytial virus F-protein 20010525US20000206946P
20000525
US20010865499
20010525
Methods for producing self-replicating infectious RSV particles comprising recombinant RSV genomes or antigenomes and the N, P, L, and M2 proteins 20010503US199********
19960927
US20010847173
20010503
US199********P
19950927
Nucleotide sequences encoding bovine respiratory syncytial virus immunogenic proteins 20040430US199********
19900724
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19930908
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20000508
US20040836673
20040430
Respiratory synctial vaccine 19770817US19770766995
19770209
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19860127
Enhanced immune response to attachment (G) protein of respiratory Syncytial virus 20040220US20040783455
20040220
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19970919
US20000526195
20000315
WO1998US19656
19980917
US199********P
19980508
Production of recombinant respiratory syncytial viruses expressing immune modulatory molecules 20040108US199********P
19970509
US20040754895
20040108
US199********P
19970523
US199********P
19960715
US199********
19990413
US20000614285
20000712
US199********P
19990713
US199********
19970715
Methods for preventing cattle reproductive diseases 20070315US20070724624
20070315
US20030419661
20030421
Production of attenuated chimeric respiratory syncytial virus vaccines from cloned nucleotide sequences 20031125US199********P
19960715
US199********P
19970509
US199********P
19970523
US199********
19970715
US199********
19990413
US20030722000
20031125
Subunit respiratory syncytial virus vaccine preparation 19960712US199********
19960712
Production of attenuated respiratory syncytial virus vaccines involving modification of M2 ORF2 20000707US20000611829
20000707
US199********
19990413
US199********
19970715
US199********P
19990709
US199********P
19970523
US199********P
19970509
US199********P
19960715
Inactivated respiratory syncytial viral vaccines 19960628US199********
19930806
US199********
19960628
WO1994CA00425
19940804 Subunit respiratory syncytial virus vaccine preparation 20040927US20010950655
20010913
WO2002CA01347
20020903
US20040488241
20040927 Inactivated respiratory syncytial viral vaccines 19950607US199********
19930806
US199********
19940805
US199********
19950607
Construction and use of recombinant parainfluenza viruses expressing a chimeric glycoprotein 19991210US199********
19991210
US199********
19980522
US199********P
19970523
US199********P
19970919
Use of recombinant live-attenuated parainfluenza virus (PIV) as a vector to protect against disease caused by PIV and respiratory syncytial virus (RSV) 19991210US199********
19991210
US199********
19980522
US199********P
19970919
US199********P
19970523 Attenuated respiratory syncytial virus vaccine compositions 19950530US199********
19930409
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19941021
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19950530
US199********
19920421 Methods 20060511GB20030026439
20031113
WO2004GB04827
20041115
Virus vaccines 19950428US199********
19950428 Respiratory syncytial virus vaccine 20030626WO2001CA01104
20010731
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20000731
Respiratory syncytial virus vaccines expressing protective antigens from promotor- proximal genes 20030701US20030312191
20030701
WO2001US20107
20010622
Production of attenuated chimeric respiratory syncytial virus vaccines from cloned nucleotide sequences 19990413US199********P
19970523
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19970509
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19960715
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19950927
US199********
19960927
US199********
19990413
US199********
19970715
Recombinant respiratory syncytial viruses with deleted surface glycoprotein genes and uses thereof 20021001US20010326259P
20011001
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20020719
20021001
Polynucleotide vaccine formula in particular against bovine respiratory pathology 19990115FR199********
19960719
WO1997FR01325
19970716
Production of novel bovine respiratory syncytial viruses from cDNAs 20020703US20000554131
20000911
WO1998US23231
19981109
US199********P
19971110
US20020187790
20020703
Nucleotide sequences encoding bovine respiratory syncytial virus immunogenic proteins 19930908US199********
19930908
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19900724
PEPTIDES DERIVED FROM THE ATTACHMENT (G) PROTEIN OF RESPIRATORY SYNCYTIAL VIRUS 19980917US199********P
19970919
US199********P
19980508
ADJUVANTS FOR VACCINES AGAINST RESPIRATORY SYNCYTIAL VIRUS 19940524US199********
19930525
ANTI-IDIOTYPIC VACCINE FOR PROTECTION AGAINST BOVINE RESPIRATORY SYNCYTIAL VIRUS 19921210US199********
19911210
HRSV VACCINE 19910730US199********
19900831
HUMAN RESPIRATORY SYNCYTIALVIRUS VACCINE DERIVED FROM THE 1A (9.5 kD) PROTEIN 19881020US198********
19871120
US198********
19880427
US198********
19880912
Respiratory syncytial virus vaccines expressing protective antigens from promotor-proximal genes 20050208US20050054343
20050208
US20000602212
20000623
US199********
19970715
US199********
19991119
US199********P
19990709
20010622
US20000213708P 20000623
Method of preparing high titer anti-respiratory syncytial virus intravenous immune globulin 19870309US198********
19870309
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19860127
Production of attenuated respiratory syncytial virus vaccines involving modification of M2 ORF2 20041213US199********P
19990713
US199********P
19950927
US199********P
19960715
US199********P
19970509
US20000213708P
20000623
US199********P
19970523
US20030722000
20031125
US199********
19960927
US20010847173
20010503
US20010887469
20010622
WO2000US19042
20000712
US20020031095
20020618
US20040917984
20040811
US199********
19970715
US199********
19990413
US20000611829
20000707
US20040774341
20040206
US20040011502
20041213
VACCINE AGAINST RSV 20010809US20000224011P
20000810
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20000901
RESPIRATORY SYNCYTIAL VIRUS VACCINES EXPRESSING PROTECTIVE ANTIGENS FROM PROMOTOR-PROXIMAL GENES 20010622US20000213708P
20000623
PRODUCTION OF ATTENUATED RESPIRATORY SYNCYTIAL VIRUS VACCINES INVOLVING MODIFICATION OF M2 ORF2 20000707US199********P
19990709
PRODUCTION OF ATTENUATED CHIMERIC RESPIRATORY SYNCYTIAL VIRUS VACCINES FROM CLONED NUCLEOTIDE SEQUENCES 20000331US199********
19990413
HYBRID PROTEIN, HYBRID GENE, METHOD OF PREPARING A HYBRID PROTEIN, VACCINE AGAINST UPPER RESPIRATORY WAY VIRAL DISEASE, BACULOVIRAL EXPRESSION VECTOR (VARIANTS) 19930105GB199********
19920106
Vectors comprising the sequnece for a respiratory syncytial virus (RSV) F protein with a heterologous signal sequence (HSV I gD) for vaccines 20000303US199********
19990305
WO2000CA00227
20000303
Immunomodulators for vaccines 19990510WO1999GB01461
19990510
GB199********
19980603
GB199********
19980608
GB199********
19980508
VACCINE CONTAINING MODIFIED LIVE BOVINE RESPIRATORY SYNCYTIAL VIRUS (BRSV) WITH AN ADJUVANT AND PHARMACEUTICALLY ACCEPTABLE CARRIER 19950508US199********
19940510
WO1995US06053
19950508
USE OF AN OUTER MEMBRANE PROTEIN A OF AN ENTEROBACTERIUM ASSOCIATED WITH A RSV IMMUNOGENIC PEPTIDE FOR PREPARING VACCINES FOR INTRANASAL ADMINISTRATION. 20020325FR199********
19990923
WO2000FR02626
20000922
RESPIRATORY SYNCYTIAL VIRUS VACCINE AND DIAGNOSIS 19890529US198********
19870929
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19880920
WO1988US03399
19880929 PROCESS FOR PREPARING RESPIRATORY SYNCYTIAL VACCINE 19780503KR19780001342
19780503 RESPIRATORY SYNCYTIAL VIRUS VACCINE 19780419IE19780000768
19780419
Combination vaccine against streptococcus preumoniae and respiratory syncytial virus (rsv). 20000430GC2000P000642
20000430
RESPIRATORY SYNCYTICAL VIRUS VACCINE 19780206US19770825520
19770817
US19770766995
19770209
RESPIRATORY SYNCYTIAL VIRUS PROTEIN G EXPRESSED ON BACTERIAL MEMBRANE 19951107FR199********
19941107
NON-GLYCOSYLATED PEPTIDES DERIVED FROM THE RSV G PROTEIN AND USE THEREOF IN A VACCINE 20020123FR20010000875
20010123
Reconstituted respiratory syncytial virus membranes and use as respiratory syncytial virus vaccine 20071031EP20070075946
20071031
Production of attenuated chimeric respiratory syncytial virus vaccines from cloned nucleotide sequences 20000331EP20000920058
20000331
US199********
19990413
VACCINE 20000417GB199********
19990628
GB199********
19990420
HBV CORE ANTIGEN PARTICLES WITH MULTIPLE IMMUNOGENIC COMPONENTS ATTACHED VIA PEPTIDE LIGANDS 19991203US199********P
19981204
WO1999US28755
19991203
LIPOSOMATIC VACCINE COMPOSITION, USE SAME AND METHOD FOR TREATING A MAMMAL 19960401WO1996EP01464
19960401
GB199********
19950425
GB199********
19950628
SUBUNIT RESPIRATORY SYNCYTIAL VIRUS VACCINE PREPARATION 19970711CA199********
19970711
US199********
19960712
PRODUCTION OF INFECTIOUS RESPIRATORY SYNCYTIAL VIRUS FROM CLONED NUCLEOTIDE SEQUENCES 19960927US199********P
19950927
WO1996US15524
19960927
Recombinant parainfluenza virus expression systems and vaccines comprising heterologous antigens derived from metapneumovirus 20080521AU20030219839
20030221
AU20080202252
20080521
CD40 LIGAND ADJUVANT FOR RESPIRATORY SYNCYTIAL VIRUS VACCINE 20010202WO2001US03584
20010202
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20000202
四、五、六、七、八、九、。