表达人呼吸道合胞病毒融合蛋白的重组腺病毒的免疫保护作用
摘要
人呼吸道合胞病毒(Human Respiratory Syncytial Virus,RSV)广泛分布于世界各地,是导致婴幼儿严重下呼吸道感染的最重要的病毒病原之一,老年人和免疫缺陷病人也易遭受RSV引起的严重感染。RSV属于副粘病毒科肺病毒属,基因组为15.2 Kb的单股负链RNA,编码11种蛋白,其中G、F系包膜糖蛋白,为RSV中和抗原。与G蛋白相比,F蛋白不但具有B细胞抗原表位也有CD8+细胞毒性T淋巴细胞(cytotoxic T lymphocyte,CTL)抗原表位,且其抗原性极为保守,可产生交叉保护性免疫。
从福尔马林灭活疫苗开始,人们已经研制了多种形式的RSV疫苗,但由于安全性和免疫原性等问题,至今尚未有能够用于预防人RSV感染的疫苗问世,因此世界卫生组织将发展RSV疫苗列为二十一世纪最优先发展的疫苗项目之一。
非复制型第一代腺病毒载体(first generation replication deficient recombinantadenoviral vector,FGAd)具有繁殖滴度高、易纯化、能够感染分裂和非分裂细胞等优点而被广泛用于疫苗研究。FGAd曾被用于表达经基因工程改造的RSV G蛋白,在动物实验中获得了较好的免疫保护作用,然而以FGAd为基础开展RSVF蛋白疫苗研究尚未见报道。与FGAd相比,辅助病毒依赖型腺病毒载体(helper-dependent adenoviral vector,HDAd)可大大降低腺病毒(Adenovirus,Ad)特异性的细胞免疫反应,增强转染DC细胞能力,且转基因表达时间更加持久。以HDAd作为黏膜疫苗载体,开展RSV F蛋白疫苗研究有待深入研究。
本课题首先用表达RSV F蛋白的FGAd重组腺病毒(FGAd-F)滴鼻免疫BALB/c小鼠,观察免疫保护效果和保护作用特点。结果表明:FGAd-F滴鼻免疫BALB/c小鼠能够诱导产生RSV特异性的血清IgG、黏膜IgA和CD8+CTL,抗体亚类分析显示诱导产生了Th1和Th2平衡的CD4+T细胞免疫应答,没有产生疾病增强,对RSV攻击具有一定的免疫保护作用。
随后,我们用表达EGFP蛋白的HDAd重组腺病毒(HDAd-EGFP)滴鼻免疫BALB/c小鼠,探讨HDAd作为黏膜疫苗载体的可行性和合理性。结果表明:尽管与等量的FGAd-EGFP诱导产生相似的anti-Ad抗体,但HDAd-EGFP经鼻免疫小鼠可诱导产生更高的EGFP特异性的血清IgG、黏膜IgA和细胞免疫,且抗体亚类分析显示诱导产生了Th1和Th2平衡的CD4+T细胞免疫应答。另外HDAd-EGFP同源加强免疫也能提高EGFP特异性的体液免疫和细胞免疫。
在上述研究的基础上,我们用表达RSV F蛋白的HDAd重组腺病毒(HDAd-F)经滴鼻途径免疫BALB/c小鼠,初步探讨了HDAd-F的免疫效果。结果表明:与等量的FGAd-F相比,HDAd-F经鼻两次免疫小鼠可诱导更好的RSV F特异性的黏膜免疫,HDAd-F经鼻一次免疫小鼠可诱导更高的RSV F特异性的血清抗体。
综上所述,FGAd-F能够诱导有效的免疫保护作用,以FGAd为载体的疫苗是预防RSV等通过黏膜途径感染的病毒疫苗的一个重要方法。HDAd是一种理想的黏膜疫苗载体,适于经呼吸道黏膜感染的RSV疫苗的研制,通过提高转基因表达量、降低载体用量等措施,有望获得较好的免疫效果和免疫保护作用。
Human respiratory syncytial virus (RSV) is the major viral agent of severe lower respiratory tract infection in infants and young children, worldwide, and causes deadly illness in the elderly and adults with underlying risk factors such as immunodeficiency. RSV is an enveloped, negative stranded RNA virus belonging to the subfamily Pneumovirinae of the family Paramyxoviridae with a genome that encodes 11 proteins. Two transmembrane surface glycoproteins of fusion protein (F) and attachment protein (G) are the neutralization antigens. Additionally, F is also a major target antigen of CD8+ cytotoxic T lymphocyte (CTL) in humans and mice, and sufficiently conserved between two RSV antigenic subgroups, A and B, being capable of evoking cross-protective antibodies against both subgroups.
Since the failure of formalin-inactivated RSV vaccine, there have been various RSV vaccines developed. But none of these has been approved for use in humans. The World Health Organization has affirmed RSV vaccine as one of the highest priority vaccine to be developed.
The replication-deficient first generation adenoviral vector (FGAd) is readily grown and purified in large scale, and able to express high level transgene in dividing and non-dividing cells, therefore, it is considered to be an attractive vaccine vector. Recent report showed that FGAd encoding genetically engineered G protein could successfully elicit a long-term protective immunity against RSV infection in mice. Whereas, there has been no FGAd encoding F protein (FGAd-F) vaccine reported. In contrast to FGAd, helper-dependent adenoviral vector (HDAd) is the vector with its all coding regions deleted, displaying much more reduced adenovirus (Ad) specific cellular immunity, possesing potent and long-term capacity of transgene expression in vivo. Additionally, HDAd is also a potent stimulator of dendritic cell (DC) maturation. Till now, neither is known about the potentiality for HDAd as a vaccine vector administered intranasally, nor the efficacy of RSV F vaccine based on HDAd vector.
In this study, FGAd-F was constructed and evaluated for its protective role as an candidate RSV vaccine in a murine model. Intranasal (i.n.) immunization with FGAd-F generated serum IgG, mucosal secretory IgA , and RSV-specific CD8+ T-cell responses in BALB/c mice, with characteristic balanced or mixed Th1/Th2 CD4+ T-cell responses. Serum IgG was significantly elevated after boosting with i.n. immunization with FGAd-F. Upon challenge, i.n. immunization with FGAd-F displayed an effectivly protective role against RSV infection.
To evaluate the potentiality of HDAd vaccine vector via mucosal route, mice were immunized intranasally with HDAd or FGAd encoding EGFP (HDAd-EGFP or FGAd-EGFP), and monitored for the induction of anti-EGFP and anti-Ad immunity. Although similar anti-Ad antibody responses were obtained in mice i.n. with FGAd, HDAd-EGFP induced some more transgene-specific serum IgG, mucosal IgA and cellular responses, as well as a longer-term serum IgG comparing to the same amount of FGAd, with the characteristic of balanced or mixed Th1/Th2 CD4+ T-cell responses. In addition, the homologous booster immunization with HDAd-EGFP can also enhance EGFP-specific humoral and cellular responses.
HDAd encoding F protein (HDAd-F) was constructed and evaluated for its efficacy as RSV vaccine in a murine model. BALB/c mice were immunized intranasally with HDAd-F or FGAd-F, and monitored for the induction of RSV F-specific immune responses. HDAd vaccine could induce superior transgene-specific humoral and longer-term serum IgG compared to the same amount of FGAd.
In summary, FGAd-F is able to effectivly induce protective immunity and is apromising candidate vaccine against RSV infection. By our view ,HDAd is even abetter mucosal vaccine vector in comparing with FGAd, employing EGFP as a modelantigen , examining in a murine model. The efficacy of HDAd-F vaccine may beelevated significantly by improving the expression level of transgene and reducing thedosage.
从福尔马林灭活疫苗开始,人们已经研制了多种形式的RSV疫苗,但由于安全性和免疫原性等问题,至今尚未有能够用于预防人RSV感染的疫苗问世,因此世界卫生组织将发展RSV疫苗列为二十一世纪最优先发展的疫苗项目之一。
非复制型第一代腺病毒载体(first generation replication deficient recombinantadenoviral vector,FGAd)具有繁殖滴度高、易纯化、能够感染分裂和非分裂细胞等优点而被广泛用于疫苗研究。FGAd曾被用于表达经基因工程改造的RSV G蛋白,在动物实验中获得了较好的免疫保护作用,然而以FGAd为基础开展RSVF蛋白疫苗研究尚未见报道。与FGAd相比,辅助病毒依赖型腺病毒载体(helper-dependent adenoviral vector,HDAd)可大大降低腺病毒(Adenovirus,Ad)特异性的细胞免疫反应,增强转染DC细胞能力,且转基因表达时间更加持久。以HDAd作为黏膜疫苗载体,开展RSV F蛋白疫苗研究有待深入研究。
本课题首先用表达RSV F蛋白的FGAd重组腺病毒(FGAd-F)滴鼻免疫BALB/c小鼠,观察免疫保护效果和保护作用特点。结果表明:FGAd-F滴鼻免疫BALB/c小鼠能够诱导产生RSV特异性的血清IgG、黏膜IgA和CD8+CTL,抗体亚类分析显示诱导产生了Th1和Th2平衡的CD4+T细胞免疫应答,没有产生疾病增强,对RSV攻击具有一定的免疫保护作用。
随后,我们用表达EGFP蛋白的HDAd重组腺病毒(HDAd-EGFP)滴鼻免疫BALB/c小鼠,探讨HDAd作为黏膜疫苗载体的可行性和合理性。结果表明:尽管与等量的FGAd-EGFP诱导产生相似的anti-Ad抗体,但HDAd-EGFP经鼻免疫小鼠可诱导产生更高的EGFP特异性的血清IgG、黏膜IgA和细胞免疫,且抗体亚类分析显示诱导产生了Th1和Th2平衡的CD4+T细胞免疫应答。另外HDAd-EGFP同源加强免疫也能提高EGFP特异性的体液免疫和细胞免疫。
在上述研究的基础上,我们用表达RSV F蛋白的HDAd重组腺病毒(HDAd-F)经滴鼻途径免疫BALB/c小鼠,初步探讨了HDAd-F的免疫效果。结果表明:与等量的FGAd-F相比,HDAd-F经鼻两次免疫小鼠可诱导更好的RSV F特异性的黏膜免疫,HDAd-F经鼻一次免疫小鼠可诱导更高的RSV F特异性的血清抗体。
综上所述,FGAd-F能够诱导有效的免疫保护作用,以FGAd为载体的疫苗是预防RSV等通过黏膜途径感染的病毒疫苗的一个重要方法。HDAd是一种理想的黏膜疫苗载体,适于经呼吸道黏膜感染的RSV疫苗的研制,通过提高转基因表达量、降低载体用量等措施,有望获得较好的免疫效果和免疫保护作用。
Human respiratory syncytial virus (RSV) is the major viral agent of severe lower respiratory tract infection in infants and young children, worldwide, and causes deadly illness in the elderly and adults with underlying risk factors such as immunodeficiency. RSV is an enveloped, negative stranded RNA virus belonging to the subfamily Pneumovirinae of the family Paramyxoviridae with a genome that encodes 11 proteins. Two transmembrane surface glycoproteins of fusion protein (F) and attachment protein (G) are the neutralization antigens. Additionally, F is also a major target antigen of CD8+ cytotoxic T lymphocyte (CTL) in humans and mice, and sufficiently conserved between two RSV antigenic subgroups, A and B, being capable of evoking cross-protective antibodies against both subgroups.
Since the failure of formalin-inactivated RSV vaccine, there have been various RSV vaccines developed. But none of these has been approved for use in humans. The World Health Organization has affirmed RSV vaccine as one of the highest priority vaccine to be developed.
The replication-deficient first generation adenoviral vector (FGAd) is readily grown and purified in large scale, and able to express high level transgene in dividing and non-dividing cells, therefore, it is considered to be an attractive vaccine vector. Recent report showed that FGAd encoding genetically engineered G protein could successfully elicit a long-term protective immunity against RSV infection in mice. Whereas, there has been no FGAd encoding F protein (FGAd-F) vaccine reported. In contrast to FGAd, helper-dependent adenoviral vector (HDAd) is the vector with its all coding regions deleted, displaying much more reduced adenovirus (Ad) specific cellular immunity, possesing potent and long-term capacity of transgene expression in vivo. Additionally, HDAd is also a potent stimulator of dendritic cell (DC) maturation. Till now, neither is known about the potentiality for HDAd as a vaccine vector administered intranasally, nor the efficacy of RSV F vaccine based on HDAd vector.
In this study, FGAd-F was constructed and evaluated for its protective role as an candidate RSV vaccine in a murine model. Intranasal (i.n.) immunization with FGAd-F generated serum IgG, mucosal secretory IgA , and RSV-specific CD8+ T-cell responses in BALB/c mice, with characteristic balanced or mixed Th1/Th2 CD4+ T-cell responses. Serum IgG was significantly elevated after boosting with i.n. immunization with FGAd-F. Upon challenge, i.n. immunization with FGAd-F displayed an effectivly protective role against RSV infection.
To evaluate the potentiality of HDAd vaccine vector via mucosal route, mice were immunized intranasally with HDAd or FGAd encoding EGFP (HDAd-EGFP or FGAd-EGFP), and monitored for the induction of anti-EGFP and anti-Ad immunity. Although similar anti-Ad antibody responses were obtained in mice i.n. with FGAd, HDAd-EGFP induced some more transgene-specific serum IgG, mucosal IgA and cellular responses, as well as a longer-term serum IgG comparing to the same amount of FGAd, with the characteristic of balanced or mixed Th1/Th2 CD4+ T-cell responses. In addition, the homologous booster immunization with HDAd-EGFP can also enhance EGFP-specific humoral and cellular responses.
HDAd encoding F protein (HDAd-F) was constructed and evaluated for its efficacy as RSV vaccine in a murine model. BALB/c mice were immunized intranasally with HDAd-F or FGAd-F, and monitored for the induction of RSV F-specific immune responses. HDAd vaccine could induce superior transgene-specific humoral and longer-term serum IgG compared to the same amount of FGAd.
In summary, FGAd-F is able to effectivly induce protective immunity and is apromising candidate vaccine against RSV infection. By our view ,HDAd is even abetter mucosal vaccine vector in comparing with FGAd, employing EGFP as a modelantigen , examining in a murine model. The efficacy of HDAd-F vaccine may beelevated significantly by improving the expression level of transgene and reducing thedosage.
引文
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