HPV58mE6E7融合基因疫苗构建及其免疫效果的研究
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摘要
子宫颈癌是常见的妇科恶性肿瘤之一,发病率在女性恶性肿瘤中居第二位。据世界范围内统计,每年大约有50万左右的宫颈癌新发病例,其中80%的病例发生在发展中国家。我国每年有新发病例约13.15万,占世界宫颈癌新发病例总数的28.8%。近10余年来以大规模人群为基础的流行病学资料显示：在99%以上的宫颈癌中存在HPV DNA, HPV感染是宫颈癌发生的首要因素且为始动因素。由于几乎所有宫颈癌细胞中都有HPV DNA和病毒转化蛋白的表达,HPV病毒蛋白可作为一种抗原刺激机体产生针对HPV的免疫反应,这就促使人们希望通过疫苗的方法来治疗和预防宫颈癌。由于各型HPV之间没有交叉保护作用而HPV基因型的分布又存在地域差异,并且目前尚无关于广西地区宫颈癌HPV感染分子流行病学的详细报道。为使本地区疫苗研制更具有针对性,我们对广西地区HPV感染情况、基因型分布以及感染率高的HPV基因型病毒负载量进行了调查,拟提供一份比较可信的的资料,为广西HPV疫苗研制提供有力的依据。
我们采用以PCR测序为基础的方法检测了135例宫颈癌确诊病人的宫颈组织DNA。结果显示：133例宫颈癌病人感染了HPV,感染率98.52%。感染HPV16、18、31、33、35、45、52、58、59型的患者分别为125、76、17、0、0、1、2、63、5例,感染率分别为：93.98%、57.14%、12.78%、0、0、0.75%、1.50%、47.37%、3.76%,其中感染率排在前三位的是16、18和58型。通过real-time Q-PCR对HPV16、18和58型进行定量检测,三者的病毒负载量均值分别为7.89×109、9.55×103和2.38×10。HPV16型的病毒负载量明显高于18和58型(P值<0.05),而HPV18型的病毒负载量与58型比较无显著差异(P值>0.05)。
由于HPV58型在广西的感染率非常高,因此,研制HPV58型疫苗非常必要。HPV58 E6和E7基因作为癌转化蛋白,能在HPV58(+)肿瘤中将病毒DNA整合到细胞染色体中并持续表达E6、E7蛋白,使宿主细胞向恶性方向转化。尽管如此,E6和E7蛋白作为持续存在病毒抗原,却能刺激机体产生较强的以病毒抗原为靶分子的特异性CTL。因此,E6、E7作为一种较理想的肿瘤相关抗原,适用于免疫治疗和预防与HPV58感染导致的宫颈癌的免疫治疗,但前提是必须消除E6、E7基因的转化活性以保证疫苗的安全性。因此,我们在构建疫苗之前,对E6和E7基因的6个转化活性位点进行了点突变,以消除转化活性而保留免疫原性。在证实已消除了HPV58mE6E7(突变后)融合基因转化活性的基础上,将其与人IgG Fc段融合在一起形成HPV58mE6E7-Fc,在其前端加上信号肽,后端加上膜锚定蛋白GPI,使上述肿瘤抗原能够锚定在细胞膜上表达。最后将sig-HPV58mE6E7Fc-GPI片段插入我室前期构建的能够融合表达GM-CSF和B7.1蛋白的真核表达载体PVAX1-IRES-GM/B7的IRES上游,构建了PVAX1-HPV58mE6E7FcGB疫苗。使该疫苗在表达上游融合抗原的同时,又能表达下游的GM-CSF和B7.1分子,以此来增进疫苗的协同免疫作用。随后,我们又构建了稳定表达HPV58E6E7融合基因的小鼠黑色素瘤B16-HPV58E6E7细胞系,原核表达并纯化了HPV58E6E7-GST融合蛋白抗原,为后续动物实验奠定基础。
动物实验中,我们采用肌肉注射加在体局部电脉冲的方法,将前期构建的P VAX 1-HP V58mE6E7FcGB融合基因疫苗免疫C57BL/6小鼠。结果表明,经疫苗免疫后的小鼠,对HPV58E6E7(+)肿瘤的攻击具有免疫保护作用。在抗肿瘤移植保护实验中,疫苗组小鼠皮下接种的成瘤潜伏期时间长于对照组(P<0.05)。在肿瘤生长抑制实验中,疫苗组小鼠肿瘤生长速度较对照组明显减慢,最终使小鼠生存期延长,平均瘤重低于对照组(P<0.05)。研究结果还证实经疫苗免疫的小鼠,可诱发血清特异性抗体,抗体滴度最高可达1：25600,与对照组比较,差异有显著性(P<0.05)。ELISPOT可以检测到重组抗原HPV58E6E7-GST蛋白诱导的特异性、分泌IFN-γ的效应T细胞,疫苗组小鼠ELISPOT的斑点数明显多于单独抗原组(P 为提高疫苗的免疫效果,我们随后将分子佐剂更换为hIL12,构建了PVAX1-HPV58mE6E7Fc-hIL 12疫苗并实现了真核表达,准备进行动物实验。
总之,我们在对广西HPV感染分子流行病学调查的基础上构建并表达了的PVAX1-HPV58mE6E7FcGB融合基因疫苗,对免疫后小鼠能够产生有效的体液免疫和细胞免疫,可以作为HPV58(+)宫颈癌及其癌前病变的免疫治疗的候选疫苗,对于清除HPV58型感染相关的肿瘤细胞、阻止病变的发展将有一定的临床价值。
Cervical carcinoma is one of the common gynecological malignancies, which incidence is the second in the female malignant tumor. According to statistics, there are about 50 million new cases of cerical carcinoma in worldwide annually, including 80% of cases will take place in developing countries. Our new cases a year, accounting for 13.15 million, approximately 28.8% of total, new cases of cerical carcinoma in the world Nearly 10 years, epidemiological data based with large cases shows:HPV DNA exists in 99% of cerical carcinoma cases. HPV infection is the primary factor which results in cervical carcinoma and CIN. Almost all cerical carcinoma cells exist HPV DNA and protein. HPV transformation protein can be used as one kind of antigen to stimulate the immune response against HPV. People hope through HPV vaccine to prevent and treat cerical carcinoma. No cross immunoprotection between various HPV genotypes, pertinence is necessary to develop HPV vaccine. Without detailed epidemiology reports about guangxi HPV infection, developing HPV vaccine is blind. To enable pertinence of Guangxi HPV vaccine, we researched the region of HPV genotype in Guangxi and provided a credible information as a strong basis of Guangxi HPV vaccine development
We adopted PCR and sequencing methods to test 135 cases of diagnosed cervical carcinoma tissue DNA. The results showed:98.52% of 133 cases cervical carcinoma patients infected HPV. Patients infected HPV16,18,31,33,35,45,52,58,59 types were 76,17,125 0,0,1,2,63,5, respectively. Infection rates of the 9 types are 93.98%, 57.14%,12.78%,0,0,0.75%,1.50%,47.37% and 3.76%, respectively. Type 16,18 and 58 rank 1,2,3. Quantitative detection by real-time Q-PCR, average virus load of types HPV 16,18 and 58 are 7.89 x 109,9.55 x 103 and 2.38 x 10, respectively. Virus load of type HPV 16 is obviously higher than types 18 and 58 (P<0.05), and the difference of virus load of types HPV18 and 58 was no significant values (P>0.05).
Because infection rate of type HPV58 in guangxi is very high, developing type HPV58 vaccine is very necessary. As transformation protein of type HPV58, E6 and E7 gene can integrate HPV DNA in HPV58(+) tumor cells chromosomes and continuously express E6 and E7 protein, which make host cells transform to malignant direction. However, E6 and E7 protein as persistent viral antigens, it can stimulate body to produce strong CTL to HPV58. Therefore, HPV58 E6, E7 as two ideal tumor antigens, are suitable for immunotherapy and prevention for HPV58 (+) cerical carcinoma and CIN, but the prerequisite is that you must eliminate transformation activity of E6 and E7 gene to ensure the safety of vaccine. Before constructing the vaccine, we designed six mutations in the transformation sites of E6 and E7 gene to eliminate transformation active while retaining immunogenicity. Having removed HPV58mE6E7 fusion gene transformation, human IgG Fc was fused together with HPV58mE6E7 to form HPV58mE6E7-Fc, which plus signal peptide in the front and membrane anchor protein GPI in the end. GP can anchor and express the tumor antigen in the cell membrane. Finally, sig-HPV58mE6E7Fc-GPI was inserted eukaryotic expression vector PVAX1-IRES-GM/ B7 which can express GM-CSF and B7.1 fusion protein. PVAX1-HPV58mE6E7FcGB vaccine can express the fusion antigen and GM-CSF and B7.1 synchronously, which can enhance the collaborative immune action of the vaccine. Then, we constructed mice melanoma cell line B16-HPV58E6E7, which can stablely express HPV58E6E7 fusion gene. HPV58E6E7-GST fusion protein was be obtained by the way of prokaryotic expression and purify.
We immuned C57BL/6 mice with PVAX1-HPV58mE6E7FcGB vaccine by intramuscular injection plus local electrical pulses Results indicated that the immuned mice were protected from HPV58E6E7 (+) tumor cells attack. mice subcutaneous tumor formation time in vaccine group was later than in control group (P＜0.05). Tumor of vaccine group mice growed significantly slower than in control group, so average tumor weigh less than in control group (P< 0.05). This resulted survival time in vaccine group was longer than control group (P<0.05). Results also confirmed that the vaccine immuned mice can induce specific serum antibody, which can reach maximal 1:25600, compared with the control group (P＜0.05). ELISPOT can detect specificial T cells of vaccine immuned mice which activated by HPV58E6E7-GST recombinant protein antigen Numbers of spots in vaccine group are higher than in single antigen group (P<0.05), indicating that HPV58mE6E7 fusion with adjuvants as human IgG Fc, GM-CSF and B7.1 can obviously increase immunogenicity of HPV58mE6E7and enhance its immunical effect., We also detected special CTL response of the mice immuned by PVAX1-HPV58mE6E7FcGB vaccine by LDH way and obtained the highest data of 45%. Thest datas proved that the mice immuned by the vaccine r can produce effective humoral immune and cellullar immunity and protect the mice against B16-HPV58E6E7 cells(1-2 x 105)attack.
To improve the effect of HPV58 vaccine, the following vaccine named PVAX1-HPV58mE6E7Fc-hIL12 has been structured and succeed in expressing in eukaryotic cell.
In brief, we constructed PVAX1-HPV58mE6E7FcGB gene vaccine on the basis of Guangxi HPV epidemiology investigation. This vaccine can produce effective humoral and cellular immunity in the immumed mice and be used to treat HPV58 (+) cerical carcinoma and CIN as a candidate vaccine. It can show some clinical value by removing the tumor cells infected by type HPV58 and preventing the development of the disease.
我们采用以PCR测序为基础的方法检测了135例宫颈癌确诊病人的宫颈组织DNA。结果显示：133例宫颈癌病人感染了HPV,感染率98.52%。感染HPV16、18、31、33、35、45、52、58、59型的患者分别为125、76、17、0、0、1、2、63、5例,感染率分别为：93.98%、57.14%、12.78%、0、0、0.75%、1.50%、47.37%、3.76%,其中感染率排在前三位的是16、18和58型。通过real-time Q-PCR对HPV16、18和58型进行定量检测,三者的病毒负载量均值分别为7.89×109、9.55×103和2.38×10。HPV16型的病毒负载量明显高于18和58型(P值<0.05),而HPV18型的病毒负载量与58型比较无显著差异(P值>0.05)。
由于HPV58型在广西的感染率非常高,因此,研制HPV58型疫苗非常必要。HPV58 E6和E7基因作为癌转化蛋白,能在HPV58(+)肿瘤中将病毒DNA整合到细胞染色体中并持续表达E6、E7蛋白,使宿主细胞向恶性方向转化。尽管如此,E6和E7蛋白作为持续存在病毒抗原,却能刺激机体产生较强的以病毒抗原为靶分子的特异性CTL。因此,E6、E7作为一种较理想的肿瘤相关抗原,适用于免疫治疗和预防与HPV58感染导致的宫颈癌的免疫治疗,但前提是必须消除E6、E7基因的转化活性以保证疫苗的安全性。因此,我们在构建疫苗之前,对E6和E7基因的6个转化活性位点进行了点突变,以消除转化活性而保留免疫原性。在证实已消除了HPV58mE6E7(突变后)融合基因转化活性的基础上,将其与人IgG Fc段融合在一起形成HPV58mE6E7-Fc,在其前端加上信号肽,后端加上膜锚定蛋白GPI,使上述肿瘤抗原能够锚定在细胞膜上表达。最后将sig-HPV58mE6E7Fc-GPI片段插入我室前期构建的能够融合表达GM-CSF和B7.1蛋白的真核表达载体PVAX1-IRES-GM/B7的IRES上游,构建了PVAX1-HPV58mE6E7FcGB疫苗。使该疫苗在表达上游融合抗原的同时,又能表达下游的GM-CSF和B7.1分子,以此来增进疫苗的协同免疫作用。随后,我们又构建了稳定表达HPV58E6E7融合基因的小鼠黑色素瘤B16-HPV58E6E7细胞系,原核表达并纯化了HPV58E6E7-GST融合蛋白抗原,为后续动物实验奠定基础。
动物实验中,我们采用肌肉注射加在体局部电脉冲的方法,将前期构建的P VAX 1-HP V58mE6E7FcGB融合基因疫苗免疫C57BL/6小鼠。结果表明,经疫苗免疫后的小鼠,对HPV58E6E7(+)肿瘤的攻击具有免疫保护作用。在抗肿瘤移植保护实验中,疫苗组小鼠皮下接种的成瘤潜伏期时间长于对照组(P<0.05)。在肿瘤生长抑制实验中,疫苗组小鼠肿瘤生长速度较对照组明显减慢,最终使小鼠生存期延长,平均瘤重低于对照组(P<0.05)。研究结果还证实经疫苗免疫的小鼠,可诱发血清特异性抗体,抗体滴度最高可达1：25600,与对照组比较,差异有显著性(P<0.05)。ELISPOT可以检测到重组抗原HPV58E6E7-GST蛋白诱导的特异性、分泌IFN-γ的效应T细胞,疫苗组小鼠ELISPOT的斑点数明显多于单独抗原组(P
总之,我们在对广西HPV感染分子流行病学调查的基础上构建并表达了的PVAX1-HPV58mE6E7FcGB融合基因疫苗,对免疫后小鼠能够产生有效的体液免疫和细胞免疫,可以作为HPV58(+)宫颈癌及其癌前病变的免疫治疗的候选疫苗,对于清除HPV58型感染相关的肿瘤细胞、阻止病变的发展将有一定的临床价值。
Cervical carcinoma is one of the common gynecological malignancies, which incidence is the second in the female malignant tumor. According to statistics, there are about 50 million new cases of cerical carcinoma in worldwide annually, including 80% of cases will take place in developing countries. Our new cases a year, accounting for 13.15 million, approximately 28.8% of total, new cases of cerical carcinoma in the world Nearly 10 years, epidemiological data based with large cases shows:HPV DNA exists in 99% of cerical carcinoma cases. HPV infection is the primary factor which results in cervical carcinoma and CIN. Almost all cerical carcinoma cells exist HPV DNA and protein. HPV transformation protein can be used as one kind of antigen to stimulate the immune response against HPV. People hope through HPV vaccine to prevent and treat cerical carcinoma. No cross immunoprotection between various HPV genotypes, pertinence is necessary to develop HPV vaccine. Without detailed epidemiology reports about guangxi HPV infection, developing HPV vaccine is blind. To enable pertinence of Guangxi HPV vaccine, we researched the region of HPV genotype in Guangxi and provided a credible information as a strong basis of Guangxi HPV vaccine development
We adopted PCR and sequencing methods to test 135 cases of diagnosed cervical carcinoma tissue DNA. The results showed:98.52% of 133 cases cervical carcinoma patients infected HPV. Patients infected HPV16,18,31,33,35,45,52,58,59 types were 76,17,125 0,0,1,2,63,5, respectively. Infection rates of the 9 types are 93.98%, 57.14%,12.78%,0,0,0.75%,1.50%,47.37% and 3.76%, respectively. Type 16,18 and 58 rank 1,2,3. Quantitative detection by real-time Q-PCR, average virus load of types HPV 16,18 and 58 are 7.89 x 109,9.55 x 103 and 2.38 x 10, respectively. Virus load of type HPV 16 is obviously higher than types 18 and 58 (P<0.05), and the difference of virus load of types HPV18 and 58 was no significant values (P>0.05).
Because infection rate of type HPV58 in guangxi is very high, developing type HPV58 vaccine is very necessary. As transformation protein of type HPV58, E6 and E7 gene can integrate HPV DNA in HPV58(+) tumor cells chromosomes and continuously express E6 and E7 protein, which make host cells transform to malignant direction. However, E6 and E7 protein as persistent viral antigens, it can stimulate body to produce strong CTL to HPV58. Therefore, HPV58 E6, E7 as two ideal tumor antigens, are suitable for immunotherapy and prevention for HPV58 (+) cerical carcinoma and CIN, but the prerequisite is that you must eliminate transformation activity of E6 and E7 gene to ensure the safety of vaccine. Before constructing the vaccine, we designed six mutations in the transformation sites of E6 and E7 gene to eliminate transformation active while retaining immunogenicity. Having removed HPV58mE6E7 fusion gene transformation, human IgG Fc was fused together with HPV58mE6E7 to form HPV58mE6E7-Fc, which plus signal peptide in the front and membrane anchor protein GPI in the end. GP can anchor and express the tumor antigen in the cell membrane. Finally, sig-HPV58mE6E7Fc-GPI was inserted eukaryotic expression vector PVAX1-IRES-GM/ B7 which can express GM-CSF and B7.1 fusion protein. PVAX1-HPV58mE6E7FcGB vaccine can express the fusion antigen and GM-CSF and B7.1 synchronously, which can enhance the collaborative immune action of the vaccine. Then, we constructed mice melanoma cell line B16-HPV58E6E7, which can stablely express HPV58E6E7 fusion gene. HPV58E6E7-GST fusion protein was be obtained by the way of prokaryotic expression and purify.
We immuned C57BL/6 mice with PVAX1-HPV58mE6E7FcGB vaccine by intramuscular injection plus local electrical pulses Results indicated that the immuned mice were protected from HPV58E6E7 (+) tumor cells attack. mice subcutaneous tumor formation time in vaccine group was later than in control group (P＜0.05). Tumor of vaccine group mice growed significantly slower than in control group, so average tumor weigh less than in control group (P< 0.05). This resulted survival time in vaccine group was longer than control group (P<0.05). Results also confirmed that the vaccine immuned mice can induce specific serum antibody, which can reach maximal 1:25600, compared with the control group (P＜0.05). ELISPOT can detect specificial T cells of vaccine immuned mice which activated by HPV58E6E7-GST recombinant protein antigen Numbers of spots in vaccine group are higher than in single antigen group (P<0.05), indicating that HPV58mE6E7 fusion with adjuvants as human IgG Fc, GM-CSF and B7.1 can obviously increase immunogenicity of HPV58mE6E7and enhance its immunical effect., We also detected special CTL response of the mice immuned by PVAX1-HPV58mE6E7FcGB vaccine by LDH way and obtained the highest data of 45%. Thest datas proved that the mice immuned by the vaccine r can produce effective humoral immune and cellullar immunity and protect the mice against B16-HPV58E6E7 cells(1-2 x 105)attack.
To improve the effect of HPV58 vaccine, the following vaccine named PVAX1-HPV58mE6E7Fc-hIL12 has been structured and succeed in expressing in eukaryotic cell.
In brief, we constructed PVAX1-HPV58mE6E7FcGB gene vaccine on the basis of Guangxi HPV epidemiology investigation. This vaccine can produce effective humoral and cellular immunity in the immumed mice and be used to treat HPV58 (+) cerical carcinoma and CIN as a candidate vaccine. It can show some clinical value by removing the tumor cells infected by type HPV58 and preventing the development of the disease.
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