摘要
鸡新城疫(ND)是由新城疫病毒(NDV)引起的家禽最严重的传染病之一。NDV的病毒囊膜含有2个主要的糖蛋白,即融合蛋白(F)和血凝素-神经氨酸酶蛋白(HN),它们都被用于重组鸡痘病毒疫苗的研究。本研究从我们实验室已构建的单表达、共表达新城疫病毒(NDV)融合蛋白(F)和血凝素-神经氨酸酶蛋白(HN)基因的重组鸡痘病毒中筛选一个作为疫苗候选株,进一步完善实验室试验,并在GMP条件下完成中间试制,为新城疫重组鸡痘病毒活疫苗顺利进入临床试验打好了基础。
1.单表达和共表达NDV F和HN基因重组鸡痘病毒活疫苗的免疫效力比较试验
为评价母源抗体对抗新城疫(ND)重组鸡痘病毒(rFPV)活疫苗免疫效力的影响,本研究用单表达、共表达NDV基因Ⅶ型病毒ZJ1株F、HN基因的rFPV活疫苗rFPV-12LSF、rFPV-12LSHN、rFPV-12LSFHN和油乳剂灭活疫苗分别免疫14日龄商品蛋鸡,重组鸡痘病毒疫苗的免疫剂量均为2×104PFU,免疫后21d分别用106ELD50NDV不同强毒株攻毒。其中F48E8株攻毒的免疫保护率分别为30.3%、73.2%、41.1%、89.3%;而ZJ1株攻毒的免疫保护率分别为35.8%、67.9%、78.6%、100%。用表达鸡IL-2基因的重组鸡痘病毒rFPV-12LSIL-2与rFPV-12LSHN联合免疫没有提高rFPV-12LSHN疫苗的免疫保护力。试验结果表明,单表达NDV HN基因的重组鸡痘病毒rFPV-12LSHN可作为ND活疫苗候选株,为ND重组鸡痘病毒活疫苗的进一步应用性开发奠定了基础。
2.表达新城疫病毒HN基因的重组鸡痘病毒的部分生物学特性研究
为了评价转基因对鸡痘病毒(FPV)生物学特性的影响,通过电镜观察重组鸡痘病毒(rFPV)感染的鸡胚成纤维细胞(CEF),结果表明在FPV中插入NDV血凝素-神经氨酸酶蛋白(HN)基因(rFPV-12LSHN)后,不改变rFPV的形态、病毒成熟过程。rFPV-12LSHN与FPV在CEF上的产量无显著差异。rFPV-12LSHN接种11日龄鸡胚,在尿囊膜(CAM)上观察到典型痘斑或水肿,鸡胚最小感染量≤100PFU。免疫荧光试验证明,rFPV-12LSHN在CEF上传代能稳定表达NDV HN抗原。rFPV (103PFU/羽)接种SPF鸡快速诱导NDV HI抗体应答,免疫3周后完全保护NDV强毒攻击。
3.表达新城疫HN基因的重组鸡痘病毒活疫苗的免疫持续期和加强免疫研究
为了评价表达新城疫病毒(NDV)血凝素-神经氨酸酶(HN)基因的重组鸡痘病毒(rFPV-12LSHN)活疫苗的免疫持续期和加强免疫对疫苗免疫效力的影响。用rFPV-12LSHN活疫苗免疫14日龄SPF鸡,103PFU/羽,7d即可检测到NDV HI抗体应答,对NDV强毒F48E8株攻毒保护率达100%。一次免疫18周后,对NDV强毒攻击依然提供完全保护。鸡痘病毒(FPV)疫苗免疫4周,再接种rFPV-12LSHN活疫苗,攻毒保护率降低至50%。相反,rFPV-12LSHN免疫4周,随后二次免疫可显著提高对NDV的体液免疫应答水平(P<0.01),对NDV强毒攻击的保护率没有影响。结果表明,表达NDV HN基因的重组鸡痘病毒(rFPV-12LSHN)活疫苗,能够快速建立坚强免疫力,免疫持续期至少可达18周,rFPV-12LSHN勺二次免疫可以提高疫苗的免疫力。
4.重组鸡痘病毒活疫苗X-gal染色空斑计数法的建立
建立了一种简易的携带LacZ基因重组鸡痘病毒(rFPV)活疫苗的X-gal染色空斑计数法。rFPV接种次代鸡胚成纤维细胞(CEF)72h后,加2mL/L戊二醛固定液室温固定15min,再加500ug/mL X-gal染色液37℃过夜,倒置显微镜下直接计数蓝染空斑。染色空斑计数法的空斑数是不染色直接计数法的1.6-3.3倍。该方法在重组鸡痘病毒活疫苗研究及其工业化生产检验中具有较大的应用价值。
5.鸡新城疫重组鸡痘病毒活疫苗的中试生产
为了给临床试验提供疫苗,在GMP条件下进行了鸡新城疫重组鸡痘病毒活疫苗(rFPV-ND-HN)的中试生产。CEF作为制苗材料,培养于10000ml转瓶,按0.2PFU/细胞接种毒种rFPV-12LSHN,37℃12转/h旋转培养,待细胞病变达到80%,收获感染细胞,加适量的5%蔗糖-脱脂奶粉,随后冻干。共生产了5批rFPV-ND-HN冻干疫苗,质量指标全部达到标准要求。
总结
1.筛选出单表达NDV HN基因的重组鸡痘病毒(rFPV-12LSHN)作为疫苗候选株。
2. rFPV-12LSHN与亲本毒株FPV-LP在CEF细胞内的病毒形态、繁殖方式以及病毒产量没有明显变化。
3. rFPV-12LSHN活疫苗,能够快速建立坚强免疫力,免疫持续期至少可达18周。
4. rFPV-12LSHN勺二次免疫可以显著提高疫苗的NDV HI抗体应答。
5.建立了一种简易、快速、敏感的重组鸡痘病毒活疫苗的X-gal染色空斑计数方法。
6.在GMP条件下中试生产了5批rFPV-ND-HN疫苗。
Newcastle Disease (ND) is one of the most serious of all avian diseases, which is caused by Newcastle disease virus (NDV). The fusion (F) protein and haemagglutinin-neuraminidase (HN) protein are two major glycoprotein components on its envelope, both of which are target genes expressed in fowlpox virus for vaccine development. In this study, recombinant fowlpox viruses expressing Newcastle disease virus F gene or HN gene and coexpressing F and HN genes were screened by comparison of their protective efficacy. The best one was chosen for further study and pilotscale experiment. This work lays the foundation for clinical trial of recombinant fowlpox virus vector vaccine against ND.
1. Protective efficacy of recombinant fowlpox viruses expressing Newcastle disease virus F gene or HN gene and coexpressing F and HN genes
To investigate the effect of maternal antibody to recombinant fowlpox viurs (rFPV) against Newcastle disease, two-week-old commercial layer chickens were immunized with2×104PFU rFPVs expressing fusion gene (rFPV-12LSF) or hemagglutinin-neuraminidase gene (rFPV-12LSHN) of genotype VII Newcastle disease virus (NDV) strain ZJ1and co-expressing F and HN genes (rFPV-12LSFHN) and0.2ml inactivated NDV oil-emulsion vaccine, respectively. At21days post-inoculation, chickens were challenged with106ELD5o of either virulent NDV strain F48E8or ZJ1. The protective efficacies against F48E8of rFPV-12LSF, rFPV-12LSHN, rFPV-12LSFHN and inactivated vaccine were30.3%、73.2%、41.1%and89.3%, while the protective efficacies against ZJ1were35.8%、67.9%、78.6%and100%. A recombinant fowlpox virus expressing chicken IL-2(rFPV-12LSIL-2) did not improve the protective efficacy of rFPV-12LSHN when combined with rFPV-12LSHN. The results indicated that the rFPV-12LSHN may be a effective candidate vaccine against NDV, which lays the foundation for further application of the live vector vaccine.
2. Partial biological characteristics of a recombinant fowlpox virus expressing Newcastle disease virus HN gene
To evaluate the effect of transferring gene on biological characteristics fowlpox virus, the rFPV was first subjected to ultrastructural analysis. The result demonstrated that morphology of mature virions, replication pattern, and production of rFPV-12LSHN in infected cells was similar as that of FPV. When11-day-old chicken embryonated egg were inoculated with rFPV by chorioallantoic membrane (CAM) route, typical pock lesions were observed on the CAM, the chicken embryo minimal infecting dose was less than100PFU. The expression of NDV HN gene in rFPV was detected stably by Immunofluorescence assay when rFPV was passed in CEF. SPF chickens vaccinated with one dose of vaccine containing103PFU of rFPV-12LSHN were completely protected from virulent NDV challenge after3weeks vaccination.
3. Duration of immunity and boost vaccination of a recombinant fowlpox virus expressing Newcastle disease virus HN gene
To evaluate the duration of immunity and the efficacy of boost vaccination of a recombinant fowlpox virus(rFPV-12LSHN) expressing HN gene from a Newcastle disease virus (NDV) isolate(ZJ1). Two-week old SPF chickens vaccinated with one dose of vaccine containing103plaque forming units (PFU) of rFPV-12LSHN were completely protected from virulent NDV after7days vaccination, hemagglutination inhibition (HI) antibody against NDV could be detected as early as7days postvaccination and Immune protection lasted up to18weeks postvaccination. The efficacy of different vaccination schedules was evaluated in SPF chickens, the lowest efficacy (50%) were observed in the group of chickens, which was vaccinated with fowlpox vaccine and followed by rFPV-12LSHN vaccine at4weeks interval.However, the chickens primed and boosted with rFPV-12LSHN at4weeks interval produced significant increase of the HI antibody against NDV (P<0.01)and provided100%protection against virulent NDV challenge. The result indicated that the fowlpox vector—based vaccine for ND could induce an earlier onset of immunity and a long duration of at least18weeks.Furthermore,a second vaccination with rPFV is valuable for induction of optimal immunity..
4. Establishment of a plaque forming unit counting method with X-gal staining for detection of recombinant fowlpox virus vaccine
A plaque forming unit counting method with X-gal staining was established for detection of recombinant fowlpox virus(rFPV) live vaccine, which genome contained LacZ gene insertion. The secondary chicken embryo fibroblast(CEF) infected with rFPV was grown for72h and fixed in2mL/L glutaraldehyde solution for15min,then incubated in a500ug/mL X-gal staining solution at37℃overnight. The blue-stained plaques were counted under an inverted microscope. The number of plaque forming unit counted with staining was1.6to3.3times more than that without staining.
5. Pilotscale production of recombinant fowlpox virus vaccine
In order to provide vaccine for clinical trials, a recombinant fowlpox virus vaccine expressing HN gene from a Newcastle disease virus (NDV) was produced on a pilot scale under Good Manufacturing Practice (GMP). CEFs in10000ml roller bottles were infected with rFPV-12LSHN at a multiplicity of infection (MOI) of approximately0.2PFU/cell and incubated at37℃with rolling at12revs h-1. The rPFVs infected CEFs were harvested when80%of the cells showed cytopathic effcct (CPE), stabilized by the addition of5%sucrose-milk powder and lyophilized. Five lots of vaccine products were manufactured, and the quality of vaccines met the criteria of document requirements.
Conclusion
1. A rFPV expressing HN gene (rFPV-12LSHN) of NDV was chosen as a effective vaccine candidate against NDV.
2. rFPV-12LSHN showed similar replication and production as FPV in CEF.
3. The duration of protective immunity by rFPV-12LSHN vaccination was more than18weeks.
4. The chickens primed and boosted with rFPV-12LSHN produced significant increase of the HI antibody against NDV.
5. A plaque forming unit counting method with X-gal staining for detection of recombinant fowlpox virus vaccine was established.
6. Five lots of qualified recombinant fowlpox virus vaccines were produced on a pilot scale under Good Manufacturing Practice.
引文
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