CN110237248A - A kind of preparation method of shingles zoster vaccine - Google Patents
A kind of preparation method of shingles zoster vaccine Download PDFInfo
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- CN110237248A CN110237248A CN201910585105.0A CN201910585105A CN110237248A CN 110237248 A CN110237248 A CN 110237248A CN 201910585105 A CN201910585105 A CN 201910585105A CN 110237248 A CN110237248 A CN 110237248A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K39/00—Medicinal preparations containing antigens or antibodies
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- A61P31/22—Antivirals for DNA viruses for herpes viruses
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- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16711—Varicellovirus, e.g. human herpesvirus 3, Varicella Zoster, pseudorabies
- C12N2710/16722—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16711—Varicellovirus, e.g. human herpesvirus 3, Varicella Zoster, pseudorabies
- C12N2710/16734—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
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Abstract
The invention belongs to viral vaccine fields, disclose a kind of preparation method of shingles zoster vaccine.The glycoprotein E coating extracellular portion of shingles zoster and the glycosylation site region building shingles zoster vaccine of envelope glycoprotein I is applied in combination, the glycoprotein E coating extracellular portion of shingles zoster is assisted to prepare shingles zoster vaccine by the envelope glycoprotein I on herpes zoster virus coating with the herpes zoster virus of the glycoprotein E of shingles zoster interaction, improve the glycosylation modified level of vaccine protein complex, the similitude of vaccine protein complex and native viral enve-lope is improved, the immunocompetence of shingles zoster vaccine is enhanced.
Description
Technical field
The invention belongs to viral vaccine fields, and the present invention is more particularly directed to a kind of preparation methods of shingles zoster vaccine.
Background technique
Vaccine is prevention and control infectious disease is most economical, most effective means, more till now from earliest inoculation cowpox
The vaccine of kind multiplicity plays an important role for protection human health.
There are mainly three types of types for currently used vaccine: attenuated live vaccine, inactivated vaccine, recombinant vaccine.Attenuated live
It is that cost induces body to form antibody that vaccine, which is using hypotoxicity, and immune effect is undesirable and has security risk.Inactivated vaccine is only
It is to make inactivation of virus in service stage, to be still the virus using infectious in production process, there are risks for production link.Base
Because engineered vaccine induces human body to form antibody by the envelope protein of heterogenous expression virus, challenge virus, mistake are not used in the process
Cheng Anquan.
It is glycosylation modified be improve vaccine activity effective ways, but gene engineering method production herpes zoster virus epidemic disease
Seedling uses glycoprotein E coating extracellular portion, only 2 glycosylation sites more, effectively improves the glycosylation journey of vaccine envelope protein
Degree is the important method for improving shingles zoster vaccine activity.
Summary of the invention
For overcome the deficiencies in the prior art, the present invention provides a kind of preparation method of shingles zoster vaccine, passes through increase
The degree of glycosylation of vaccine envelope protein improves the immunocompetence of shingles zoster vaccine.
Above-mentioned purpose of the invention is achieved through the following technical solutions:
A kind of preparation method of shingles zoster vaccine, comprising the following steps:
S1 utilizes gene engineering method single expression herpes zoster virus envelope protein, avoids viral full-length genome bring
Potential danger；
S2 is by the sugar of the glycoprotein E coating extracellular portion gene of shingles zoster and the envelope glycoprotein I of herpes zoster virus
Base site areas Gene Fusion synthesizes fusion；
S3 selects expression vector to complete expressing fusion protein using eukaryocyte:
S4 isolates and purifies glycosylated fusion protein and prepares shingles zoster vaccine.
Further, the glycosylation site area of the envelope glycoprotein I of the herpes zoster virus assists shingles zoster
Glycoprotein E coating extracellular portion, enhances the level of glycosylation of vaccine.
Further, the eukaryocyte that shingles zoster vaccine protein is expressed in the step S3 is yeast cells, including is finished
Chinese hamster ovary celI, insect expression cell etc. also can be used in red yeast, Hansenula yeast, saccharomyces cerevisiae etc..
Further, expression vector described in step S3 using secreted expression carrier carry out protein expression, it is preferable to use
Signal alpha secreting signal peptide.
Further, fusion protein described in step S3 is (band-like by peptide chain two albumen of completion rich in glycine
The glycoprotein E of bleb and the envelope glycoprotein I of herpes zoster virus) connection, amino acid number guarantees two eggs in 0-50
Effective combination between white.
Further, fusion protein described in step S3, wherein the glycosylation position of the envelope glycoprotein I of herpes zoster virus
Point area can also be tied in the aminoterminal of the glycoprotein E coating extracellular portion of shingles zoster outside the glycoprotein E coating of shingles zoster
The c-terminus in structure domain.
According to the glycoprotein I in natural herpes zoster virus envelope protein can in conjunction with the glycoprotein E of shingles zoster, and
The envelope glycoprotein I of herpes zoster virus has 4 glycosylation sites, utilizes the envelope glycoprotein I and sugar of herpes zoster virus
Albumen E binding characteristic can additionally increase by 4 glycosylation sites for the glycoprotein E of shingles zoster, improve the glycosyl of vaccine protein
Change degree is to improve the immunocompetence of shingles zoster vaccine.
Wherein, the glycosylation site area of the envelope glycoprotein I of herpes zoster virus has the following institute of 4 glycosylation sites
Show:
Note: 4 glycosylation sites are marked with italic+underscore.
Wherein, the coating exterior domain area containing glycosylation site of the glycoprotein E of shingles zoster includes that 2 glycosylation sites are as follows
It is shown:
Note: 2 glycosylation sites are marked with italic+underscore.
Compared with the prior art, the invention has the advantages that:
The present invention using the herpes zoster virus to interact on herpes zoster virus coating envelope glycoprotein I mating band
The glycoprotein E of shape bleb carries out vaccine preparation, improves the similitude of vaccine protein complex and native viral enve-lope, enhances band-like
The immunocompetence of herpes vaccine.Vaccine is carried out using the glycoprotein E of the envelope glycoprotein I cooperation shingles zoster of herpes zoster virus
The envelope glycoprotein I of preparation, herpes zoster virus has 4 glycosylation sites, and the fusion protein of eukaryotic cell expression is made to have 6
It is a can glycosylation site, improve the glycosylation modified level of vaccine, enhance the immunocompetence of shingles zoster vaccine.
Compared with prior art, the preparation method is that passing through the sugar on herpes zoster virus coating with shingles zoster
The glycoprotein E coating extracellular portion preparation of the envelope glycoprotein I auxiliary shingles zoster of the herpes zoster virus of albumen E interaction
The similitude of vaccine protein complex and native viral enve-lope can be improved in shingles zoster vaccine, and it is multiple that vaccine protein can be improved
Fit glycosylation modified level, can be enhanced the immunocompetence of shingles zoster vaccine.
Detailed description of the invention
Fig. 1 is that testing result figure is identified in the digestion of 1 expression vector of the embodiment of the present invention, and M is marker in figure, and 1 is plasmid
Digestion products, 2 be plasmid.
Fig. 2 is the protein induced expression result chart of 1 yeast-positive of embodiment of the present invention clone, and M is marker in figure, and 1 is
Supernatant after non-inducing cell is broken；2 be to precipitate after non-inducing cell is broken, and 3 be the supernatant of clasmatosis after induction, and 4 be induction
The precipitating of clasmatosis afterwards.
Specific embodiment
The present invention is described in detail below by specific embodiment, but is not limited the scope of the invention.Unless otherwise specified, originally
Experimental method used by inventing is conventional method, and experiment equipment used, material, reagent etc. commercially obtain.
Embodiment 1
Three genes: the glycosylation site of the envelope glycoprotein I of herpes zoster virus are obtained using bioinformatics software
Area's gene, the gene of envelope glycoprotein E coating extracellular portion, glycine connect the encoding gene of peptide chain, and press yeast codons
Preference carries out codon optimization.
Three genes are arranged in the order: after envelope glycoprotein E coating extracellular portion gene is located at signal peptide, then
It is the encoding gene containing 35 glycine connection peptide chains, followed by the glycosylation position of the envelope glycoprotein I of herpes zoster virus
Point area's gene, separately designs restriction enzyme sites at the both ends of fusion: EcoRI and XhoI is used for target gene to pPICZ α A
Expression vector recombination；Chemical method synthesis has the target gene in the site EcoRI and XhoI, with Yeast expression carrier pPICZ α A weight
Group simultaneously converts for Pichia pastoris X33 bacterial strain, mass propgation is carried out after screening and identification and obtains secreting, expressing by methanol induction
The herpes zoster virus envelope protein of high glycosylation, the condition of the culture are as follows: be inoculated in positive yeast single colonie
In BMGY culture medium (adding biotin), 30 DEG C, 250-300rpm, culture to OD600=2-6；Cell, bacterium is collected by centrifugation in 4000g
Weight is suspended from BMMY culture medium, 1% methanol induction, per the continuous 30 DEG C of inductions of methanol are added for 24 hours, monitors egg using SDS-PAGE
White expression.Expression protein is collected, carries out isolating and purifying for envelope protein using histidine tag, it will albumen blood coagulation after purification
Digestion completes the band-like of protein glycosylation except the auxiliary expressions part of polypeptide such as histidine-tagged protein, final obtain using ultrafiltration
Shingles zoster vaccine is made in herpesviral envelope protein complex.
Wherein, the glycine connects peptide chain are as follows:GGGGGAGGGG GSGGGGSGGG GGAGGGGGAG GGGGSGGGGG
Glycine chain for connecting two peptide zones contains 35 glycine, is spaced using alanine and serine.
It can be obtained by Fig. 1, select not having in former expression vector, only the restriction enzyme existing for target gene is recombinated
The digestion of carrier detects, the chosen restriction enzyme cutting of plasmid vector, it was demonstrated that target gene has been binned in expression and has carried
In body；Target gene is confirmed by nucleic acid sequencing.
Can be obtained by Fig. 2, compared with the control not induced, carry out after induction processing the broken centrifuged supernatant of saccharomycete with
All occur characteristic bands in precipitating, molecular weight is consistent with the protein molecular weight of prediction, it was demonstrated that protein expression success.
Embodiment 2
The gene of envelope glycoprotein E coating extracellular portion, the packet of herpes zoster virus are obtained using bioinformatics software
The glycosylation site area gene of membrane glycoprotein I is simultaneously directly connected into fusion, and carries out codon by yeast codons preference
Optimization.Separately design restriction enzyme sites at the both ends of fusion: EcoRI and XhoI is expressed for target gene to pPICZ α A
Carrier recombination；Chemical method synthesis has the fusion in the site EcoRI and XhoI, simultaneously with Yeast expression carrier pPICZ α A recombination
It is converted for Pichia pastoris X33 bacterial strain, mass propgation is carried out after screening and identification and secreting, expressing height is obtained by methanol induction
Glycosylated herpes zoster virus envelope protein, positive yeast single colonie is inoculated in BMGY culture medium, and 30 DEG C, 250-
400rpm, culture to OD600=2-6；Expansion is inoculated in BSM culture medium and carries out a large amount of saccharomycete amplifications, and initial stage, saccharomycete was with sweet
Oil is 30 DEG C of carbon source growths, and the later period is every to add the continuous 25 DEG C of inductions of methanol, benefit for 24 hours with 1% methanol (adding microelement) induction
Protein expression is monitored with SDS-PAGE.Expression protein is collected, carries out isolating and purifying for envelope protein using histidine tag, it will
Albumen fibrin ferment cuts off the auxiliary expressions part of polypeptide such as histidine-tagged protein after purification, is finally completed using ultrafiltration
Shingles zoster vaccine is made in the herpes zoster virus envelope protein complex of protein glycosylation.
Embodiment 3
Target gene, the glycosylation of the envelope glycoprotein I including herpes zoster virus are obtained using bioinformatics software
Site area gene, the gene of envelope glycoprotein E coating extracellular portion, the link peptide chain encoding gene containing 50 glycine.Wherein,
The glycine connects peptide chain are as follows:GGGGGAGGGG GSGGGGSGGG GGAGGGGGAG GGGGSGGGGG GGAGGGGGAG GGGGSGGGGGlycine chain for connecting two peptide zones contains 50 glycine, uses alanine and silk between glycine small peptide
Propylhomoserin is spaced.
Three genes are arranged in the order: the glycosylation site area gene of the envelope glycoprotein I of herpes zoster virus
After signal peptide, it is followed by the encoding gene containing 50 glycine connection peptide chains, is finally envelope glycoprotein E coating knot outside
Structure domain gene, three genomes become fusion and separately design restriction enzyme sites at the both ends in fusion: BamHI and
EcoRI is recombinated for target gene to pEF1/Myc-His series expression vector；Chemical method synthesis has BamHI and EcoRI
Fusion is inserted into pEF1/Myc-His series expression vector by BamHI and EcoRI and is used for CHO- by the fusion of point
K1 cell transformation.The expression vector that row linearizes when using the method for electrotransformation by after recombination is transferred in CHO-K1 cell, benefit
Transformant screening is carried out with Neomycin, recon is completed using the western blot of expression label and target protein and identifies.
After the screening and identification for completing recon, CHO-K1 cell mass propgation is carried out, cell, lytic cell are collected after digesting using pancreatin
And supernatant is harvested, expression protein is collected, the herpes zoster virus packet of high glycosylation is carried out using histidine separation tags
Memebrane protein fusion protein purification will cut off the auxiliary expressions part of polypeptide such as histidine-tagged protein by albumen fibrin ferment after purification,
It is final that the herpes zoster virus envelope protein complex for completing protein glycosylation is obtained using ultrafiltration, shingles zoster epidemic disease is made
Seedling.
The glycosylation site area gene of the envelope glycoprotein I of herpes zoster virus described in embodiment 1-3 is as follows:
1 LIFKGDHVSL QVNSSLTSIL IPMQNDNYTE IKGQLVFIGE QLPTGTNYSG TLELLYADTV
61 AFCFRSVQVI RYDGCPRIRT SAFISCRYKH SWHYGNSTDR ISTEPDA
The gene of envelope glycoprotein E coating extracellular portion described in embodiment 1-3 is as follows:
Embodiment described above is merely a preferred embodiment of the present invention, and simultaneously the whole of the feasible implementation of non-present invention implement
Example.For persons skilled in the art, the appointing to made by it under the premise of without departing substantially from the principle of the invention and spirit
What obvious change, should all be contemplated as falling within claims of the invention.
Claims (6)
1. a kind of preparation method of shingles zoster vaccine, characterized in that the following steps are included:
S1 utilizes gene engineering method single expression herpes zoster virus envelope protein；
S2 is by the glycosylation of the glycoprotein E coating extracellular portion gene of shingles zoster and the envelope glycoprotein I of herpes zoster virus
Site areas Gene Fusion synthesizes fusion；
S3 selects expression vector to complete expressing fusion protein using eukaryocyte:
S4 isolates and purifies glycosylated fusion protein and prepares shingles zoster vaccine.
2. a kind of preparation method of shingles zoster vaccine as described in claim 1, characterized in that the herpes zoster virus
Envelope glycoprotein I glycosylation site area auxiliary shingles zoster glycoprotein E coating extracellular portion.
3. a kind of preparation method of shingles zoster vaccine as described in claim 1, characterized in that express band in the step S3
The eukaryocyte of shape herpes vaccine albumen is yeast cells, including Pichia pastoris, Hansenula yeast, saccharomyces cerevisiae；Or Chinese hamster ovary celI,
Insect expression cell.
4. a kind of preparation method of shingles zoster vaccine as described in claim 1, characterized in that albumen table described in step S3
Up to using the type expression vector that point oozes to carry out protein expression.
5. a kind of preparation method of shingles zoster vaccine as described in claim 1, characterized in that fusion egg described in step S3
White is the connection that two albumen is completed by the peptide chain rich in glycine, and amino acid number is at 0-50.
6. a kind of preparation method of shingles zoster vaccine as described in claim 1, characterized in that fusion egg described in step S3
It is white, wherein glycoprotein E coating extracellular portion of the glycosylation site area of the envelope glycoprotein I of herpes zoster virus in shingles zoster
Aminoterminal, or the c-terminus of the glycoprotein E coating extracellular portion in shingles zoster.
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