CN105238766A - Application and preparation method of candidate strain of human type-3 adenovirus expressed human type-14 adenovirus neutralization epitope vaccine - Google Patents
Application and preparation method of candidate strain of human type-3 adenovirus expressed human type-14 adenovirus neutralization epitope vaccine Download PDFInfo
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Abstract
The invention relates to the technical field of genetic engineering of recombinant viruses, in particular to an application and preparation method of a candidate strain of a human type-3 adenovirus expressed human type-14 adenovirus neutralization epitope vaccine. Two human type-14 adenovirus neutralization epitopes are respectively embedded to hexons of human type-3 adenoviruses to be displayed on the surfaces of the hexons. The candidate strain of the vaccine is capable of inducing strong anti-HAdv14 and anti-HAdv3 infection immunoreactions and can be used for preparation of bivalent vaccines for prevention of HAdv14 and HAdv3 infection.
Description
Technical field
The present invention relates to recombinant viral genome field of engineering technology, be specifically related to the preparation method and application that a kind of human 3-type adenovirus shows the strain of people 14 type adenovirus Neutralization and crystallization vaccine candidate.
Background technology
Adenovirus Late Cambrian, in nineteen fifty-three, can cause numerous disease, comprises acute respiratory disease (ARD), pneumonia, epidemic keratoconjunctivitis, acute gastroenteritis.According to homology and the difference of its genomic dna, adenovirus hominis (HAdVs) is divided into seven large classes (A-G), and more than 65 kinds of serotypes, different adenovirus can cause different diseases.(be also referred to as " agentdeWit " or HAdV-14p) be found in nineteen fifty-five the earliest, be separated to obtain in the military camp of Holland's outburst acute respiratory disease to adenovirus 14 type.In succession find on Britain's (nineteen fifty-five), Uzbekistan (1962), Czechoslovakia (1963) and other places subsequently.Adenovirus 14 type belongs to B2 subspecies adenovirus, ends in eighties of last century nineties, is mainly found in Europe and parts of Asia, does not have report on the Western Hemisphere, and do not cause serious respiratory system disease, as being in hospital or death.But at 2006-2007, adenovirus 14 type causes serious lower respiratory illness in the U.S., in New York, Oregon, Washington and Texas cause at least 10 people dead, 140 routine cases.Research shows, this adenovirus 14 type again broken out belongs to new genotype HAdV-14p1(and is also referred to as HAdV-14a), the place maximum with prototype difference is that cilium gene exists the disappearance of 6 base pairs.Because most of crowd there is no antibody to this variation strain, and this strain tool is highly pathogenic, and relative death rate is higher, does not have effective medicine and method at present, therefore the optimal path that vaccine inoculation prevents adenovirus 14 type to infect beyond doubt.
Adenovirus (Adenovirus; ADV) be an icosahedral symmetrical structure, housing is made up of 252 housing subunits, what be wherein positioned at icosahedral 12 drift angles be penton protein and a length is the fiber initiation of 10-30nm, other 240 non-drift angle particles are made up of six adjacent body tripolymers, and body can be stimulated to produce neutralizing antibody and group and type Ⅱ diabete.The aminoacid sequence of the hexon of different type adenovirus has very high homology, and its difference mainly concentrates on the height being exposed to hexonmer surface and becomes (HypervariableRegions; And the recognition site of type specificity neutralizing antibody just concentrates on these hypervariable regions HVRs).The hypervariable region of adenovirus contains main neutrality epitope, and body can be stimulated to produce the protectiveness neutralizing antibody of high titre, is the most important albumen of adenovirus subunit vaccine.There is a lot of unique epi-positions out identified in recent years and be applied to the vaccine research of transmissible disease, cancer and autoimmune disorder.But independent epitope peptide immunogenicity is weak, can not induce immune response and immunological memory, thus a lot of method of development in recent years, if novel adjuvant, lipopeptid coupling, application Universal T-cell epitopes, multiple antigenic peptide, nanometer are delivery system and virus vector etc., facilitates the development of epiposition vaccine.
Inoculation adenovirus vaccine is one of most effective means of prevention 14 type adenovirus infection, but there is no vaccine listing at present clinically.Virus vector some can induce body fluid and cellullar immunologic response, therefore be widely used in the vaccine of cancer prevention and treatment and infectious diseases, comprise rhinovirus vectors, adenovirus carrier, poxvirus vector, measles vector, lentiviral vectors, influenza vectors etc.Wherein in the adenovirus carrier gene therapy that has been widely used in cancer and infectious diseases and vaccine research.Result of study shows, under the prerequisite not affecting the copying of virus, infectious and stability, small peptide directly can be replaced or be inserted in some hypervariable region of the adjacent body of human 3-type six, produce the virus particle with new antigen-specific.This epitope presentation system based on adenovirus has very many advantages: the first, and adenovirus molecular weight is large, itself is a kind of fabulous immunological adjuvant, effectively stimulates body to produce specific cellular immunization and humoral immunization.Second, six adjacent bodies are immunogens the abundantest on adenovirus housing, and in hexon, insert a Surface Display of Foreign Epitopes, then each adenovirus just can represent 720 epitopes, and epitope can be given full expression to.3rd, object antigen peptide is the surface being exposed to capsid after inserting six adjacent bodies, body effectively can be stimulated to produce immune response, do not need to carry out transgene expression, overcome the shortcoming of adenoviral transgene carrier.4th, adenovirus carrier vaccine has high security, high yield, and is easy to produce.Formation replication defect type can be changed after vaccine virus strain successfully constructs further and improve its security.5th, the adjacent body of adenovirus six there is multiple epitope can be replaced, the polyvalent vaccine recombinant virus for multiple Virus type can be built.
Therefore, human 3-type adenovirus capsid is utilized to show people 14 type adenovirus Neutralization and crystallization, two of HAdv14 neutrality epitope A14R2 and A14R4(aminoacid sequence are respectively " LEVPAEGDP " and " TEEAGNIEY ") insert the adjacent body capsid protein of 3 type adenovirus six respectively, the recombinant human 14 type adenovirus-human 3-type adenovirus vaccine candidate strain simultaneously retaining human 3-type adenovirus major antigen is expected to for preventing HAdv14 to infect and HAdv3 infection simultaneously.
Summary of the invention
In order to overcome the shortcoming and defect existed in prior art, the object of the present invention is to provide a kind of restructuring human 3-type adenovirus and its preparation method and application.
The invention provides a kind of restructuring human 3-type adenovirus, embedded in two kinds of HAdv14 neutralizing epitope A14R2 and A14R4 in six adjacent bodies of described restructuring human 3-type adenovirus, the aminoacid sequence of described HAdv14 neutralizing epitope A14R2 is LEVPAEGDP, and the aminoacid sequence of described HAdv14 neutralizing epitope A14R4 is TEEAGNIEY.
Preferably, the replacement district of the neutralizing epitope A14R2 of described HAdv14 is described HAdv3 six Lin Ti HVR2 district, and the replacement district of the neutralizing epitope A14R4 of described HAdv14 is the HVR4 district of the adjacent body of described HAdv3 six.
More preferred, the aminoacid sequence that described HAdv14 neutralizing epitope A14R2 replaces is the KDITTTEGEE in HAdv3 six Lin Ti HVR2 district, and the aminoacid sequence that described HAdv14 neutralizing epitope A14R4 replaces is the PTTEGGVETEEP in HAdv3 six Lin Ti HVR4 district.
Present invention also offers a kind of bivalent vaccine candidate of human 3-type adenovirus-people 14 type adenovirus, described bivalent vaccine candidate contains the restructuring human 3-type adenovirus described in any one of claim 1-3.
Present invention also offers a kind of carrier, described carrier comprises the restructuring human 3-type adenovirus described in any one of claim 1-3.
Present invention also offers a kind of preparation method of human 3-type adenovirus of recombinating, comprise the steps:
The adjacent body of human 3-type adenovirus six embedded in two HAdv14 neutralizing epitope A14R2 and A14R4; Wherein,
The aminoacid sequence of described HAdv14 neutralizing epitope A14R2 is LEVPAEGDP, and the aminoacid sequence of described HAdv14 neutralizing epitope A14R4 is TEEAGNIEY;
The aminoacid sequence that described HAdv14 neutralizing epitope A14R2 replaces is the KDITTTEGEE in HAdv3 six Lin Ti HVR2 district, and the aminoacid sequence that described HAdv14 neutralizing epitope A14R4 replaces is the PTTEGGVETEEP in HAdv3 six Lin Ti HVR4 district.
Restructuring human 3-type adenovirus provided by the present invention, allows the disappearance of HAdv14 neutralizing epitope Individual amino acids, replacement or interpolation, but needs the immunogenicity keeping neutralizing epitope; Allow the disappearance of replaced HVR2 district and HVR4 region sequence Individual amino acids, replacement or interpolation, but need the stability keeping adenovirus, ensure the immunocompetence of foreign epitope simultaneously; The HAdv14 neutralizing epitope embedded in the present invention is not limited to A14R2 and A14R4, also can be other protectiveness t cell epitope or B cell epi-position, but needs keep the stability of adenovirus and ensure the immunogenicity of foreign epitope.
Beneficial effect of the present invention is: in the present invention, and six adjacent body capsids are shown two kinds of main neutralizing epitopes of HAdv14 simultaneously, produces the protective immune response that strong anti-HAdv14 infects, multiple injection energy booster immunization.Meanwhile, the major antigen that restructuring human 3-type adenovirus of the present invention remains HAdv3 is active, and this recombinant virus can simultaneously for preventing the infection of HAdv3.
Accompanying drawing explanation
Fig. 1 is that the recombinant plasmid enzyme that six adjacent bodies that the present invention recombinates human 3-type adenovirus are modified cuts qualification electrophorogram.Wherein, M is that DL15000,1-2 are pAd △ E3GFPA14R2,3-4 and are pAd △ E3GFPA14R4,5 for contrast skeleton plasmid pBRAd △ E3GFP(is through BamHI single endonuclease digestion); 6-7 is pAd △ E3GFPA14R2,8-9 and is pAd △ E3GFPA14R4,10 for contrast skeleton plasmid pBRAd △ E3GFP(is through SalI single endonuclease digestion); 11-12 is pAd △ E3GFPA14R2,13-14 and is pAd △ E3GFPA14R4,15 for contrast skeleton plasmid pBRAd △ E3GFP(is through HindIII single endonuclease digestion).
Embodiment
For the ease of the understanding of those skilled in the art, below in conjunction with embodiment and accompanying drawing 1, the present invention is further illustrated, and the content that embodiment is mentioned not is limitation of the invention.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention, NM specific experiment method in the following example, conveniently experimental technique carries out usually.
No. Genbank, HAdv3 full-length genome described in this specification sheets embodiment is DQ099432.4; No. GenBank, the adjacent body sequence of HAdv14 six described in this specification sheets embodiment is DQ149612.1.
Embodiment 1: the surface exposed regions of the adjacent body of bioinformatic analysis prediction human 3-type adenovirus six
Use BLAST-P program at ProteinDataBank(PDB) the middle formwork structure searching for the modeling of HAdv3 six adjacent body homology, and use Modeller9.9 to carry out homology modeling, build the 3D model of HAdv3 hexon.The hypervariable region sequence being exposed to capsid surface is selected to carry out next step experiment.
By analyzing 3D model, can position the Neutralization and crystallization on the adjacent body of human 3-type adenovirus six, analysis is wherein exposed to capsid surface most probable and is substituted and does not affect the sequence of six adjacent body structure stability.HVR1, HVR2, HVR4, HVR5, HVR7 are potential Neutralization and crystallization districts, wherein partial amino-acid is likely substituted and does not affect six adjacent body structure stability, two hypervariable region sequence are as follows, wherein, the amino acid of underscore mark is for being sequence that A14R2 and A14R4 replaces in the present invention.
1）HAdv3HVR2：KEGLQIG
KDITTTEGEEKPIYADK
2）HAdv3HVR4：KVK
PTTEGGVETEEPDID。
Embodiment 2: construction of recombinant virus carrier
With the six adjacent body genes that the amplification of over-lap PCR (overlappingPCR) method is modified, first with HAdv3 genome for template overlapping PCR method obtains A14R2(5'-TTGGAAGTCCCAGCTGAAGGTGACCCT-3') DNA sequence dna replace the adjacent body piece section of sudden change six of the HVR2 corresponding sequence of HAdv3 six adjacent body gene, to be connected in carrier T and qualification of checking order; Again with HAdv3 genome for template overlapping PCR method obtains A14R4(5'-ACAGAAGAAGCAGGCAACATTGAATAT-3') DNA sequence dna replace the adjacent body piece section of sudden change six of the HVR4 corresponding sequence of HAdv3 six adjacent body gene, to be connected in carrier T and qualification of checking order;
bamhI+
clabe connected on PBRHLR carrier after I double digestion, obtain shuttle vectors pBRHLRA14R2 and pBRHLRA14R4.With
ecoRi+
sali double digestion shuttle vectors, with
avRiI+
pacthe skeleton plasmid pBRAd △ E3GFP of I double digestion carries out homologous recombination in E.coli BJ5183, obtains recombinant plasmid pAd △ E3GFPA14R2 and pAd △ E3GFPA14R4.Warp
bamhI/
salI/
hindIII enzyme cuts qualification, and recombinant plasmid is not undergone mutation, as shown in Figure 1.The primer used is in table 1, A14R2r and A14R4r is PCR Screening and Identification special primer.
The primer that the adjacent body gene of HAdv3 six that table 1 over-lap PCR method amplification foreign epitope embeds uses
By the plasmid that above-mentioned restructuring obtains
asistransfection AD293 cell after I linearization for enzyme restriction, rescue is packaged to be recombinant viral vector Ad3A14R2 and Ad3A14R4, mass propgation CsCl density gradient centrifugation purification of Recombinant virus particle.Purified virus particle reaches 1 × 10
12vPs/ml, measure OD260/OD280 ratio and be about 1.2-1.4, intracellular toxin detects <10EU/ml.Recombinant virus Ad3A14R2 and Ad3A14R4 extracts viral genome in AD293 cell after continuous passage 10 generation carries out enzyme and cuts qualification, order-checking qualification, shows that recombinant virus genomes keeps stable, does not have gene to lack, Reorganization.
Embodiment 3: recombinant viral vector Study On Immunogenicity
Prepare antiserum(antisera), carry out serum neutralization test, the immunogenicity of checking recombinant viral vector.By the recombinant virus Ad3A14R2 of purifying and Ad3A14R4 intramuscular injection immune mouse, obtain polyclonal serum, then carry out external neutralization test, the antibody produced to detect recombinant virus whether have external in and HAdv14 virus and the ability of HAdv3 virus.
The experimental result of the mice serum neutralization reaction that twice immunity gathers for latter 35 days is in table 2, and twice immunity can induce the anti-HAdv14 virus of high titre and the neutralizing effect antibody of anti-HAdv3 virus.
Table 2 twice immune serum Neutralizing titer
Above-described embodiment is the present invention's preferably implementation, and in addition, the present invention can also realize by alternate manner, and any apparent replacement is all within protection scope of the present invention without departing from the inventive concept of the premise.
Claims (6)
1. a restructuring human 3-type adenovirus, it is characterized in that: in six adjacent bodies of described restructuring human 3-type adenovirus, embedded in two kinds of HAdv14 neutralizing epitope A14R2 and A14R4, the aminoacid sequence of described HAdv14 neutralizing epitope A14R2 is LEVPAEGDP, and the aminoacid sequence of described HAdv14 neutralizing epitope A14R4 is TEEAGNIEY.
2. one restructuring human 3-type adenovirus according to claim 1, it is characterized in that: the replacement district of the neutralizing epitope A14R2 of described HAdv14 is described HAdv3 six Lin Ti HVR2 district, and the replacement district of the neutralizing epitope A14R4 of described HAdv14 is the HVR4 district of the adjacent body of described HAdv3 six.
3. one restructuring human 3-type adenovirus according to claim 1, it is characterized in that: the aminoacid sequence that described HAdv14 neutralizing epitope A14R2 replaces is the KDITTTEGEE in HAdv3 six Lin Ti HVR2 district, the aminoacid sequence that described HAdv14 neutralizing epitope A14R4 replaces is the PTTEGGVETEEP in HAdv3 six Lin Ti HVR4 district.
4. a bivalent vaccine candidate for human 3-type adenovirus-people 14 type adenovirus, is characterized in that: described bivalent vaccine candidate contains the restructuring human 3-type adenovirus described in any one of claim 1-3.
5. a carrier, is characterized in that: described carrier comprises the restructuring human 3-type adenovirus described in any one of claim 1-3.
6. the preparation method of a kind of human 3-type adenovirus of recombinating as described in any one of claim 1-3, is characterized in that: comprise the steps:
The adjacent body of human 3-type adenovirus six embedded in two HAdv14 neutralizing epitope A14R2 and A14R4; Wherein,
The aminoacid sequence of described HAdv14 neutralizing epitope A14R2 is LEVPAEGDP, and the aminoacid sequence of described HAdv14 neutralizing epitope A14R4 is TEEAGNIEY;
The aminoacid sequence that described HAdv14 neutralizing epitope A14R2 replaces is the KDITTTEGEE in HAdv3 six Lin Ti HVR2 district, and the aminoacid sequence that described HAdv14 neutralizing epitope A14R4 replaces is the PTTEGGVETEEP in HAdv3 six Lin Ti HVR4 district.
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| CN106754760A (en) * | 2017-01-20 | 2017-05-31 | 华南农业大学 | A kind of preparation method and application of the restructuring human 3-type adenovirus of chimeric IBDV neutralizing epitopes |
| CN106906186A (en) * | 2017-01-24 | 2017-06-30 | 东莞市儿科研究所 | It is a kind of while preventing the polyepitope vaccines Candidate Strain of the type adenovirus of human 3-type adenovirus people 55 type adenovirus people 7 |
| CN107365364A (en) * | 2016-05-12 | 2017-11-21 | 兰州雅华生物技术有限公司 | A kind of quick detection kit of Adenovirus Antigen preparation method and the detection adenovirus antibody prepared using the antigen |
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| CN103966263A (en) * | 2013-02-04 | 2014-08-06 | 广州医学院第一附属医院 | Recombinant human adenovirus 3, and preparation method and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107365364A (en) * | 2016-05-12 | 2017-11-21 | 兰州雅华生物技术有限公司 | A kind of quick detection kit of Adenovirus Antigen preparation method and the detection adenovirus antibody prepared using the antigen |
| CN106754760A (en) * | 2017-01-20 | 2017-05-31 | 华南农业大学 | A kind of preparation method and application of the restructuring human 3-type adenovirus of chimeric IBDV neutralizing epitopes |
| CN106906186A (en) * | 2017-01-24 | 2017-06-30 | 东莞市儿科研究所 | It is a kind of while preventing the polyepitope vaccines Candidate Strain of the type adenovirus of human 3-type adenovirus people 55 type adenovirus people 7 |
| CN106906186B (en) * | 2017-01-24 | 2019-10-11 | 东莞市儿科研究所 | It is a kind of while preventing 55 type adenovirus of human 3-type adenovirus-people -7 type adenovirus of people polyepitope vaccines Candidate Strain |
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