CN100413537C - SARS coronary virus full virus vaccine - Google Patents
SARS coronary virus full virus vaccine Download PDFInfo
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- CN100413537C CN100413537C CNB2004100160628A CN200410016062A CN100413537C CN 100413537 C CN100413537 C CN 100413537C CN B2004100160628 A CNB2004100160628 A CN B2004100160628A CN 200410016062 A CN200410016062 A CN 200410016062A CN 100413537 C CN100413537 C CN 100413537C
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Abstract
The present invention relates to a vaccine composition which comprises complete virus particles of early SARS virus, and physiologically acceptable carriers. The present invention relates to an application of the vaccine composition in the preparation of SARS resisting antibody and medicines for preventing SARS virus infection.
Description
Technical field
The present invention relates to the molecular epidemiology field, specifically is vaccine at severe acute respiratory syndrome virus and preparation method thereof.
Background technology
China in 2003 and many in the world countries have suffered the once invasion and attack of large-scale atypical pneumonia (Atypicalpneumonias), (Severe AcuteRespiratory Sydrome SARS) takes place 22 countries and regions the severe acute respiratory syndrome that is caused by atypical pneumonia.(WorldHealth Organization WHO) sets up cooperating research and the monitoring network of being made up of 13 laboratorys of 10 countries in the whole world rapidly after epidemic situation takes place in World Health Organization (WHO).April 16, the pathogen of WHO official confirmation SARS is a kind of novel coronavirus, and this is a kind of single strand RNA virus.
The existing 8000 many cases atypical pneumonia patients in the whole world, its mortality rate reaches 15% in some region of disease, has brought great fear to the people.The research worker of medical personnel and field of biology is in time carried out the nosetiology of sars coronavirus and the research of prevention, diagnosis and treatment, and for the toxicity in this viral mutation process and each stage and the characteristics of infectivity certain understanding has been arranged all.But at present for the still not significant progress of the work of SARS virus vaccine.
The vaccine candidate strain of report at present all is the strain that comes from the SARS critical patient generally.Because SARS virus is dangerous strong, requirement for experiment condition height, and the difficulty of on the person, testing, the vaccine of SARS virus is difficult to research and development.
Though the somebody develops dna vaccination and the genetic engineering subunit vaccine of prevention and treatment SARS, historical experience shows, as long as safety is guaranteed that whole virus vaccine is a kind of very effective vaccine always.Therefore develop the research emphasis that whole virus vaccine is an anti-SARS vaccin always.
Yet, people find in In vitro culture, thereby the SARS virus of epidemic diseases middle and advanced stage is easier to obtain virion at In vitro culture, and the SARS virus granule that comes from masked civet is difficult at In vitro culture, therefore when preparation inactivated vaccine and attenuated vaccine, adopt the SARS virus strain of middle and advanced stage mostly.
The SARS virus strain that being used to of having attempted at present prepares vaccine comprises BJ-01,02 and 03 (GenBank accession number: AY278488, AY278487 and AY278490).What abroad may attempt is and TOR2 (GenBank accession number: AY27419) similar strain.Because these viruses all are the SARS virus of middle and advanced stage, strong toxicity, the infection ability is strong, has very high danger.And,, be not equal to effective checking has been carried out in the safety of middle and advanced stage SARS whole virus vaccine though the reaction that vaccine produces in the monkey body is very little because laboratory animal monkey itself is also insensitive to SARS virus.
Therefore, this area presses for exploitation can both can effectively produce anti-SARS virus immunity, has vaccine, the especially whole virus vaccine of safety again.
Summary of the invention
Purpose of the present invention just provides and a kind ofly both can effectively produce anti-SARS virus immunity, has the SARS whole virus vaccine of safety again.
Therefore, in one aspect of the invention, provide a kind of vaccine combination, it is characterized in that, whole virus particles and physiology that this vaccine combination contains early stage SARS virus go up acceptable carrier.
In a preference aspect this, has at least one the nucleotide attenuation that is selected from down group variation in the nucleotide sequence of this SARS virus: 9404 → C, 17564 → G, 21721 → A, 22222 → C, 23823 → G, 27827 → C and combination thereof among the SEQ ID NO:1.
In another preference aspect this, the albumen of this SARS virus has amino acid mutation, described amino acid mutation corresponding to being selected under the nucleotide attenuation variation of group: 9404 → C, 17564 → G, 21721 → A, 22222 → C, 23823 → G, 27827 → C and combination thereof among the SEQ ID NO:1.
In another preference aspect this, this SARS virus is the GZ-02 Strain, has the nucleotide sequence that the GenBank accession number is AY390556.
In another preference of the present invention, this SARS virus is deactivation.
Also have in the preference of the present invention, the contained acceptable carrier biologically of this vaccine combination is an adjuvant.
In another aspect of the present invention, provide above-mentioned vaccine combination to be used to prepare the purposes of the antibody of anti-SARS.
Of the present invention also have one aspect, provide above-mentioned vaccine combination to be used to prepare the purposes of the medicine that the prevention SARS virus infects
Description of drawings
Fig. 1 has described the proximity relations of 60 kinds of sars coronavirus genome sequences, has shown the dendrogram of the source of variation of each Strain.Be the variation in early stage, mid-term, late period from bottom to up.
The specific embodiment
Inventor's process further investigation discovery, though thereby the SARS of middle and advanced stage is easy to cultivate is convenient to obtain a large amount of virions, and its toxicity is too strong, and the infection ability is strong, has very high danger, so safety is difficult to be protected.On the contrary, though masked civet SARS virus In vitro culture is comparatively difficult, because toxicity is lower, the infection ability is lower, therefore expects that safety is good.Human early stage SARS virus can In vitro culture, still, toxicity and infectivity a little less than, therefore, be the strain of candidate preferably of vaccine.In addition, research has confirmed that also early stage SARS totivirus is enough to produce the anti-early, middle and late immunity that waits the SARS in each period, and therefore the whole virus vaccine that makes with early stage SARS virus has extraordinary safety and protective immunity.
Attenuation mutation SARS virus (GZ02) sequence of using among the present invention (the accession number AY390556 of Genbank) that has is the early stage Strain of SARS virus that the applicant is separated to from Guangzhou, and its gene order is deposited in GenBank, has accession number AY390556.The gene order (the accession number AY274119 of Genbank) of the SARS virus strain TOR2 that is separated to Canada is compared, have a series of sudden change differences, may be relevant with toxicity or infectivity, particularly be selected from the attenuation sudden change of 9404 → C, 17564 → G, 21721 → A, 22222 → C, 23823 → G, 27827 → C and combination thereof.
From epidemiological analysis as seen, this sudden change belongs to the early stage sudden change of SARS, and (GZ02 has these sudden changes in the virus sequence that AY390556) is separated to primary masked civet sequence (SZ16, GenBank accession number AY304488) and early stage patient.According to clinical observation, this early stage SARS virus of GZ02 toxicity in human body is little, a little less than the appeal.Though this GZ02 strain separates the postmortem material that derives from a gerontal patient,, other early stage patients all have similar sudden change, and the state of an illness a little less than.This shows, carries out immunity with early stage virus, can have better protection immunity and lower toxicity than the middle and advanced stage virus of present use.
Before the present invention, there are three to be middle and advanced stage virus preparation vaccine according to what those skilled in the art's use was described.At first, on popular medical history and the region as seen, this region has belonged to middle and advanced stage on the route that SARS propagates, therefore, these geographic research worker the source of the SARS virus that can obtain be limited, in view of the danger in the transportation, and the clinical genovariation of not determining SARS virus at that time, the research worker of these regions can only be studied with locally collected virus.Fig. 1 is the dendrogram of each Strain variation of SARS virus, and wherein the virus of visible middle and advanced stage is compared with early stage virus and passed through repeatedly variation.And gene order has wherein also had very big difference, and table 1 has hereinafter shown that several representational SARS virus nucleotides sequences list the variation in several main sites.
The important site of table 1SARS virus single nucleotide variations
| The position | 1206 | 9404 | 9479 | 17564 | 20840 | 21721 | 22222 | 23823 | 27827 |
| Early stage type | C | C | C | G | A | A | C | G | C |
| Mid-term type I | T | T | T | G | G | A | C | T | C |
| Mid-term type II | T | C | T | G | G | A | C | T | C |
| Late period type | T | T | T | T | G | G | T | T | T |
Secondly, described in background of invention, the virus in mid-term and late period is because infection effectiveness is strong, and is strong in the ability of Vero time multiplexed cell system propagation, therefore is easy to cultivation.Though have certain danger under study for action, this still is the effective way of a large amount of virions of the fastest acquisition.
The 3rd, therefore masked civet and early stage virus collect difficulty owing to a little less than the infection ability, be difficult to cultivate.Make research worker temporarily not consider to prepare vaccine with it.
The present inventor passes through the EPDML research of Chinese SARS, the coronavirus of finding early stage patient's SARS virus separated strain and masked civet is closely similar, and collected the Strain that is enough to prepare vaccine by cultivation, overcome primary masked civet coronavirus in the difficulty that still can not cultivate at present.The virus (for the SARS virus of middle and advanced stage, this virus has belonged to the attenuation form) of these attenuations is prepared into vaccine, or preferably uses its deactivation form to prepare vaccine, be used for immune animal, produce antiserum.These antiserums can with the SARS virus of middle and advanced stage in conjunction with producing neutralization reaction, illustrate to have produced protective immunity.
With infected person and animal reservoir's middle and advanced stage virus, for example TOR2 compares with BJ01, and early stage GZ02 attenuated virus of the present invention shows virulence significantly to be weakened.The attenuation degree reaches at great majority to be accepted slight infection symptoms only to occur in the immune individuality, and infectiousness is very little and can cause required type of immune response.
Available this SARS virus is prepared vaccine.For this reason, attenuated virus is adjusted to suitable concentration also with suitable vaccine adjuvant, diluent or carrier preparation.The physiology can be gone up acceptable medium as carrier.They include but not limited to: suitable isotonic solution, phosphate buffer or the like.
Adjuvant can classify with several different methods (Cox and Coulter, 1997; Gupta and Siber, 1995; Hughes and Babiuk, 1994).Two big class, graininess or non-particulate shape adjuvants are arranged in the broadest sense.In the graininess adjuvant, have aluminum salt, calcium salt, water-in-oil emulsion, O/w emulsion, immunostimulating complex (ISCOM) and ISCOM substrate, liposome, nanometer and micron particle, aleuroplast, virion, hard ester acyl tyrosine and-inulin.Non-particulate adjuvant comprises muramyldipeptide (MDP) and derivant (as threonyl MDP, muramyl peptide etc.), non-ionic block copolymer, saponin (as Quil A and QS21), lipid A or derivatives thereof 4 ' one phosphatidyl fat A (MPL), two mycolic acid Sargassum glycolipids (TDM), various cytokine (comprising gamma interferon and interleukin II or 4), carbohydrate polymer, deutero-polysaccharide (as the diethylamino ethyl glucuronide) etc.Modern adjuvant formulation usually is designed to the combination of various compositions to produce maximum specific immune response.
In one embodiment of the invention, use attenuated virus or inactivated vaccine to prepare vaccine combination.Attenuated virus can mix with freezing protection additive or stabilizing agent, for example protein (as albumin, gelatin), sugar (as sucrose, lactose, Sorbitol), aminoacid (as sodium glutamate), saline or other protective agent.This mixture is maintained liquid condition, and probable after drying or lyophilizing are so that transportation and preservation mix with water before use more temporarily.
The preparation that comprises attenuated virus of the present invention can be used for that immunity is gone into or animal, the protection that infects with the corresponding wild-type virus of reactance attenuated virus.
In order to excite immunne response, must give individual capacity vaccine with suitable number of times.Those skilled in the art can easily determine this consumption mediating recipe.Administration can be by arbitrary conventional effective means, subcutaneous injection for example, and intranasal, parenteral, per os or be locally applied to mucomembranous surface for example pass through aerosol spray.Preferable administering mode is a parenteral.
In preference, can carry out further deactivation to early stage SARS virus after, the preparation inactivated vaccine.Method to inactivation of virus has irradiation, ozone, formalin-inactivated, high-temperature inactivation etc. at present.These methods all are well known to those skilled in the art.
In addition, the present invention also provides the method for preparing the antibody of anti-SARS with early stage SARS totivirus.For example, can use SARS totivirus immune animal, obtain antiserum then.In addition, also splenocyte and other cell fusion of immune animal (as monkey) can be formed hybridoma, thus the monoclonal antibody of preparation SARS virus.
Understand the present invention better for making, provide following examples.Embodiment is in order to describe the present invention, it can not be understood as to limit the scope of the invention.
Embodiment
Standard molecular biological technique is according to Sambrook etc., Molecular Cloning, and A LaboratoryMannual, second edition, Cold Spring Harbor Laboratory, Cold Spring Harbor, 1989 use.
Embodiment 1
With the early stage virus preparation of SARS vaccine
The early stage virus of the SARS that present embodiment uses is the GZ-02 Strain, and its sequence is deposited in GenBank, and accession number is AY39556.This Strain is available from CDC (CDC).
This Strain is compared with TOR2, and its nucleotide sequence mainly has six attenuation sudden changes: 9404 → C, 17564 → G, 21721 → A, 22222 → C, 23823 → G, 27827 → C.
Clinically, the patient who infects this Strain to show mild symptoms little.Simultaneously, infectivity is low.Therefore, this virus has the superperformance as attenuated vaccine.
This Strain is cultivated in Vero, get supernatant, obtain the virus of purification by the immunoaffinity chromatography technology.Its adjuvant with routine is mixed with vaccine.
Embodiment 2
Evaluation with the early stage viral vaccine immune animal of SARS
According to the routine immunization method with the vaccine immunity of embodiment 1 preparation Rhesus Macacus.
The animal that experiment is adopted is a Rhesus Macacus, and the Rhesus Macacus experiment is carried out at Harbin animal and veterinary institute.
The vaccine intravenous injection of embodiment 1 preparation is arrived in the Rhesus Macacus body, and frequency injection and dosage are decided according to conventional by those skilled in the art.In the immunologic process, Rhesus Macacus does not have tangible virus attack symptom, as symptoms such as heating, pulmonary infection, coughs.Immunity is got blood to every Rhesus Macacus, the serum analysis antibody response after finishing.With the virion of middle and advanced stage, for example TOR2 and BJ-01 virus (available from CDC) is as envelope antigen, with the indirect ELISA test detected can with they bonded antibody.(PRNT) tested neutralizing antibody with plaque reduction neutralization test, measures compared with the control, causes plaque quantity to reduce by 80% o'clock highest serum dilution factor at least.
The ELISA result of experiment shows that the antiserum that produces with the GZ-02 totivirus can produce the specificity combination with the TOR2 of middle and advanced stage and the S albumen of BJ-01 virus.
Plaque reduction neutralization test shows that a large amount of SARS middle and advanced stage viruses are neutralized.The titre of anti-SARS virus antibody is very high in the antiserum.
The Rhesus Macacus after immunity with TOR2 and BJ-01 virus attack does not all have the SARS infection symptoms.The X-ray sheet does not detect pulmonary infection, essentially no heating, cough symptom.
From above-mentioned test as seen, have good immunogenicity and safety, can produce high protective immune response with early stage SARS virus immunity Rhesus Macacus.
Also carried out identical experiment with masked civet, tested with masked civet also from Harbin animal and veterinary institute with test.Obtained identical experimental result.
Therefore, we think, can produce good immunogenicity and safety with early stage SARS virus, and high protective immune response, and good prospects for application is arranged.
Sequence table
＜110〉Nanfang Research Centre, State Human Gene Group
The Guangdong Prov. Disease Prevention-control Center
＜120〉sars coronavirus whole virus vaccine
<130>040486
<160>1
<170>PatentIn version 3.1
<210>1
<211>29751
<212>DNA
＜213〉SARS virus (SARS virus)
<400>1
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ctctaaacga actttaaaat ctgtgtagct gtcgctcggc tgcatgccta gtgcacctac 120
gcagtataaa caataataaa ttttactgtc gttgacaaga aacgagtaac tcgtccctct 180
tctgcagact gcttacggtt tcgtccgtgt tgcagtcgat catcagcata cctaggtttc 240
gtccgggtgt gaccgaaagg taagatggag agccttgttc ttggtgtcaa cgagaaaaca 300
cacgtccaac tcagtttgcc tgtccttcag gttagagacg tgctagtgcg tggcttcggg 360
gactctgtgg aagaggccct atcggaggca cgtgaacacc tcaaaaatgg cacttgtggt 420
ctagtagagc tggaaaaagg cgtactgccc cagcttgaac agccctatgt gttcattaaa 480
cgttctgatg ccttaagcac caatcacggc cacaaggtcg ttgagctggt tgcagaaatg 540
gacggcattc agtacggtcg tagcggtata acactgggag tactcgtgcc acatgtgggc 600
gaaaccccaa ttgcataccg caatgttctt cttcgtaaga acggtaataa gggagccggt 660
ggtcatagct atggcatcga tctaaagtct tatgacttag gtgacgagct tggcactgat 720
cccattgaag attatgaaca aaactggaac actaagcatg gcagtggtgc actccgtgaa 780
ctcactcgtg agctcaatgg aggtgcagtc actcgctatg tcgacaacaa tttctgtggc 840
ccagatgggt accctcttga ttgcatcaaa gattttctcg cacgcgcggg caagtcaatg 900
tgcactcttt ccgaacaact tgattacatc gagtcgaaga gaggtgtcta ctgctgccgt 960
gaccatgagc atgaaattgc ctggttcact gagcgctctg ataagagcta cgagcaccag 1020
acacccttcg aaattaagag tgccaagaaa tttgacactt tcaaagggga atgcccaaag 1080
tttgtgtttc ctcttaactc aaaagtcaaa gtcattcaac cacgtgttga aaagaaaaag 1140
actgagggtt tcatggggcg tatacgctct gtgtaccctg ttgcatctcc acaggagtgt 1200
aacaatatgc acttgtctac cttgatgaaa tgtaatcatt gcgatgaagt ttcatggcag 1260
acgtgcgact ttctgaaagc cacttgtgaa cattgtggca ctgaaaattt agttattgaa 1320
ggacctacta catgtgggta cctacctact aatgctgtag tgaaaatgcc atgtcctgcc 1380
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attgaaactc gactccgcaa gggaggtagg actagatgtt ttggaggctg tgtgtttgcc 1500
tatgttggct gctataataa gcgtgcctac tgggttcctc gtgctagtgc tgatattggc 1560
tcaggccata ctggcattac tggtgacaat gtggagacct tgaatgagga tctccttgag 1620
atactgagtc gtgaacgtgt taacattaac attgttggcg attttcattt gaatgaagag 1680
gttgccatca ttttggcatc tttctctgct tctacaagtg cctttattga cactataaag 1740
agtcttgatt acaagtcttt caaaaccatt gttgagtcct gcggtaacta taaagttacc 1800
aagggaaagc ccgtaaaagg tgcttggaac attggacaac agagatcagt tttaacacca 1860
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gatgcagcaa accactcaat tcctgatttg caaagagcag ctgtcaccat acttgatggt 1980
atttctgaac agtcattacg tcttgtcgac gccatggttt atacttcaga cctgctcacc 2040
aacagtgtca ttattatggc atatgtaact ggtggtcttg tacaacagac ttctcagtgg 2100
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attacaggtg tttttgacat cgtcaagggt caaatacagg ttgcttcaga taacatcaag 2280
gattgtgtaa aatgcttcat tgatgttgtt aacaaggcac tcgaaatgtg cattgatcaa 2340
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attaaggaca aagaacaata ctgcgcattg tctcctggtt tactggctac aaacaatgtc 2700
tttcgcttaa aagggggtgc accaattaaa ggtgtaacct ttggagaaga tactgtttgg 2760
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aacatgggta ttgatcttga tgagtggagt gtagctacat tctacttatt tgatgatgct 3000
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gaggacgatg cagagtgtga ggaagaagaa attgatgaaa cctgtgaaca tgagtacggt 3120
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tatgaaaatt tcaattcaca ggacatctta cttgcaccat tgttgtcagc aggcatattt 3660
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gccataatgg caaccatcca acgtaagtat aaaggaatta aaattcaaga gggcatcgtt 4440
gactatggtg tccgattctt cttttatact agtaaagagc ctgtagcttc tattattacg 4500
aagctgaact ctctaaatga gccgcttgtc acaatgccaa ttggttatgt gacacatggt 4560
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gtatcatcac cagatgctgt tactacatat aatggatacc tcacttcgtc atcaaagaca 4680
tctgaggagc actttgtaga aacagtttct ttggctggct cttacagaga ttggtcctat 4740
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cacactctgg agagccccgt cgagtttcat cttgacggtg aggttctttc acttgacaaa 4860
ctaaagagtc tcttatccct gcgggaggtt aagactataa aagtgttcac aactgtggac 4920
aacactaatc tccacacaca gcttgtggat atgtctatga catatggaca gcagtttggt 4980
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aagactttct ttgtactacc tagtgatgac acactacgta gtgaagcttt cgagtactac 5100
catactcttg atgagagttt tcttggtagg tacatgtctg ctttaaacca cacaaagaaa 5160
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caagaggctt attatagagc ccgtgctggt gatgctgcta acttttgtgc actcatactc 5340
gcttacagta ataaaactgt tggcgagctt ggtgatgtca gagaaactat gacccatctt 5400
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ggtcagaaaa ctactacctt aacgggtgta gaagctgtga tgtatatggg tactctatct 5520
tatgataatc ttaagacagg tgtttccatt ccatgtgtgt gtggtcgtga tgctacacaa 5580
tatctagtac aacaagagtc ttcttttgtt atgatgtctg caccacctgc tgagtataaa 5640
ttacagcaag gtacattctt atgtgcgaat gagtacactg gtaactatca gtgtggtcat 5700
tacactcata taactgctaa ggagaccctc tatcgtattg acggagctca ccttacaaag 5760
atgtcagagt acaaaggacc agtgactgat gttttctaca aggaaacatc ttacactaca 5820
accatcaagc ctgtgtcgta taaactcgat ggagttactt acacagagat tgaaccaaaa 5880
ttggatgggt attataaaaa ggataatgct tactatacag agcagcctat agaccttgta 5940
ccaactcaac cattaccaaa tgcgagtttt gataatttca aactcacatg ttctaacaca 6000
aaatttgctg atgatttaaa tcaaatgaca ggcttcacaa agccagcttc acgagagcta 6060
tctgtcacat tcttcccaga cttgaatggc gatgtagtgg ctattgacta tagacactat 6120
tcagcgagtt tcaagaaagg tgctaaatta ctgcataagc caattgtttg gcacattaac 6180
caggctacaa ccaagacaac gttcaaacca aacacttggt gtttacgttg tctttggagt 6240
acaaagccag tagatacttc aaattcattt gaagttctgg cagtagaaga cacacaagga 6300
atggacaatc ttgcttgtga aagtcaacaa cccacctctg aagaagtagt ggaaaatcct 6360
accatacaga aggaagtcat agagtgtgac gtgaaaacta ccgaagttgt aggcaatgtc 6420
atacttaaac catcagatga aggtgttaaa gtaacacaag agttaggtca tgaggatctt 6480
atggctgctt atgtggaaaa cacaagcatt accattaaga aacctaatga gctttcacta 6540
gccttaggtt taaaaacaat tgccactcat ggtattgctg caattaatag tgttccttgg 6600
agtaaaattt tggcttatgt caaaccattc ttaggacaag cagcaattac aacatcaaat 6660
tgcgctaaga gattagcaca acgtgtgttt aacaattata tgccttatgt gtttacatta 6720
ttgttccaat tgtgtacttt tactaaaagt accaattcta gaattagagc ttcactacct 6780
acaactattg ctaaaaatag tgttaagagt gttgctaaat tatgtttgga tgccggcatt 6840
aattatgtga agtcacccaa attttctaaa ttgttcacaa tcgctatgtg gctattgttg 6900
ttaagtattt gcttaggttc tctaatctgt gtaactgctg cttttggtgt actcttatct 6960
aattttggtg ctccttctta ttgtaatggc gttagagaat tgtatcttaa ttcgtctaac 7020
gttactacta tggatttctg tgaaggttct tttccttgca gcatttgttt aagtggatta 7080
gactcccttg attcttatcc agctcttgaa accattcagg tgacgatttc atcgtacaag 7140
ctagacttga caattttagg tctggccgct gagtgggttt tggcatatat gttgttcaca 7200
aaattctttt atttattagg tctttcagct ataatgcagg tgttctttgg ctattttgct 7260
agtcatttca tcagcaattc ttggctcatg tggtttatca ttagtattgt acaaatggca 7320
cccgtttctg caatggttag gatgtacatc ttctttgctt ctttctacta catatggaag 7380
agctatgt tc atatcatgga tggttgcacc tcttcgactt gcatgatgtg ctataagcgc 7440
aatcgtgcca cacgcgttga gtgtacaact attgttaatg gcatgaagag atctttctat 7500
gtctatgcaa atggaggccg tggcttctgc aagactcaca attggaattg tctcaattgt 7560
gacacatttt gcactggtag tacattcatt agtgatgaag ttgctcgtga tttgtcactc 7620
cagtttaaaa gaccaatcaa ccctactgac cagtcatcgt atattgttga tagtgttgct 7680
gtgaaaaatg gcgcgcttca cctctacttt gacaaggctg gtcaaaagac ctatgagaga 7740
catccgctct cccattttgt caatttagac aatttgagag ctaacaacac taaaggttca 7800
ctgcctatta atgtcatagt ttttgatggc aagtccaaat gcgacgagtc tgcttctaag 7860
tctgcttctg tgtactacag tcagctgatg tgccaaccta ttctgttgct tgaccaagct 7920
cttgtatcag acgttggaga tagtactgaa gtttccgtta agatgtttga tgcttatgtc 7980
gacacctttt cagcaacttt tagtgttcct atggaaaaac ttaaggcact tgttgctaca 8040
gctcacagcg agttagcaaa gggtgtagct ttagatggtg tcctttctac attcgtgtca 8100
gctgcccgac aaggtgttgt tgataccgat gttgacacaa aggatgttat tgaatgtctc 8160
aaactttcac atcactctga cttagaagtg acaggtgaca gttgtaacaa tttcatgctc 8220
acctataata aggttgaaaa catgacgccc agagatcttg gcgcatgtat tgactgtaat 8280
gcaaggcata tcaatgccca agtagcaaaa agtcacaatg tttcactcat ctggaatgta 8340
aaagactaca tgtctttatc tgaacagctg cgtaaacaaa ttcgtagtgc tgccaagaag 8400
aacaacatac cttttagact aacttgtgct acaactagac aggttgtcaa tgtcataact 8460
actaaaatct cactcaaggg tggtaagatt gttagtactt gttttaaact tatgcttaag 8520
gccacattat tgtgcgttct tgctgcattg gtttgttata tcgttatgcc agtacataca 8580
ttgtcaatcc atgatggtta cacaaatgaa atcattggtt acaaagccat tcaggatggt 8640
gtcactcgtg acatcatttc tactgatgat tgttttgcaa ataaacatgc tggttttgac 8700
gcatggttta gccagcgtgg tggttcatac aaaaatgaca aaagctgccc tgtagtagct 8760
gctatcatta caagagagat tggtttcata gtgcctggct taccgggtac tgtgctgaga 8820
gcaatcaatg gtgacttctt gcattttcta cctcgtgttt ttagtgctgt tggcaacatt 8880
tgctacacac cttccaaact cattgagtat agtgattttg ctacctctgc ttgcgttctt 8940
gctgctgagt gtacaatttt taaggatgct atgggcaaac ctgtgccata ttgttatgac 9000
actaatttgc tagagggttc tatttcttat agtgagcttc gtccagacac tcgttatgtg 9060
cttatggatg gttccatcat acagtttcct aacacttacc tggagggttc tgttagagta 9120
gtaacaactt ttgatgctga gtactgtaga catggtacat gcgaaaggtc agaagtaggt 9180
atttgcctat ctaccagtgg tagatgggtt cttaataatg agcattacag agctctatca 9240
ggagttttct gtggtgttga tgcgatgaat ctcatagcta acatctttac tcctcttgtg 9300
caacctgtgg gtgctttaga tgtgtctgct tcagtagtgg ctggtggtat tattgccata 9360
ttggtgactt gtgctgccta ctactttatg aaattcagac gtgtttttgg tgagtacaac 9420
catgttgttg ctgctaatgc acttttgttt ttgatgtctt tcactatact ctgtctggta 9480
ccagcttaca gctttctgcc gggagtctac tcagtctttt acttgtactt gacattctat 9540
ttcaccaatg atgtttcatt cttggctcac cttcaatggt ttgccatgtt ttctcctatt 9600
gtgccttttt ggataacagc aatctatgta ttctgtattt ctctgaagca ctgccattgg 9660
ttctttaaca actatcttag gaaaagagtc atgtttaatg gagttacatt tagtaccttc 9720
gaggaggctg ctttgtgtac ctttttgctc aacaaggaaa tgtacctaaa attgcgtagc 9780
gagacactgt tgccacttac acagtataac aggtatcttg ctctatataa caagtacaag 9840
tatttcagtg gagccttaga tactaccagc tatcgtgaag cagcttgctg ccacttagca 9900
aaggctctaa atgactttag caactcaggt gctgatgttc tctaccaacc accacagaca 9960
tcaatcactt ctgctgttct gcagagtggt tttaggaaaa tggcattccc gtcaggcaaa 10020
gttgaagggt gcatggtaca agtaacctgt ggaactacaa ctcttaatgg attgtggttg 10080
gatgacacag tatactgtcc aagacatgtc atttgcacag cagaagacat gcttaatcct 10140
aactatgaag atctgctcat tcgcaaatcc aaccatagct ttcttgttca ggctggcaat 10200
gttcaacttc gtgttattgg ccattctatg caaaattgtc tgcttaggct taaagttgat 10260
acttctaacc ctaagacacc caagtataaa tttgtccgta tccaacctgg tcaaacattt 10320
tcagttctag catgctacaa tggttcacca tctggtgttt atcagtgtgc catgagacct 10380
aatcatacca ttaaaggttc tttccttaat ggatcatgtg gtagtgttgg ttttaacatt 10440
gattatgatt gcgtgtcttt ctgctatatg catcatatgg agcttccaac aggagtacac 10500
gctggtactg acttagaagg taaattctat ggtccatttg ttgacagaca aactgcacag 10560
gctgcaggta cagacacaac cataacatta aatgttttgg catggctgta tgctgctgtt 10620
atcaatggtg ataggtggtt tcttaataga ttcaccacta ctttgaatga ctttaacctt 10680
gtggcaatga agtacaacta tgaacctttg acacaagatc atgttgacat attgggacct 10740
ctttctgctc aaacaggaat tgccgtctta gatatgtgtg ctgctttgaa agagctgctg 10800
cagaatggta tgaatggtcg tactatcctt ggtagcacta ttttagaaga tgagtttaca 10860
ccatttgatg ttgttagaca atgctctggt gttaccttcc aaggtaagtt caagaaaatt 10920
gttaagggca ctcatcattg gatgctttta actttcttga catcactatt gattcttgtt 10980
caaagtacac agtggtcact gtttttcttt gtttacgaga atgctttctt gccatttact 11040
cttggtatta tggcaattgc tgcatgtgct atgctgcttg ttaagcataa gcacgcattc 11100
ttgtgcttgt ttctgttacc ttctcttgca acagttgctt actttaatat ggtctacatg 11160
cctgctagct gggtgatgcg tatcatgaca tggcttgaat tggctgacac tagcttgtct 11220
ggttataggc ttaaggattg tgttatgtat gcttcagctt tagttttgct tattctcatg 11280
acagctcgca ctgtttatga tgatgctgct agacgtgttt ggacactgat gaatgtcatt 11340
acacttgttt acaaagtcta ctatggtaat gctttagatc aagctatttc catgtgggcc 11400
ttagttattt ctgtaacctc taactattct ggtgtcgtta cgactatcat gtttttagct 11460
agagctatag tgtttgtgtg tgttgagtat tacccattgt tatttattac tggcaacacc 11520
ttacagtgta tcatgcttgt ttattgtttc ttaggctatt gttgctgctg ctactttggc 11580
cttttctgtt tactcaaccg ttacttcagg cttactcttg gtgtttatga ctacttggtc 11640
tctacacaag aatttaggta tatgaactcc caggggcttt tgcctcctaa gagtagtatt 11700
gatgctttca agcttaacat taagttgttg ggtattggag gtaaaccatg tatcaaggtt 11760
gctactgtac agtctaaaat gtctgacgta aagtgcacat ctgtggtact gctctcggtt 11820
cttcaacaac ttagagtaga gtcatcttct aaattgtggg cacaatgtgt acaactccac 11880
aatgatattc ttcttgcaaa agacacaact gaagctttcg agaagatggt ttctcttttg 11940
tctgttttgc tatccatgca gggtgctgta gacattaata ggttgtgcga ggaaatgctc 12000
gataaccgtg ctactcttca ggctattgct tcagaattta gttctttacc atcatatgcc 12060
gcttatgcca ctgcccagga ggcctatgag caggctgtag ctaatggtga ttctgaagtc 12120
gttctcaaaa agttaaagaa atctttgaat gtggctaaat ctgagtttga ccgtgatgct 12180
gccatgcaac gcaagttgga aaagatggca gatcaggcta tgacccaaat gtacaaacag 12240
gcaagatctg aggacaagag ggcaaaagta actagtgcta tgcaaacaat gctcttcact 12300
atgcttagga agcttgataa tgatgcactt aacaacatta tcaacaatgc gcgtgatggt 12360
tgtgttccac tcaacatcat accattgact acagcagcca aactcatggt tgttgtccct 12420
gattatggta cctacaagaa cacttgtgat ggtaacacct ttacatatgc atctgcactc 12480
tgggaaatcc agcaagttgt tgatgcggat agcaagattg ttcaacttag tgaaattaac 12540
atggacaatt caccaaattt ggcttggcct cttattgtta cagctctaag agccaactca 12600
gctgttaaac tacagaataa tgaactgagt ccagtagcac tacgacagat gtcctgtgcg 12660
gctggtacca cacaaacagc ttgtactgat gacaatgcac ttgcctacta taacaattcg 12720
aagggaggta ggtttgtgct ggcattacta tcagaccacc aagatctcaa atgggctaga 12780
ttccctaaga gtgatggtac aggtacaatt tacacagaac tggaaccacc ttgtaggttt 12840
gttacagaca caccaaaagg gcctaaagtg aaatacttgt acttcatcaa aggcttaaac 12900
aacctaaata gaggtatggt gctgggcagt ttagctgcta cagtacgtct tcaggctgga 12960
aatgctacag aagtacctgc caattcaact gtgctttcct tctgtgcttt tgcagtagac 13020
cctgctaaag catataagga ttacctagca agtggaggac aaccaatcac caactgtgtg 13080
aagatgttgt gtacacacac tggtacagga caggcaatta ctgtaacacc agaagctaac 13140
atggaccaag agtcctttgg tggtgcttca tgttgtctgt attgtagatg ccacattgac 13200
catccaaatc ctaaaggatt ctgtgacttg aaaggtaagt acgtccaaat acctaccact 13260
tgtgctaatg acccagtggg ttttacactt agaaacacag tctgtaccgt ctgcggaatg 13320
tggaaaggtt atggctgtag ttgtgaccaa ctccgcgaac ccttgatgca gtctgcggat 13380
gcatcaacgt ttttaaacgg gtttgcggtg taagtgcagc ccgtcttaca ccgtgcggca 13440
caggcactag tactgatgtc gtctacaggg cttttgatat ttacaacgaa aaagttgctg 13500
gttttgcaaa gttcctaaaa actaattgct gtcgcttcca ggagaaggat gaggaaggca 13560
atttattaga ctcttacttt gtagttaaga ggcatactat gtctaactac caacatgaag 13620
agactattta taacttggtt aaagattgtc cagcggttgc tgtccatgac tttttcaagt 13680
ttagagtaga tggtgacatg gtaccacata tatcacgtca gcgtctaact aaatacacaa 13740
tggctgattt agtctatgct ctacgtcatt ttgatgaggg taattgtgat acattaaaag 13800
aaatactcgt cacatacaat tgctgtgatg atgattattt caataagaag gattggtatg 13860
acttcgtaga gaatcctgac atcttacgcg tatatgctaa cttaggtgag cgtgtacgcc 13920
aatcattatt aaagactgta caattctgcg atgctatgcg tgatgcaggc attgtaggcg 13980
tactgacatt agataatcag gatcttaatg ggaactggta cgatttcggt gatttcgtac 14040
aagtagcacc aggctgcgga gttcctattg tggattcata ttactcattg ctgatgccca 14100
tcctcacttt gactagggca ttggctgctg agtcccatat ggatgctgat ctcgcaaaac 14160
cacttattaa gtgggatttg ctgaaatatg attttacgga agagagactt tgtctcttcg 14220
accgttattt taaatattgg gaccagacat accatcccaa ttgtattaac tgtttggatg 14280
ataggtgtat ccttcattgt gcaaacttta atgtgttatt ttctactgtg tttccaccta 14340
caagttttgg accactagta agaaaaatat ttgtagatgg tgttcctttt gttgtttcaa 14400
ctggatacca ttttcgtgag ttaggagtcg tacataatca ggatgtaaac ttacatagct 14460
cgcgtctcag tttcaaggaa cttttagtgt atgctgctga tccagctatg catgcagctt 14520
ctggcaattt attgctagat aaacgcacta catgcttttc agtagctgca ctaacaaaca 14580
atgttgcttt tcaaactgtc aaacccggta attttaataa agacttttat gactttgctg 14640
tgtctaaagg tttctttaag gaaggaagtt ctgttgaact aaaacacttc ttctttgctc 14700
aggatggcaa cgctgctatc agtgattatg actattatcg ttataatctg ccaacaatgt 14760
gtgatatcag acaactccta ttcgtagttg aagttgttga taaatacttt gattgttacg 14820
atggtggctg tattaatgcc aaccaagtaa tcgttaacaa tctggataaa tcagctggtt 14880
tcccatttaa taaatggggt aaggctagac tttattatga ctcaatgagt tatgaggatc 14940
aagatgcact tttcgcgtat actaagcgta atgtcatccc tactataact caaatgaatc 15000
ttaagtatgc cattagtgca aagaatagag ctcgcaccgt agctggtgtc tctatctgta 15060
gtactatgac aaatagacag tttcatcaga aattattgaa gtcaatagcc gccactagag 15120
gagctactgt ggtaattgga acaagcaagt tttacggtgg ctggcataat atgttaaaaa 15180
ctgtttacag tgatgtagaa actccacacc ttatgggttg ggattatcca aaatgtgaca 15240
gagccatgcc taacatgctt aggataatgg cctctcttgt tcttgctcgc aaacataaca 15300
cttgctgtaa cttatcacac cgtttctaca ggttagctaa cgagtgtgcg caagtattaa 15360
gtgagatggt catgtgtggc ggctcactat atgttaaacc aggtggaaca tcatccggtg 15420
atgctacaac tgcttatgct aatagtgtct ttaacatttg tcaagctgtt acagccaatg 15480
taaatgcact tctttcaact gatggtaata agatagctga caagtatgtc cgcaatctac 15540
aacacaggct ctatgagtgt ctctatagaa atagggatgt tgatcatgaa ttcgtggatg 15600
agttttacgc ttacctgcgt aaacatttct ccatgatgat tctttctgat gatgccgttg 15660
tgtgctataa cagtaactat gcggctcaag gtttagtagc tagcattaag aactttaagg 15720
cagttcttta ttatcaaaat aatgtgttca tgtctgaggc aaaatgttgg actgagactg 15780
accttactaa aggacctcac gaattttgct cacagcatac aatgctagtt aaacaaggag 15840
atgattacgt gtacctgcct tacccagatc catcaagaat attaggcgca ggctgttttg 15900
tcgatgatat tgtcaaaaca gatggtacac ttatgattga aaggttcgtg tcactggcta 15960
ttgatgctta cccacttaca aaacatccta atcaggagta tgctgatgtc tttcacttgt 16020
atttacaata cattagaaag ttacatgatg agcttactgg ccacatgttg gacatgtatt 16080
ccgtaatgct aactaatgat aacacctcac ggtactggga acctgagttt tatgaggcta 16140
tgtacacacc acatacagtc ttgcaggctg taggtgcttg tgtattgtgc aattcacaga 16200
cttcacttcg ttgcggtgcc tgtattagga gaccattcct atgttgcaag tgctgctatg 16260
accatgtcat ttcaacatca cacaaattag tgttgtctgt taatccctat gtttgcaatg 16320
ccccaggttg tgatgtcact gatgtgacac aactgtatct aggaggtatg agctattatt 16380
gcaagtcaca taagcctccc attagttttc cattatgtgc taatggtcag gtttttggtt 16440
tatacaaaaa cacatgtgta ggcagtgaca atgtcactga cttcaatgcg atagcaacat 16500
gtgattggac taatgctggc gattacatac ttgccaacac ttgtactgag agactcaagc 16560
ttttcgcagc agaaacgctc aaagccactg aggaaacatt taagctgtca tatggtattg 16620
ccactgtacg cgaagtactc tctgacagag aattgcatct ttcatgggag gttggaaaac 16680
ctagaccacc attgaacaga aactatgtct ttactggtta ccgtgtaact aaaaatagta 16740
aagtacagat tggagagtac acctttgaaa aaggtgacta tggtgatgct gttgtgtaca 16800
gaggtactac gacatacaag ttgaatgttg gtgattactt tgtgttgaca tctcacactg 16860
taatgccact tagtgcacct actctagtgc cacaagagca ctatgtgaga attactggct 16920
tgtacccaac actcaacatc tcagatgagt tttctagcaa tgttgcaaat tatcaaaagg 16980
tcggcatgca aaagtactct acactccaag gaccacctgg tactggtaag agtcattttg 17040
ccatcggact tgctctctat tacccatctg ctcgcatagt gtatacggca tgctctcatg 17100
cagctgttga tgccctatgt gaaaaggcat taaaatattt gcccatagat aaatgtagta 17160
gaatcatacc tgcgcgtgcg cgcgtagagt gttttgataa attcaaagtg aattcaacac 17220
tagaacagta tgttttctgc actgtaaatg cattgccaga aacaactgct gacattgtag 17280
tctttgatga aatctctatg gctactaatt atgacttgag tgttgtcaat gctagacttc 17340
gtgcaaaaca ctacgtctat attggcgatc ctgctcaatt accagccccc cgcacattgc 17400
tgactaaagg cacactagaa ccagaatatt ttaattcagt gtgcagactt atgaaaacaa 17460
taggtccaga catgttcctt ggaacttgtc gccgttgtcc tgctgaaatt gttgacactg 17520
tgagtgcttt agtttatgac aataagctaa aagcacacaa ggataagtca gctcaatgct 17580
tcaaaatgtt ctacaaaggt gttattacac atgatgtttc atctgcaatc aacagacctc 17640
aaataggcgt tgtaagagaa tttcttacac gcaatcctgc ttggagaaaa gctgttttta 17700
tctcacctta taattcacag aacgctgtag cttcaaaaat cttaggattg cctacgcaga 17760
ctgttgattc atcacagggt tctgaatatg actatgtcat attcacacaa actactgaaa 17820
cagcacactc ttgtaatgtc aaccgcttca atgtggctat cacaagggca aaaattggca 17880
ttttgtgcat aatgtctgat agagatcttt atgacaaact gcaatttaca agtctagaaa 17940
taccacgtcg caatgtggct acattacaag cagaaaatgt aactggactt tttaaggact 18000
gtagtaagat cattactggt cttcatccta cacaggcacc tacacacctc agcgttgata 18060
taaagttcaa gactgaagga ttatgtgttg acataccagg cataccaaag gacatgacct 18120
accgtagact catctctatg atgggtttca aaatgaatta ccaagtcaat ggttacccta 18180
atatgtttat cacccgcgaa gaagctattc gtcacgttcg tgcgtggatt ggctttgatg 18240
tagagggctg tcatgcaact agagatgctg tgggtactaa cctacctctc cagctaggat 18300
tttctacagg tgttaactta gtagctgtac cgactggtta tgttgacact gaaaataaca 18360
cagaattcac cagagttaat gcaaaacctc caccaggtga ccagtttaaa catcttatac 18420
cactcatgta taaaggcttg ccctggaatg tagtgcgtat taagatagta caaatgctca 18480
gtgatacact gaaaggattg tcagacagag tcgtgttcgt cctttgggcg catggctttg 18540
agcttacatc aatgaagtac tttgtcaaga ttggacctga aagaacgtgt tgtctgtgtg 18600
acaaacgtgc aacttgcttt tctacttcat cagatactta tgcctgctgg aatcattctg 18660
tgggttttga ctatgtctat aacccattta tgattgatgt tcagcagtgg ggctttacgg 18720
gtaaccttca gagtaaccat gaccaacatt gccaggtaca tggaaatgca catgtggcta 18780
gttgtgatgc tatcatgact agatgtttag cagtccatga gtgctttgtt aagcgcgttg 18840
attggtctgt tgaataccct attataggag atgaactgag ggttaattct gcttgcagaa 18900
aagtacaaca catggttgtg aagtctgcat tgcttgctga taagtttcca gttcttcatg 18960
acattggaaa tccaaaggct atcaagtgtg tgcctcaggc tgaagtagaa tggaagttct 19020
acgatgctca gccatgtagt gacaaagctt acaaaataga ggaactcttc tattcttatg 19080
ctacacatca cgataaattc actgatggtg tttgtttgtt ttggaattgt aacgttgatc 19140
gttacccagc caatgcaatt gtgtgtaggt ttgacacaag agtcttgtca aacttgaact 19200
taccaggctg tgatggtggt agtttgtatg tgaataagca tgcattccac actccagctt 19260
tcgataaaag tgcatttact aatttaaagc aattgccttt cttttactat tctgatagtc 19320
cttgtgagtc tcatggcaaa caagtagtgt cggatattga ttatgttcca ctcaaatctg 19380
ctacgtgtat tacacgatgc aatttaggtg gtgctgtttg cagacaccat gcaaatgagt 19440
accgacagta cttggatgca tataatatga tgatttctgc tggatttagc ctatggattt 19500
acaaacaatt tgatacttat aacctgtgga atacatttac caggttacag agtttagaaa 19560
atgtggctta taatgttgtt aataaaggac actttgatgg acacgccggc gaagcacctg 19620
tttccatcat taataatgct gtttacacaa aggtagatgg tattgatgtg gagatctttg 19680
aaaataagac aacacttcct gttaatgttg catttgagct ttgggctaag cgtaacatta 19740
aaccagtgcc agagattaag atactcaata atttgggtgt tgatatcgct gctaatactg 19800
taatctggga ctacaaaaga gaagccccag cacatgtatc tacaataggt gtctgcacaa 19860
tgactgacat tgccaagaaa cctactgaga gtgcttgttc ttcacttact gtcttgtttg 19920
atggtagagt ggaaggacag gtagaccttt ttagaaacgc ccgtaatggt gttttaataa 19980
cagaaggttc agtcaaaggt ctaacacctt caaagggacc agcacaagct agcgtcaatg 20040
gagtcacatt aattggagaa tcagtaaaaa cacagtttaa ctactttaag aaagtagacg 20100
gcattattca acagttgcct gaaacctact ttactcagag cagagactta gaggatttta 20160
agcccagatc acaaatggaa actgactttc tcgagctcgc tatggatgaa ttcatacagc 20220
gatataagct cgagggctat gccttcgaac acatcgttta tggagatttc agtcatggac 20280
aacttggcgg tcttcattta atgataggct tagccaagcg ctcacaagat tcaccactta 20340
aattagagga ttttatccct atggacagca cagtgaaaaa ttacttcata acagatgcgc 20400
aaacaggttc atcaaaatgt gtgtgttctg tgattgatct tttacttgat gactttgtcg 20460
agataataaa gtcacaagat ttgtcagtga tttcaaaagt ggtcaaggtt acaattgact 20520
atgctgaaat ttcattcatg ctttggtgta aggatggaca tgttgaaacc ttctacccaa 20580
aactacaagc aagtcaagcg tggcaaccag gtgttgcgat gcctaacttg tacaagatgc 20640
aaagaatgct tcttgaaaag tgtgaccttc agaattatgg tgaaaatgct gttataccaa 20700
aaggaataat gatgaatgtc gcaaagtata ctcaactgtg tcaatactta aatacactta 20760
ctttagctgt accctacaac atgagagtta ttcactttgg tgctggctct gataaaggag 20820
ttgcaccagg tacagctgtg ctcagacaat ggttgccaac tggcacacta cttgtcgatt 20880
cagatcttaa tgacttcgtc tccgacgcag attctacttt aattggagac tgtgcaacag 20940
tacatacggc taataaatgg gaccttatta ttagcgatat gtatgaccct aggaccaaac 21000
atgtgacaaa agagaatgac tctaaagaag ggtttttcac ttatctgtgt ggatttataa 21060
agcaaaaact agccctgggt ggttctatag ctgtaaagat aacagagcat tcttggaatg 21120
ctgaccttta caagcttatg ggccatttct catggtggac agcttttgtt acaaatgtaa 21180
atgcatcatc atcggaagca tttttaattg gggctaacta tcttggcaag ccgaaggaac 21240
aaattgatgg ctataccatg catgctaact acattttctg gaggaacaca aatcctatcc 21300
agttgtcttc ctattcactc tttgacatga gcaaatttcc tcttaaatta agaggaactg 21360
ctgtaatgtc tcttaaggag aatcaaatca atgatatgat ttattctctt ctggaaaaag 21420
gtaggcttat cattagagaa aacaacagag ttgtggtttc aagtgatatt cttgttaaca 21480
actaaacgaa catgtttatt ttcttattat ttcttactct cactagtggt agtgaccttg 21540
accggtgcac cacttttgat gatgttcaag ctcctaatta cactcaacat acttcatcta 21600
tgaggggggt ttactatcct gatgaaattt ttagatcaga cactctttat ttaactcagg 21660
atttatttct tccattttat tctaatgtta cagggtttca tactattaat catacgtttg 21720
gcaaccctgt catacctttt aaggatggta tttattttgc tgccacagag aaatcaaatg 21780
ttgtccgtgg ttgggttttt ggttctacca tgaacaacaa gtcacagtcg gtgattatta 21840
ttaacaattc tactaatgtt gttatacgag catgtaactt tgaattgtgt gacaaccctt 21900
tctttgctgt ttctaaaccc atgggtacac agacacatac tatgatattc gataatgcat 21960
ttaattgcac tttcgagtac atatctgatg ccttttcgct tgatgtttca gaaaagtcag 22020
gtaattttaa acacttacga gagtttgtgt ttaaaaataa agatgggttt ctctatgttt 22080
ataagggcta tcaacctata gatgtagttc gtgatctacc ttctggtttt aacactttga 22140
aacctatttt taagttgcct cttggtatta acattacaaa ttttagagcc attcttacag 22200
ccttttcacc tgctcaagac atttggggca cgtcagctgc agcctatttt gttggctatt 22260
taaagccaac tacatttatg ctcaagtatg atgaaaatgg tacaatcaca gatgctgttg 22320
attgttctca aaatccactt gctgaactca aatgctctgt taagagcttt gagattgaca 22380
aaggaattta ccagacctct aatttcaggg ttgttccctc aggagatgtt gtgagattcc 22440
ctaatattac aaacttgtgt ccttttggag aggtttttaa tgctactaaa ttcccttctg 22500
tctatgcatg ggagagaaaa aaaatttcta attgtgttgc tgattactct gtgctctaca 22560
actcaacatt tttttcaacc tttaagtgct atggcgtttc tgccactaag ttgaatgatc 22620
tttgcttctc caatgtctat gcagattctt ttgtagtcaa gggagatgat gtaagacaaa 22680
tagcgccagg acaaactggt gttattgctg attataatta taaattgcca gatgatttca 22740
tgggttgtgt ccttgcttgg aatactagga acattgatgc tacttcaact ggtaattata 22800
attataaata taggtatctt agacatggca agcttaggcc ctttgagaga gacatatcta 22860
atgtgccttt ctcccctgat ggcaaacctt gcaccccacc tgctcttaat tgttattggc 22920
cattaaatga ttatggtttt tacaccacta ctggcattgg ctaccaacct tacagagttg 22980
tagtactttc ttttgaactt ttaaatgcac cggccacggt ttgtggacca aaattatcca 23040
ctgaccttat taagaaccag tgtgtcaatt ttaattttaa tggactcact ggtactggtg 23100
tgttaactcc ttcttcaaag agatttcaac catttcaaca atttggccgt gatgtttctg 23160
atttcactga ttccgttcga gatcctaaaa catctgaaat attagacatt tcaccttgcg 23220
cttttggggg tgtaagtgta attacacctg gaacaaatgc ttcatctgaa gttgctgttc 23280
tatatcaaga tgttaactgc actgatgttt ctacagcaat tcatgcagat caactcacac 23340
cagcttggcg catatattct actggaaaca atgtattcca gactcaagca ggctgtctta 23400
taggagctga gcatgtcgac acttcttatg agtgcgacat tcctattgga gctggcattt 23460
gtgctagtta ccatacagtt tctttattac gtagtactag ccaaaaatct attgtggctt 23520
atactatgtc tttaggtgct gatagttcaa ttgcttactc taataacacc attgctatac 23580
ctactaactt ttcaattagc attactacag aagtaatgcc tgtttctatg gctaaaacct 23640
ccgtagattg taatatgtac atctgcggag attctactga atgtgctaat ttgcttctcc 23700
aatatggtag cttttgcaca caactaaatc gtgcactctc aggtattgct gctgaacagg 23760
atcgcaacac acgtgaagtg ttcgctcaag tcaaacaaat gtacaaaacc ccaactttga 23820
aatattttgg tggttttaat ttttcacaaa tattacctga ccctctaaag ccaactaaga 23880
ggtcttttat tgaggacttg ctctttaata aggtgacact cgctgatgct ggcttcatga 23940
agcaatatgg cgaatgccta ggtgatatta atgctagaga tctcatttgt gcgcagaagt 24000
tcaatggact tacagtgttg ccacctctgc tcactgatga tatgattgct gcctacactg 24060
ctgctctagt tagtggtact gccactgctg gatggacatt tggtgctggc gctgctcttc 24120
aaataccttt tgctatgcaa atggcatata ggttcaatgg cattggagtt acccaaaatg 24180
ttctctatga gaaccaaaaa caaatcgcca accaatttaa caaggcgatt agtcaaattc 24240
aagaatcact tacaacaaca tcaactgcat tgggcaagct gcaagacgtt gttaaccaga 24300
atgctcaagc attaaacaca cttgttaaac aacttagctc taattttggt gcaatttcaa 24360
gtgtgctaaa tgatatcctt tcgcgacttg ataaagtcga ggcggaggta caaattgaca 24420
ggttaattac aggcagactt caaagccttc aaacctatgt aacacaacaa ctaatcaggg 24480
ctgctgaaat cagggcttct gctaatcttg ctgctactaa aatgtctgag tgtgttcttg 24540
gacaatcaaa aagagttgac ttttgtggaa agggctacca ccttatgtcc ttcccacaag 24600
cagccccgca tggtgttgtc ttcctacatg tcacgtatgt gccatcccag gagaggaact 24660
tcaccacagc gccagcaatt tgtcatgaag gcaaagcata cttccctcgt gaaggtgttt 24720
ttgtgtttaa tggcacttct tggtttatta cacagaggaa cttcttttct ccacaaataa 24780
ttactacaga caatacattt gtctcaggaa attgtgatgt cgttattggc atcattaaca 24840
acacagttta tgatcctctg caacctgagc ttgactcatt caaagaagag ctggacaagt 24900
acttcaaaaa tcatacatca ccagatgttg atcttggcga catttcaggc attaacgctt 24960
ctgtcgtcaa cattcaaaaa gaaattgacc gcctcaatga ggtcgctaaa aatttaaatg 25020
aatcactcat tgaccttcaa gaattgggaa aatatgagca atatattaaa tggccttggt 25080
atgtttggct cggcttcatt gctggactaa ttgccatcgt catggttaca atcttgcttt 25140
gttgcatgac tagttgttgc agttgcctca agggtgcatg ctcttgtggt tcttgctgca 25200
agtttgatga ggatgactct gagccagttc tcaagggtgt caaattacat tacacataaa 25260
cgaacttatg gatttgttta tgagattttt tactcttaga tcaattactg cacagccagt 25320
aaaaattgac aatgcttctc ctgcaagtac tgttcatgct acagcaacga taccgctaca 25380
agcctcactc cctttcggat ggcttgttat tggcgttgca tttcttgctg tttttcagag 25440
cgctaccaaa ataattgcgc tcaataaaag atggcagcta gccctttata agggcttcca 25500
gttcatttgc aatttactgc tgctatttgt taccatctat tcacatcttt tgcttgtcgc 25560
tgcaggtatg gaggcgcaat ttttgtacct ctatgccttg atatattttc tacaatgcat 25620
caacgcatgt agaattatta tgagatgttg gctttgttgg aagtgcaaat ccaagaaccc 25680
attactttat gatgccaact actttgtttg ctggcacaca cataactatg actactgtat 25740
accatataac agtgtcacag atacaattgt cgttactgaa ggtgacggca tttcaacacc 25800
aaaactcaaa gaagactacc aaattggtgg ttattctgag gataggcact caggtgttaa 25860
agactatgtc gttgtacatg gctatttcac cgaagtttac taccagcttg agtctacaca 25920
aattactaca gacactggta ttgaaaatgc tacattcttc atctttaaca agcttgttaa 25980
agacccaccg aatgtgcaaa tacacacaat cgacggctct tcaggagttg ctaatccagc 26040
aatggatcca atttatgatg agccgacgac gactactagc gtgcctttgt aagcacaaga 26100
aagtgagtac gaacttatgt actcattcgt ttcggaagaa acaggtacgt taatagttaa 26160
tagcgtactt ctttttcttg ctttcgtggt attcttgcta gtcacactag ccatccttac 26220
tgcgcttcga ttgtgtgcgt actgctgcaa tattgttaac gtgagtttag taaaaccaac 26280
ggtttacgtc tactcgcgtg ttaaaaatct gaactcttct gaaggagttc ctgatcttct 26340
ggtctaaacg aactaactat tattattatt ctgtttggaa ctttaacatt gcttatcatg 26400
gcagacaacg gtactattac cgttgaggag cttaaacaac tcctggaaca atggaaccta 26460
gtaataggtt tcctattcct agcctggatt atgttactac aatttgccta ttctaatcgg 26520
aacaggtttt tgtacataat aaagcttgtt ttcctctggc tcttgtggcc agtaacactt 26580
gcttgttttg tgcttgctgc tgtctacaga attaattggg tgactggcgg gattgcgatt 26640
gcaatggctt gtattgtagg cttgatgtgg cttagctact tcgttgcttc cttcaggctg 26700
tttgctcgta cccgctcaat gtggtcattc aacccagaaa caaacattct tctcaatgtg 26760
cctctccggg ggacaattgt gaccagaccg ctcatggaaa gtgaacttgt cattggtgct 26820
gtgatcattc gtggtcactt gcgaatggcc ggacactccc tagggcgctg tgacattaag 26880
gacctgccaa aagagatcac tgtggctaca tcacgaacgc tttcttatta caaattagga 26940
gcgtcgcagc gtgtaggcac tgattcaggt tttgctgcat acaaccgcta ccgtattgga 27000
aactataaat taaatacaga ccacgccggt agcaacgaca atattgcttt gctagtacag 27060
taagtgacaa cagatgtttc atcttgttga cttccaggtt acaatagcag agatattgat 27120
tatcattatg aggactttca ggattgctat ttggaatctt gacgttataa taagttcaat 27180
agtgagacaa ttatttaagc ctctaactaa gaagaattat tcggagttag atgatgaaga 27240
acctatggag ttagattatc cataaaacga acatgaaaat tattctcttc ctgacattga 27300
ttgtatttac atcttgcgag ctatatcact atcaggagtg tgttagaggt acgactgtac 27360
tactaaaaga accttgccca tcaggaacat acgagggcaa ttcaccattt caccctcttg 27420
ctgacaataa atttgcacta acttgcacta gcacacactt tgcttttgct tgtgctgacg 27480
gtactcgaca tacctatcag ctgcgtgcaa gatcagtttc accaaaactt ttcatcagac 27540
aagaggaggt tcaacaagag ctctactcgc cactttttct cattgttgct gctctagtat 27600
ttttaatact ttgcttcacc attaagagaa agacagaatg aatgagctca ctttaattga 27660
cttctatttg tgctttttag cctttctgct attccttgtt ttaataatgc ttattatatt 27720
ttggttttca ctcgaaatcc aggatctaga agaaccttgt accaaagtct aaacgaacat 27780
gaaacttctc attgttttga cttgtatttc tctatgcagt tgcatatgca ctgtagtaca 27840
gcgctgtgca tctaataaac ctcatgtgct tgaagatcct tgtaaggtac aacactaggg 27900
gtaatactta tagcactgct tggctttgtg ctctaggaaa ggttttacct tttcatagat 27960
ggcacactat ggttcaaaca tgcacaccta atgttactat caactgtcaa gatccagctg 28020
gtggtgcgct tatagctagg tgttggtacc ttcatgaagg tcaccaaact gctgcattta 28080
gagacgtact tgttgtttta aataaacgaa caaattaaaa tgtctgataa tggaccccaa 28140
tcaaaccaac gtagtgcccc ccgcattaca tttggtggac ccacagattc aactgacaat 28200
aaccagaatg gaggacgcaa tggggcaagg ccaaaacagc gccgacccca aggtttaccc 28260
aataatactg cgtcttggtt cacagctctc actcagcatg gcaaggagga acttagattc 28320
cctcgaggcc agggcgttcc aatcaacacc aatagtggtc cagatgacca aattggctac 28380
taccgaagag ctacccgacg agttcgtggt ggtgacggca aaatgaaaga gctcagcccc 28440
agatggtact tctattacct aggaactggc ccagaagctt cacttcccta cggcgctaac 28500
aaagaaggca tcgtatgggt tgcaactgag ggagccttga atacacccaa agaccacatt 28560
ggcacccgca atcctaataa caatgctgcc accgtgctac aacttcctca aggaacaaca 28620
ttgccaaaag gcttctacgc agagggaagc agaggcggca gtcaagcctc ttctcgctcc 28680
tcatcacgta gtcgcggtaa ttcaagaaat tcaactcctg gcagcagtag gggaaattct 28740
cctgctcgaa tggctagcgg aggtggtgaa actgccctcg cgctattgct gctagacaga 28800
ttgaaccagc ttgagagcaa agtttctggt aaaggccaac aacaacaagg ccaaactgtc 28860
actaagaaat ctgctgctga ggcatctaaa aagcctcgcc aaaaacgtac tgccacaaaa 28920
cagtacaacg tcactcaagc atttgggaga cgtggtccag aacaaaccca aggaaatttc 28980
ggggaccaag acctaatcag acaaggaact gattacaaac attggccgca aattgcacaa 29040
tttgctccaa gtgcctctgc attctttgga atgtcacgca ttggcatgga agtcacacct 29100
tcgggaacat ggctgactta tcatggagcc attaaattgg atgacaaaga tccacaattc 29160
aaagacaacg tcatactgct gaacaagcac attgacgcat acaaaacatt cccaccaaca 29220
gagcctaaaa aggacaaaaa gaaaaagact gatgaagctc agcctttgcc gcagagacaa 29280
aagaagcagc ccactgtgac tcttcttcct gcggctgaca tggatgattt ctccagacaa 29340
cttcaaaatt ccatgagtgg agcttctgct gattcaactc aggcataaac actcatgatg 29400
accacacaag gcagatgggc tatgtaaacg ttttcgcaat tccgtttacg atacatagtc 29460
tactcttgtg cagaatgaat tctcgtaact aaacagcaca agtaggttta gttaacttta 29520
atctcacata gcaatcttta atcaatgtgt aacattaggg aggacttgaa agagccacca 29580
cattttcatc gaggccacgc ggagtacgat cgagggtaca gtgaataatg ctagggagag 29640
ctgcctatat ggaagagccc taatgtgtaa aattaatttt agtagtgcta tccccatgtg 29700
attttaatag cttcttagga gaatgacaaa aaaaaaaaaa aaaaaaaaaa a 29751
Claims (7)
1. a vaccine combination is characterized in that, whole virus particles and physiology that this vaccine combination contains early stage SARS virus go up acceptable carrier, and described SARS virus is the GZ-02 Strain, has the nucleotide sequence that the GenBank accession number is AY390556.
2. vaccine combination as claimed in claim 1, it is characterized in that having at least one the nucleotide attenuation that is selected from down group variation in the nucleotide sequence of described SARS virus: 9404 → C, 17564 → G, 21721 → A, 22222 → C, 23823 → G, 27827 → C and combination thereof among the SEQ ID NO:1.
3. vaccine combination as claimed in claim 1, it is characterized in that, the albumen of described SARS virus has amino acid mutation, described amino acid mutation corresponding to being selected under the nucleotide attenuation variation of group: 9404 → C, 17564 → G, 21721 → A, 22222 → C, 23823 → G, 27827 → C and combination thereof among the SEQ IDNO:1.
4. vaccine combination as claimed in claim 1 is characterized in that described SARS virus is deactivation.
5. vaccine combination as claimed in claim 1 is characterized in that, described acceptable carrier biologically is an adjuvant.
6. the purposes of vaccine combination as claimed in claim 1 is characterized in that, this vaccine combination is used to prepare the antibody of anti-SARS.
7. the purposes of vaccine combination as claimed in claim 1 is characterized in that, this vaccine combination is used to prepare the medicine that the prevention SARS virus infects.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100160628A CN100413537C (en) | 2004-01-29 | 2004-01-29 | SARS coronary virus full virus vaccine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100160628A CN100413537C (en) | 2004-01-29 | 2004-01-29 | SARS coronary virus full virus vaccine |
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| CN1647823A CN1647823A (en) | 2005-08-03 |
| CN100413537C true CN100413537C (en) | 2008-08-27 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2004100160628A Expired - Fee Related CN100413537C (en) | 2004-01-29 | 2004-01-29 | SARS coronary virus full virus vaccine |
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| GB201413020D0 (en) * | 2014-07-23 | 2014-09-03 | Pribright The Inst | Coronavirus |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6642359B2 (en) * | 1990-11-14 | 2003-11-04 | Pfizer Inc. | Recombinant feline coronavirus S proteins |
| CN1462635A (en) * | 2003-05-16 | 2003-12-24 | 余国华 | Microzyme vaccine and bacterin for SARS epidemical tissue and its manufacturing method |
| CN1468955A (en) * | 2003-06-12 | 2004-01-21 | 中国人民解放军军事医学科学院微生物 | New type of coronavirus |
-
2004
- 2004-01-29 CN CNB2004100160628A patent/CN100413537C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6642359B2 (en) * | 1990-11-14 | 2003-11-04 | Pfizer Inc. | Recombinant feline coronavirus S proteins |
| CN1462635A (en) * | 2003-05-16 | 2003-12-24 | 余国华 | Microzyme vaccine and bacterin for SARS epidemical tissue and its manufacturing method |
| CN1468955A (en) * | 2003-06-12 | 2004-01-21 | 中国人民解放军军事医学科学院微生物 | New type of coronavirus |
Non-Patent Citations (2)
| Title |
|---|
| SARS corovirus GD 01 isolate genome sequence，AY278489. Qin，E等.. 2003 |
| SARS corovirus GD 01 isolate genome sequence，AY278489. Qin，E等.. 2003 * |
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| CN1647823A (en) | 2005-08-03 |
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