CN105963691A - Streptococcus pneumoniae vaccine - Google Patents
Streptococcus pneumoniae vaccine Download PDFInfo
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- CN105963691A CN105963691A CN201610524959.4A CN201610524959A CN105963691A CN 105963691 A CN105963691 A CN 105963691A CN 201610524959 A CN201610524959 A CN 201610524959A CN 105963691 A CN105963691 A CN 105963691A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
- A61K39/092—Streptococcus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/315—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Streptococcus (G), e.g. Enterococci
- C07K14/3156—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Streptococcus (G), e.g. Enterococci from Streptococcus pneumoniae (Pneumococcus)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6068—Other bacterial proteins, e.g. OMP
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6075—Viral proteins
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Abstract
The invention discloses a streptococcus pneumoniae vaccine and a preparation method thereof. The streptococcus pneumoniae vaccine is prepared by mixing S3CS recombinant antigens or mutant protein antigens with additives. The vaccine can be applied to immunity; the protection of organisms on streptococcus pneumonia can be improved; a specific antibody can be generated. A preparation method of the vaccine is simple; the requirements of large-scale industrial production can be met.
Description
Technical field
The present invention relates to vaccine, specifically, relate to a kind of Streptococcus pneumoniae vaccine.
Background technology
By the infection caused by streptococcus pneumoniae (lung chain) be whole world M & M act primarily as because of.Lung
Inflammation, heat generation bacteremia and meningitis are the most common forms of expression of invasive pneumococcal disease, and breathe
Antibacterial diffusion in road may result in middle ear infection, sinusitis or recurrent bronchitis.Compared with invasive disease,
The form of expression of Noninvasive is the most serious, but more common.Expansion due to antibiotics resistance sexually transmitted disease
Dissipating, and pneumococcal pneumonia often occurs after influenza infection, pneumococcal disease shows effect during influenza
Probability increase further.The disease caused by streptococcus pneumoniae has become one the important public health in the whole world
Problem.Streptococcus pneumoniae has become the number one killer of whole world child.
The case fatality rate of China's pneumonia is that 16.4%, wherein more than 50 years old middle-aged and elderly people and 1 years old Infants Below divide
Gao Da 28.6% and 22.0%.China streptococcus pneumoniae carrying rate in healthy children is higher, and statistics show
Showing, the carrying rate in northern area healthy children is 24.2%, and southern area is 31.3%.And this disease is
Cause the major reason of less than 5 years old death of child.Main reason is that the growth of infant immunisation system the most not
Perfect, immunity is more weak.And the baby that the age is the least, immunity is the most weak.
About 90 kinds serotypes (bacterial strain) of streptococcus pneumoniae, the statistics display pneumococcal infection of China
Before bacterial strain, several serotypes are followed successively by: 5,6,19,23,14,2,4 type.Have collected 860 strain lungs according to one
The research that scorching coccus separates strain shows have 109 strains (12.7%) to show as sero-group 6, at China's pneumonia ball
The erythromycin resistance of bacterium serotype 6 reaches 100%, and 6A, 6B and 6C type therein is respectively 62 strains
(56.9%), 38 strains (34.9%) and 9 strains (8.2%).
The 23 valency Pnu-Imune 23s that Chengdu Inst. of Biological Products of Chinese biological technology group produces are to have chosen
23 kinds of modal pathogenic bacterium (1,2,3,4,5,6B, 7F, 8,9N, 9V, 10A, 11A, 12F, 14,
15B, 17F, 18C, 19A, 19F, 20,22F, 23F, 33F), fermentation culture separating-purifying respectively
Various polysaccharide on pneumococcal capsule, is mixed and made into vaccine by equal proportion.
The polysaccharide of antibacterial is a kind of thymus independent antigen, this antigen and the main region of thymus dependent antigen
It is not that the former need not the auxiliary of T lymphocyte to produce antibody.Therefore polysaccharide vaccine there is problems in that
(1) faint immunoreation can only be produced in brood or infants, even not produce immunoreation,
Immunoreation strengthens with the growth at age；(2) antibody of low-affinity is produced；(3) of short duration exempting from only is produced
Epidemic disease is reacted, and does not possess immunological memory when repeatedly inoculating and immune-enhancing effect；(4) immunologic tolerance is easily produced；
(5) common adjuvant is difficult to play the effect of immunostimulant to this antigen.23 valency polysaccharide vaccines are for intrusion type
The protective rate that lung chain infects is 50-70%.And it is only used for crowd's inoculation of more than 2 years old, and the height of pneumonia
Peak age of onset is the 6-12 monthly age.
At disclosed W098/18930 on May 7th, 1998, entitled " antigen of streptococcus pneumoniae and vaccine "
(PCT Patent of Streptococcus Pneumoniae antigens and vaccine s describes much tool antigen
The specific polypeptide of property, but for the biological activity of these polypeptide but without correlation report.
Therefore, it is badly in need of at present with streptococcal antigen as the component of vaccine, in order to prevent and/or to treat streptococcus
Infecting, this becomes more and more important.
Summary of the invention
The present invention provides a kind of Streptococcus pneumoniae vaccine, the such as SEQ ID of the protein amino acid sequence in described vaccine
Shown in NO:1.
The other side of the present invention provides carrier, and it comprises the present invention being operatively connected to express control zone
Polynucleotide, additionally provide the host cell transfected with described carrier and the method preparing polypeptide, the method bag
Include and cultivate described host cell under conditions of being suitable to express this gene.
On the other hand, it is provided that by the new polypeptide coded by multinuclear of the present invention former times acid.
According to an aspect of the present invention, the present invention provides the polynucleotide of a separation, its coded polypeptide and choosing
From the homogeneity containing SEQ ID NO:1 at least 95%.
According to an aspect of the present invention, the present invention provides the polynucleotide of a separation, its coded polypeptide and choosing
From the homogeneity containing SEQ ID NO:1 at least 90%.
According to an aspect of the present invention, the present invention provides the polynucleotide of a separation, its coded polypeptide and choosing
From the homogeneity containing SEQ ID NO:1 at least 85%.
According to an aspect of the present invention, the present invention provides the polynucleotide of a separation, its coded polypeptide and choosing
From the homogeneity containing SEQ ID NO:1 at least 80%.
In a particular embodiment, the invention still further relates to mosaic type polypeptide, it comprises defined in coupling protein
One or several polypeptide or its fragment, homologue or derivant.
Described coupling protein is and couples the protein of combination is diphtheria toxoid, tetanus toxoid, carrier egg
White CRM197, bloodthirsty hemophilus influenza surface protein HiD, pertussis Prn surface protein, pertussis Fha resists
Former and/or pneumococcal surface protein PspA.
In one embodiment, according to polypeptide or the mosaic type polypeptide tool antigenicity of the present invention.
In one embodiment, polypeptide or mosaic type polypeptide according to the present invention can cause individual immunity
Reaction.
In a particular embodiment, the invention also relates to produce the polypeptide defined in the present invention or chimeric
Type polypeptide is signed an undertaking and is closed the polypeptide of specific antibody.
The antibody of " tool binding specificity " represent antibody can the specific polypeptide of identification in connection, but for
Sample comprises other molecules the most substantially nonrecognition in the biological specimen of selected peptide the most natively and combines.Profit
With enzyme linked immunosorbent assay (ELISA), can determine specific binding as during antigen of selected polypeptide
Ability.
According to the present invention, polypeptide includes polypeptide and mosaic type polypeptide simultaneously.Also include that oneself is through melting with other compounds
Close and the biological polypeptide with pharmacological property of oneself change, such as: merge with Polyethylene Glycol to increase the half-life；With front
Lead or secretion sequence merge with
Facilitate purification；Also have front former (prepro) sequence and merge with former (pro) sequence and (many) saccharides.
Furthermore, in the case of some amino acid regions are polymorphism, more there is a need to change one or several especially
Aminoacid so that it is more effectively imitate epitopes different on different streptococcus strain.
Described sports what applicant was obtained by screening in nearly 800 sudden change possibilities.
Described mutational site is the point mutation carried out on the basis of SEQ ID NO:1.F23V (represents
The F aminoacid in the 23rd site replaces with V), K42C, P60T, K92S, P122D, E133F, D180S,
F189H, K243S, I304G, L320Y, V329P, F332K, I339V, I352M, F361W, K369P,
S372K, F380M, L401E.
Additionally, the polypeptide of the present invention can be via phthalein (such as, second phthalein or the ethyl thioglycollic acid phthalein amine of terminal amino group
Change) modified with end shuttle base phthalein amination (such as: utilize ammonia or methylamine), it is provided that stability and enhancing hydrophobicity,
To link or be bound on holder or other molecules.
According on the other hand, the invention provides vaccine combination, it is including at least in the present invention or number
The many skins of individual streptococcus and the pharmaceutically useful carrier diluent being mixed with or adjuvant.Suitable adjuvant includes oil, example
As: not formula Freund's complete adjuvant or Freund's incomplete adjuvant；Salt, such as: AlK (S04) 2, AINa (S04) 2,
A1NH4 (S04) a, silicon dioxide, kaolin；The acid of carbon multinuclear former times, such as: poly-IC (poly IC) and poly-AU (poly
AU).Preferably adjuvant includes Kui Er A (QuilA) and aluminum hydrogel (Alhydrogel).The vaccine of the present invention can
Injection, quick infusion, nasopharyngeal absorption, skin absorption or the parenteral such as buccal or oral cavity is utilized to use.
Pharmaceutically useful carrier also includes tetanus toxoid.
The vaccine combination of the present invention is to treat or prevent streptococcic infection and/or as P.R.Murry is (main
Compile), E.J.Baron, M.A.Pfaller, F.C.Tenover and R.H.Yolken et al. are in Manual of
Clinical Microbiology, ASM Press, Washington, D.C. the 6th edition, in 1,995 1 books the 1482nd
The disease caused by streptococcal infection described in Ye and symptom (this piece has been incorporated into herein by reference).
In one embodiment, the vaccine combination of the present invention is used to treatment and prevention meningitis, middle ear
Inflammation, antibacterial mass formed by blood stasis and pneumonia.In one embodiment, the vaccine combination of the present invention be used to treatment with
Prevent streptococcic infection and/or by streptococcus, particularly streptococcus pneumoniae, A group streptococcus (suppuration hammer
Bacterium) [Grouup Astrepococcus (pyogenes)], B group streptococcus (GBS or streptococcus agalactiae) [Grouup
Bstrepococcus (GBS or agalactiae)], abnormal lactation bacterium (dysgalactiae), nipple bacterium (uberis),
Soil silk bacterium (nocardia) and staphylococcus aureus (streptococcus aureus) metainfective disease and disease
Shape.In one embodiment, streptococcic infection is streptococcus pneumoniae.
Particularly embodying in embodiment one, vaccine is applied to be in the individuality by streptococcal infection danger
On, such as baby, old people and immunity relatively weak person.
" individual " that this specification is used, including mammals.This mammals is in one embodiment
The mankind.
The preferable unit dose of vaccine combination is about 0.001 to 100p, g/kg (antigen/body weight), more preferably
It is 0.01 to 1Opg/kg, most preferably 0.1 to 1p, g/kg, there is the interval in one to six week between immunity inoculation,
Use one to three time.
There is the effect of justice: the invention provides one and have preferable immunogenic albumen, the preparation of this albumen becomes
Vaccine the immune protection of preferable streptococcus pneumoniae can be provided, the preparation of this albumen is simple, with low cost,
And human body is had no side effect, is suitable for large-area popularization.
Detailed description of the invention
The expression of embodiment 1 albumen
With the DNA of streptococcus pneumoniae as template, obtained shown in SEQ ID NO:1 by design primer amplification
The gene order of aminoacid sequence, then utilize QIAgen (the QIAquick gel extraction of Chatworth, CA
Take test kit PCR primer to be reclaimed from agar gel.With Superlinker carrier pSL301 (Invitrogen,
San Diego, CA) together by after enzyme action, extract with the QIAquick gel of QIAgen (Chatworth, CA)
Take test kit to reclaim from agar gel.The genomic DNA fragment crossed by restriction enzyme action is crossed with restriction enzyme action
PSL301 carrier is bonding.Product after bonding further according to Simanis method (Hanahan, D.DNA Cloning,
1985, D.M.Glover (ed), pp.109-13 5) convert to DH5a escherichia coli.Examination with QIAgen
Agent box carrys out the pSL301 recombiant plasmid (rpSL301) that purification contains genes of interest, identifies through order-checking, identifies weight
Group is correct.
By genes of interest by enzyme action connect be building up to pET-32c (+) expression vector (Novagen, Madison,
WT) after, convert and enter BL21 cell, carry out prokaryotic expression, obtain supernatant by conventional expression and express
Protein form, by cross column purification, it is thus achieved that destination protein, concentration is 100mg/mL.
The acquisition of embodiment 2 mutain
The introducing of catastrophe point
(1), design corresponding mutagenic primer according to corresponding mutational site, use PCR fixed-point mutation method in institute
On corresponding S3CS gene, amino acid sites corresponding for wild type is suddenlyd change；Described mutational site be
The point mutation carried out on the basis of SEQ ID NO:1.F23V (represents that the F aminoacid in the 23rd site is replaced
For V), K42C, P60T, K92S, P122D, E133F, D180S, F189H, K243S, I304G,
L320Y, V329P, F332K, I339V, I352M, F361W, K369P, S372K, F380M,
L401E。
(2), above-mentioned PCR primer reclaim after purification through glue, carry out enzyme action with restricted enzyme, and through phase
After connecting with the plasmid pSL301 carrier segments of enzyme action, convert bacillus coli DH 5 alpha competent cell；
(3), recombiant plasmid is identified: by enzyme action, PCR method, recombiant plasmid is identified, and inspection of checking order
Test, the nucleotide sequence after thus being suddenlyd change.
S3CS gene after these being suddenlyd change uses the expression in embodiment 1 to express accordingly,
By after purification, protein concentration is adjusted to 100mg/mL equally.
The generation antibody effects of embodiment 3 pneumoprotein vaccine is evaluated
The female 3 week old BALB/c. children Mus of 12-14g, are randomly divided into 23 groups, often group 20, respectively abdominal cavity note
Penetrate the combined vaccine prepared as immunological adjuvant according to embodiment 1 and 2 albumen with Al (OH) 3, commercially available
13 valency lung chain combination vaccines, blank (PBS).
In the 0th, 2,4 weeks programmed injection 3 times, every young Mus 0.5ml is containing (0.5ug albumen).Each experiment
Group blood samplings in 7 days after the 3rd pin injection, separate serum, put-20 DEG C and save backup.
Indirect elisa method is respectively adopted, by protein dissolution in 0.05mol/L for the detection of protein antibodies titre
In the carbonate buffer solution of pH9.6, with 20ug/ml concentration coated elisa plate, the BSA fluid-tight of 2% is closed.
By test serum 100 during experiment, 200,400,800,1600,3200,6400,12800,25600,
Add ELISA Plate after 51200,102400,204800,409600 times of dilutions, put 37 DEG C of reaction 40min,
The sheep anti mouse two adding horseradish peroxidase-labeled after conventional wash resists.It is simultaneously introduced the buffer without serum
As negative control.Develop the color with tetra-amino-biphenyl amine, at microplate reader 450nm wavelength, read A value.Calculate every
In hole, A value and negative hole A are worth ratio, but ratio is in serum more than the extension rate of 2.1 epoch maximums
Antibody titer, the titre of 20 mices is carried out geometric average, and calculates logarithm value, result with 20 the end of for
It is shown in Table 1.
Finding out from data, protein vaccine and the corresponding mutant protein vaccine on mouse of the present invention are many to lung chain
The immunoreation of sugar is obviously enhanced, and the ability producing antibody than commercially available vaccine also strengthens.
Embodiment 4 immune mouse effect assessment
1) first immunisation, with S3CS or the recombinant protein antigen of its sudden change of PBS dilution 2mg, adds dense
Degree is the Al (OH) 3 of 1mg/mL；With No. 5 half mould syringe needles, bilateral inguinal, vola and dorsal sc are to point
Injection, every BALB/C mice injection volume is l00uL, and arranges positive controls, negative control group and sky
White matched group；
2) second time immunity, within the 14th day, carry out second time immunity, immune component ibid, injection volume proteantigen
Amount is the 1/2 of first immunisation, and immunization route is ibid；
3) third time immunity, within the 21st day, carry out third time immunity, immune component ibid, injection volume proteantigen
Measuring identical with second time immunity, immunization route is ibid；
Using fatal dose at the 14th day, tail vein injection S. pneumoniae strains WU2 viable bacteria carries out counteracting toxic substances
Experiment, every BALB/C mice injection bacterium solution amount is 1.5*109CFU, observes 14 days, adds up each group of mice
Survival rate.Result is shown in table 2.
Table 2 shows；The average immune protective rate of negative control group and blank group is respectively 0%, the present invention
Antigen protein or its mutain have about 100% protection feature, have than the vaccine effect of prior art
Improve.
Safety evaluatio
By the mice after above-mentioned protein immunization after challenge viral dosage terminates, continue to cultivate January, dissect, send out
Existing each organ of mice is normal, does not has any variation.This sufficiently illustrates, the vaccine safety of the present invention is reliable.
The foregoing is only presently preferred embodiments of the present invention, be not used for limiting the practical range of the present invention；If
Without departing from the spirit and scope of the present invention, the present invention is modified or equivalent, all should contain at this
In the middle of invention scope of the claims.
Sequence table
It is beautiful that ＜ 110 ＞ looks into literary composition
＜ 120 ＞ Streptococcus pneumoniae vaccine
〈160〉1
〈210〉1
〈211〉887
〈212〉PRT
＜ 213 ＞ artificial sequence
〈400〉S3CS
1 MYTFILMLLD FLKNHDFHFF MLFFVFILIR
WAVIYFHAVR YKSYSCSVSD EKLFSSVIIP
61 VVDEPLNLFE SVLNRISRHK PSEIIVVING
PKNERLLKLC HDFNEKLENN MTPIQCYYTP
121 VPGKRNAIRV GLEHVDSQSD ITVLVDSDTV
WTPRTLSELL KPFVCDKKIG GVTTRQRIFD
181 PERNLVTMFA NLLEEIRAEG SMKAMSVTGK
VGCLPGRTIA FRTEILRECI HEFMNETFMG
241 FHKEVSDDRS LTNLTLKKGY KTVMQDTSVV
YTDAPTSWKK FIRQQLRWAE GSQYNNLKMT
301 PWMIRNAPLM FFIYFTDMIL PMLLISFGVN
IFLLKILNIT TVVYTASWLE IILYVLFGMI
361 FSFGGRNFKA MSRMKWYYVF LIPVFIIVLS
IIMCPIRLLG LMRCSDDLGW GTRNLIEGGG
421 SGGGSGGGSG GGSGGGSMSK YKELAKNTGI
FALANFSSKI LIFLLVPIYT RVLTTTEYGF
481 YDLVYTTIQL FVPILTLNIS EAVMRFLMKD
GVSKKSVFSI AVLDIFIGSI AFALLLLVNN
541 LFSLSDLISQ YSIYIFVIFV FYTLNNFLIQ
FSKGIDKIGV TAISGVISTA VMLAMNVILL
601 VVFDWGLLGF FIANVCGYVI PCIYIVSRLR
LWELFEIKID KKLQWEMVYY ALPLVLNILS
661 WWVNNTSDRY IVTAIVGIQA SAIISVAYKI
PQILSTISAI FIQSWQISAI KIQEDKSDTT
721 FVSNMLLYYN ALLLIIASGI ILFVKPISNI
LFGISFYSAW ELVPFLIISS LFNAISGCIG
781 AIMGAKMDTH NIAKSALVGM IANIILNIVL
TFLMGPQGIT ISTLIASFLI FYMRKDSVKE
841 INSETYRAIY LSWILLVVEA CLLIYMDFII
GALIAMVINL FLLKDVI
Claims (3)
1. a Streptococcus pneumoniae vaccine, it contains antigen protein and adjuvant.
2. vaccine as claimed in claim 1, wherein antigen protein is SEQ
Sequence shown in ID NO:1, or its point mutation carried out on the basis of SEQ ID NO:1, concrete mutational site is F23V, K42C, P60T, K92S, P122D, E133F, D180S, F189H, K243S, I304G, L320Y, V329P, F332K, I339V, I352M, F361W, K369P, S372K, F380M or L401E.
3. the method preventing pneumonia, including using the vaccine shown in any one of claim 1-2.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610524959.4A CN105963691B (en) | 2016-07-03 | 2016-07-03 | Streptococcus pneumoniae vaccine |
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|---|---|---|---|
| CN201610524959.4A CN105963691B (en) | 2016-07-03 | 2016-07-03 | Streptococcus pneumoniae vaccine |
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| CN105963691B CN105963691B (en) | 2020-05-01 |
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| CN101024079A (en) * | 2006-02-17 | 2007-08-29 | 福州昌晖生物工程有限公司 | Pneumo-streptococcal-polysaccharide adventitia jointed vaccine and preparing method |
| CN101977927A (en) * | 2008-03-17 | 2011-02-16 | 英特塞尔股份公司 | Peptides protective against s. pneumoniae and compositions, methods and uses relating thereto |
| CN105008539A (en) * | 2012-11-07 | 2015-10-28 | 格林考瓦因有限公司 | Production of recombinant vaccine in e. coli by enzymatic conjugation |
| CN103830723A (en) * | 2012-11-26 | 2014-06-04 | 天士力制药集团股份有限公司 | Preparation method of streptococcus pneumoniae capsular polysaccharide protein conjugate vaccine |
| CN103893751A (en) * | 2014-03-26 | 2014-07-02 | 天津康希诺生物技术有限公司 | Pneumococcal polysaccharide and protein conjugated vaccine and preparation method thereof |
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Effective date of registration: 20200423 Address after: 100176 room 01-12, floor 1, building 1, No. 3, Yongchang North Road, Beijing Economic and Technological Development Zone, Daxing District, Beijing Patentee after: Nuosa Union (Beijing) Biomedical Technology Co., Ltd Address before: 310027 Zhejiang University, 38 Zhejiang Road, Hangzhou, Zhejiang, Xihu District Patentee before: Zha Wenjuan |