CN111333704B - Novel coronavirus COVID-19 vaccine, preparation method and application thereof - Google Patents
Novel coronavirus COVID-19 vaccine, preparation method and application thereof Download PDFInfo
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- CN111333704B CN111333704B CN202010112679.9A CN202010112679A CN111333704B CN 111333704 B CN111333704 B CN 111333704B CN 202010112679 A CN202010112679 A CN 202010112679A CN 111333704 B CN111333704 B CN 111333704B
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Abstract
The invention relates to the field of biomedicine, and relates to a novel coronavirus COVID-19 vaccine, a preparation method and application thereof. The invention obtains the dominant antigen (RBD) epitope of the novel coronavirus COVID-19 vaccine through screening, and in order to improve the immunogenicity of the antigen, the antigen is connected with immunoglobulin to prepare RBD-Fc fusion protein, and the fusion protein can be used for developing the protein vaccine of the novel coronavirus COVID-19 and medicaments for preventing or treating the novel coronavirus COVID-19.
Description
Technical Field
The invention relates to the field of immunotherapy, and relates to a novel coronavirus COVID-19 vaccine, a preparation method and application thereof.
Background
The new coronavirus COVID-19 has devastating effects and is an effective method for preventing virus infection. The application screens and optimizes the dominant antigen epitope fragment which can be used for preparing the novel coronavirus COVID-19 vaccine by analyzing the sequence characteristics of the novel coronavirus COVID-19, and fuses the protein fragment and the human Fc fragment to prepare the novel virus vaccine.
Disclosure of Invention
According to a first aspect of the present invention, the present invention provides a dominant epitope fragment of a novel coronavirus covi-19 vaccine, wherein the epitope fragment comprises an amino acid sequence shown in SEQ ID No.1 or a sequence derivative thereof.
According to a second aspect of the invention, there is also provided a nucleic acid molecule encoding an epitope fragment as hereinbefore described.
Further, the nucleic acid molecule comprises the polynucleotide sequence shown in SEQ ID NO.2 or a degenerate sequence thereof.
According to a third aspect of the invention, there is also provided a vector comprising a nucleic acid molecule as hereinbefore described.
According to a fourth aspect of the invention, there is also provided a cell comprising a nucleic acid molecule as hereinbefore described or a vector as hereinbefore described.
According to a fifth aspect of the present invention, there is provided a method of producing an epitope fragment as defined above, said method comprising culturing a cell as defined above under suitable conditions.
According to a sixth aspect of the present invention there is provided a vaccine comprising an epitope fragment as hereinbefore described, a nucleic acid molecule as hereinbefore described or a vector as hereinbefore described.
According to a seventh aspect of the present invention, there is provided a pharmaceutical composition comprising the epitope fragment, the nucleic acid molecule, the vector, the cell, or the vaccine, and a pharmaceutically acceptable carrier.
According to an eighth aspect of the invention there is provided a fusion protein comprising an epitope fragment as hereinbefore described.
Further, the fusion protein further comprises an immunoglobulin Fc fragment.
Further, the source of the immunoglobulin Fc fragment includes other animals such as human, mouse, rabbit, cow, goat, pig, mouse, rabbit, hamster, rat, and guinea pig.
The immunoglobulin Fc fragment may be an Fc fragment from IgG, IgA, IgD, IgE, and IgM, or an Fc fragment prepared by a combination or hybrid thereof; preferably from IgG or IgA.
Further, the immunoglobulin Fc fragment is a human IgG Fc fragment.
Further, the human IgG Fc fragment is selected from any one of Fc fragments of human IgG1, IgG2, IgG3, IgG 4.
In a particular embodiment of the invention, the human IgG Fc fragment comprises the amino acid sequence shown in SEQ ID NO.3 or a sequence derivative thereof.
In a particular embodiment of the invention, the fusion protein comprises the amino acid sequence shown in SEQ ID No.4 or a sequence derivative thereof.
According to a ninth aspect of the invention, there is provided a nucleic acid molecule encoding a fusion protein as hereinbefore described.
Further, the nucleic acid molecule comprises the polynucleotide sequence shown in SEQ ID NO.5 or a degenerate sequence thereof.
According to a tenth aspect of the present invention there is provided a vector comprising a nucleic acid molecule according to the ninth aspect.
According to an eleventh aspect of the invention, there is provided a cell comprising the nucleic acid molecule of the ninth aspect or the vector of the tenth aspect.
According to a twelfth aspect of the present invention, there is provided a method of producing a fusion protein as described above, the method comprising culturing a cell of the eleventh aspect under suitable conditions.
According to a thirteenth aspect of the present invention, there is provided a vaccine comprising the fusion protein of the preceding aspect, the nucleic acid molecule of the ninth aspect, or the vector of the tenth aspect.
According to a fourteenth aspect of the present invention, there is provided a pharmaceutical composition comprising the fusion protein of the preceding aspect, the nucleic acid molecule of the ninth aspect, the vector of the tenth aspect, the cell of the eleventh aspect, or the vaccine of the thirteenth aspect, and a pharmaceutically acceptable carrier.
According to a fifteenth aspect of the present invention there is provided a method for inducing antibodies to the novel coronavirus covi-19 in a subject, the method comprising administering to the subject a vaccine as described hereinbefore, an epitope fragment as described hereinbefore, a fusion protein as described hereinbefore, a nucleic acid molecule as described hereinbefore, a vector as described hereinbefore, a cell as described hereinbefore or a pharmaceutical composition as described hereinbefore.
According to a sixteenth aspect of the invention there is provided an antibody prepared according to the method described hereinbefore.
According to a seventeenth aspect of the present invention, there is provided a vaccine comprising an antibody or functional part thereof as described hereinbefore.
According to an eighteenth aspect of the invention, there is provided a pharmaceutical composition comprising an antibody as hereinbefore described or a vaccine as described in the seventeenth aspect.
According to a nineteenth aspect of the present invention, there is provided a method of inhibiting infection by a novel coronavirus covi-19, said method comprising administering to said subject a vaccine as described hereinbefore, an epitope fragment as described hereinbefore, a fusion protein as described hereinbefore, a nucleic acid molecule as described hereinbefore, a vector as described hereinbefore, a cell as described hereinbefore, a pharmaceutical composition as described hereinbefore or an antibody as described hereinbefore.
According to a twentieth aspect of the present invention, there is provided a method of increasing the immunogenicity of an epitope fragment as hereinbefore described, said method comprising linking said epitope fragment to an immunoglobulin Fc fragment.
The immunoglobulin Fc fragment is as described above.
According to a twenty-first aspect of the present invention, there is provided a method of preparing a fusion protein as hereinbefore described, the method comprising linking an epitope fragment as hereinbefore described to an immunoglobulin Fc fragment.
The immunoglobulin Fc fragment is as described above.
According to a twenty-second aspect of the present invention, there is provided the use of an epitope fragment as hereinbefore described for the preparation of a fusion protein as hereinbefore described, a vaccine as hereinbefore described, a pharmaceutical composition as hereinbefore described or an antibody as hereinbefore described.
According to a twenty-second aspect of the invention, there is provided the use of a fusion protein as hereinbefore described in the manufacture of a vaccine as hereinbefore described in the thirteenth or seventeenth aspect, or a pharmaceutical composition as hereinbefore described in the fourteenth or eighteenth aspect, or an antibody as hereinbefore described.
Use of a nucleic acid molecule of the second or third aspect, a vector of the fourth aspect, in the preparation of a vaccine as described above, a pharmaceutical composition as described above, or an antibody as described above.
Use of a cell according to the fifth aspect for the preparation of a pharmaceutical composition as described above, or an antibody as described above.
Use of a nucleic acid molecule according to the ninth aspect, a vector according to the tenth aspect, in the preparation of a vaccine according to the thirteenth or seventeenth aspect, a pharmaceutical composition according to the fourteenth or eighteenth aspect, or an antibody as described above.
Use of a cell of the eleventh aspect in the manufacture of a pharmaceutical composition of the fourteenth or eighteenth aspect, or an antibody as hereinbefore described.
Use of a vaccine according to the sixth aspect in the manufacture of a pharmaceutical composition as hereinbefore described, or an antibody as hereinbefore described.
Use of a vaccine according to the thirteenth aspect in the manufacture of a pharmaceutical composition according to the fourteenth or eighteenth aspect, or an antibody as hereinbefore described.
Use of a vaccine according to the seventeenth aspect in the manufacture of a pharmaceutical composition according to the eighteenth aspect, or an antibody as hereinbefore described.
Use of an epitope fragment as defined above, a fusion protein as defined above, a vaccine as defined above, a nucleic acid molecule as defined above, a vector as defined above, a cell as defined above or a pharmaceutical composition as defined above for the preparation of an antibody against the novel coronavirus COVID-19.
Use of an epitope fragment as defined above, a fusion protein as defined above, a vaccine as defined above, a nucleic acid molecule as defined above, a vector as defined above, a cell as defined above, or a pharmaceutical composition as defined above for the manufacture of a medicament for combating infection by a novel coronavirus covi-19.
The amino acid sequence derivative of the present invention is a sequence which is different from a natural amino acid sequence due to deletion, insertion, non-conservative or conservative substitution of one or more amino acid residues or a combination thereof, and is a derivative having the same biological activity as a natural amino acid sequence of fish or having improved structural stability (e.g., heat resistance, pH resistance, etc.).
The amino acid sequence derivatives of the invention have at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the native amino acid sequence.
The vaccine also comprises an adjuvant, wherein the adjuvant comprises one or more of an alumina Gel adjuvant, saponin, a water-in-oil emulsion, an oil-in-water emulsion, a water-in-oil-in-water emulsion, a polymer of acrylic acid or methacrylic acid, a copolymer of maleic anhydride and alkenyl (alkenyl) derivatives, a RIBI adjuvant system, a Block co-polymer, SAF-M, monophosphoryl lipid A, Avridine lipid-amine adjuvant, escherichia coli heat-labile enterotoxin, cholera toxin, 1314, muramyl dipeptide or Gel adjuvant.
Drawings
FIG. 1 shows a SEC purity assay result chart for a fusion protein of the present invention;
FIG. 2 is a diagram showing the result of SDS-PAGE of the fusion protein of the present invention;
FIG. 3 is a graph showing the results of the biological activity of the fusion proteins of the present invention binding to hACE2 receptor;
FIG. 4 shows a graph of ELISA results of RBD-Fc protein-immunized mice.
Detailed Description
Example 1 screening of dominant antigen (RBD) epitopes of a novel coronavirus COVID-19 vaccine
The dominant antigen (RBD) epitope of the novel coronavirus COVID-19 vaccine is obtained by screening, the amino acid sequence is shown as SEQ ID NO.1, and the optimized coding nucleic acid sequence is shown as SEQ ID NO. 1.
Example 2 fusion, expression and identification of the dominant epitope and Fc protein (RBD-Fc) of the novel coronavirus COVID-19 vaccine
The amino acid sequence of the adopted immunoglobulin Fc fragment is shown as SEQ ID NO.3, and the coding nucleic acid sequence is shown as SEQ ID NO. 6. The RBD-Fc amino acid sequence is shown as SEQ ID NO.4, the RBD-Fc amino acid sequence is determined and then optimized and synthesized, and the RBD-Fc coding nucleic acid sequence is shown as SEQ ID NO. 5. In order to facilitate the smooth operation of the test, a tool vector used in the plasmid construction process is a ZY-CDMO vector (which is independently designed and synthesized by Beijing Sho-derivative technology Limited company and applied for a patent, and the application number is 201910738072.9) to exchange the positions of a PmeI restriction site and a HindIII restriction site, the 5 'end of a synthesized RBD-Fc sequence is provided with an EcoRI restriction site, the 3' end is provided with a HindIII restriction site, and the synthesized RBD-Fc sequence is inserted between EcoRI and HindIII of the vector to construct and obtain the eukaryotic expression novel coronavirus COVID-19 vaccine vector plasmid.
Inoculating 30ml of cell culture shake flask with density of 0.5X 106cells/ml HEK293 cells grown to 3X 10 cell density6cell/ml, and cell survival rate of 95% or more. Inoculating cells into a shake flask at a concentration of 1-2 × 107vc/ml for later use, uniformly mixing a transfection buffer solution and plasmids, uniformly mixing the transfection buffer solution and a transfection reagent in a certain proportion, adding the transfection reagent mixed solution into the plasmid mixed solution, uniformly mixing, standing at room temperature for 10min, finally dropwise adding a transfection compound into the shake flask containing a cell suspension, and carrying out a reaction at 37 ℃ and 5% CO treatment2Culturing for 5-7 days in a shaking table with the rotation speed of 125rpm, and collecting and purifying culture solution supernatant. The RBD-Fc protein was isolated and purified by AKTA (GE corporation). Firstly, collecting eluate with pH of 3.4-3.6 (monitored at 280 nm) of Protein A affinity chromatography column (Mabselect Sure), adjusting pH to 7.0, loading onto molecular sieve chromatography column (SUPERDEX 200), monitoring and collecting sample at 280nm, ultrafiltering and concentrating to obtain RBD-FC Protein.
The SEC purity of the obtained protein was 97.04%, as shown in FIG. 1.
The SDS-PAGE of the resulting protein is shown in FIG. 2, in which lane 1 is a protein Marker and lane 2 is RBD-Fc.
Example 3 biological Activity of binding of recombinant RBD-Fc protein to hACE2 receptor
The biological activity of the recombinant RBD-Fc protein for binding to hACE2 receptor is identified by the method of flow cytometry.
The experimental steps are as follows:
1. diluted test serum was added to 96 well cell culture plates at 25. mu.l per well. Serum first dilution 1:5, four serial equal dilution were performed. Then 2019-nCoV RBD-Fc protein is added, the concentration of the RBD-Fc protein is 1 mu g/ml, and each well is 25 mu l. Shaking at room temperature for 30min, and standing at 37 deg.C for 10 min.
2. Cells were digested with pancreatin and digestion was stopped with 10ml of complete medium. Then centrifuged horizontally (1600rpm, 4 ℃, 6 min).
3. The cells were resuspended in 10ml FPBS and then centrifuged horizontally (1600rpm, 4 ℃, 6 min).
4. The cells were resuspended in 10ml FPBS, counted, and the total number was estimated, and then centrifuged horizontally (1600rpm, 4 ℃, 6 min).
5. Based on the total cell count estimation, an appropriate amount of FPBS was added to a concentration of 5X 106One per ml. Cells were added to 96-well plates at 50. mu.l/well. Shaking at room temperature for 10min, and standing at 37 deg.C for 30 min.
6. A corresponding number of flow tubes were prepared, labeled and 1ml of FPBS was added. And (4) lightly blowing and sucking the mixture in the 96-well plate, uniformly mixing, transferring to a corresponding flow tube, and lightly shaking and uniformly mixing. Horizontal centrifugation (1600rpm, 4 ℃, 6 min).
7. The supernatant was discarded and the flow tube was inverted onto absorbent paper and then immediately set upright on the flow tube stand. Beating the side wall of the tube frame to loosen the cells.
8. This was followed by two more washes.
9. FPBS-diluted secondary antibody was added to the flow tube at 100. mu.l/tube and the flow tube was covered with tinfoil. Shaking at room temperature for 10min, and standing at 37 deg.C for 30 min.
10. Washed three times as before.
11. Adding 200 mul FPBS, gently blowing and sucking, mixing, transferring 200 mul to 96-well plate, and detecting on machine.
The experimental results are as follows:
as shown in FIG. 3, the results indicate that the RBD-Fc protein efficiently binds to HeLa-hACE2 cells highly expressing hACE2 molecule, but not to normal HeLa. Thus, the recombinant RBD-Fc protein is confirmed to have the biological activity of binding to hACE 2.
Example 4 immunization of a novel coronavirus COVID-19 vaccine (RBD-Fc) in mice and identification of antibody Titers
ELISA identification of RBD-Fc protein immune mouse serum
After mice are immunized by 2019-nCoV RBD-m/hFc protein, the serum of the mice is subjected to antibody titer detection.
The experimental steps are as follows:
1. and (3) taking a 96-well enzyme label plate, respectively coating corresponding antigen protein, wherein the coating concentration is 1 mu g/ml, and each well is 50 mu l. The mixture was allowed to stand at 4 ℃ overnight.
2. And washing the ELISA plate once by using a plate washing machine, and patting the ELISA plate dry.
3. Add 3% BSA blocking solution 100. mu.l per well. Standing at 37 ℃ for 1 h.
4. And washing the ELISA plate once by using a plate washing machine, and patting the ELISA plate dry.
5. Another 96-well ELISA plate was used to perform serial equal-ratio dilution of mouse serum.
6. The diluted serum was added to the three microplate wells in step 1, 50. mu.l per well. Standing at 37 deg.C for 45 min.
7. The microplate was washed three times using a plate washer and patted dry.
8. Diluted goat anti-mouse antibody (dilution 1: 5000) was added at 50. mu.l per well. Standing at 37 deg.C for 30 min.
9. The microplate was washed three times using a plate washer and patted dry.
10. Color developing solution was added to each well in an amount of 50. mu.l. The color development is about 1 min.
11. Stop solution was added in 50. mu.l per well.
12. The absorbance at OD450 was read using a microplate reader.
The experimental results are as follows:
the serum ELISA results of the RBD-hFc protein immunized mice are shown in Table 1 and FIG. 4. The result shows that the recombinant RBD-hFc protein has good immunogenicity, can effectively induce and generate specific antibodies aiming at the virus Spike protein RBD, and can be used for preventing or treating the infection of the novel coronavirus COVID-19.
TABLE 1 statistics of ELISA results for RBD-hFc protein immunized mice
(401 to 405 as an aluminum adjuvant)
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Academy of military medicine, Academy of Military Sciences, PLA
Beijing zhaoderivative Technology Co.,Ltd.
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<213> Artificial Sequence (Artificial Sequence)
<400> 4
Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg
1 5 10 15
Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val
20 25 30
Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys
35 40 45
Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn
50 55 60
Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile
65 70 75 80
Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
85 90 95
Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp
100 105 110
Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys
115 120 125
Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln
130 135 140
Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe
145 150 155 160
Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln
165 170 175
Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala
180 185 190
Thr Val Ala Ala Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
195 200 205
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
210 215 220
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
225 230 235 240
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
245 250 255
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
260 265 270
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
275 280 285
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
290 295 300
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
305 310 315 320
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
325 330 335
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
340 345 350
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
355 360 365
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
370 375 380
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
385 390 395 400
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
405 410 415
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
420 425
<210> 5
<211> 1287
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 5
aacatcacca acctgtgccc cttcggcgag gtgttcaacg ccaccaggtt cgccagcgtg 60
tacgcctgga acaggaaaag gatcagtaac tgcgtggccg actactccgt gctgtacaac 120
tccgcctcct tctccacctt caaatgctat ggcgtgtccc ccaccaagct gaacgatctg 180
tgtttcacca acgtgtacgc cgactccttc gtgattaggg gcgacgaggt gcgccagatc 240
gcccctggtc agaccggcaa gatcgccgat tataactaca agctgcccga cgacttcacc 300
ggctgcgtga tcgcctggaa ctccaacaat ctggatagca aggtgggtgg aaactacaat 360
tacctgtaca gactgttccg caaatccaac ctgaagccct tcgaaaggga catctccaca 420
gagatctacc aggccggctc caccccctgc aacggagtgg agggcttcaa ctgctacttc 480
cccctgcagt cctacggctt ccagcccacc aacggcgtgg gataccagcc ctacagagtg 540
gtggtgctgt ccttcgagct gctgcacgcc cccgccaccg tggctgctgc tgaacctaaa 600
tcctgcgaca agacacacac ctgccccccc tgccctgccc ctgaactgct gggaggcccc 660
tccgtgttcc tgttcccccc caagcccaag gacacactga tgatctcccg gacccccgag 720
gtgacctgcg tggtggtgga cgtgtcccac gaagatcccg aagtgaaatt taattggtac 780
gtggacggcg tggaggtgca caatgcaaag acaaaaccca gggaggaaca gtacaatagt 840
acatacaggg tggtgagcgt gctgacagtg ctgcatcagg attggctgaa cgggaaggag 900
tataagtgca aggtgtccaa caaggccctg cccgccccca ttgagaagac catctccaaa 960
gccaagggcc agcccaggga gccccaggtg tacaccctgc cacccagcag agacgagctg 1020
accaagaacc aggtgagcct gacctgcctg gtgaaaggct tctacccctc cgacatcgcc 1080
gtggaatggg aatcaaacgg ccagcctgag aacaactaca aaacaacacc ccccgtgctg 1140
gacagcgacg gcagcttctt cctgtactcc aagctgacag tggacaagtc caggtggcag 1200
cagggcaacg tgttcagttg ctccgtgatg cacgaggccc tgcacaacca ttacacccag 1260
aagtccctgt ccctgtcccc cggcaag 1287
<210> 6
<211> 705
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 6
gctgctgctg aacctaaatc ctgcgacaag acacacacct gccccccctg ccctgcccct 60
gaactgctgg gaggcccctc cgtgttcctg ttccccccca agcccaagga cacactgatg 120
atctcccgga cccccgaggt gacctgcgtg gtggtggacg tgtcccacga agatcccgaa 180
gtgaaattta attggtacgt ggacggcgtg gaggtgcaca atgcaaagac aaaacccagg 240
gaggaacagt acaatagtac atacagggtg gtgagcgtgc tgacagtgct gcatcaggat 300
tggctgaacg ggaaggagta taagtgcaag gtgtccaaca aggccctgcc cgcccccatt 360
gagaagacca tctccaaagc caagggccag cccagggagc cccaggtgta caccctgcca 420
cccagcagag acgagctgac caagaaccag gtgagcctga cctgcctggt gaaaggcttc 480
tacccctccg acatcgccgt ggaatgggaa tcaaacggcc agcctgagaa caactacaaa 540
acaacacccc ccgtgctgga cagcgacggc agcttcttcc tgtactccaa gctgacagtg 600
gacaagtcca ggtggcagca gggcaacgtg ttcagttgct ccgtgatgca cgaggccctg 660
cacaaccatt acacccagaa gtccctgtcc ctgtcccccg gcaag 705
Claims (20)
1. The dominant epitope peptide of the novel coronavirus COVID-19 vaccine is characterized in that the amino acid sequence of the epitope peptide is shown as SEQ ID NO. 1.
2. A nucleic acid molecule encoding the epitope peptide according to claim 1.
3. The nucleic acid molecule of claim 2, wherein the sequence of the nucleic acid molecule is the polynucleotide sequence shown in SEQ ID No.2 or a degenerate sequence thereof.
4. A fusion protein comprising the epitope peptide of claim 1 and an immunoglobulin Fc fragment.
5. The fusion protein of claim 4, wherein the source of the immunoglobulin Fc fragment comprises a human, mouse, rabbit, cow, goat, pig, mouse, rabbit, hamster, rat, or guinea pig.
6. The fusion protein of claim 5, wherein the immunoglobulin Fc fragment is an Fc fragment of IgG, IgA, IgD, IgE, or IgM.
7. The fusion protein of claim 6, wherein the immunoglobulin Fc comprises an IgG1 Fc fragment, an IgG2 Fc fragment, an IgG3 Fc fragment, or an IgG4 Fc fragment.
8. The fusion protein of claim 7, wherein the immunoglobulin Fc fragment is a human IgG Fc fragment comprising the amino acid sequence set forth in SEQ ID No.3 or a sequence derivative thereof.
9. The fusion protein according to any one of claims 4-8, wherein the amino acid sequence of the fusion protein is as set forth in SEQ ID No. 4.
10. A nucleic acid molecule encoding the fusion protein of any one of claims 4-9.
11. The nucleic acid molecule of claim 10, wherein the sequence of the nucleic acid molecule is the polynucleotide sequence shown in SEQ ID No.5 or a degenerate sequence thereof.
12. A vector comprising the nucleic acid molecule of claim 10 or 11.
13. A cell comprising the nucleic acid molecule of claim 10 or 11 or the vector of claim 12.
14. A method of making the fusion protein of any one of claims 4-9, comprising culturing the cell of claim 13 in a suitable environment, or
The method comprises linking the epitope peptide according to claim 1 to an immunoglobulin Fc fragment.
15. A vaccine comprising the fusion protein of any one of claims 4-9, the nucleic acid molecule of claim 10 or 11, or the vector of claim 12.
16. Use of the epitope peptide of claim 1, the fusion protein of any one of claims 4 to 9, the nucleic acid molecule of claim 10 or 11, the vector of claim 12, or the cell of claim 13 for the preparation of the vaccine of claim 15.
17. Use of a fusion protein according to any one of claims 4 to 9 for the preparation of a cell according to claim 13 or a vaccine according to claim 15.
18. Use of the nucleic acid molecule of claim 10 or 11, the vector of claim 12 for the preparation of the cell of claim 13 or the vaccine of claim 15.
19. Use of the epitope peptide of claim 1, the fusion protein of any one of claims 4 to 9, the vaccine of claim 15, the nucleic acid molecule of claim 10 or 11, the vector of claim 12, or the cell of claim 13, for the manufacture of a medicament against infection by the novel coronavirus covi-19.
20. The use according to claim 19, wherein the medicament is an antibody against the novel coronavirus COVID-19.
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