CN114478719A - Dominant epitope peptide of hantavirus envelope glycoprotein, and coding gene and application thereof - Google Patents

Abstract

The invention belongs to the technical field of microbial immunity, and particularly relates to dominant epitope peptides of a group of hantaan virus envelope glycoproteins, and coding genes and application thereof. The epitope peptide consists of a sequence shown in SEQ ID NO. 1-11. The invention obtains and verifies 11 candidate epitopes by screening and verifying an antigen specificity optimization epitope prediction and identification method for HTNV GP, and then verifies by simulating molecular docking. The immunoreactivity of the epitope in different isolates around the world is subjected to deep comparative analysis so as to verify the stability of the epitope in the vaccine application. In conclusion, the invention comprehensively evaluates the pan MHC-I immunoreactivity of HTNV GP according to comparative immunology, which is helpful for understanding the immunobiology of the HTNV GP and provides guidance for developing future HTNV epitope vaccines.

Description

Dominant epitope peptide of hantavirus envelope glycoprotein, and coding gene and application thereof

Technical Field

The invention belongs to the technical field of microbial immunity, and particularly relates to dominant epitope peptides of a group of hantaan virus envelope glycoproteins, and coding genes and application thereof.

Background

Hantavirus belongs to bunyaviridae, is an enveloped segmented negative strand RNA virus that causes a common disease in both humans and animals, the renal syndrome Hemorrhagic Fever (HFRS) and Hantavirus Pulmonary Syndrome (HPS). Hantavirus (HTNV) is the major pathogen causing severe HFRS. At present, the disease occurs in more than 70 countries around the world, approximately 20000-. Thus, the high prevalence of HFRS is still considered to be a serious public health problem.

The HTNV genome consists of S, M and L3 fragments, encoding respectively the Nucleocapsid Protein (NP), the envelope Glycoprotein (GP) and the RNA-dependent RNA polymerase (RdRp). GP plays an important role in eliciting both humoral and cellular immune responses against HTNV. Meanwhile, protective immunity can be induced by vaccination with recombinant HTNV-GP in a mouse model, and the use of HTNV GP as a potent immunogen to induce T cell responses has also been demonstrated. Therefore, an immune control strategy against GP is considered as an effective method to treat and prevent HFRS caused by HTNV infection.

Activation of an anti-viral CD8+ effector T cell response requires the presentation of viral antigens by Antigen Presenting Cells (APCs) through Major Histocompatibility Complex (MHC) class I molecules. CD8+ T cells play an important role in the recognition of viral peptides against viral infections. However, only polypeptides that bind tightly with high affinity to MHC class I molecules are expressed on the surface of APC cells and presented for recognition by CD8+ T cells, thereby eliciting an immune response. Thus, epitopes with immunogenicity are crucial for elucidating antiviral immunity. Meanwhile, the role of antigen conservation is indispensable in the interaction of pathogens with hosts and in establishing population immunity. The presence of evolutionary conserved epitopes is crucial for virus survival, so vaccination with vaccines possessing conserved epitopes will be able to provide broad and long lasting protection against viruses for a long period of time, regardless of their strain.

Recently, vaccines based on epitope strategies have become one direction for alternative vaccine design and antiviral immunotherapy. By the epitope vaccine which is reasonably designed, the safety can be improved by reducing adverse reactions, a wide range of people can be covered, and the immune efficiency of the vaccine is finally improved. Therefore, screening and identifying dominant epitope peptides of HTNV GP are very important for designing epitope vaccines of hantavirus.

Disclosure of Invention

In view of the above technical problems, it is an object of the present invention to provide a group of dominant epitope peptides of hantaan virus envelope glycoprotein, which consist of the sequences shown in SEQ ID NO. 1-11.

It is another object of the present invention to provide a gene encoding the dominant epitope peptide.

The invention also aims to provide application of the dominant epitope peptide in preparing a medicament for inducing or enhancing hantavirus specific immune response.

The fourth purpose of the invention is to provide the application of the dominant epitope peptide in preparing medicines for preventing and/or treating hantavirus-related diseases or infections.

The fifth purpose of the invention is to provide the application of the gene in preparing a medicament for inducing or enhancing hantavirus specific immune response.

The invention also aims to provide application of the gene in preparing a medicament for preventing and/or treating hantavirus-related diseases or infection.

The seventh purpose of the invention is to provide a hantavirus epitope vaccine, the active ingredients of which are derived from one or more combinations of dominant epitope peptides.

The invention also provides a hantavirus epitope vaccine, and the active ingredients of the hantavirus epitope vaccine are from one or more combinations of the genes.

Compared with the prior art, the invention has the following beneficial effects:

the invention carries out a plurality of in-depth analyses on the protection property of the potential epitope derived from HTNV76-118 GP (gene number: KT885048.1) in different variants around the world by predicting the potential epitope. We predicted the binding affinity, immunogenicity and interspecies conservation of these epitopes to the appropriate sites of pan-MHC class I molecules, which would help understand the immunobiology of HTNV GP and in the future perfect epitope vaccine design against hantavirus. The dominant epitope peptides of the present invention can be viewed as viral subunits, i.e., highly conserved regions required for virosomal function, that are effective in stimulating cellular immune responses in the body. The polypeptide vaccine can be designed by the method, the aim of the strategy is to inoculate a minimum structure consisting of definite antigens to excite effective specific cellular immune response, the influence of individual difference or national region distribution characteristics on the application effect of the vaccine is theoretically overcome, and the polypeptide vaccine has incomparable advantages compared with the traditional vaccine, is safe and convenient to use and has wide application prospect in the antiviral process.

Drawings

FIG. 1.HTNV GP 9 peptide interaction with pan MHC-I subtype.

FIG. 2A chart of the affinity heatmap of HTNV GP 9 peptide with pan MHC-I subtype.

FIG. 3. docking model of inter-species selective epitopes with the corresponding MHC-I alleles.

FIG. 4 is a WebLoco map of high-frequency mutation sites.

FIG. 5 shows that 7 high-frequency mutations and mutation frequencies are involved in six high-frequency mutation sites.

FIG. 6 is a differential scattergram before and after mutation of an epitope involved in a mutation site.

Detailed Description

The invention is described in detail below with reference to the figures and the specific embodiments, but the invention should not be construed as being limited thereto. The technical means used in the following examples are conventional means well known to those skilled in the art, and materials, reagents and the like used in the following examples can be commercially available unless otherwise specified.

Example 1: obtaining dominant epitope peptide of hantavirus envelope glycoprotein

Step 1: amino acid sequence search:

glycoprotein sequences of hantavirus 76-118 (GP, gene number: KT885048.1) were obtained from the NCBI GenBank database as input for various bioinformatics tools for epitope prediction, conservation analysis, molecular docking and multiple sequence alignment.

Step 2: epitope prediction:

for mouse H2-Db, H2-Dd, H2-Kb, H2-Kd, H2-Kk and H2-Ld epitope prediction, web-based Tools such as the IEDB method (http:// Tools. IEDB. org/mhci /), SMMPMBEC method from immune epitope databases (http:// Tools. org/mhci /), NetMHCpan4.1 method (http:// www.cbs.dtu.dk/services/NetMHCpan /), SYFPEITH method (http:// www.syfpeithi.de/bin/MHCServer. dll/Epitopsedicion. htm) and Rankpep method (http:// Tools. med. um. holes. Tools/Tools. htm). The predicted epitope was selected to be the first 2% of the total predicted epitope. Finally, epitopes predicted by at least three prediction tools are selected for subsequent in-depth analysis.

Human major leukocyte antigen (HLA) -class I subtype allele epitopes such as HLA-A1 (-A0101, HLA-A2601, -A3001, -A3002), HLA-A2 (HLA-A0201, -A0203, -A0206, -A6802), HLA-A3 (HLA-A0301, -A1101, -A3001, -A3101, -A3301, -A6801), HLA-A24 (HLA-A2301, -A2402, -A3201), HLA-B7 (HLA-B0702, -B3501, -B5101, -B5301), HLA-B0802 (HLA-B080483 1), HLA-B0805 (HLA-B3875), HLA-B-A4001, HLA-B5301, HLA-B0802, HLA-B0805, HLA-B-3, HLA-A0206, -A6802, HLA-B3001, HLA-B471, HLA-B-3, HLA-B-B475, and HLA-B, -B4402, -B4403) and HLA-B58(H LA-B5701, -B5801), cumulatively covering more than 97% of the population of MHC class I subtypes, epitope prediction was performed using the same tools as described above. Finally, all the first 2% epitopes of the respective subtypes predicted by these tools were selected and subjected to subsequent studies.

For mouse MHC class I subtypes, 3 occurrences and above in 5 prediction software are considered dominant epitopes. For human HLA class I subtypes, all 9 peptides present in the first 2% of predicted outcomes were considered dominant epitopes. As described above, bioinformatic analysis was performed using a variety of computational tools to predict potential MHC class I epitopes with different binding affinities across the HTNV envelope glycoprotein. Mouse H-2 subtype (H2-Db, H2-Dd, H2-Kb, H2-Kd, H2-Kk and H2-Ld) and major HLA class I subtype alleles were analyzed. The 9-peptide affinity prediction of the HTNV envelope glycoprotein was derived from 1127 peptides. Tables 1 and 2 list the number of dominant epitopes produced by each prediction tool. After recalculation to exclude repeat 9 peptides, we obtained 83 dominant epitopes in the H-2 subtype and 229 dominant epitopes in the HLA class I subtype. Among the H-2 subtypes, H2-Db has the most dominant epitopes, and 18 peptides are used. Among HLA class I subtypes, HLA-A3 has the most dominant epitope number, and is 57 peptides 9.

TABLE 1 HLA-I dominant epitope number of HTNV GP

TABLE 2 dominant epitope of murine MHC-I of HTNV GP

Step 3: computer analysis:

3.1 clustering of 9 peptides on pan MHC:

the polymorphism of MHC-I molecules and the diversity of epitope peptide amino acid sequences form an interaction between two groups thereof. To visualize the relationship between them, affinity indices of MHC-I superfamily and HTNV GP related peptides were bi-directionally hierarchical clustered using TBtools. After the affinity ranking data were processed with base 2 logarithm and Z-Score, two-way hierarchical clustering of Euclidean distances was performed using Complete method. And analysis showed that the higher the score, the stronger the affinity of the peptide for MHC-I molecules. Analysis contained 33 pan MHC-I molecules interacting with 1127 HTNV GP epitopes, shown by heat mapping.

FIG. 1 shows the differences between different MHC I subtypes. The 33 MHC class I molecules were divided into 3 groups, including HLA class I subtype group and cross-reactive group (HLA major), cross-reactive group (H2 major). In the HLA I subtype group, HLA-A3001, although belonging to HLA-A1 super family, has a score more similar to HLA-A3(-A0301, -A1101, -A3101, -A3301, -A6801), suggesting that HLA-A3001 genotype exhibits HLA-A3-like characteristics in presentation of HTNV GP antigen; the scores of four genotypes in HLA-A2(-A0201, -A0203, -A0206, -A6802) are similar; HLA-B7(-B3501, -B5301) has similar antigen presentation results to HLA-A1(-A2601, -A0101); HLA-A1(-A3002), HLA-B15(-B1501), HLA-A3201 and HLA-B58(-B5701, -B5801) have similar antigen presentation results. For the cross-reactive group (H2 predominant), H2-Ld scores were similar to HLA-B7(-B0702, -B2101); H2-Kd scores were similar to HLA-A24(-A2301, -A2402); the H2-Db, H2-Dd, and H2-Kb scores reflect the similarity of presenting HTNV GP in murine species. In the cross-reactive cluster (HLA major), the H2-Kk score was similar to HLA-B44(-B4001, -B4402, -B4403).

3.2 binding affinity assay:

heatmaps were drawn to show regional affinities based on the affinity ranking between HTNV 9 peptide and different MHC-I molecules (fig. 2). The GP of HTNV76-118 derived 1127 single residue push-in 9 peptides over a 1135 amino acid distribution, data from the NetMHCPAN4.1 ranking, with columns of the heatmap labeled with the MHC-I subtype and rows labeled with the epitope. The graph shows a single gradient, the smaller the% Rank, the darker the color.

As can be seen from the figure, the epitope binding strength is generally regionally distributed. The affinity was good in the range of No.134-No.162, No.184-No.205, No.212-No.214, No.438-No.456, No.495-No.499, No.791-No.793, No.922-No.926, No.955-No.996, No.1057-No. 1104. However, the different subtypes of No. 759-780, No. 800-815, No. 953-982, No. 988-1010, No. 1040-1047 showed poor binding ability. The dominant epitope region of HLA-A is most concentrated, and the dominant epitope region of H2 has better coverage than HLA-B subtype. Thus the overall coverage of the HTNV GP-derived 9 peptide with good affinity for different MHC-I subtypes is HLA-A2> HLA-A1> HLA-A3> HLA-A24> H2> HLA-B7> HLA-B58> HLA-B15 and HLA-B44. The pan MHC-I dominant epitope falls mostly on the high affinity 9 hot spots.

3.3. Immunogenicity analysis:

high affinity peptides may not be able to adequately induce an immune response. In addition to being immunoreactive, the antigen should also be immunogenic. Therefore, we performed an immunogenicity analysis of all GP 9 peptide epitopes. The immunogenicity of the 9 peptide epitope was calculated by VaxiJen2.0(http:// www.ddg-pharmifac. net/VaxiJen/Vaxijen. html). Peptides were considered immunogenic with a score >0.5 as a positive criterion, otherwise non-immunogenic.

The results are shown in table 3, 551 out of 1127 HTNV GP 9 peptide epitopes are immunogenic. Specifically, 124 out of 229 dominant epitopes of the HLA-I subtype were considered immunogenic peptides, and 39 of 83 dominant epitopes of the H2 subtype were immunogenic.

TABLE 3HTNV GP MHC-I immunogenicity of the restricted dominant epitopes

3.4. Conservation assay

To determine the degree of evolutionary conservation of the dominant epitope in the sequence of the virus species, a conservation analysis was performed on the predicted high affinity 9 peptide using the BLASTP tool. Wherein, except for the hantavirus (taxi: 1980471), the rest of the evaluation criteria of interspecies conservation are the orthohantavirus (taxi: 1980442); the criterion for intra-species conservation was Hantaan virus (taxid: 1980471), except for Hantaan virus (strain 76-118) (taxid: 11602). In the analysis result, if the E value<10^-5Peptide sequences that are conserved between HTNV and human (taxi: 9606) or mouse (taxi: 10088) are excluded and considered conserved. Dominant epitopes can therefore be classified into 4 classes according to conservation: interspecific-intraspecific-, interspecific-intraspecific +, interspecific + intraspecific-, and interspecific + intraspecific +.

Table 4 lists the statistical results of the conservation analysis of all dominant epitopes. The conserved HLA-I restriction dominant epitope is more than the H-2 restriction dominant epitope. The reason may be that HLA-I summarizes the results of multiple MHC-I superfamilies, and the identification of the H2 restricted epitope requires the 3/5 algorithm to satisfy 6 subtypes. At the same time, the results show stronger intraspecies conservation and weaker interspecies conservation of the dominant epitope.

TABLE 4 HTNV GP MHC-I conservation of the restricted dominant epitope

Example 2: application of dominant epitope peptide of hantavirus envelope glycoprotein

The invention lays a foundation for the research of novel HTNV genetic engineering vaccines by predicting dominant MHC I epitope peptide on HTNV GP and analyzing various computers.

Step 1: peptide-MHC molecule docking

HPEPDOCK is a novel network server, and can simulate molecule docking by inputting a 9-peptide dominant epitope sequence and an MHC class I molecule RDB format file, so that a docking model is obtained. Relevant MHC class I molecule 3D structural data { HLA-A1[ HLA-A0206 (3OXR) ], HLA-B7[ HLA-B0702 (5EO1), HLA-B3501 (1A9E), HLA-B5101 (1E28), HLA-B5301 (1A1N) ], HLA-B8[ HLA-B QR 0801 (4P) ], HLA-B15[ HLA-B1501 (1XR9), HLA-A0101 (4NQV) ], HLA-B44[ HLA-B4402 (3KPL) ], H2-Ld (6L M), H8-686 Kb (6JQ 356), and H3573742 (DKP27). Docking of each 9 peptide with the same MHC class I molecule resulted in 100 mock docking structures, but the top 10 mock docking structures were considered the most important predictors in silico.

The results are shown in FIG. 3, where we can observe the ubiquitous genotype, superfamily, population, and even cross-species immunological cross-reactivity of HTNV GP-derived 9 peptide epitopes in MHC-I. Computer simulation verification is carried out through docking of the 11 dominant epitopes with human and mouse MHC-I molecules, and the first ten simulated docking modes and docking scores are obtained. Lower scores indicate better peptide-MHC docking performance. The results show that the docking scores of the 9 epitopes shown in SEQ ID NO.1-9 are lower, namely the docking performance of the 9 epitopes in HLA-I subtype is better than that of mouse H-2 subtype. In contrast, the 2 epitopes shown in SEQ ID NO.10-11 may have better docking performance with the mouse H-2 subtype.

Step 2: sequence alignment of HTNV variants

Based on the HTNV76-118 strain, we performed multiple sequence alignments of the hot spots of 148 variants using ClustalX2.1 and analyzed the alignment results on WebLoo (http:// webbloo. bergeley. edu/logo. cgi). The height of the letters in the WebLogo plots represents the frequency of amino acid mutants between different variants. Based on the alignment, all 9 relevant polypeptides (finger mutated residues) were further analyzed for affinity changes using HLA-I molecules. TBtools were heatmapped to delta values for binding affinities of 76-118 to corresponding HLA-I and 9 peptide epitope variants, where the binding affinities were logarithmized to base 2. If the value of delta is negative, it indicates that the HTNV76-118 strain has better epitope avidity. Conversely, a positive value indicates a better affinity for the mutated epitope.

Thereafter, a scattergram was made using Origin 2021(Origin lab, USA) with the affinity for GP epitope of HTNV76-118 strain as abscissa and the affinity for GP epitope of the variant strain as ordinate. Finally, dominant epitopes were predicted and analyzed for all mutated 9 peptides to determine if amino acid mutations altered epitope dominance.

From the affinity heatmap we obtained 9 pan MHC HTNV GP peptides with high affinity. Based on these 9 high affinity peptides, sequence comparisons were made between the HTNV76-118 strain and the other 147 variant strains. Through comparison results, we found 4 peptides with high-frequency mutations in the 9 high-affinity peptides (fig. 4), which involved 6 high-frequency mutation sites (fig. 5), 7 mutations (I222L, I502L, I502V, V996L, I1073M, S1076N, and I1088V), and the mutation frequencies were I222L 39.189%, I502L 27.702%, I502V 9.459%, V996L 35.135%, I1073M 39.864%, S1076N 25.676%, and I1088V 27.027.027%, respectively.

FIG. 6 further shows the difference between before and after the epitope mutation related to the above 6 mutation sites. The horizontal axis represents the affinity of the HTNV GP 9 peptide, base 2 logarithm, and the vertical axis represents the affinity in the variant, likewise base 2 logarithm. Different colors represent different HLA types and different shapes represent different mutations. Each dot in the scatter plot represents a nonapeptide epitope and the dots in the gray region represent the first 2% affinity ranking for the epitope. The closer the point is to the straight line y-x, the closer the affinity between HTNV strain 76-118 and the variant. As can be seen from the figure, the epitope in aa214-aa230 has the largest difference before and after mutation, and 7 epitopes are not 2% before mutation, but enter 2% after mutation; there were 1 epitope that was the top 2% of the rank before mutation, but not the top 2% after mutation. Suggesting that mutations of HTNV have less effect on the affinity of the selected epitope, and even that mutations have a promoting effect on the affinity of the epitope.

The research shows that: the dominant MHC I epitope peptide on HTNV GP has high affinity, immunogenicity and interspecies conservation. Meanwhile, a possible docking model is simulated by molecular docking, and the docking model can play a better role in coping with hantavirus variation.

In recent years, although inactivated vaccines related to HTNV have been developed at home and abroad, from the application point of view, the vaccines still have a plurality of defects, and the most important point is that the inactivated vaccines rarely cause cellular immune response or long-term memory, so that the effectiveness is impaired. If the dominant MHC I epitope peptide on the HTNV GP screened by the method is applied to the stimulation of the cellular immune response reaction of an organism, the dominant MHC I epitope peptide has the following advantages:

1. following viral infection, Antigen Presenting Cells (APCs) activate CD8+ T cells by presenting antigenic peptides through MHC class I molecules. In the case of MHC class I molecules, the antigen binding groove is blocked at both ends by conserved tyrosine residues, resulting in the size of the bound peptide being generally limited to 8-10 amino acid residues. Therefore, we selected a9 amino acid peptide as the predicted epitope. At the same time, the cellular immune response mediated by CTL plays an important role in combating viral infections. After the CTL recognizes virus infected cells (target cells), the target cells are cracked and killed by releasing perforin and granzyme and passing through the FasL-Fas pathway, so that the effect of effectively removing virus infected cells in an organism is achieved. The level of a certain virus-specific CTL in the organism and the activity thereof are positively correlated with the virus-removing effect.

2. Neutralizing antibodies specifically bind to the virus and prevent it from infecting host cells, but for already infected host cells, CD8+ T cells are required to exert a cytotoxic effect to clear the virus of intracellular infection.

3. Peptide prediction methods were used to predict the binding affinity of each 9 peptides to specific MHC class I molecules. Currently, there are many different principles for algorithms for predicting peptide affinity, and therefore we use a variety of prediction methods to predict polypeptides with stronger binding affinity. At the same time, we performed an immunogenicity analysis on all predicted 9 peptides to eliminate high affinity non-immunogenic epitopes.

4. More of the previous studies were in the HLA-a x 02 subtype. In this patent, we predicted 33 MHC class I genotypes, including 27 human genotypes and 6 murine genotypes. It can be said that our selective epitopes have pan-MHC-I reactivity, overcoming MHC-I molecular differences caused by population and regional distribution. The immune effect can be generated among different races in different regions, which is beneficial to obtaining more broad-spectrum and more effective population immunity.

5. After the conservation analysis between Hantaan virus species and in-species is carried out on the dominant epitope of the 9 peptide, the dominant epitope can be simply classified. Compared with other epitopes, the dominant epitope conserved in interspecies is more suitable for vaccine development and immune research. The interspecies conservation dominant mouse epitope and corresponding mouse MHC class I and human HLA class I molecules are subjected to simulated docking, and immune docking effects are generated.

6. Sequence alignment and affinity analysis of the HTNV76-118 strain and the 147 variants suggest that mutations in HTNV have less effect on the affinity of the selected epitope, and even that mutations have a promoting effect on the affinity of the epitope. The dominant epitope is applied to the development and application of the epitope vaccine, and the stability of the effect of the epitope vaccine is improved.

In the partial research, the method of bioinformatics is used for carrying out polypeptide affinity prediction, immunogenicity analysis and conservation analysis on HTNV GP, and carrying out butt simulation and variation comparison on polypeptide and MHC class I molecules, so that another idea is provided for the subsequent research on relevant immunology of hantaviruses, and the method is helpful for designing epitope-based anti-HTNV epitope vaccines in the future. Meanwhile, the method for predicting the high-affinity peptide and carrying out subsequent correlation analysis can also be used for basic immunity research and infectious disease prevention and control of other pathogens. Furthermore, epitope prediction has also been documented as being useful in the treatment and intervention of cancer.

While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

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Claims (8)

1. A group of dominant epitope peptides of hantavirus envelope glycoprotein is characterized in that the epitope peptides consist of sequences shown in SEQ ID NO. 1-11.

2. A gene encoding the dominant epitope peptide of claim 1.

3. Use of the dominant epitope peptide of claim 1 for the manufacture of a medicament for inducing or enhancing a hantavirus-specific immune response.

4. Use of the dominant epitope peptide of claim 1 for the preparation of a medicament for the prevention and/or treatment of hantavirus-related diseases or infections.

5. Use of the gene of claim 2 for the preparation of a medicament for inducing or enhancing a hantavirus-specific immune response.

6. Use of the gene of claim 2 for the preparation of a medicament for the prevention and/or treatment of hantavirus-related diseases or infections.

7. A hantavirus epitope vaccine comprising as an active ingredient a combination of one or more dominant epitope peptides of claim 1.

8. A hantavirus epitope vaccine comprising as active components a combination of one or more of the genes of claim 2.

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