37 results about "Tuberculosis vaccines" patented technology

Provided herein are nucleic acid vaccine constructs comprising synthetic polynucleotides encoding a Mycobacterium tuberculosis (Mtb) RelA-SpoT homolog (RSH) protein, RelMtb, or a functional portion, fragment, or variant thereof, conjugated to a macrophage inflammatory protein-3 alpha (MIP-3α) or other chemokine that binds to a chemokine receptor 6 (CCR6), or a functional portion, fragment, or variant thereof, or to an antibody, or antigen binding portion thereof, that binds to a CCR6. Methods for making the vaccine constructs and their use in prophylaxis and treatment of Mtb infections are also provided.

The invention relates to the technical field of biological medicines, in particular to a tuberculosis vaccine antigen and a vaccine. In particular to application of a mycobacterium tuberculosis Rv1787 gene in preparation of a vaccine for preventing and / or treating tuberculosis, in the application, the sequence of the Rv1787 gene or an encoding product thereof is defined, and the Rv1787 gene and the encoding product thereof serve as antigens, have mycobacterium tuberculosis specificity, and can be used for preparing a vaccine for preventing and / or treating tuberculosis. According to the mycobacterium tuberculosis vaccine, identification and response of an organism immune system to mycobacterium tuberculosis can be accurately stimulated, non-specific immune response to other normal tissues is avoided, a brand new and specific molecular target spot is provided for preventing and treating tuberculosis, and the limitation that a traditional vaccine depends on a single antigen or an attenuated strain is broken through. A specific expression product of the gene can stimulate directional recognition and attack of an organism immune system on mycobacterium tuberculosis, the pertinence and effectiveness of vaccines are remarkably improved, and a new path is provided for solving the problem of tuberculosis prevention and treatment.

Disclosed are an mRNA pharmaceutical composition for preventing and treating tuberculosis and use thereof. The mRNA pharmaceutical composition comprises: an mRNA molecule encoding a Mycobacterium tuberculosis antigen, and a pharmaceutically acceptable excipient. The Mycobacterium tuberculosis antigen comprises the following antigen components: at least one early-secreted antigen of Mycobacterium tuberculosis or an immunologically active fragment thereof; PE / PPE family antigen WAG22 of Mycobacterium tuberculosis or an immunologically active fragment thereof; and at least one latent-related antigen of Mycobacterium tuberculosis or an immunologically active fragment thereof. The mRNA pharmaceutical composition does not comprise or further comprises an mRNA molecule encoding a cytokine. The pharmaceutical composition is used for preparing a tuberculosis vaccine, which may serve as a prophylactic vaccine for preventing latent activation or as a therapeutic drug for treating active tuberculosis, exhibiting a significant inhibitory effect on Mycobacterium tuberculosis.

The invention provides an mRNA (messenger ribonucleic acid) pharmaceutical composition for preventing and treating tuberculosis and application of the mRNA pharmaceutical composition. The mRNA pharmaceutical composition for preventing and treating tuberculosis comprises mRNA molecules for coding mycobacterium tuberculosis antigens and pharmaceutically acceptable auxiliary materials, the mycobacterium tuberculosis antigen comprises the following antigen components: at least one mycobacterium tuberculosis early secretion antigen or an immunocompetence fragment thereof; a mycobacterium tuberculosis PE / PPE family antigen Rv3872 or an immunocompetence fragment thereof; and at least one mycobacterium tuberculosis latent associated antigen or an immunocompetent fragment thereof; the mRNA pharmaceutical composition does not include or further includes an mRNA molecule encoding a cytokine. The pharmaceutical composition provided by the invention is used for preparing tuberculosis vaccines, can be used as a prophylactic vaccine for preventing latent activation, can also be used as a therapeutic drug for treating active tuberculosis, and has a remarkable inhibition effect on mycobacterium tuberculosis.

The application belongs to the technical field of biological medicine, and particularly relates to a non-classical IFN-gamma-dependent mycobacterium tuberculosis peptide epitope P15, a coding sequence and application thereof, and an anti-tuberculosis vaccine. The amino acid sequence of the mycobacterium tuberculosis peptide epitope P15 is shown as SEQ ID NO. 1. The application is found through research that the mycobacterium tuberculosis peptide epitope P15 has good immunogenicity, in-vivo immunity has a significant anti-tuberculosis protection effect, and the protection effect is not dependent on the host cell IFN-gamma response, and can be used as an ideal target antigen of a tuberculosis vaccine, and is made into an epitope vaccine, and has a good application prospect.

The invention relates to the field of vaccines, in particular to application of a bacillus calmette-guerin vaccine and a complete freund's adjuvant in preparation of tuberculosis prevention vaccines. The invention provides a novel inoculation strategy of subcutaneous combined inoculation of the bacillus calmette guerin vaccine and the complete freund's adjuvant, the safety consistent with that of the existing tuberculosis prevention vaccine in the clinical stage is achieved, and the immune protection effect higher than that of the existing tuberculosis prevention vaccine in the clinical stage and the preclinical research stage is achieved. The compound is expected to be used as a novel tuberculosis vaccine for preventing tuberculosis.

The invention is applicable to the field of gene engineering, and provides a mycobacterium tuberculosis Ag85B-TB8.4-LS protein nanoparticle, a preparation method and application thereof, the mycobacterium tuberculosis Ag85B-TB8.4-LS protein nanoparticle is formed by sequence fusion of mycobacterium tuberculosis Ag85B protein, TB8.4 protein and LS protein, and the amino acid sequence of the mycobacterium tuberculosis Ag85B-TB8.4-LS protein nanoparticle is shown as SEQ ID NO: 2 in a sequence table. According to the invention, by virtue of a gene recombination technology, key immunogens Ag85B and TB8.4 of mycobacterium tuberculosis are combined with an LS protein fusion vector, and the Ag85B-TB8.4-LS protein nanoparticles with uniform particle size and stable structure are efficiently produced by virtue of an escherichia coli expression system. Animal experiment results show that the Ag85B-TB8.4-LS protein nanoparticle can simultaneously excite strong humoral immunity and cellular immunity response, not only brings a new idea for research and development of tuberculosis vaccines, but also can be popularized and applied to research and development of other infectious disease vaccines due to the modular design, and has important scientific significance and industrialization prospects.

The invention discloses a composite milk adjuvant, a preparation method and application of the composite milk adjuvant in vaccines, and belongs to the technical field of medicines. The technical problems to be solved are relatively weak cell immunocompetence, relatively poor immunogenicity and relatively weak immunoregulation capability. According to the technical scheme, squalene, polyoxyethylated castor oil 35 and poloxamer 407 are used as raw materials to prepare a basic formula of the milk adjuvant, an immunologic stimulant is added on the basis to prepare the composite milk adjuvant, and the physicochemical properties and safety of the composite milk adjuvant are represented. The synergistic effect of the milk adjuvant on humoral immunity and cellular immunity is further evaluated by being matched with a recombinant tuberculosis antigen Ag85B to immunize mice, and data support is provided for application of the milk adjuvant in development of novel vaccines such as tuberculosis vaccines and the like. The composite milk adjuvant prepared by the invention not only keeps good humoral immunity and induces generation of high-level IgG1 and IgG2a, but also remarkably improves the response level of cellular immunity.

The invention relates to the technical field of tuberculosis vaccines, in particular to a tuberculosis VLP nanoparticle vaccine and preparation and application thereof. According to the tuberculosis VLP nanoparticle vaccine, through up-regulation of Th1 type, Th2 type and TH17 type cellular immune response and down-regulation of Treg cellular immune response, the H37Rv growth inhibition ability of splenic lymphocytes and lung cells in vitro is enhanced, and the cellular immune response induced by EPPE + mi3 / AS01E and the H37Rv growth inhibition ability of the cells in vitro are higher than those of BCG and a corresponding subunit vaccine EPPE / AS01E; in addition, the EPPE + mi3 / AS01E can be used as a BCG booster vaccine, and the cell immune response after BCG immunization and the H37Rv growth inhibition capacity of cells in vitro are improved.

The invention discloses a Mycobacterium tuberculosis epitope mRNA (messenger Ribonucleic Acid) vaccine simulated, predicted and screened by a computer, which is prepared by the following steps: bacterial protein sequence acquisition and signal peptide analysis: acquiring amino acid sequences of proteins ESAT6, CFP10, Ag85A, Ag85B, TB10.4, PPE68, PPE18 and Rv1813c through a database; the method comprises the following steps: analyzing physicochemical properties of proteins, including the number of amino acids, the molecular weight, the instability index and the overall average value of water solubility, analyzing and predicting the allergy of the epitopes by using a server, and generating all potential mutants by using the server to predict and measure the toxicity of the epitopes; the multi-epitope mRNA vaccine candidate is successfully constructed by adopting computer simulation screening and optimization of the mycobacterium tuberculosis multi-epitope antigen, the vaccine design scheme is efficient, controllable and broad-spectrum, a theoretical basis and a candidate construct are provided for early research and development of tuberculosis vaccines, and the vaccine is expected to be used for prevention and control of tuberculosis and has positive influence on public health.

The invention is applicable to the field of gene engineering, and provides a mycobacterium tuberculosis Ag85B-LS protein nanoparticle, a preparation method and application thereof, the mycobacterium tuberculosis Ag85B-LS protein nanoparticle is formed by sequence fusion of mycobacterium tuberculosis Ag85B protein and LS protein, and the amino acid sequence of the mycobacterium tuberculosis Ag85B-LS protein nanoparticle is shown as SEQ ID NO: 2 in a sequence table. The Ag85B-LS protein nanoparticles with uniform particle size and stable structure are efficiently prepared through an escherichia coli expression system. Animal experiments prove that the Ag85B-LS protein nanoparticles can simultaneously activate strong humoral immune and cellular immune responses, and the technical platform provides a new thought for research and development of tuberculosis vaccines, and has important scientific value and industrialization potential.

The present application provides a tuberculosis vaccine based on bovine beta defensin 5 and its application in preventing tuberculosis, which comprises a fusion protein of tuberculosis AH antigen and bovine beta defensin 5 or a coding sequence thereof. The present application fuses and expresses Ag85A and HspX, which are surface dominant antigens of Mycobacterium tuberculosis, and an optimized sequence of bovine beta defensin 5, and then purifies the protein to mix with poly I:C to prepare a fusion protein vaccine AHB-P. Or the coding sequence of the fusion gene is optimized and then connected to a vector pVAX1 to prepare a fusion DNA vaccine pVAX1-AHB. The respiratory mucosa of mice is immunized with the two fusion vaccines, and it is proved that the two fusion vaccines can enhance the body's resistance to tuberculosis infection.

An mRNA pharmaceutical composition for preventing and treating tuberculosis and use thereof. The mRNA pharmaceutical composition comprises: an mRNA molecule encoding a Mycobacterium tuberculosis antigen, and a pharmaceutically acceptable excipient. The Mycobacterium tuberculosis antigen comprises the following antigen components: at least one Mycobacterium tuberculosis early-secreted antigen or an immunologically active fragment thereof; Mycobacterium tuberculosis PE / PPE family antigen Rv3872 or an immunologically active fragment thereof; and at least one Mycobacterium tuberculosis latency-associated antigen or an immunologically active fragment thereof. The mRNA pharmaceutical composition does not comprise or further comprises an mRNA molecule encoding a cytokine. The pharmaceutical composition is used for preparing a tuberculosis vaccine, which can be used not only as a prophylactic vaccine for preventing latency activation, but also as a therapeutic drug for treating active tuberculosis, and has a significant inhibitory effect on Mycobacterium tuberculosis.

The invention provides an application of a mycobacterium tuberculosis antigen Rv1471 in preparation of drugs or vaccines for preventing and / or treating diseases caused by mycobacterium infection. In a cell model, the antigen Rv1471 can promote the maturation of phenotypes and functions of macrophages, and also can mediate training immunity. On the basis, a subunit protein vaccine for expressing the antigen Rv1471 is further constructed. In a mouse immune model, the immunogenicity of the subunit protein vaccine expressing the antigen Rv1471 in a mouse which is not immunized by BCG is measured, and the subunit protein vaccine can promote antigen-specific T cell immune response. In a cell model and an acute infection mouse model, the antigen Rv1471 can provide an effective protection effect against mycobacterium tuberculosis infection. Therefore, the antigen Rv1471 and the subunit vaccine thereof are expected to become a novel preventive / therapeutic tuberculosis vaccine.

The invention provides an mRNA (messenger ribonucleic acid) pharmaceutical composition for preventing and treating tuberculosis and application of the mRNA pharmaceutical composition. The mRNA pharmaceutical composition for preventing and treating tuberculosis comprises mRNA molecules for coding mycobacterium tuberculosis antigens and pharmaceutically acceptable auxiliary materials, the mycobacterium tuberculosis antigen comprises the following antigen components: at least one mycobacterium tuberculosis early secretion antigen or an immunocompetence fragment thereof; at least one Mycobacterium tuberculosis PE / PPE family antigen or an immunologically active fragment thereof; and at least one mycobacterium tuberculosis latent associated antigen or an immunocompetent fragment thereof; the mRNA pharmaceutical composition does not include or further includes an mRNA molecule encoding a cytokine. The pharmaceutical composition provided by the invention is used for preparing tuberculosis vaccines, can be used as a prophylactic vaccine for preventing latent activation, can also be used as a therapeutic drug for treating active tuberculosis, and has a remarkable inhibition effect on mycobacterium tuberculosis.

An mRNA pharmaceutical composition for preventing and treating tuberculosis and use thereof. The mRNA pharmaceutical composition comprises: an mRNA molecule encoding a Mycobacterium tuberculosis antigen, and a pharmaceutically acceptable excipient. The Mycobacterium tuberculosis antigen comprises the following antigen components: at least one Mycobacterium tuberculosis early-secreted antigen or an immunologically active fragment thereof; at least one Mycobacterium tuberculosis PE / PPE family antigen or an immunologically active fragment thereof; and at least one Mycobacterium tuberculosis latency-associated antigen or an immunologically active fragment thereof. The mRNA pharmaceutical composition does not comprise or further comprises an mRNA molecule encoding a cytokine. The pharmaceutical composition is used for preparing a tuberculosis vaccine, which can be used not only as a prophylactic vaccine for preventing latency activation, but also as a therapeutic drug for treating active tuberculosis, and has a significant inhibitory effect on Mycobacterium tuberculosis.

The Mtb protein Rv2140c, specific peptide epitopes derived, and polynucleotide sequences encoding such polypeptides are disclosed herein as a useful TB antigen for generating a protective immune response to development of tuberculosis. In some embodiments the Rv2140c polypeptide or polynucleotide is formulated as a vaccine. In some embodiments the Rv2140c vaccine is administered to a naïve recipient. In some embodiments the Rv2140c vaccine is administered as a booster to a previously vaccinated to exposed individual. In some embodiments the previous vaccination is a BCG vaccination.

An mRNA tuberculosis vaccine, a preparation method therefor, and a use thereof. An antigen, comprising the following antigen components: a fusion protein or chimeric protein formed by at least one of Mycobacterium tuberculosis early-secreted antigens Ag85a, Ag85b and / or an immunologically active fragment thereof, at least one Mycobacterium tuberculosis PE / PPE family antigen Rv1759c or an immunologically active fragment thereof, and at least one Mycobacterium tuberculosis latency-associated antigen Rv1813c or an immunologically active fragment thereof.

The invention describes a recombinant Mycobacterium strain such as M. smegmatis that is recombinantly converted to express the M. tb complex ESX protein expression system, e.g. M. tb complex ESX-1 protein expression system. The recombinant strain exports virulence effector proteins (such as EspA, EspB, EspC, EsxA or EsxB) similar to M. tb, when administered to a subject, and is therefore useful as a potential tuberculosis vaccine candidate. The recombinant strain is non-pathogenic and the vaccinated subject does not give a false positive result when tested with any standard tuberculosis diagnostic test e.g. CCT, as the recombinant strain does not sensitize the vaccinated host to M. tb antigens or protein derivate of M. bovis.

The invention relates to the technical field of preparation of tuberculosis vaccines, in particular to preparation and application of a VLP vaccine APEH + mi3 + AS01E for enhancing BCG immunity. The preparation method comprises the following steps: mixing Ag85B-mi3, PPE33-mi3, ESAT-6-mi3 and HSPX-mi3 to obtain multivalent nanoparticles, and fully emulsifying the multivalent nanoparticles and an AS01E adjuvant to obtain the VLP vaccine APEH + mi3 + AS01E. After the VLP vaccine APEH + mi3 + AS01E provided by the invention is immunized, strong Th1 type, Th2 type and Th17 type cellular immune responses are induced; after H37Rv challenge, the immune response of Th1 type, Th2 type and Th17 type cells induced by the multivalent mi3VLP vaccine is stronger than that of BCG, and the Mtb H37Rv infection resistance is slightly higher than that of BCG; the vaccine is used as a BCG reinforcing vaccine, and can effectively reinforce the short-term protective immune response of the BCG and the anti-tubercle bacillus protection effect.

An mRNA tuberculosis vaccine, a preparation method therefor, and a use thereof. First, provided is an antigen, comprising the following antigen components: a fusion protein or chimeric protein formed by at least one Mycobacterium tuberculosis early secreted antigen Ag85a, Ag85b and / or an immunologically active fragment thereof, at least one Mycobaterium tuberculosis PE / PPE family antigen Rv3872 (PE35) or an immunologically active fragment thereof, and at least one Mycobacterium tuberculosis latency-associated antigen Rv1813c or an immunologically active fragment thereof; selectively, two or more of these antigens or immunologically active fragments thereof can form a fusion protein and / or a chimeric protein as antigen components. By means of multiple antigen components, mRNA vaccines are more effective in preventing tuberculosis.

The invention relates to the technical field of preparation of tuberculosis vaccines, in particular to preparation of a novel tuberculosis nanoparticle vaccine Rv1794 + mi3 as well as adjuvant screening and application of the novel tuberculosis nanoparticle vaccine Rv1794 + mi3. After a mouse is immunized by the Rv1794 + mi3, the immune response reaction of H37Rv infected cells and the anti-tubercle bacillus H37Rv infection capability are stronger than those of a single antigen Rv1794 immunization; the vaccine Rv1794 + mi3 + AS01E is used for immunizing mice to induce immune response to H37Rv infected cells, and the anti-tubercle bacillus H37Rv infection capability is higher than that of vaccines Rv1794 + mi3, Rv1794 + mi3 + AS04D and Rv1794 + mi3 + MF59; the adjuvant nanoparticle vaccine Rv1794 + mi3 + AS01E is used as a BCG booster vaccine, and the short-term cellular immune response reaction induced by BCG immunity and the anti-tubercle bacillus H37Rv infection capability are synergistically increased.

This invention relates to a tuberculosis vaccine composition comprising a fusion protein that induces sterilization immunity against Mycobacterium tuberculosis. Specifically, the tuberculosis vaccine composition comprising a fusion protein of Rv2299cD2D3-ESAT6-Ag85B (REA) or Rv2299cD2D3-Rv3463-Ag85B (RRA) induces sterilization of Mycobacterium tuberculosis by more than 99%, thereby enabling it to be used not only for the prevention of tuberculosis in adults but also as a vaccine for infants and young children.

The invention discloses preparation and application of a novel mycobacterium tuberculosis subunit vaccine LK35. The mycobacterium tuberculosis subunit vaccine is composed of fusion protein LK35 and a DP adjuvant. The fusion protein LK35 is prepared by sequentially connecting EsxL, EsxK and Rv2656c with one another. The invention also provides a preparation method of the fusion protein. The subunit vaccine can be used as a preventive vaccine for diseases related to mycobacterium tuberculosis / environmental mycobacterium, and can also be used as a therapeutic vaccine after mycobacterium tuberculosis / environmental mycobacterium infection. The vaccine immunized mice can provide good antigen-specific immune response, and the vaccine combined with fusion proteins LT20, LT57 and LT28 can provide effective long-term protective efficacy against mycobacterium bovis. Therefore, the subunit vaccine involved in the invention is expected to become a novel tuberculosis vaccine, and has good application and development prospects.

The present invention belongs to the field of vaccine technology, and specifically relates to a self-assembled ferritin nanoparticle recombinant protein SFT, a preparation method thereof, and an application thereof. The recombinant protein SFT is self-assembled from the SpyCatcher003-Fer protein and the SpyTag003-TB10.4 protein. The tuberculosis vaccine prepared using the self-assembled ferritin nanoparticle recombinant protein SFT of the present invention, compared with monomeric TB10.4, significantly increased the level of lymphocyte proliferation after subcutaneous immunization with SFT without the aid of an adjuvant, and has the ability to induce T cell activation and can stimulate a variety of TB-related cytokines. These results show that SFT is significantly superior to traditional recombinant proteins and vaccines, which helps to broaden the types of new tuberculosis candidate vaccines and provide a nanoparticle capture platform for other tuberculosis antigens in the future.

The invention relates to the technical field of preparation of tuberculosis vaccines, in particular to preparation and application of a novel anti-tuberculosis mi3VLP nanoparticle vaccine. The preparation method comprises the following steps: mixing ESAT-6-mi3, PPE68-mi3, ESPC-mi3 and Rv1794-mi3 to obtain multivalent nanoparticles, and fully emulsifying the multivalent nanoparticles and an AS01E adjuvant, so as to obtain the mi3VLP nanoparticle vaccine. The multivalent nanoparticle vaccine enhances the ability of short-term cell in-vitro H37Rv growth inhibition; the multivalent nanoparticle vaccine EPER + mi3 + AS01E can be used as a BCG (Bacillus Calmette-Guerin) booster vaccine, and the cellular immune response reaction induced after BCG immunization and the anti-tubercle bacillus H37Rv infection capability are improved.

The application discloses a preparation method of a mycobacterium bovis polysaccharide antigen, the polysaccharide antigen is a glycosyl part of a phenolic glycolipid PGL in a cell wall of mycobacterium bovis, the polysaccharide antigen has a clear and single chemical structure, can be prepared in a large scale and efficiently through a chemical synthesis method, and effectively solves problems of a complex natural extraction process, non-uniform structure, limited yield and the like. The polysaccharide antigen can be used as a core immunogen and is used for preparation of a mycobacterium PGL polysaccharide conjugate vaccine, provides a stable and controllable key raw material for tuberculosis vaccine research and development, and has a good industrial application prospect.

Provided are a BCG recombinant strain ΔBCG_1820 in which BCG_1820 gene is knocked out, a preparation method therefor, and the use thereof in preparing a tuberculosis vaccine. The BCG recombinant strain ΔBCG_1820 can induce macrophages to produce more antibacterial peptides, so as to endow a host with a stronger capability to resist tubercle bacillus infection, and has the potential to be a candidate vaccine for tubercle bacillus.

The invention provides a genetically modified tubercle bacillus strain as well as a preparation method and application thereof, the strain is tubercle bacillus obtained by knocking out virulence-related genes by adopting a genetic engineering method and simultaneously supplementing and enhancing immunogenicity antigen genes, and can be used for preparing attenuated live vaccines. The attenuated live vaccine prepared by using the strain has lower adverse reaction rate and stronger immunogenicity, and can be used for replacing a bacillus calmette guerin vaccine or a booster vaccine. Moreover, the DTH reaction caused by vaccination or infection can be identified through TBST (based on Mycobacterium tuberculosis antigen skin test) by using the vaccine prepared by the strain, and the strain has important application in tuberculosis vaccine production.

The application relates to the technical field of biological medicine, in particular to a tuberculosis vaccine antigen and a vaccine. Specifically, the application provides an application of a mycobacterium tuberculosis Rv1787 gene in preparation of a vaccine for preventing and / or treating tuberculosis, and the application is characterized in that the sequence of the Rv1787 gene or a coded product thereof is determined, wherein the Rv1787 gene and the coded product thereof are used as antigens, have mycobacterium tuberculosis specificity, can precisely stimulate the immune system of the body to recognize and respond to the mycobacterium tuberculosis, avoid non-specific immune reactions to other normal tissues, provide a new specific molecular target for preventing and treating tuberculosis, and break through the limitation of traditional vaccines depending on single antigens or attenuated strains. The specific expression product of the gene can stimulate the immune system of the body to directionally recognize and attack the mycobacterium tuberculosis, significantly improves the pertinence and effectiveness of the vaccine, and provides a new path for solving the tuberculosis prevention and treatment problem.