CN111281973A - Vaccine adjuvant containing TRPV2 agonist and application thereof - Google Patents
Vaccine adjuvant containing TRPV2 agonist and application thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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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- 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
- A61K39/025—Enterobacteriales, e.g. Enterobacter
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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
- A61K39/025—Enterobacteriales, e.g. Enterobacter
- A61K39/0266—Klebsiella
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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
- A61K39/07—Bacillus
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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
- A61K39/02—Bacterial antigens
- A61K39/095—Neisseria
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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
- A61K39/102—Pasteurellales, e.g. Actinobacillus, Pasteurella; Haemophilus
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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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39516—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum from serum, plasma
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
- C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
- C07K16/1275—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Streptococcus (G)
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56911—Bacteria
- G01N33/56944—Streptococcus
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
- G01N2333/315—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Streptococcus (G), e.g. Enterococci
- G01N2333/3156—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Streptococcus (G), e.g. Enterococci from Streptococcus pneumoniae (Pneumococcus)
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/26—Infectious diseases, e.g. generalised sepsis
Abstract
The invention provides a vaccine adjuvant, which comprises: a TRPV2 agonist. The vaccine adjuvant containing the TRPV2 agonist can effectively activate B lymphocytes and enhance the immune response of T lymphocyte independent antibodies, is particularly suitable for treating diseases caused by pathogenic bacteria carrying capsular polysaccharide, and has good application prospect.
Description
Technical Field
The present invention relates to the field of medicine. In particular, the invention relates to vaccine adjuvants containing TRPV2 and uses thereof.
Background
Streptococcus pneumoniae infection is a leading cause of childhood death worldwide and is also one of the recognized global serious public health problems. Streptococcus pneumoniae is a gram-positive diplococcus which usually parasitizes in the nasopharynx of healthy people and is not pathogenic under normal conditions, but when the resistance of the human body is reduced or respiratory tract infection caused by other viruses occurs, the streptococcus pneumoniae can break through a mucosal defense system to cause extensive infection of children and adults, including invasive (meningitis, bacteremia and bacterial pneumonia) and non-invasive infection (non-bacterial pneumonia, otitis media, sinusitis and conjunctivitis). Invasive streptococcus pneumoniae infection is a major cause of pneumonia morbidity and mortality. It is estimated that about 43 million children under the age of 5 die of streptococcus pneumoniae infection worldwide in 2008. For the control after pneumonia infection, antibiotic treatment is generally adopted, and the death rate after pneumonia infection can be effectively reduced by properly using the antibiotic. However, in areas of poor medical resources and poor treatment experience, the inability to screen for the specific causative pathogen of the infection at the time of pneumonia occurrence can lead to the overuse of ineffective antibiotics. Improper use of antibiotics can lead to the emergence and development of resistant bacterial strains that can seriously threaten public health safety. The evolution of bacteria has exceeded our ability to respond effectively, not just streptococcus pneumoniae, but also multidrug-resistant (MDR) gram-negative bacteria such as klebsiella pneumoniae, acinetobacter baumannii, and pathogenic escherichia coli, and there are few candidate drugs that can be clinically applied and effectively inhibited all over the world.
Based on the dramatic increase in multidrug resistant (MDR) bacteria and the bottleneck in the development of new antibiotics, there is an urgent need for alternative approaches. Vaccines can reduce the prevalence of disease by reducing the total number of cases, thereby effectively reducing the use of antibacterial drugs. Therefore, the prevention of pneumonia through vaccine is now a very urgent need, and is also the most effective means for preventing pneumonia. In the case of pneumococcus, the capsular polysaccharide is the main virulence factor, and depending on the composition of the capsular polysaccharide, pneumococcus can be divided into different serotypes, up to 90 serotypes have been found. Capsular polysaccharide is a multivalent molecule that exhibits a repetitive structure, and at the same time is considered to be an important target for pneumococcal vaccine development. Pneumococcal capsular polysaccharides are typically T lymphocyte-independent antibody response type 2 antigens because polysaccharide antigens are not processed and presented by major histocompatibility complexes and thus do not induce T lymphocyte-assisted B lymphocyte antibody subtype switching. B cell mediated antibody responses are crucial for human health, and polysaccharide antigens tend to promote extensive cross-linking of B Cell Receptors (BCRs). Cross-linking of BCRs triggers B cell activation through a complex network in the immune synapse, thereby generating protective humoral immunity. An effective pneumococcal vaccine requires stimulation of B lymphocytes for antibody production and induction of a memory antibody response. Taking pneumococcus as an example, there are 2 main pneumococcal vaccines widely used at present, one is 23-valent pneumococcal polysaccharide vaccine (Pneumovax, nemadex) and 13-valent pneumococcal polysaccharide conjugate vaccine (Prevenar 13, pei 13). Where valency refers to the number of serotypes in Streptococcus pneumoniae. In addition, klebsiella pneumoniae, acinetobacter baumannii and pathogenic escherichia coli are also multi-drug resistant gram-negative pathogenic bacteria coated by capsular polysaccharide, and several vaccine-related researches have been carried out on the capsular polysaccharide structure.
It has long been believed that children under 2 years of age, because the adaptive capacity of the immune reservoir (repotoreire) has not yet developed, are poorly immunogenic as represented by capsular polysaccharides, do not elicit long-term protective antibody immune responses, and are weak or non-durable in antibody responses to most pneumococcal capsules. In the case of the 23-valent pneumococcal polysaccharide vaccine nemo method, it covers the most serotypes, but the age range of vaccinated subjects allowed worldwide is children over 2 years of age. In children, the risk of streptococcus pneumoniae infection is greatest within 2 years of age, however there is currently no ideal vaccine available with the broadest coverage. The current proposal is a 13-valent pneumococcal polysaccharide conjugate vaccine, which induces T-cell dependent antibody responses by covalently attaching capsular polysaccharide to a carrier protein adsorbed onto aluminium phosphate. However, currently, pneumococcal polysaccharide conjugate vaccines are recommended for infants aged 6 weeks or more. It follows that there is a lack of effective vaccination against infants under 6 weeks of age to prevent pneumonia, while there is a lack of protective vaccines of the high coverage serotype in children under 2 years of age.
Adjuvants are components used in vaccines and help to generate a stronger immune response in a human being immunized with the vaccine, i.e., adjuvants can help the vaccine to function better and help the human being to generate a sufficiently strong immune response to protect the human being from diseases caused by vaccination. Adjuvants can be largely divided into two categories: a vaccine which is inherently immunogenic, such as Bordetella pertussis, Mycobacterium tuberculosis, and gram-negative bacilli, and is made from weakened or killed bacteria, i.e., contains natural adjuvants, which can help the body generate strong protective immune response; another substance which is not immunogenic per se, such as aluminium hydroxide, calcium phosphate, mineral oil emulsions, surfactants, etc., for example Freund's adjuvant (Freund's adjuvant). Aluminium salts (such as aluminium hydroxide, aluminium phosphate and aluminium potassium sulphate) have been used safely in vaccines for over 70 years, initially in diphtheria and tetanus vaccines, and have later been found to enhance the immune response in humans to these vaccines. However, due to some limitations of aluminum adjuvants, such as weak adjuvant effect, it is necessary to match with antigens with stronger immunogenicity to play a good role, and particularly, the Th1 reaction mediating cellular immunity cannot be promoted well. An adjuvant vaccine can cause more local reactions (e.g., redness, swelling, and pain at the injection site) and more systemic reactions (e.g., fever, chills, and body pain) than a non-adjuvant vaccine. To date, clinically approved adjuvants for use worldwide include the use of aluminum salts, CpG 1018, squalene based oil-in-water emulsions (MF59, AS03 and AF03) and AS04, AS01B(Monophoryl lipid A in combination with aluminium salt or QS 21). The mechanism of adjuvant effect is still not well studied, and at presentThe known molecular targets are mainly Toll-like receptors (TLRs). Furthermore, in the field of polysaccharide vaccines, no mature adjuvant can stimulate a stronger immune response, so that the existing 23-valent pneumococcal polysaccharide vaccine (Pneumovax, nemours) is a vaccine without adjuvant. The field of polysaccharide vaccines has now presented a state of immobility, and new adjuvants and/or delivery systems directed to enhancing B lymphocyte activation are urgently needed.
Disclosure of Invention
The present invention aims to solve at least to some extent at least one of the technical problems of the prior art. Therefore, the vaccine adjuvant, the vaccine composition, the method for preparing the antibody, the application of the antibody, the artificial antibody, the TRPV2 agonist in preparing the vaccine adjuvant or the vaccine composition and the application of the reagent in preparing the kit are provided by the invention, the vaccine adjuvant containing the TRPV2 agonist can effectively activate B lymphocytes and enhance the immune response of T lymphocyte independent antibodies, is particularly suitable for treating diseases caused by pathogenic bacteria (such as Klebsiella pneumoniae, Acinetobacter baumannii, pathogenic escherichia coli, Haemophilus influenzae type B, Neisseria meningitidis and streptococcus pneumoniae) carrying capsular polysaccharide, and has better application prospect.
In one aspect of the invention, a vaccine adjuvant is provided. According to an embodiment of the invention, the vaccine adjuvant comprises: a TRPV2 agonist. The inventor finds that activating transient receptor potential vanilloid channel (TRPV 2) can trigger B cell activation and enhance T lymphocyte independent antibody immune response, is particularly suitable for treating diseases caused by pathogenic bacteria carrying polysaccharide capsules, and has a good application prospect in generating immune response to capsular polysaccharide of pathogenic bacteria.
According to an embodiment of the present invention, the vaccine adjuvant may further have the following additional technical features:
according to an embodiment of the invention, the TRPV2 agonist is selected from cannabidiol, probenecid, 2-aminoethylbiphenylboronic acid ester (2-APB) or tetrahydrocannabinol (Δ 9-THC), preferably cannabidiol. The inventor finds that the TRPV2 agonist (especially cannabidiol) can effectively activate B lymphocytes and enhance T lymphocyte independent antibody immune response, and is particularly suitable for treating pathogenic bacteria carrying polysaccharide capsules, and generates immune response to the capsular polysaccharide of the pathogenic bacteria.
According to an embodiment of the present invention, the vaccine adjuvant further comprises a solvent selected from vegetable oils, preferably corn oil and/or sunflower oil, more preferably corn oil. Thus, the TRPV2 agonist is dissolved in a solvent for storage.
In another aspect of the invention, a vaccine composition is provided. According to an embodiment of the invention, the vaccine composition comprises: a vaccine; and a vaccine adjuvant as described above. The vaccine adjuvant containing the TRPV2 agonist can effectively help a vaccine to better play a role, activate B lymphocytes and enhance T lymphocyte independent antibody immune response so as to help an organism to generate a strong enough immune response, and is particularly suitable for treating diseases caused by pathogenic bacteria carrying polysaccharide capsules.
According to an embodiment of the invention, the vaccine is selected from the group consisting of capsular polysaccharide vaccines.
According to an embodiment of the invention, the vaccine is selected from the group consisting of streptococcus pneumoniae vaccines.
In yet another aspect of the invention, a method of making an antibody is provided. According to an embodiment of the invention, the method comprises: contacting the animal with the vaccine composition described above; isolating the antibody from the blood of the animal. Vaccine adjuvants or vaccine compositions containing TRPV2 agonists may be effective in helping vaccines to function better, activating B lymphocytes, and enhancing T lymphocyte-independent antibody immune responses. Thus, upon contacting the vaccine adjuvant or vaccine composition with an animal, the immune response is activated to produce the corresponding antibody.
In yet another aspect of the invention, an antibody is provided. According to an embodiment of the present invention, the antibody is obtained by the method for producing an antibody described above. Thus, TRPV2 agonists can activate B lymphocytes, enhance T lymphocyte-independent antibody immune responses, and thereby produce antibodies.
In yet another aspect of the invention, an artificial antibody is provided. According to an embodiment of the invention, the artificial antibody has the same antigenic determinant as the antibody described above.
In yet another aspect of the invention, the invention proposes the use of a TRPV2 agonist in the preparation of a vaccine adjuvant or vaccine composition. According to an embodiment of the invention, the vaccine adjuvant or vaccine composition is for activating B lymphocytes. The inventors found that TRPV2 agonists can efficiently activate B lymphocytes, thereby generating an immune response.
According to an embodiment of the invention, the vaccine adjuvant or vaccine composition is for enhancing a T lymphocyte independent antibody immune response.
According to an embodiment of the invention, the TRPV2 agonist is for use in generating an immune response to a capsular polysaccharide.
According to an embodiment of the invention, the vaccine adjuvant or vaccine composition is used for the treatment of a disease caused by pathogenic bacteria carrying capsular polysaccharides selected from the group consisting of klebsiella pneumoniae, acinetobacter baumannii, pathogenic escherichia coli, haemophilus influenzae type b, neisseria meningitidis and/or streptococcus pneumoniae, preferably streptococcus pneumoniae.
According to an embodiment of the invention, the TRPV2 agonist is selected from cannabidiol, probenecid, 2-aminoethylbiphenylboronic acid ester or tetrahydrocannabinol, preferably cannabidiol.
According to the embodiment of the invention, the mice are administrated with 0.2-2 mg of TRPV2 agonist.
In another aspect of the invention, the invention provides the use of the reagent in the preparation of a kit. According to an embodiment of the invention, the kit is for diagnosing a disease caused by pathogenic bacteria carrying capsular polysaccharides, said reagents comprising the vaccine composition as described above. The TRPV2 agonist can effectively activate B lymphocytes, enhance T lymphocyte independent antibody immune response, generate immune response to capsular polysaccharide and generate a detectable signal, and can be used for diagnosing diseases caused by pathogenic bacteria carrying capsular polysaccharide, especially diseases caused by streptococcus pneumoniae.
According to an embodiment of the invention, the reagent further comprises an antibody or an artificial antibody as described above.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 shows a schematic representation of the dynamic antibody response of mice immunized with type 1 (CPS1) and type 3 (CPS3) capsular polysaccharides according to one embodiment of the present invention;
FIG. 2 shows a TRPV2 transcript level profile of real-time fluorescent quantitative PCR detection of peripheral blood mononuclear cells of healthy persons of different ages, one dot representing an individual, 101 persons in total, according to one embodiment of the present invention;
FIG. 3 shows a profile of TRPV2 transcript levels from real-time fluorescent quantitative PCR assays of mice of different age groups according to one embodiment of the present invention;
FIG. 4 shows a schematic diagram of an antibody response after mouse cells overexpress TRPV2 according to one embodiment of the present invention;
FIG. 5 shows a schematic diagram of an analysis of the degree of aggregation of B lymphocyte surface receptors (BCRs) according to one embodiment of the present invention;
FIG. 6 shows the effect of different doses of CBD on IgM antibody titers after immunization of mice with pneumococcal capsular polysaccharide according to one embodiment of the present invention;
FIG. 7 shows the effect of different doses of CBD on IgG antibody titers after immunization of mice with pneumococcal capsular polysaccharide, according to one embodiment of the present invention.
FIG. 8 shows the effect of different doses of CBD on IgG antibody titers after immunization of mice with the model antigen NP-Ficoll according to one embodiment of the present invention.
FIG. 9 shows a schematic representation of an analysis of antibody levels of pneumococcal capsular polysaccharide after immunization of neonatal mice, according to one embodiment of the invention.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention.
The invention provides a vaccine adjuvant, a vaccine composition, a method for preparing an antibody, an artificial antibody, application of a TRPV2 agonist in preparing the vaccine adjuvant or the vaccine composition and application of a reagent in preparing a kit, which are respectively described in detail below.
Vaccine adjuvant
In one aspect of the invention, a vaccine adjuvant is provided. According to an embodiment of the invention, the vaccine adjuvant comprises: a TRPV2 agonist.
The inventors found that activation of the transient receptor potential vanilloid channel (TRPV 2) can trigger B cell activation. Various biological effects of the TRPV2 channel include nociceptive, mechanical force sensing, epidermal differentiation, calcium/magnesium absorption, and heat sensing effects. As shown in fig. 1, mice (number of individuals ═ 4) were bled on day-1 (day before immunization), and then immunized with CPS1 and CPS3 on the day, and gene transcription levels in spleen cells of blood (B) mice were collected on days 6 and 12 after immunization, C-WT, C-Het were both normal mice, and C-KO was a TRPV 2-knocked-out mouse in B lymphocytes. The inventors found that B cell specific TRPV2 deficient mice had severely impaired antibody responses to streptococcus pneumoniae capsular polysaccharide.
Further, the inventors showed that after sample analysis for 101 different age groups, the expression level of TRPV2 in newborns (within 2 months of age) exhibited the lowest level compared to other age groups (fig. 2). This conclusion was further corroborated in the mouse model that the TRPV2 levels were significantly higher in the adult mice than in the neonatal (age group 1) and infant (age group 2) mice (fig. 3, where age group 1 represents within 7 days of birth, age group 2 represents 7 days-3 weeks of birth, age group 3 represents 3-8 weeks of birth, age group 4 represents more than 8 weeks of birth, and the number of individuals was 4). Furthermore, enhancement of TRPV2 expression in mouse B lymphocytes (TRPV2+ group) was effective in increasing the level of T cell-independent antibody response in mice (fig. 4).
The results show that the deficiency of low expression of TRPV2 in the low age group can be compensated by improving the T lymphocyte independent antibody response, and the re-supplementation of children with insufficient expression of TRPV2 can improve the antibody production and play an effective immune protection role in streptococcus pneumoniae infection.
According to an embodiment of the invention, the TRPV2 agonist is selected from cannabidiol, probenecid, 2-aminoethylbiphenylboronic acid ester or tetrahydrocannabinol, preferably cannabidiol. The inventor finds that the TRPV2 agonist (especially cannabidiol) can effectively activate B lymphocytes and enhance T lymphocyte independent antibody immune response, is particularly suitable for treating pathogenic diseases carrying capsular polysaccharide and generates immune response to the capsular polysaccharide.
Vaccine composition
In another aspect of the invention, a vaccine composition is provided. According to an embodiment of the invention, the vaccine composition comprises: a vaccine; and a vaccine adjuvant as described above. The vaccine adjuvant containing the TRPV2 agonist can effectively help a vaccine to better play a role, activate B lymphocytes and enhance T lymphocyte independent antibody immune response so as to help an organism to generate a strong enough immune response, and is particularly suitable for treating diseases caused by pathogenic bacteria carrying capsular polysaccharide.
According to an embodiment of the invention, the vaccine is selected from the group consisting of capsular polysaccharide vaccines. Therefore, the immune response of the capsular polysaccharide can be effectively enhanced by using the TRPV 2-containing agonist.
According to an embodiment of the invention, the vaccine is selected from the group consisting of streptococcus pneumoniae vaccines. Thus, the use of an agonist comprising TRPV2 is effective in enhancing the streptococcus pneumoniae immune response.
It will be appreciated by those skilled in the art that the features and advantages previously described for vaccine adjuvants apply equally to the vaccine composition and will not be described in detail here.
Method for producing antibody
In yet another aspect of the invention, a method of making an antibody is provided. According to an embodiment of the invention, the method comprises: contacting the animal with the vaccine composition described above; isolating the antibody from the blood of the animal. Vaccine adjuvants or vaccine compositions containing TRPV2 agonists may be effective in helping vaccines to function better, activating B lymphocytes, and enhancing T lymphocyte-independent antibody immune responses. Thus, upon contacting the vaccine adjuvant or vaccine composition with an animal, the immune response is activated to produce the corresponding antibody.
It will be appreciated by those skilled in the art that the features and advantages previously described for vaccine compositions apply equally to the method of producing antibodies and will not be described in detail here.
Antibodies
In yet another aspect of the invention, an antibody is provided. According to an embodiment of the present invention, the antibody is obtained by the method for producing an antibody described above. Thus, TRPV2 agonists can activate B lymphocytes, enhance T lymphocyte-independent antibody immune responses, and thereby produce antibodies.
It will be appreciated by those skilled in the art that the features and advantages described above in relation to the method of making the antibody apply equally to the antibody and will not be described further herein.
Artificial antibodies
In yet another aspect of the invention, an artificial antibody is provided. According to an embodiment of the invention, the artificial antibody has the same antigenic determinant as the antibody described above.
It will be appreciated by those skilled in the art that the features and advantages described above for antibodies apply equally to the artificial antibody and will not be described in detail here.
Use of TRPV2 agonist in the preparation of vaccine adjuvant or vaccine composition
In yet another aspect of the invention, the invention proposes the use of a TRPV2 agonist in the preparation of a vaccine adjuvant or vaccine composition. According to an embodiment of the invention, the vaccine adjuvant or vaccine composition is for activating B lymphocytes. The inventors found that TRPV2 agonists can efficiently activate B lymphocytes, thereby generating an immune response.
According to an embodiment of the invention, the vaccine adjuvant or vaccine composition is for enhancing a T lymphocyte independent antibody immune response. The inventors found that TRPV2 agonists can effectively activate B lymphocytes, enhancing T lymphocyte-independent antibody immune responses.
According to an embodiment of the invention, the TRPV2 agonist is for use in generating an immune response to a capsular polysaccharide. The inventors found that TRPV2 agonists can effectively activate B lymphocytes and generate an immune response to capsular polysaccharides.
According to an embodiment of the invention, the vaccine adjuvant or vaccine composition is used for the treatment of a disease caused by pathogenic bacteria carrying capsular polysaccharides selected from the group consisting of klebsiella pneumoniae, acinetobacter baumannii, pathogenic escherichia coli, haemophilus influenzae type b, neisseria meningitidis and/or streptococcus pneumoniae, preferably streptococcus pneumoniae.
According to an embodiment of the invention, the TRPV2 agonist is selected from cannabidiol, probenecid, 2-aminoethylbiphenylboronic acid ester or tetrahydrocannabinol, preferably cannabidiol. The inventor finds that the TRPV2 agonist (especially cannabidiol) can effectively activate B lymphocytes and enhance T lymphocyte independent antibody immune response, is particularly suitable for treating diseases caused by pathogenic bacteria carrying capsular polysaccharide and generates immune response to the capsular polysaccharide.
According to the embodiment of the invention, the mice are administrated with 0.2-2 mg of TRPV2 agonist. Thus, within this dose range TRPV2 agonists can effectively mask mouse T cell independent pattern antigens, producing strong IgG antibody levels.
It will be appreciated by those skilled in the art that the features and advantages previously described for vaccine adjuvants or vaccine compositions are equally applicable to this use and will not be described in further detail herein.
Use of reagent in preparation of kit
In another aspect of the invention, the invention provides the use of the reagent in the preparation of a kit. According to an embodiment of the invention, the kit is for diagnosing a disease caused by pathogenic bacteria carrying capsular polysaccharides, said reagents comprising the vaccine composition as described above. The TRPV2 agonist can effectively activate B lymphocytes, enhance T lymphocyte independent antibody immune response, generate immune response to capsular polysaccharide and generate a detectable signal, and can be used for diagnosing diseases caused by pathogenic bacteria carrying the capsular polysaccharide.
According to an embodiment of the invention, the reagent further comprises an antibody or an artificial antibody as described above. The TRPV2 agonist can effectively activate B lymphocytes, enhance T lymphocyte independent antibody immune response and generate immune response to capsular polysaccharide, so that if organisms are infected with related diseases caused by pathogenic bacteria carrying capsular polysaccharide, the pathogenic bacteria can be specifically combined with the antibody or artificial antibody to generate detectable signals, thereby realizing diagnosis of the related diseases of the pathogenic bacteria.
It will be appreciated by those skilled in the art that the features and advantages previously described for vaccine adjuvants, vaccine compositions, antibodies or artificial antibodies are equally applicable to this use and will not be described in further detail herein.
It is noted that the term "treatment" as used herein is intended to mean obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the disease or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure for the disease and/or adverse effects resulting from the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) preventing the onset of a disease (e.g., preventing a disease associated with pathogenic bacteria carrying capsular polysaccharides) or condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting a disease, e.g., arresting disease progression; or (c) alleviating the disease, e.g., alleviating symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, reduce, or inhibit a disease in the individual, including, but not limited to, administering a drug containing a formulation herein to an individual in need thereof.
The administration frequency and dose of the preparation of the present invention can be determined by a number of relevant factors, including the type of disease to be treated, the administration route, the age, sex, body weight and severity of the disease of the patient, and the type of drug as an active ingredient. According to some embodiments of the invention, the daily dose may be divided into 1, 2 or more doses in a suitable form for administration 1, 2 or more times over the entire period, as long as a therapeutically effective amount is achieved.
The term "therapeutically effective amount" refers to an amount of a compound sufficient to significantly ameliorate some of the symptoms associated with a disease or condition, i.e., to provide a therapeutic effect for a given condition and administration regimen. For example, in the treatment of a streptococcus pneumoniae-related disease, a drug or compound that reduces, prevents, delays, inhibits or retards any symptom of the disease or disorder should be therapeutically effective. A therapeutically effective amount of a drug or compound need not cure a disease or condition, but will provide treatment for a disease or condition such that the onset of the disease or condition in an individual is delayed, prevented or prevented, or the symptoms of the disease or condition are alleviated, or the duration of the disease or condition is altered, or the disease or condition becomes less severe, or recovery is accelerated, for example.
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Known conventional methods and conventional conditions, or according to the conditions recommended by the manufacturers of the kits and instruments.
Example 1
Determining the Effect of CBD on B lymphocyte surface receptor recruitment
Material and equipment sources: wild type B6 mouse (provided by the animal center of the university of qinghua), CBD (yunnan han element biotechnology limited), edible corn oil, hbss (gibco), lipid bilayer based B cell activation system, olympus total internal reflection fluorescence microscopy system and Image J analysis software (self-contained in the laboratory where the above inventors are located).
The experimental method comprises the following steps: CBD was dissolved in edible grade corn oil to make a stock solution with a final concentration of 2mg CBD/100 μ L (corn oil). After dilution with HBSS, the final concentration of CBD was 10. mu.M, and was designated as CBD group, and an equal volume of corn oil was added to the HBSS reaction solution for the control group, and was designated as Ctrl group. The spleen is obtained after the mice are euthanized, and the spleen cell suspension is obtained after the mice are treated by a cell sieve and a MACS buffer solution and then treated by an erythrocyte lysate. The B cell surface receptor was labeled with an antibody conjugated with a fluorescent probe, and then the cells were added to the prepared lipid bilayer-based B lymphocyte activation system (the reaction solution in the system was the above-mentioned CBD or corn oil containing a certain volume), respectively, and after allowing the cells to react at 37 ℃ for 7 minutes, the reaction was terminated with 4% paraformaldehyde.
The detection method comprises the following steps: and the Olympus total internal reflection fluorescence microscopic imaging system is used for shooting a B cell surface receptor image on the contact surface. The fluorescence signal intensity is controlled within 2000. After the pictures were saved and exported, the total signal intensity of the contact surface of each cell was analyzed using ImageJ software.
The experimental results are shown in fig. 5, the aggregation degree of the B lymphocyte surface receptor (BCR) in the CBD group is significantly higher than that in the Ctrl group, and the mechanism layer surface indicates that the CBD can effectively stimulate the aggregation capability of the mouse BCR, thereby providing a reasonable explanation of the mechanism layer for the in vivo application.
Example 2
Determination of the adjuvant Effect of CBD on pneumococcal capsular polysaccharide vaccine in adult mice
Material sources are as follows: wild type B6 mice (provided by the animal center of the university of qinghua), CBD (yunnan hansu biotechnology limited), edible corn oil, CPS1 and CPS3 pneumococcal capsular polysaccharide (provided by the worship laboratory of the university of qinghua).
An enzyme-linked immunosorbent assay evaluation system is adopted, and the activity of the adjuvant is reflected by antibody titer.
The experimental method comprises the following steps: the CBD was dissolved in edible corn oil to make a suspension with a final concentration of 2mg CBD/100 μ L (corn oil) or 0.2mg CBD/100 μ L (corn oil). CPS1 and CPS3 pneumococcal capsular polysaccharide are dissolved in normal saline to prepare solutions with final concentration of 25 μ g CPS1 and CPS3/100 μ L (normal saline). Mice in the experimental group were pre-injected with 100 μ L of the prepared CBD suspension each. Control mice were replaced with the same volume of corn oil. The number of mice was 4 in both the experimental group and the control group. The injection site is intramuscular injection. After injection of the CBD or control corn oil, in situ immune antigen injection was performed. 7 days after immunization, mice were bled from the tail vein, 50. mu.L of blood was taken from each mouse. And (3) placing the taken blood at 4 ℃ overnight, centrifuging for 8min at 800g the next day, sucking the upper layer serum out, and determining the titer of anti-CPS 1 and CPS3 pneumococcal capsular polysaccharide IgM antibodies in the serum by adopting an enzyme-linked immunosorbent assay.
Detection of antibody titer: CPS1 and CPS3 proteins were diluted with PBS to a concentration of 4. mu.g/mL, coated in 96-well microtiter plates at 50. mu.L per well and incubated overnight at 4 ℃. The microplate was washed 3 times with PBS containing 0.05% Tween 20, blocked with 0.3% gelatin solution at 200. mu.L per well for 2h at room temperature. The microplate was washed 5 times with PBST (Tween phosphate buffer), and 50. mu.L of diluted immune OVA-diluted mouse serum was added to each well and incubated at room temperature for 2 hours. After washing the microplate 5 times with PBST, goat anti-mouse IgM antibody labeled with HRP (horse radish peroxidase) was added and incubated at room temperature for 45 min. Washing the enzyme label plate with PBST for 5 times, adding sodium citrate OPD (o-phenylenediamine) color development solution, developing for 10min in dark place, and adding sulfuric acid to terminate. And reading by using an enzyme labeling instrument OD490, wherein the maximum serum dilution times when the light absorption ratio of the experimental group to the control group is more than or equal to 2.0 are the titers of CPS1 and CPS3 antibodies in the serum.
The experimental results are shown in FIG. 6. Both doses of CBD were effective in stimulating IgM antibody responses to pneumococcal capsular polysaccharides in mice following primary immunization.
Example 3
Evaluation of the effect of CBD on the memory immune response of pneumococcal capsular polysaccharide vaccine in adult mice
Material sources are as follows: wild type B6 mice (provided by the animal center of the university of qinghua), CBD (yunnan hansu biotechnology limited), edible corn oil, CPS1 and CPS3 pneumococcal capsular polysaccharide (provided by the worship laboratory of the university of qinghua).
The memory immune response level is reflected by the anti-CPS 1 and CPS3 IgG antibody titers by an enzyme-linked immunosorbent assay evaluation system.
The experimental method comprises the following steps: CPS1 and CPS3 pneumococcal capsular polysaccharide are dissolved in normal saline to prepare solutions with final concentrations of 25 μ g CPS1 and CPS3/100 μ L (normal saline). Mice in example 2 were kept on rearing during which antibody levels were followed every 1 month. When antibody levels had fallen back to basal levels (data not shown), secondary booster immunizations were given. The antigen dose was equivalent to the initial immunization, but was not injected with adjuvant CBD. 7 days after immunization, mice were bled from the tail vein, 50. mu.L of blood was taken from each mouse. And (3) placing the taken blood at 4 ℃ overnight, centrifuging at 800g for 8min the next day, sucking the upper layer serum out, and determining the titer of anti-CPS 1 and CPS3 pneumococcal capsular polysaccharide IgG antibody in the serum by adopting an enzyme-linked immunosorbent assay. Enzyme-linked immunosorbent assay evaluation was similar to example 1.
The experimental results are shown in FIG. 7. After the second booster immunization, mice that had been initially immunized with the CBD adjuvant produced higher levels of IgG antibodies in the booster immunization.
Example 4
Determination of the adjuvant Effect of CBD on T lymphocyte independent Pattern antigens in adult mice
Material sources are as follows: wild type B6 mouse (from animal center of Qinghua university), CBD (Yunnan Hansu Biotech Co., Ltd.), edible corn oil, NP-Ficoll (Biosearch Co.).
An enzyme-linked immunosorbent assay evaluation system is adopted, and the activity of the adjuvant is reflected by antibody titer. NP-Ficoll, which is totally called 4-Hydroxy-3-nitrophenylacetic acid combined on amino ethyl carboxymethyl-Ficoll, is a classic T lymphocyte independent pattern antigen for researching B lymphocyte in vivo activation.
The experimental method comprises the following steps: the CBD was dissolved in edible corn oil to make a suspension with a final concentration of 2mg CBD/100 μ L (corn oil) or 0.2mg CBD/100 μ L (corn oil). The NP-Ficoll antigen was dissolved in physiological saline to prepare a solution having a final concentration of 5. mu.g NP-Ficoll/100. mu.L (physiological saline). Mice in the experimental group were pre-injected with 100 μ L of the prepared CBD suspension each. The control mice were replaced with corn oil of the same volume and the injection site was intramuscular. The number of mice was 4 in both the experimental group and the control group. After injection of the CBD or control corn oil, in situ immune antigen (NP-Ficoll) injections were performed. After 7 days of immunization, mice were bled from the tail vein, 50. mu.L of blood was taken from each mouse. The blood taken out is placed at 4 ℃ overnight, centrifuged for 8min at 800g the next day, the upper serum is sucked out, and the titer of the IgG antibody against NP in the serum is determined by adopting an enzyme-linked immunosorbent assay.
The experimental results are shown in FIG. 8. Both doses of CBD were effective in stimulating mice to the T cell independent pattern antigen NP-Ficoll, producing strong IgG antibody levels.
Example 5
Determination of the adjuvant Effect of CBD on pneumococcal capsular polysaccharide vaccine in neonatal mice
Material sources are as follows: 5-day-old B6 strain suckling mice (provided by animal center of the university of qinghua), CBD (yunnan hansu biotechnology limited), edible corn oil, CPS1 and CPS3 pneumococcal capsular polysaccharide (provided by zhangren laboratory of the university of qinghua).
The experimental method comprises the following steps: the CBD was dissolved in edible corn oil to a final concentration of 2mg CBD/50 μ L (corn oil). CPS1 and CPS3 pneumococcal capsular polysaccharide are dissolved in normal saline to prepare solutions with final concentration of 25 μ g CPS1 and CPS3/50 μ L (normal saline). The experimental mice were pre-injected with 50 μ L of the formulated CBD suspension each. The control mice were replaced with corn oil of the same volume and the injection site was intramuscular. The number of mice was 4 in both the experimental group and the control group. After injection of the CBD or control corn oil, in situ immune antigen injection was performed. The mice were then returned to functionally live with the mother mice. After 14 days, mice were bled from the tail vein, and 25 μ L of blood was taken from each mouse. The blood is left at 4 deg.C overnight, centrifuged at 800g for 8min the next day, the upper serum layer is aspirated, and the titer of IgM antibodies against CPS1 and CPS3 in the serum is determined by enzyme-linked immunosorbent assay. Enzyme-linked immunosorbent assay evaluation was similar to example 1.
Experimental results referring to fig. 9, neonatal mice are nearly incompetent for T lymphocyte-independent antibody responses. The results show that there is no change in the IgM antibodies against CPS1 and CPS3 in the serum before and after immunization in the control group of mice. However, neonatal mice receiving CBD adjuvant assistance produced higher IgM antibodies compared to the control group.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A vaccine adjuvant, comprising: a TRPV2 agonist.
2. The vaccine adjuvant according to claim 1, characterized in that the TRPV2 agonist is selected from cannabidiol, probenecid, 2-aminoethylbiphenylboronic acid ester or tetrahydrocannabinol, preferably cannabidiol;
optionally, the vaccine adjuvant further comprises a solvent selected from vegetable oils, preferably corn oil and/or sunflower oil, more preferably corn oil.
3. A vaccine composition, comprising:
a vaccine; and
a vaccine adjuvant according to claim 1 or 2.
4. The vaccine composition of claim 3, wherein the vaccine is selected from the group consisting of a capsular polysaccharide vaccine;
optionally, the vaccine is selected from a streptococcus pneumoniae vaccine.
5. A method of producing an antibody, comprising:
contacting the animal with the vaccine composition of claim 3 or 4;
isolating the antibody from the blood of the animal.
6. An antibody obtained by the method for producing an antibody according to claim 5.
7. An artificial antibody having the same epitope as the antibody of claim 6.
Use of a TRPV2 agonist in the preparation of a vaccine adjuvant or vaccine composition, characterized in that the vaccine adjuvant or vaccine composition is for the activation of B lymphocytes.
9. The use according to claim 8, wherein the vaccine adjuvant or vaccine composition is for enhancing a T lymphocyte independent antibody immune response;
optionally, the TRPV2 agonist is for use in generating an immune response to a capsular polysaccharide;
optionally, the vaccine adjuvant or vaccine composition is used for treating diseases caused by pathogenic bacteria carrying capsular polysaccharide, the pathogenic bacteria being selected from Klebsiella pneumoniae, Acinetobacter baumannii, pathogenic Escherichia coli, Haemophilus influenzae type B, Neisseria meningitidis and/or Streptococcus pneumoniae, preferably Streptococcus pneumoniae;
optionally, the TRPV2 agonist is selected from cannabidiol, probenecid, 2-aminoethylbiphenylboronic acid ester or tetrahydrocannabinol, preferably cannabidiol;
optionally, the mice are administered at a dose of 0.2-2 mg of TRPV2 agonist.
10. The application of the reagent in the preparation of the kit is characterized in that the kit is used for diagnosing diseases caused by pathogenic bacteria carrying capsular polysaccharide,
the agent comprises the vaccine composition of claim 3 or 4;
optionally, the reagent further comprises the antibody of claim 6 or the artificial antibody of claim 7.
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| CN112569213A (en) * | 2020-12-30 | 2021-03-30 | 中国医学科学院医学生物学研究所 | Application of cannabidiol in preparation of medicine for treating acute B lymphocyte leukemia |
| CN113262298A (en) * | 2020-03-31 | 2021-08-17 | 清华大学 | Vaccine adjuvant containing TRPV2 agonist and application thereof |
| CN114324889A (en) * | 2021-12-01 | 2022-04-12 | 清华大学 | Vaccine quality control method, vaccine quality control reagent and application thereof |
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