CN118001385A - Influenza vaccine composition, preparation method and application thereof - Google Patents
Influenza vaccine composition, preparation method and application thereof Download PDFInfo
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Abstract
The present invention relates to an influenza vaccine composition comprising a first component comprising an influenza virus antigenic material and a second component comprising an oil-in-water adjuvant comprising squalene, alpha-tocopherol and tween 80, packaged separately. The vaccine composition of the invention does not need to prepare two components into a finished product preparation during preparation, and the two components can be independently packaged, so that the mutual influence between an antigen and an emulsion adjuvant can be avoided, the more efficient, safer and more stable technical effects can be achieved, the immune response can be effectively improved, and the generation of antibodies can be rapidly stimulated.
Description
Technical Field
The invention belongs to the field of biomedical engineering, and in particular relates to an influenza vaccine composition, a preparation method thereof and application thereof in the field of immunotherapy and prevention.
Background
Influenza is a common viral infectious disease and constitutes a major threat to human health. One of the effective means of preventing influenza is by vaccination with influenza vaccine. Existing influenza vaccines mainly comprise inactivated influenza virus vaccines, live attenuated vaccines and subunit vaccines. Because of strong variability of influenza virus, vaccine strains of inactivated vaccine and attenuated live vaccine need to be replaced in time along with antigenic variation of influenza strain, otherwise, immune effect is not guaranteed, and even ineffective. The influenza subunit vaccine utilizes the virus surface antigen of gene recombination to induce immune protection, and the virus surface antigen also needs to be replaced in time along with the antigenic variation of influenza strains. Currently, a more common approach is to employ multivalent vaccines to enhance immune protection.
Nevertheless, the protective effect of influenza vaccination is still not satisfactory. Thus, researchers have attempted to improve the immune effect by adding adjuvants. The most common adjuvants are aluminum salt adjuvants, which exert an effect of enhancing the immune response through the antigen-depot effect and the immunostimulatory effect of inducing inflammation and the like. However, aluminum salt adjuvants also have a number of limitations, such as inability to induce cellular immune responses, undesirable antigen presentation effects, delayed immune response generation time, susceptibility to side reactions, and the like.
Emulsion-type adjuvants (including oil-in-water emulsions, water-in-oil emulsions, etc.) are an important branch of new adjuvants, and emulsions can be used in combination with a variety of weak antigens (recombinant proteins, polypeptides, etc.) and elicit high titers of antigen-specific antibodies. Milk-type adjuvants generally comprise an oil phase component, an aqueous phase component and an emulsifier. The oil-in-water emulsion mainly comprises water phase components, has high tolerance to human body and has good compatibility with most vaccine antigens.
Although both dairy-based adjuvants and aluminum adjuvants have been widely used, there remains a need to date for new immune formulations and methods of immunization that provide vaccine formulations that are safer and more effective, easier to formulate, and less costly, and that are capable of rapidly inducing an immune response that is more efficient.
Disclosure of Invention
The invention aims to provide an influenza vaccine composition which has good safety and immunostimulation activity, is convenient to prepare, has low cost and can quickly induce high-efficiency immune response. Meanwhile, the invention provides a simple preparation method and application with wide prospect.
To achieve the above object, the present invention provides in one aspect an influenza vaccine composition comprising a first component comprising an influenza virus antigenic material and a second component comprising an oil-in-water adjuvant comprising squalene, alpha-tocopherol and tween 80, packaged separately.
In some embodiments, the influenza virus antigenic material is a live attenuated vaccine, an inactivated vaccine, a toxoid vaccine, a subunit vaccine, a vector vaccine, a genetically engineered vaccine, or a finished nucleic acid vaccine formulation. In a preferred embodiment of the invention, the first component is an inactivated influenza vaccine finished formulation.
In some embodiments, the first component may further comprise an aluminum adjuvant.
In some embodiments, the aluminum adjuvant is selected from at least one of aluminum hydroxide, aluminum phosphate, aluminum sulfate, and alum.
The aluminum adjuvant for vaccine mainly comprises three kinds of aluminum hydroxide, aluminum phosphate and alum, and the commonly used aluminum adjuvant refers to aluminum hydroxide adjuvant. Aluminum hydroxide adjuvant for vaccines is usually prepared by adding alkali liquor into aluminum salt solution to generate neutral Al (H 2O)3(OH)3) which is not charged and is mutually aggregated to form precipitate, wherein aggregates can generate bimolecular and polymolecular condensation through hydroxyl bridging to form macromolecules, aluminum salt is added with alkali to obtain fluffy flocculent aluminum hydroxide precipitate, the flocculent aluminum hydroxide precipitate is loosely aggregated together to form fibrous crystal form due to the fact that the flocculent aluminum hydroxide precipitate contains more coordination water, the action mechanism of the aluminum hydroxide adjuvant is also called crystalline aluminum hydroxide AlO (OH), the action mechanism of the aluminum hydroxide adjuvant is mainly a 'repository effect' and an 'immunostimulation effect', aluminum hydroxide is an amphoteric compound, isoelectric point (isoelectric point, pI) is 11.4, the aluminum hydroxide is positively charged in buffer solution with pH close to that of interstitial fluid of human body pH=7.4, and can absorb acidic protein antigens well.
The main mechanisms of adsorption of antigens by aluminum adjuvants include electrostatic forces, hydrophobic interactions and ligand exchange. Adsorption by hydrophobic interactions is limited by reduced exposure to hydrophobic regions of the aqueous environment due to protein folding. The adsorption is generated by ligand exchange of hydroxyl groups of the aluminum adjuvant and phosphate groups of the antigen. The phosphate group is more strongly bonded to the aluminum atom than the hydroxyl group, thereby replacing the hydroxyl group. Wherein ligand exchange dominates.
In some embodiments, the content of aluminium adjuvant in the first component is from 10 to 1000 μg, preferably from 50 to 800 μg, more preferably from 100 to 600 μg, for example 200 μg, 300 μg, 400 μg or 500 μg.
In some embodiments, the first component is a lyophilized formulation, solution, or suspension.
In some embodiments, the solution or suspension of the first component has a volume of 0.2 to 1ml, preferably 0.5ml.
In some embodiments, the oil-in-water adjuvant comprises 5-15mg squalene, 5-15mg alpha tocopherol and 2-10mg tween80, preferably the oil-in-water adjuvant comprises 10.69mg squalene, 11.86mg alpha tocopherol and 4.86mg tween 80.
In some embodiments, the volume of the oil-in-water adjuvant is 0.2-1ml, preferably 0.5ml.
In some embodiments, the aqueous phase of the oil-in-water adjuvant is a buffer solution selected from the group consisting of phosphate buffer, citrate buffer, tris-HCl buffer, acetate buffer, carbonate buffer, and citric acid-phosphate buffer.
In some embodiments, the first component does not comprise a surfactant.
In some embodiments, the first component comprises an individually packaged influenza virus antigen, does not comprise the surfactants Triton X-100 and tween 80, and the second component is an oil-in-water adjuvant, the aqueous phase of which is an acetate buffer comprising acetic acid and sodium acetate at a pH of 5.65±0.5.
In some embodiments, the first component is an individually packaged influenza virus antigen, does not comprise the surfactants Triton X-100 and tween 80, and the second component is 0.5ml of an oil-in-water emulsion adjuvant comprising 10.69mg squalene, 11.86mg alpha-tocopherol, 4.86mg tween 80, 6.72mg anhydrous sodium acetate, and 0.49mg acetic acid.
In some embodiments, the first component is an individually packaged influenza virus antigenic material, each of a type of 1.5 μg, e.g., in some examples, the influenza virus antigenic material is a tetravalent influenza vaccine comprising 1.5 μg H1N1,1.5 μg H3N2,1.5 μg B/V, and 1.5 μg B/Y, or a bivalent influenza vaccine comprising 1.5 μg H1N1 and 1.5 μg H3N2, and does not comprise the surfactants Triton X-100 and tween 80.
The second component was 0.5ml of an oil-in-water emulsion adjuvant comprising 10.69mg squalene, 11.86mg alpha tocopherol, 4.86mg tween 80, 6.72mg anhydrous sodium acetate and 0.49mg acetic acid.
In some embodiments, the oil-in-water adjuvant further comprises one or more of 3D-MPL, saponins, polyI: C, and CpG. The saponin is selected from one or more of QS-7, QS-17, QS-18, and QS-21, preferably QS-21. In some embodiments, the oil-in-water adjuvant preferably further comprises 3D-MPL.
3D-MPL is a mixture of 3-deacylated monophosphoryl lipids A with 3,4, 5 or 6 acylated chains, sold by Corixa corporation, primarily promoting CD4+ T cell responses with the IFN gamma (Th 1) phenotype. 4'-monophosphoryl lipid A (4' -monophosphoryl lipid A, MPL) can be obtained by subjecting LPS (Lipopolysaccharide) extracted from deep rough mutants of gram negative bacteria to acid hydrolysis, which retains the adjuvant properties of LPS while demonstrating a reduction in toxicity by a factor of more than 1000 (measured by lethal dose in chick embryo eggs) (Johnson et al, 1987Rev. Effect. Dis.9suppl: S512-S516). A suitable dose of MPL is capable of enhancing the immune response against an antigen in humans.
The invention also provides a preparation method of the influenza vaccine composition, which comprises the following steps:
(i) Preparing a first component comprising an influenza virus antigen;
(ii) Preparing as a second component an oil-in-water adjuvant comprising squalene, alpha-tocopherol and tween 80;
(iii) Packaging the first component and the second component separately to obtain influenza vaccine composition,
Wherein steps (i) and (ii) may be performed in any order, including sequentially, simultaneously or in a split site.
In some embodiments, the method comprises the steps of:
(i) Preparing a first component comprising an influenza virus antigen;
(ii) Preparing as a second component an aqueous phase comprising an acetate buffer having a pH of 5.65±0.5, an oil-in-water adjuvant of squalene, α -tocopherol and tween 80;
(iii) Packaging the first component and the second component separately to obtain influenza vaccine composition,
Wherein steps (i) and (ii) may be performed in either order, including sequentially, simultaneously or in separate sites.
In some embodiments, the method of preparing the first component may include adsorbing the influenza virus antigen to an aluminum adjuvant to maintain stability and enhance immunogenicity of the influenza virus antigen.
According to an embodiment of the present invention, a method of preparing a second component includes: firstly, mixing squalene and alpha-tocopherol, then adding phosphate buffer solution containing tween 80, emulsifying by stirring, and finally homogenizing to obtain the oil-in-water adjuvant.
The invention also provides application of the vaccine composition in preparing medicines for treating or preventing diseases.
According to an embodiment of the invention, the influenza vaccine composition is administered 2-3 times within 28 days.
According to an embodiment of the invention, the influenza vaccine composition is administered 3 times within 28 days, each time 14 days apart; alternatively, the influenza vaccine composition is administered 2 times within 28 days, each time 28 days apart.
In another aspect, the invention provides a kit comprising the influenza vaccine composition comprising a first component comprising an influenza virus antigenic material and a second component comprising an oil-in-water adjuvant comprising squalene, alpha-tocopherol and tween 80, separately packaged, the aqueous phase being a pH 5.65±0.5 acetic acid buffer.
In another aspect, the present invention provides a multi-chamber syringe comprising the influenza vaccine composition comprising a first chamber and a second chamber, the first chamber containing a first component comprising an influenza virus antigenic material; the second compartment contains a second component comprising an oil-in-water adjuvant comprising squalene, alpha-tocopherol and tween 80, the aqueous phase being an acetate buffer having a pH of 5.65±0.5.
In another aspect, the invention provides a method of inducing an immune response using the influenza vaccine composition by separately administering a first component and a second component to a subject. The method comprises the following steps:
(i) Applying the first component to the application subject;
(ii) Applying the second component to the application subject,
Wherein the steps may be performed simultaneously in any order or at specific times intervals.
In some embodiments, the first component and the second component are applied to the same site of the subject. In other embodiments, the first component and the second component are applied to different sites of the subject separately.
The present invention also provides another method of inducing an immune response using the influenza vaccine composition, which simultaneously applies the first component and the second component to a subject. The method comprises the following steps:
(i) Mixing the first component and the second component;
(ii) Applying the mixture obtained in step (i) to the application subject.
In another aspect, the invention provides a method of improving a CD 4T-cell immune response and/or improving a B-memory cell response using the influenza vaccine composition, wherein the first component and the second component are administered to a subject simultaneously or not simultaneously, respectively, or wherein the first component and the second component are mixed and administered to a subject.
Compared with the prior art, the invention has the following beneficial effects:
the invention further adds emulsion adjuvant on the basis of immune component containing influenza virus antigen, the two components can be applied separately or jointly and can basically achieve synergistic adjuvant effect consistent with or even better than the traditional preparation form, thus effectively improving immune response and rapidly stimulating antibody production.
On the other hand, the vaccine composition of the invention does not need to prepare the immune component containing the influenza virus antigenic substance and the emulsion adjuvant into finished preparations when being prepared, the emulsion adjuvant and the immune component containing the influenza virus antigenic substance can be independently packaged, so that the interaction between the antigenic substance and the emulsion adjuvant can be avoided, under the condition of containing the aluminum adjuvant, the aluminum adjuvant can adsorb the antigenic substance to play a role of protecting antigen, meanwhile, the aluminum adjuvant and the antigenic substance form a whole, and when being mixed with the emulsion, the antigenic substance can be adsorbed by the aluminum adjuvant or carried by the emulsion, and the double adjuvant effect of the aluminum adjuvant and the emulsion can be simultaneously exerted, so that the vaccine composition of the invention can achieve more efficient, safer and more stable technical effects.
Drawings
The following drawings are only for purposes of illustration and explanation of the present invention and are not intended to limit the scope of the invention. Wherein:
FIG. 1 shows the titers of hemagglutination-inhibiting antibodies against H1N 1-type influenza virus in example 5 of the present invention;
FIG. 2 shows the titers of hemagglutination-inhibiting antibodies against H3N 2-type influenza virus in example 5 of the present invention;
FIG. 3 shows the titer of a hemagglutination-inhibiting antibody against influenza B/V virus in example 5 of the present invention;
FIG. 4 shows the titer of a hemagglutination-inhibiting antibody against influenza B/Y virus in example 5 of the present invention.
Detailed Description
The present invention will be further described in detail below with reference to specific embodiments and with reference to the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent.
The influenza vaccine compositions of the present invention comprise a first component comprising an influenza virus antigen and a second component comprising an oil-in-water adjuvant, packaged separately.
In some embodiments, the influenza virus antigen is a live attenuated vaccine, an inactivated vaccine, a toxoid vaccine, a subunit vaccine, a vector vaccine, a genetically engineered vaccine, or a nucleic acid vaccine finished formulation. In a preferred embodiment of the invention, the first component is an inactivated influenza vaccine finished formulation.
Alternatively, commercially available influenza vaccine finished formulations such as: trivalent inactivated influenza vaccine of Beijing Kexing biological products Limited company, vinca biological products research all liability Limited company, da Lian Yali peak biological pharmaceutical Limited company, hualan biological vaccine Limited company, shenzhen Sainofil Pasteur biological products Limited company; beijing Kong Xingzhi biological products Limited company, changchun biological products research all Limited company, national optical biotechnology Co., hualan biological vaccine Limited company, jiangsu Dike biological technology Co., shanghai biological products research all Limited company, wuhan biological products research all Limited company tetravalent inactivated influenza vaccine; trivalent attenuated live vaccine of vinca biotechnological stock company; trivalent subunit influenza vaccine from Zhongyi An Ke biotechnology Co., ltd.
In a preferred embodiment, the prepared influenza virus antigen may be further mixed with an aluminum adjuvant to prepare the first component of the present invention. Wherein the aluminum adjuvant may be selected from aluminum hydroxide, aluminum phosphate, aluminum sulfate and alum. The aluminum adjuvant may be prepared using any of the existing techniques, and commercially available aluminum adjuvants such as CRODA's aluminum hydroxide adjuvant ALHYDROGEL may also be used.
In the present invention, the oil-in-water adjuvant as the second component comprises an aqueous phase, an oil phase, and a surfactant. Wherein the aqueous phase may be a buffer solution selected from the group consisting of phosphate buffer, citrate buffer, tris-HCl buffer, acetate buffer, carbonate buffer or citric acid-phosphate buffer. The oil phase comprises a metabolisable oil, preferably squalene, and preferably further comprises alpha-tocopherol. The surfactant comprises one or more of polyoxyethylene sorbitan fatty acid ester (Tween), sorbitan fatty acid ester (span), octoxynol-9 (triton X-100) or polyethylene glycol octyl phenyl ether and lecithin. For example, the oil-in-water adjuvant may comprise squalene, span 85 and tween 80, more preferably the oil-in-water adjuvant comprises squalene, alpha-tocopherol and tween 80.
Example 1 preparation of a two-component influenza vaccine comprising an emulsion adjuvant and an influenza Virus antigen
Raw materials and sources:
Influenza virus vaccine: the tetravalent influenza virus split vaccine is a Jiangsu Dikkan Biotechnology Co., ltd, and comprises four influenza virus strains with equal amounts of A1 (A/California/7/2009, H1N 1), A3 (A/hongKong/4801/2014, H3N 2), B1 (B/Brisbane/60/2008, B/Victoria, B/V for short) and B2 (B/Phuket/3073/2013, B/Yamagata, B/Y for short).
Preparation of oil-in-water adjuvants:
2.14g of squalene and 2.37g of alpha-tocopherol were mixed, 45ml of a phosphate buffer containing 5wt.% Tween 80 was added thereto, and after mixing, stirring was performed at 12000rpm for 20 minutes at a stirring temperature of 20℃and then homogenization was performed. The homogenizing temperature is 20 ℃, the homogenizing pressure is 80-120 MPa, and 2-4 cycles are carried out, so that the oil-in-water adjuvant with the particle size smaller than 160nm is prepared.
Preparation: the adjuvant bottle for human dose is 0.5ml, and the components comprise squalene 10.69mg, alpha-tocopherol 11.86mg, tween 80 4.86mg, naCl 3.53mg, KCl 0.09mg, na 2HPO4 mg, KH 2PO4 0.09mg and sterilized water for injection.
The average particle size of the emulsion was measured to be 160nm and the PDI was measured to be 0.088.
In order to examine the influence of the buffer system on the immune effect of the adjuvant, the invention also utilizes citrate buffer (pH 6.49+/-0.5), acetate buffer (pH 5.65+/-0.5) and carbonate buffer (pH 10.63+/-0.5) to replace phosphate buffer (pH 7.20+/-0.5) to prepare the oil-in-water adjuvant.
Example 2 preparation of a two-component influenza vaccine comprising an emulsion adjuvant and an influenza Virus antigen
Raw materials and sources:
Influenza virus vaccine: the tetravalent influenza virus split vaccine is a Jiangsu Dikkan Biotechnology Co., ltd, and comprises four influenza virus strains with equal amounts of A1 (A/California/7/2009, H1N 1), A3 (A/hongKong/4801/2014, H3N 2), B1 (B/Brisbane/60/2008, B/Victoria, B/V for short) and B2 (B/Phuket/3073/2013, B/Yamagata, B/Y for short).
Preparation of oil-in-water adjuvants:
2.14g squalene and 2.37g alpha-tocopherol were mixed, and 45ml of a citrate buffer containing 5wt.% Tween 80 was added thereto, followed by stirring at 12000rpm for 20min at a stirring temperature of 20℃and then homogenizing. The homogenizing temperature is 20 ℃, the homogenizing pressure is 80-120 MPa, and 2-4 cycles are carried out, so that the oil-in-water adjuvant with the particle size smaller than 160nm is prepared.
Preparation: the adjuvant bottle for human dose is 0.5ml, and the components comprise 10.69mg squalene, 11.86mg alpha-tocopherol, 4.86mg tween 80,1.25mg sodium citrate, 0.08mg citric acid and sterilized water for injection.
The average particle size of the emulsion was found to be 152.3nm and PDI was found to be 0.092.
Example 3 preparation of a two-component influenza vaccine comprising an emulsion adjuvant and an influenza Virus antigen
Raw materials and sources:
Influenza virus vaccine: the tetravalent influenza virus split vaccine is a Jiangsu Dikkan Biotechnology Co., ltd, and comprises four influenza virus strains with equal amounts of A1 (A/California/7/2009, H1N 1), A3 (A/hongKong/4801/2014, H3N 2), B1 (B/Brisbane/60/2008, B/Victoria, B/V for short) and B2 (B/Phuket/3073/2013, B/Yamagata, B/Y for short).
Preparation of oil-in-water adjuvants:
2.14g squalene and 2.37g alpha-tocopherol were mixed, and 45ml acetate buffer containing 5wt.% tween 80 was added to the mixture, followed by homogenization after stirring at 12000rpm for 20min at a stirring temperature of 20 ℃. The homogenizing temperature is 20 ℃, the homogenizing pressure is 80-120 MPa, and 2-4 cycles are carried out, so that the oil-in-water adjuvant with the particle size smaller than 160nm is prepared.
Preparation: the adjuvant bottle for human dose is 0.5ml, and the components comprise squalene 10.69mg, alpha-tocopherol 11.86mg, tween 80 4.86mg, anhydrous sodium acetate 6.72mg, acetic acid 0.49mg and sterilized water for injection.
The average particle size of the emulsion was found to be 157.7nm and the PDI was found to be 0.079.
Example 4 preparation of a two-component influenza vaccine comprising an emulsion adjuvant and an influenza Virus antigen
Raw materials and sources:
Influenza virus vaccine: the tetravalent influenza virus split vaccine is a Jiangsu Dikkan Biotechnology Co., ltd, and comprises four influenza virus strains with equal amounts of A1 (A/California/7/2009, H1N 1), A3 (A/hongKong/4801/2014, H3N 2), B1 (B/Brisbane/60/2008, B/Victoria, B/V for short) and B2 (B/Phuket/3073/2013, B/Yamagata, B/Y for short).
Preparation of oil-in-water adjuvants:
2.14g of squalene and 2.37g of alpha-tocopherol were mixed, 45ml of carbonate buffer containing 5wt.% Tween 80 was added thereto, and after mixing, stirring was performed at 12000rpm for 20 minutes at a stirring temperature of 20℃and then homogenization was performed. The homogenizing temperature is 20 ℃, the homogenizing pressure is 80-120 MPa, and 2-4 cycles are carried out, so that the oil-in-water adjuvant with the particle size smaller than 160nm is prepared.
Preparation: the adjuvant bottle for human dose was 0.5ml, and the ingredients included 10.69mg squalene, 11.86mg alpha-tocopherol, 4.86mg tween 80,0.47mg sodium bicarbonate, 4.18mg sodium carbonate and sterilized water for injection.
The average particle size of the emulsion was found to be 157.0nm and the PDI was found to be 0.084.
Example 5 influenza vaccine mouse immunization experiment
This example investigated the immunogenicity of emulsion adjuvants in combination with separately packaged tetravalent influenza virus split vaccines and provided conventional Al (OH) 3 adjuvants and no adjuvant group as controls. Meanwhile, this example also examined the immune effect after adding a surfactant to the antigen.
C57BL/6 mice were immunized with 1.5. Mu.g of antigen in each of 1.5. Mu.g/H1N 1, H3N2, B/V and B/Y (total 6. Mu.g/Y), 50. Mu.l/L of emulsion adjuvant and 50. Mu.g/L of Al (OH) 3 adjuvant, 6 mice per group, and the groups were as shown in Table 1. Blood was collected 28 days after immunization using a one-needle immunization program to separate serum, and the immune effect of each group was evaluated by detecting the titer of the hemagglutination-inhibiting antibodies in the serum.
TABLE 1
Note that: the final concentration of Tween 80 added was 0.3. Mu.l/ml, and the final concentration of Triton (Triton X-100) was 0.03. Mu.l/ml.
As can be seen from fig. 1-4, the results of the hemagglutination inhibition antibody titer tests for the different subtypes showed that the hemagglutination inhibition antibody titers of the emulsion adjuvant groups were all significantly higher than that of the adjuvant-free group, and that the hemagglutination inhibition antibody titers of the emulsion adjuvant groups were all significantly higher than that of the Al (OH) 3 adjuvant group except for the H1N1 subtype. The experimental result of the invention shows that the combined inoculation of influenza vaccine and emulsion adjuvant can obviously improve the immune effect.
Meanwhile, when different buffer systems are used, the detection results of the hemagglutination inhibition antibody titer aiming at different subtypes are different, and the detection results are suitable for different buffer systems aiming at different antigen groups.
The results of the titer detection of the hemagglutination inhibition antibody against the H1N1 antigen show that the titer detection result after adding the surfactant triton and tween 80 is higher than that of the vaccine+emulsion adjuvant group (283 group Gr5 and 126 group Gr 1) directly mixed with the buffer system in the phosphate buffer system, and the titer detection result after adding the surfactant triton and tween 80 in the carbonate buffer system is lower than that of the vaccine finished product+emulsion adjuvant group (178 group Gr8 and 200 group Gr 4) which are directly mixed and independently packaged, and meanwhile, the buffer system with the optimal comprehensive balance is Gr4 group in the aspect of avoiding the increase of preparation procedures and surfactant links by referring to the stability of the preparation process.
The results of the titer detection of the hemagglutination inhibition antibody against the H3N2 antigen show that the titer detection results after adding the surfactants of triton and Tween 80 are lower than those of the vaccine+emulsion adjuvant group directly mixed with the buffer system in the phosphate buffer system and the acetate buffer system, and meanwhile, the buffer system with the optimal comprehensive balance is Gr3 group (Gr 3 group is 763 and Gr7 group is 449) while referring to the stability of the preparation process, and the preparation process and the surfactant link are avoided.
The results of the measurement of the titer of the hemagglutination-inhibiting antibody against the B/V antigen showed that the results of the measurement of the titer after adding the surfactants triton and Tween 80 were lower in the acetate buffer system and the carbonate buffer system than in the vaccine+emulsion adjuvant group directly mixed with the buffer system, while referring to the stability of the formulation process, the buffer system with the best overall balance was Gr3 group (Gr 3 group is 2851, gr7 group is 2308) and G4 group (Gr 4 group is 2263, and Gr8 group is 2016) while avoiding the addition of the formulation process and the surfactant link.
The results of the titer detection of the hemagglutination inhibition antibody for the B/Y antigen show that the titer detection result after adding the surfactant triton and tween 80 is lower than that of the vaccine+emulsion adjuvant group directly mixed with the buffer system in the acetate buffer system, and meanwhile, the stability of the preparation process is referred to, and the buffer system with the optimal comprehensive balance is Gr3 group (Gr 3 group is 2411 and Gr7 group is 1425) in the process of avoiding adding preparation procedures and surfactant links.
Combining the tetravalent different antigens of the influenza and combining the detection results of the titer of the hemagglutination inhibition antibodies, wherein the optimal group is the G3 group, namely a vaccine finished product and an emulsion adjuvant group which are independently mixed in an acetate buffer liquid system.
The detection result of the titer of the hemagglutination inhibition antibody after the surfactant is added to the antigen is not obviously different from the detection result without the surfactant, which indicates that the buffer system and the surfactant have no obvious influence on the immune effect.
The foregoing description of the embodiments has been provided for the purpose of illustrating the general principles of the invention, and is not meant to limit the invention thereto, but to limit the invention thereto, and any modifications, equivalents, improvements and equivalents thereof may be made without departing from the spirit and principles of the invention.
Claims (21)
1. An influenza vaccine composition comprising a first component comprising an influenza virus antigenic material and a second component comprising an oil-in-water adjuvant comprising squalene, alpha tocopherol and tween 80, separately packaged.
2. The influenza vaccine composition according to claim 1, wherein the influenza virus antigenic material is an attenuated live vaccine, an inactivated vaccine, a toxoid vaccine, a subunit vaccine, a vector vaccine, a genetically engineered vaccine or a nucleic acid vaccine finished product formulation.
3. The influenza vaccine composition of claim 2, wherein the first component comprises an aluminum adjuvant.
4. The influenza vaccine composition according to claim 1, wherein the aluminium adjuvant is selected from at least one of aluminium hydroxide, aluminium phosphate, aluminium sulphate and alum.
5. Influenza vaccine composition according to claim 1, characterized in that the content of aluminium adjuvant in the first component is 10-1000 μg, preferably 50-800 μg.
6. The influenza vaccine composition of claim 1, wherein the first component is a lyophilized formulation, solution or suspension.
7. Influenza vaccine composition according to claim 6, wherein the solution or suspension of the first component has a volume of 0.2-1ml, preferably 0.5ml.
8. The influenza vaccine composition according to any one of claims 1-7, wherein said first component is an inactivated influenza vaccine finished formulation.
9. The influenza vaccine composition according to claim 1, wherein the oil-in-water adjuvant comprises 5-15mg squalene, 5-15mg alpha-tocopherol and 2-10mg tween 80, preferably the oil-in-water adjuvant comprises 10.69mg squalene, 11.86mg alpha-tocopherol and 4.86mg tween 80.
10. Influenza vaccine composition according to claim 1 or 9, wherein the volume of the oil-in-water adjuvant is 0.2-1ml, preferably 0.5ml.
11. The influenza vaccine composition according to claim 1, wherein the aqueous phase of the oil-in-water adjuvant is a buffer solution selected from the group consisting of phosphate buffer, citrate buffer, tris-HCl buffer, acetate buffer, carbonate buffer and citric acid-phosphate buffer.
12. The influenza vaccine composition of claim 1, wherein the first component does not comprise a surfactant.
13. The influenza vaccine composition of claim 12, wherein the first component comprises an individually packaged influenza virus antigen, does not comprise the surfactants Triton X-100 and tween 80, and the second component is an oil-in-water adjuvant, the aqueous phase of the adjuvant being pH 5.65 ± 0.5, an acetate buffer comprising acetic acid and sodium acetate.
14. The influenza vaccine composition of claim 13, wherein the first component is an individually packaged influenza virus antigenic material, each type of antigen is 1.5 μg, no surfactant Triton X-100 and tween 80 is included, and the second component is 0.5ml of an oil-in-water emulsion adjuvant comprising 10.69mg squalene, 11.86mg α -tocopherol, 4.86mg tween 80, 6.72mg anhydrous sodium acetate and 0.49mg acetic acid.
15. The influenza vaccine composition of claim 14, wherein the first component is an individually packaged tetravalent or trivalent influenza virus antigenic substance, each type of antigen is 1.5 μg, and the second component is 0.5ml of an oil-in-water emulsion adjuvant comprising 10.69mg squalene, 11.86mg α -tocopherol, 4.86mg tween 80, 6.72mg anhydrous sodium acetate, and 0.49mg acetic acid.
16. The influenza vaccine composition of claim 1, wherein the oil-in-water adjuvant further comprises 3D-MPL, saponins, poly I: c and CpG.
17. A method of preparing an influenza vaccine composition according to any one of claims 1 to 16, said method comprising the steps of:
(i) Preparing a first component comprising an influenza virus antigen and an aluminium adjuvant;
(ii) Preparing as a second component an oil-in-water adjuvant comprising squalene, alpha-tocopherol and tween 80;
(iii) Packaging the first component and the second component separately to obtain influenza vaccine composition,
Wherein steps (i) and (ii) may be performed in either order, including sequentially, simultaneously or in separate sites.
18. A method of preparing the influenza vaccine composition of claim 17, the method comprising the steps of:
(i) Preparing a first component comprising an influenza virus antigen;
(ii) Preparing as a second component an aqueous phase comprising an acetate buffer having a pH of 5.65±0.5, an oil-in-water adjuvant of squalene, α -tocopherol and tween 80;
(iii) Packaging the first component and the second component separately to obtain influenza vaccine composition,
Wherein steps (i) and (ii) may be performed in either order, including sequentially, simultaneously or in separate sites.
19. Use of an influenza vaccine composition according to any one of claims 1 to 16 in the manufacture of a medicament for the treatment or prophylaxis of influenza.
20. A multi-chamber syringe comprising the influenza vaccine composition of any one of claims 1-16, characterized by comprising a first chamber and a second chamber, said first chamber containing a first component, said first component comprising an influenza virus antigenic material; the second compartment contains a second component comprising an oil-in-water adjuvant comprising squalene, alpha-tocopherol and tween 80, the aqueous phase being an acetate buffer having a pH of 5.65±0.5.
21. A kit comprising the influenza vaccine composition of any one of claims 1-16, comprising a first component comprising an influenza virus antigenic material and a second component comprising an oil-in-water adjuvant comprising squalene, alpha-tocopherol and tween 80, separately packaged, the aqueous phase being a pH 5.65 ± 0.5 acetate buffer.
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