WO2021206103A1 - Vaccin pour une administration sous-cutanée - Google Patents
Vaccin pour une administration sous-cutanée Download PDFInfo
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- WO2021206103A1 WO2021206103A1 PCT/JP2021/014677 JP2021014677W WO2021206103A1 WO 2021206103 A1 WO2021206103 A1 WO 2021206103A1 JP 2021014677 W JP2021014677 W JP 2021014677W WO 2021206103 A1 WO2021206103 A1 WO 2021206103A1
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- antigen protein
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Definitions
- the present invention relates to a subcutaneously administered vaccine that effectively induces blood immune IgG.
- an immunostimulant that has been used for subcutaneously administered vaccines that pass antigen information to antigen-presenting cells in tissues by passing through a skin barrier with a syringe or the like, it has a function of retaining the antigen in the tissue for a long time and gradually releases the antigen.
- Aluminum salts (aluminum chloride / aluminum hydroxide / aluminum phosphate / aluminum sulfate, etc.), AS04 (Aluminum chloride / Aluminum hydroxide / Aluminum phosphate / Aluminum sulfate, etc.)
- Bacterial-derived substances including lipid phosphate A), emulsifier adjuvants such as squalane (AS03, MF59, etc.) are known, and among them, aluminum salts are most widely used in human subcutaneous vaccines.
- lipid phosphate A lipid phosphate A
- emulsifier adjuvants such as squalane
- it is an adjuvant (Non-Patent Document 1), according to recent academic research, it cannot be said that it has a high immunoinducing amplification effect, and it may cause symptoms such as pain at the administration site and leaving a lump. It has been pointed out as a problem.
- transmucosal-administered vaccines that enhance the function of presenting antigen information to antigen-presenting cells in mucosal tissues have attracted attention because they can induce secretory IgA antibodies as well as serum IgG antibodies.
- a lung surfantigen covering the surface of the mucosa of the lungs and airways, which acts as a surfactant, as a mucosal adjuvant in a transmucosal administration type vaccine (see, for example, Patent Documents 1 and 2).
- Antigen-specific IgG-inducing action in serum, airway mucosa (nasal lavage fluid) antigen-specific secretory IgA-inducing action see, for example, Patent Document 4 and Non-Patent Document 2)
- cell-mediated immunity-inducing action for example, Non-Patent Document 3 See).
- the inventors Based on the composition of the above-mentioned lung surfactant, the inventors have proposed an artificially synthesized pulmonary surfactant having a function of transporting an antigen to an antigen-presenting cell, and combine this with a function of retaining the antigen on the mucosal surface and a sustained-release function.
- a nasal (transairway) -administered influenza vaccine as a safe and effective mucosal adjuvant by adding carboxyvinyl polymer (CVP), which is a thickener (see, for example, Patent Documents 3 and 4). .
- CVP carboxyvinyl polymer
- the nasal mucosa has cilia and is covered with a mucous layer filled with mucus. After adhering to mucus together with dust and bacteria, it is quickly sent to the throat by a strong excretion action. Therefore, in order to enhance the effect of the transmucosal-administered vaccine, it is necessary to increase the amount of antigen, means for retaining the antigen in the mucosa for a long period of time, and the like, and it has hardly been put into practical use.
- Antigen viruses such as influenza virus, which is the cause of seasonal influenza that is prevalent in the world every year, and COVID-19, which is an urgent issue, are mutated in various ways. Therefore, vaccine manufacturers always have the problem of having to secure a large amount of suitable antigens. In such a situation, it is possible to vaccinate many humans by using a smaller amount of antigen protein than before, and it has an excellent effect of inducing an antigen-specific blood IgG antibody, and at the administration site. The challenge is to provide a subcutaneously administered vaccine that does not have problems such as leaving a painful lump.
- the present inventors have re-verified the vaccine administration route for the components used in the mucosal vaccine.
- SF-10 which has been used for mucosal vaccines, works extremely effectively even when used for subcutaneous vaccines, and the amount of antigen protein used in such subcutaneous vaccines is higher than that for mucosal vaccines.
- the vaccine of the present invention is superior to the subcutaneously administered vaccine using a conventional aluminum salt as an adjuvant in the antigen-specific IgG antibody induction promoting effect, and hardly leaves a lump at the subcutaneously administered site. After confirmation, the present invention has been completed.
- a subcutaneously-administered vaccine comprising an antigen protein and an adjuvant containing the following (a) to (c).
- the phospholipid in the phospholipid-containing liquid is one or more selected from dipalmitylphosphatidylcholine, phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, and phosphatidylic acid.
- the subcutaneous administration type vaccine according to any one of [1] to [4].
- the phospholipid-containing liquid further contains one or more types of lipids other than phospholipids selected from lauric acid, myristic acid, palmitic acid, stearic acid, palmitooleic acid, and oleic acid.
- the subcutaneous administration type vaccine according to any one of the above [1] to [5].
- a method for producing a subcutaneously administered vaccine which comprises the following steps (a) to (c) in sequence.
- (A) A step of preparing an SSF suspension by suspending a synthetic peptide consisting of an amino acid sequence of KnLm (where n is 4-8 and m is 11-20) and a phospholipid-containing liquid in water.
- step (B) A step of preparing an antigen protein-SSF uniform suspension by adding the antigen protein to the SSF suspension prepared in step (a) and mixing with shaking and stirring;
- step (C) A step of preparing a subcutaneously-administered vaccine containing an antigen protein and an adjuvant by adding a carboxyvinyl polymer solution to the antigen protein-SSF uniform suspension prepared in step (b); [12] After step (b) (B') A step of preparing an antigen protein-SSF lyophilized product by lyophilizing the antigen protein-SSF uniform suspension prepared in step (b); and before step (c), (B ′′) A step of suspending the antigen protein-SSF lyophilized product prepared in step (b ′) in water or physiological saline to prepare an antigen protein-SSF uniform suspension; The method for producing a subcutaneously administered vaccine according to the above [11].
- the subcutaneously administered vaccine of the present invention it is added to the conventional transmucosal vaccine as an adjuvant rather than the conventionally used vaccine to which aluminum hydroxide salt is added, without causing pain or lump at the vaccine administration site.
- the adjuvant of the present invention containing CVP By using the adjuvant of the present invention containing CVP, a remarkably effective effect of inducing an IgG antibody in blood, an increase in survival rate after virus infection, a recovery of body weight, and the like are brought about.
- (A) The results of the subcutaneously administered vaccine using the serum anti-HAIgG antibody titer (titer) as an index are shown. It is a graph which shows the result of having compared the effect of addition of no adjuvant, aluminum hydroxide salt adjuvant, and SF-10 adjuvant by changing the concentration of influenza virus HA antigen amount in the range of 0.1-1.0 ⁇ g.
- (B) It is a graph which shows the result of FIG. 1 (a) using the value which converted the antibody titer into the amount of anti-HAIgG antibody as an index.
- Serum anti-HAIgG when the antigen protein concentration [HA] of the HA solution was fixed at 1.0 ⁇ g / 100 ⁇ L and the CVP concentration contained in SF-10 was changed in the range of 0.01 to 0.5% by mass. It is a graph which shows the result using the antibody titer as an index. It is a graph which shows (A) the anti-HAIgG antibody titer in the serum of the mouse which was nasally infected with the virus after inoculation of the subcutaneous administration type vaccine, and (B) the survival rate with time up to 2 weeks after the nasal infection of the virus. It is a graph which shows the body weight change of the mouse which was nasally infected with the virus after inoculation of the subcutaneous administration type vaccine.
- the vaccine of the present invention includes an antigen protein; a synthetic peptide consisting of an amino acid sequence of (a) KnLm (where n is 4-8 and m is 11-20), (b) a phospholipid-containing solution, and (c).
- the vaccine of the present invention is not particularly limited as long as it is a subcutaneously administered vaccine including an adjuvant having an immunopotentiating effect (sometimes referred to as "SF-10") containing a carboxyvinyl polymer (solution).
- SF-10 immunopotentiating effect
- the subcutaneously-administered vaccine (sometimes referred to as a transdermal-administered vaccine) in the present invention includes a subcutaneously-administered vaccine in which a drug is administered (preferably injected) to the adipose tissue under the skin, as well as in the dermal tissue of the skin.
- a subcutaneously-administered vaccine in which a drug is administered (preferably injected) to the adipose tissue under the skin, as well as in the dermal tissue of the skin.
- An intradermal vaccine or an intramuscular vaccine in which a drug is administered (preferably by injection) can be exemplified.
- the synthetic peptide consisting of the above KnLm amino acid sequence is composed of n K (lysine: Lys) residues on the N-terminal side and m L (leucine: Leu) residues on the C-terminal side in succession.
- the amino acid sequence is not particularly limited as long as it is a synthetic peptide consisting of an amino acid sequence of 4-8 and m of 11-20, but specific examples thereof include the following peptides. Amino acid residues are indicated by single-letter symbols.
- the synthetic peptide having a purity of 95% or more which is prepared according to a known chemical synthesis method.
- the synthetic peptide is preferably dissolved in an organic solvent such as methanol, ethanol, or trifluoroacetic acid that does not affect the synthetic peptide structure and added to the vaccine as a K6L16 peptide-containing solution, for example, 3 mg to 7 mg / mL. It can be used as a K6L16 peptide-containing solution dissolved in methanol to a concentration.
- an organic solvent such as methanol, ethanol, or trifluoroacetic acid
- the phospholipid-containing liquid in the present invention is not particularly limited as long as it is a liquid containing phospholipids, and may further contain lipids other than phospholipids.
- phospholipids phospholipids contained in natural lung surfactants are used.
- specific examples thereof include phosphatidylcholine, dipalmitylphosphatidylcholine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidic acid, sphingomyelin and the like, and the phospholipid may be used alone or in 2 types.
- a combination of dipalmitoyl phosphatidylcholine and phosphatidylglycerol can be preferably mentioned.
- the blending ratio is as follows: dipalmitoylphosphatidylcholine: phosphatidylglycerol is 10: 1 to 1:10, 5: 1 to 1: 5. 4: 1 to 1: 1 and 3.5: 1 to 2.5: 1 can be exemplified.
- lipids other than phospholipids contained in the above phospholipid-containing liquid include lauric acid, myristic acid, palmitic acid, stearic acid, palmitooleic acid, and oleic acid.
- the ratio of the content (mass) of phospholipids and lipids other than phospholipids contained in the above phospholipid-containing liquid 100: 1 to 30 for phospholipids: lipids other than phospholipids can be mentioned, and 100: 5 To 15 is preferable, 100: 8 to 12 is more preferable, 100: 9 to 11 is further preferable, and 100: 9.5 to 10.5 is particularly preferable.
- a composition containing the above-mentioned phospholipid-containing solution, a synthetic peptide consisting of the amino acid sequence of KnLm, and an appropriate solvent, or a composition comprising the above-mentioned phospholipid-containing solution is referred to as "SSF (Synthetic pulmonary surfactant)" or "AD vehicle".
- SSF synthetic pulmonary surfactant
- the ratio of the mass of the phospholipid-containing solution to the synthetic peptide in SSF, that is, the phospholipid-containing solution: synthetic peptide can be 100: 0.1 to 50, preferably 100: 0.5 to 10, 100. 1 to 5 is more preferable, and 100: 1.5 to 3 is even more preferable.
- the antigen protein (class) is not particularly limited as long as it can be used as an antigen for a vaccine, but by inducing immunity to the antigen protein in the body, prevention of diseases caused by the pathogen from which the antigen protein is derived can be prevented.
- those that can be expected to be cured can be mentioned, and in addition to proteins derived from general pathogens, inactivated antigen proteins, recombinant antigen proteins, detoxified toxin proteins, etc. can be exemplified, and all (mature).
- antigen proteins including preproteins, preproproteins, and their functional or immunodominant antigenic peptides can also be used.
- pathogen examples include viruses, bacteria, and parasites.
- the above viruses include varicella virus, measles virus, poliovirus, rotavirus, influenza virus, herpesvirus, severe acute respiratory infection syndrome (SARS) virus, new coronavirus (COVID-19), Ebola hemorrhagic fever virus, and Westnile.
- SARS severe acute respiratory infection syndrome
- COVID-19 new coronavirus
- Ebola hemorrhagic fever virus and Westnile.
- virus hunter virus, dengue virus, Japanese encephalitis virus, yellow fever virus, tick-mediated encephalitis virus, HIV virus and the like.
- bacterium examples include pertussis, meningococcus, influenza b, pneumonia, cholera, and the like
- examples of the parasite include malaria pathogen, sleep disease pathogen, and the like.
- the antigen protein include an antigenic glycoprotein existing on the surface of a virus such as hemagglutinin (hemagglutinin: HA) antigen protein, neurominidase antigen protein, and M protein.
- hemagglutinin hemagglutinin: HA
- neurominidase antigen protein hemagglutinin: M protein
- examples include internal nucleoproteins and the like.
- the content (mass) of the antigen protein in the vaccine of the present invention is not particularly limited as long as the effect of the present invention is exhibited, but in the case where the above hemagglutinin is used as the antigen protein, the content of the hemagglutinin (HA) antigen protein is taken as an example.
- the content of the hemagglutinin (HA) antigen protein is taken as an example.
- the notation can be given by the amount of hemagglutinin antigen protein, which is easier to measure than SRD quantification, and the amount of protein indicating the total amount of other antigen proteins. .. That is, in the latter case, the mass of the HA antigen protein in the HA antigen protein solution using the hemagglutinin (HA) of the influenza virus means the mass of the total protein including the HA antigen protein and the antigenic protein other than the HA antigen protein. In that case, it is expressed as the mass (amount of HA antigen protein) or concentration of HA antigen protein in the present invention.
- the HA antigen protein concentration in the vaccine of the present invention can be exemplified by 0.05 ⁇ g to 5 ⁇ g / 100 ⁇ L, preferably 0.06 ⁇ g to 2 ⁇ g / 100 ⁇ L, more preferably 0.07 ⁇ g to 1.5 ⁇ g / 100 ⁇ L, and 0. .08 ⁇ g to 1.1 ⁇ g / 100 ⁇ L is more preferable, 0.08 to 0.5 ⁇ g / 100 ⁇ L is further preferable, and 0.09 to 0.12 ⁇ g / 100 ⁇ L is particularly preferable.
- 0.08 ⁇ g to 0.15 ⁇ g / 100 ⁇ L is more preferable, 0.08 to 0.12 ⁇ g / 100 ⁇ L is even more preferable, and 0.09 to 0.11 ⁇ g is more preferable for increasing the survival rate of the vaccinated subject.
- / 100 ⁇ L is particularly preferable.
- 0.6 ⁇ g to 2 ⁇ g / 100 ⁇ L is preferred, 0.7 ⁇ g to 1.5 ⁇ g / 100 ⁇ L is more preferred, 0.8 ⁇ g to 1.2 ⁇ g. / 100 ⁇ L is more preferable.
- the production method for sufficiently securing the above-mentioned antigen protein (or antigen peptide) for vaccine production is not particularly limited as long as it is a known method, and it is produced by a method produced by gene recombination technology or by chemical synthesis. The method can be mentioned.
- the mass ratio of the phospholipid-containing solution to the antigen protein is not particularly limited as long as the effect of the present invention can be obtained, but 0.1 to 20 can be mentioned. 1 to 18 is preferable, 5 to 15 is more preferable, 8 to 12 is further preferable, and 9 to 11 is even more preferable.
- the CVP is a hydrophilic polymer obtained by polymerizing acrylic acid, and the molecular weight and the like are not particularly limited, but it is preferable that the CVP conforms to the pharmaceutical additive standard 2018.
- Commercially available products include 971PNF (0.5%, 25 ° C, 4,000 to 11,000cps), 974PNF (0.5%, 25 ° C, 29,400 to 39,400cps), 71GNF of the CARBOPOL® series of Lubrizol Advanced Materials, Inc.
- the concentration of CVP in the subcutaneously administered vaccine of the present invention is not particularly limited as long as the effects of the present invention are exhibited, but is 0.02 to 2.0% by mass, preferably 0.05 to 2.0% by mass of CVP. If the CVP concentration is 0.01% by mass or less, the survival rate may be lowered. Further, 0.05 to 0.1% by mass is preferable in that induration is unlikely to occur at the administration site while sufficiently inducing the IgG antibody in blood. In order to maintain the antigenicity of the antigenic protein, it is preferable to adjust the pH of the CVP solution, and the pH may be pH 5.0-10.5, preferably pH 6.8-8.0. , PH 7.0-7.2 is more preferable.
- the number of administrations of the vaccine of the present invention is not particularly limited as long as the vaccine of the present invention is effective, but may be given once or multiple times, preferably once or twice. Two doses can be preferably mentioned, and it is preferable to administer the second dose 1 week to 1 month after the first dose, preferably 10 days to 2 weeks later.
- Examples of the method for producing a subcutaneously administered vaccine of the present invention include a production method in which the following steps (a) to (c) are sequentially provided.
- (A) A step of preparing an SSF suspension by suspending a synthetic peptide consisting of an amino acid sequence of KnLm (where n is 4-8 and m is 11-20) and a phospholipid-containing liquid in water.
- step (B) A step of preparing an antigen protein-SSF uniform suspension by adding the antigen protein to the SSF suspension prepared in step (a) and mixing with shaking and stirring;
- step (C) A step of preparing a subcutaneously-administered vaccine containing an antigen protein and an adjuvant by further adding a carboxyvinyl polymer solution to the antigen protein-SSF uniform suspension prepared in step (b);
- step (B) A step of preparing an antigen protein-SSF lyophilized product by lyophilizing the antigen protein-SSF uniform suspension prepared in step (b); And before step (c), (B ′′) A step of suspending the antigen protein-SSF lyophilized product prepared in step (b ′) in water or physiological saline to prepare an antigen protein-SSF uniform suspension; May be further provided.
- a synthetic peptide consisting of an amino acid sequence of KnLm (where n is 4-8 and m is 11-20) and a phospholipid-containing liquid are suspended in water.
- the liquid is not particularly limited as long as it is a liquid prepared by turbidity, and the ratio of the mass of the phospholipid-containing liquid to the synthetic peptide in the SSF suspension, that is, the phospholipid-containing liquid: synthetic peptide is 100: 0. 1 to 50 can be mentioned, 100: 0.5 to 10 is preferable, 100: 1 to 5 is more preferable, and 100: 1.5 to 3 is further preferable.
- organic solvent 100: 1 to 50, preferably 100: 2 to 25, more preferably 100: 5 to 15, and further. It is convenient to suspend it in water, preferably 100: 8 to 12), and in this case, it contains a synthetic peptide consisting of the amino acid sequence of KnLm and the lipid solution, or It becomes an SSF suspension consisting of.
- the antigen protein-SSF uniform suspension prepared in the above step (b) is the SSF suspension prepared in the above step (a) in a water bath of, for example, 30 to 60 ° C., preferably 40 to 50 ° C.
- SF-10-added final vaccination solution which is a subcutaneously administered vaccine containing SF-10 type adjuvant and an antigen protein, can be mentioned, and the concentration of CVP in the vaccine is 0.02 to 2.0% by mass, preferably 0.05 to 2.0% by mass can be mentioned.
- a homogenizer a mixer, a shaker, a stirrer or the like.
- a CVP solution is first prepared by adjusting the pH with a NaOH neutralizing solution, and then an antigen protein-SSF uniform suspension is prepared. Is preferably added.
- the step (b') and the step (b ") can be provided after the step (b), and the antigen protein-SSF freeze-dried product prepared in the step (b') includes the above-mentioned antigen protein-SSF.
- the uniform suspension is not particularly limited as long as it is a solid obtained by freeze-drying, and the freeze-drying process temperature of the above-mentioned freeze-drying can be -80 ° C to -60 ° C.
- the lyophilized product is preferably stored at ⁇ 30 ° C.
- the antigen protein-SSF lyophilized product prepared in step (b ′) is suspended in water and / or physiological saline and administered subcutaneously.
- examples thereof include an antigen protein-SSF uniform suspension prepared by adjusting the concentration to a predetermined concentration suitable for the formulation of a type vaccine.
- mice Using mice, the inducing effect of anti-influenza virus-specific IgG antibody in a subcutaneously administered influenza vaccine was evaluated. Subsequent animal experiments were conducted at the Infectious Animal Care Center (P2 level) of the Experimental Animal Center of the Tokushima University School of Medicine, and were conducted in accordance with the guidelines of the Animal Care and Use Committee of the Tokushima University School of Medicine.
- P2 level Infectious Animal Care Center
- a BALB / c mouse (6-8 weeks old, female, average body weight 20 g) was purchased from Nippon SLC Co., Ltd. and used.
- mice subcutaneous administration solutions In order to verify the effect of influenza virus hemagglutinin (HA) as a vaccine, various mouse subcutaneous administration solutions for subcutaneous administration to the dorsal neck of mice were prepared.
- HA hemagglutinin
- DPPC dipalmitoylphosphatidylcholine
- PG phosphatidylglycerol
- PA palmitic acid
- DPPC dipalmitoylphosphatidylcholine
- PG phosphatidylglycerol
- PA palmitic acid
- DPPC dipalmitoylphosphatidylcholine
- PG phosphatidylglycerol
- palmitin so that the phospholipid composed of dipalmitoylphosphatidylcholine (DPPC) and phosphatidylglycerol (PG) has a final concentration of 10 mg / mL.
- the acid (PA) was suspended in a chloroform: methanol (2: 1 (v / v)) mixture at a ratio of 75:25:10 (w / w / w) to prepare a lipid solution.
- a uniform suspension of the K6L16 mixture was prepared.
- the SSF suspension was lyophilized by a lyophilizer and stored as lyophilized SSF at ⁇ 30 ° C.
- Daiichi Sankyo Co., Ltd. prepared a vaccine antigen solution from a vaccine strain provided by the National Institute of Infectious Diseases, and prepared an HA antigen protein solution from the A / Singapore / GP1908 / 2015 (H1N1) strain provided to Tokushima University for a fee. bottom.
- HA + SF-10-containing liquid 1 For vaccine administration, it was decided to prepare 100 ⁇ L / dose of HA + SF-10-containing solution.
- the above HA + SSF is dissolved in physiological saline to adjust the HA antigen protein concentration ([HA]) of the HA antigen protein solution to 0.1 ⁇ g / 100 ⁇ L, 0.5 ⁇ g / 100 ⁇ L, and 1.0 ⁇ g / 100 ⁇ L, respectively.
- a sustained-release carboxyvinyl polymer (CVP) CARBOPOL® 971P NF POLYMER, manufactured by Lubrizol Advanced Materials, Inc.
- each 100 ⁇ L of each HA + Alm-containing solution (g) and (h) was prepared as a subcutaneous administration solution. Since the aluminum hydroxide salt was dissolved in MilliQ water and then added, the NaCl concentration here was 0.45% by mass. Details are shown in Table 3 below.
- Example 2 [Vaccine administration to mice 1] The subcutaneous administration solutions of (a) to (h) above were administered as a vaccine, and the inducing action of the serum anti-HA specific IgG antibody was evaluated. As a mouse, a 6-8 week old BALB / c female mouse (manufactured by Nippon SLC Co., Ltd.) was used.
- mice With 5-6 mice as one administration group, 100 ⁇ L of each of the subcutaneous administration solutions (a) to (h) above was subcutaneously administered to the back of the neck of the mice in each group as initial immunity. Mice to which the vaccine was administered as the primary immunization were subcutaneously administered to the back of the neck as the second vaccine (secondary immunity) with 100 ⁇ L of a mouse subcutaneous administration solution having the same composition 2 weeks after the initial immunization.
- mice administered twice in each group were euthanized by intraperitoneal overdose of titozol (200 ⁇ L), and then blood was collected from the heart to collect a blood sample and coagulate. Serum was prepared by centrifuging the blood sample at 5000 rpm for 10 minutes. Although the vaccine was administered twice in total, it was judged that a further booster immunization test was unnecessary because sufficient results were obtained with secondary immunization in an infection protection test for investigating the survival rate of mice.
- Serum prepared from the blood of each group of mice prepared above was subjected to ELISA using Mouse ELISA quantitation of BETHYL LABORATORIES (USA) according to the attached instruction manual. Specifically, 0.1 ⁇ g of HA antigen protein was added as an antigen to each well of a 96-well Nunc immunoplate (Nalgen Nunc International, USA), and 1 ⁇ g / mL of bovine serum albumin (Bovine Serum Albumin; BSA, USA) was added. (Manufactured by SIGMA, USA) and 100 ⁇ L of PBS solution were added, and an overnight solidification reaction was carried out at 4 ° C.
- the plate was then rinsed 5 times with a wash solution (50 mM Tris, 0.14M NaCl, 0.05% Tween 20, pH 8.0). Then, 200 ⁇ L of 50 mM Tris-HCl buffer (pH 8.0) containing 0.14 M NaCl and 200 ⁇ L of 1% BSA was added to each well, and a blocking reaction was carried out at 4 ° C. for 18 to 24 hours. After that, each well was rinsed 5 times with the above washing solution, and then 100 ⁇ L of serum was added with a sample binding buffer (50 mM Tris, 0.14 MNaCl, 1% BSA, 0.05% Tween 20, pH 8.0), followed by continuation.
- a wash solution 50 mM Tris, 0.14M NaCl, 0.05% Tween 20, pH 8.0
- 50 mM Tris-HCl buffer pH 8.0
- Two-step dilution was performed to prepare sample dilutions from 128,000 to 1,280,000 times as the final dilution ratio.
- the sample diluent was reacted with the immobilized antigen at 4 ° C. for 16 to 18 hours.
- TMB Microwell Peroxidase Substrate System Kirkegaard &) using Goat anti-mouse IgA-horse radish peroxidase (HRP-IgA) or Goat anti-mouse IgG-horse radish peroxidase (HRP-IgG) (BETHYL LABORATORIES INC.)
- HRP-IgA Goat anti-mouse IgA-horse radish peroxidase
- HRP-IgG Goat anti-mouse IgG-horse radish peroxidase
- BETHYL LABORATORIES INC. BETHYL LABORATORIES INC.
- the reaction was stopped by adding 50 ⁇ L of 2M H 2 SO 4 (manufactured by Wako Pure Chemical Industries, Ltd.) to each well, and the absorbance at 450 nm was measured with SPECTRA max PLUS 384 (manufactured by MOLECULAR DEVICES).
- SPECTRA max PLUS 384 manufactured by MOLECULAR DEVICES.
- FIG. 1 (a) The result of antibody titer measurement (Titor notation) is shown in FIG. 1 (a).
- HA single solution administration group (reference example) The HA single solution in which the antigen protein concentration [HA] of the HA solution of Comparative Example 1 is (d) 0.1 ⁇ g / 100 ⁇ L, (e) 0.5 ⁇ g / 100 ⁇ L, and (f) 1.0 ⁇ g / 100 ⁇ L is administered.
- the antibody titer (titer) of the anti-HA-specific IgG antibody was 36758 in the HA-only administration group, and there was no statistically significant difference between the groups. It was suggested that the plateau was exhibited when the antigen protein concentration [HA] was 0.1 ⁇ g / 100 ⁇ L or higher.
- HA + Alm-containing liquid administration group (reference example) Antibodies in the HA + Alm-containing solution-administered group to which the HA + Alm-containing solution in which the antigen protein concentration [HA] of the HA solution of Comparative Example 2 was (g) 0.5 ⁇ g / 100 ⁇ L and (h) 1.0 ⁇ g / 100 ⁇ L was administered.
- the antibody titers (titers) of the HA-specific IgG antibody were 97006 and 73517, but there was no statistically significant difference between the two groups, and in the HA + Alm-containing solution-administered group, the antigen protein concentration of the HA solution [HA].
- the antigen protein concentration [HA] of the HA solution of Example 1 is (a) 0.1 ⁇ g / 100 ⁇ L, (b) 0.5 ⁇ g / 100 ⁇ L, and (c) 1.0 ⁇ g / 100 ⁇ L, and the CVP concentration is all.
- the antibody titer (titer) of the anti-HA-specific IgG antibody was It increased as the HA concentration increased, but when [HA] was (b) 0.5 ⁇ g / 100 ⁇ L and (c) 1.0 ⁇ g / 100 ⁇ L, it showed 235253, and when it was 0.5 ⁇ g / 100 ⁇ L or more, the plateau was almost formed. It was suggested to show.
- the antigen protein concentration ([HA]) of the HA solution of Example 1 was (a) 0.1 ⁇ g / 100 ⁇ L, (b) 0.5 ⁇ g / 100 ⁇ L, and (c) 1.0 ⁇ g / 100 ⁇ L, and the CVP concentration was high.
- (A) shows 2597 ⁇ g / mL in the case of 0.1 ⁇ g / 100 ⁇ L
- (b) shows 4997 ⁇ g / mL in the case of 0.5 ⁇ g / 100 ⁇ L
- (c) shows 5651 ⁇ g / mL in the case of 1.0 ⁇ g / 100 ⁇ L, 0.5 ⁇ g. It was confirmed that the plateau was almost exhibited at / 100 ⁇ L or more.
- the antibody titer against the A / Singapore / GP1908 / 2015 (H1N1) strain in this example (FIG. 1 (b)) is the same, although the calibration curve of ELISA is different for the virus strain because there is no purified standard antibody. This is the result of quantification using the calibration curve of A / California (H1N1) shown in WO2011 / 08521 for the H1N1 strain. Since there is almost no difference in HA molecular weight between H1N1 strains, it is considered that the value of antibody titer ( ⁇ g / mL) falls within the error range.
- Example 3 [Examination of CVP concentration and NaCl concentration in HA + SF-10-containing liquid] Since the thickening action and sustained-release action of CVP may depend on the NaCl concentration in addition to the CVP concentration, it was decided to search for the optimum combination of the CVP concentration and the NaCl concentration in the HA + SF-10-containing administration solution.
- the HA antigen protein contained in 100 ⁇ L of the HA + SF-10-containing administration solution was fixed at 1 ⁇ g
- the amount of phospholipid was fixed at 10 ⁇ g
- the V / A ratio was 10.
- the concentration of CVP was 0.01% by mass, 0.1% by mass, or 0.5% by mass.
- mice With 5 to 6 mice as one administration group, 100 ⁇ L of each mouse subcutaneous administration solution of (i) to (l) above was subcutaneously administered to the back of the neck of the mice of each group as initial immunity. Two weeks after the initial immunization, 100 ⁇ L of a mouse subcutaneous administration solution having the same composition was administered to the cervical dorsal region as the second vaccine (secondary immunity) to the mice to which the vaccine was administered as the initial immunization.
- second vaccine secondary immunity
- Titer was 531400, showing the highest effect of inducing IgG antibody. This value was 14 times higher than that of the HA single solution administration group (f) 38505 and 8.3 times higher than that of the HA + Alm-containing solution administration group (h) 64000 times.
- the subcutaneous administration group of HA + SF-10 in (i) to (l) above showed a high inducing effect of IgG antibody with a significant difference as compared with the HA single solution administration group and the HA + Alm-containing solution administration group.
- HA + SF-10-containing solution HA + SF-10-containing solution (a) (0.1 ⁇ g / 100 ⁇ L [HA], 0.1% by mass CVP, 0.9% by mass NaCl) and HA + SF showing a high inducing effect of the above IgG antibody.
- Verification of infection protection effect of subcutaneously administered influenza vaccine using -10-containing solution HA + SF-10 (1.0 ⁇ g / 100 ⁇ L [HA], 0.1% by mass CVP, 0.9% by mass NaCl) bottom.
- mice With 5-6 mice as one administration group, 100 ⁇ L of each of the above-mentioned (a), (c), (h) and (f) mouse subcutaneous administration solutions was subcutaneously administered to the cervical dorsal region of the mice in each group as the initial immunization. bottom. Two weeks after the initial immunization, 100 ⁇ L of a mouse subcutaneous administration solution having the same composition was subcutaneously administered to the back of the neck as the second vaccine (secondary immunity) to the mice to which the vaccine was administered as the initial immunization.
- second vaccine secondary immunity
- the PR8 strain is derived from the human-derived Spanish flu-type H1N1 strain, but is a highly virulent virus strain for laboratories acclimatized to infect mice, and is widely and generally used in animal experiments of human influenza virus. Has been done.
- the anti-influenza HAIgG antibody titer is the same as the result shown in FIG.
- the administration group (titer: 235253) of (c) showed a 6.4-fold higher antibody titer, and the antibody titer was 3.2 times higher than that of the HA + Alm-containing solution (h) administration group (titer: 73517). showed that.
- the HA + SF-10-containing solution (a) administration group (titer: 84449) in which the amount of HA antigen was reduced to 1/10 (0.1 ⁇ g) was also 1.15 times that of the HA + Alm-containing solution administration group (h).
- the anti-influenza HA-specific IgG antibody titer was shown, even if the amount of HA antigen to be inoculated is reduced to 1/10, the effect is expected to be comparable to or higher than that of the conventional subcutaneously inoculated influenza vaccine. It has been found.
- FIG. 3 (B) showing the survival rate of the mice over time
- the mouse group to which the HA + Alm-containing solution (h) was administered and the mouse group to which the HA single solution (f) was administered were infected with the virus on the 14th day. While both eyes showed a survival rate of 40%, the mouse group administered with HA + SF-10 (a) and the mouse group administered with HA + SF-10 (c) both showed a survival rate of 100%, and HA + SF- Among the 10 subcutaneously administered groups, it showed excellent infection protection ability and survival rate. Therefore, it was judged that subcutaneous administration of 0.1 ⁇ g of HA solution antigen protein was sufficient as an effect for maintaining survival.
- the difference between the groups was clarified in the weight change during the recovery period after the 8th day of influenza infection. Among them, it was presumed that it was related to the worst weight recovery and the lowest increase in antibody titer in the HA single solution (f) -administered group.
- the HA + SF-10-containing solution (c) group (1.0 ⁇ g / 100 ⁇ L [HA], 0.1% by mass CVP, 0.9% by mass NaCl) had the highest value as compared with the other groups.
- Example 6 [Examination of CVP concentration in vaccine administration solution] In an infection experiment of a subcutaneously administered SF-10-added vaccine, the lowest concentration of CVP satisfying 100% mouse survival was examined.
- Example 3 the CVP concentration and the NaCl concentration of the HA + SF-10-containing solution were examined, but when the CVP concentration exceeds 0.1% by mass, in particular, 0.5% by mass causes caking after subcutaneous vaccination. In some cases, a slight hardening-like phenomenon is observed even at 0.1% by mass on rare occasions. This could not rule out the possibility that some CVP, which takes a long time to be absorbed at the inoculation site, remains. Therefore, the CVP concentration with a survival rate of 100% and no possibility of induration was examined. Details are shown in Table 5 below.
- mice With 6 mice as one administration group, 100 ⁇ L of each mouse subcutaneous administration solution (m) to (p) above was subcutaneously administered to the back of the neck of the mice in each group as initial immunity. Two weeks after the initial immunization, 100 ⁇ L of a mouse subcutaneous administration solution having the same composition was subcutaneously administered to the back of the neck as the second vaccine (secondary immunity) to the mice to which the vaccine was administered as the initial immunization. The results are shown in FIGS. 5-1 and 5-2.
- the HA + SF-10-containing solution administration group (m) (0.1 ⁇ g HA, 0.05% by mass CVP, 0.1% by mass NaCl) and the HA + SF-10-containing solution administration group (n).
- the IgG antibody induction value of (0.1 ⁇ g HA, 0.05% by mass CVP, 0.9% by mass NaCl) was higher in the vaccine solution containing 0.1% by mass NaCl in the vaccine solution containing 0.9% by mass NaCl. Although there was no significant difference, it tended to be higher than that. However, both infection protection effects showed 100% survival rate, and no difference was observed.
- FIG. 5-2 shows the results when the CVP concentration was further reduced and fixed at 0.01% mass% CVP.
- HA + SF-10-containing solution administration group (o) (0.1 ⁇ g HA, 0.01 mass% CVP, 0.1 mass% NaCl) and HA + SF-10-containing solution administration group (p) (0.1 ⁇ g HA, 0.01 mass)
- the IgG antibody induction value indicated by% CVP (% CVP, 0.9% by mass NaCl) remained at a low value in which the induction was enhanced by only about twice the antibody induction value of HA alone indicated by the group (f), and the CVP concentration was increased by the antibody. It was shown that it has a great influence on the induction.
- the vaccine solution containing 0.1% by mass NaCl showed a slightly higher tendency than the vaccine solution containing 0.9% by mass NaCl, although there was no significant difference.
- the infection protection effect since the survival rate decreased to 35% in both the groups (o) and (p), it was judged that the condition could not be said to show a strong infection protection effect.
- the CVP concentration is higher than 0.01% by mass CVP, optimally between 0.1 and 0.05% by mass, and 0.01% by mass CVP clearly reduces the survival rate.
- 0.01% by mass CVP clearly reduces the survival rate.
- both 0.1% by mass NaCl and 0.9% by mass NaCl are acceptable, but as shown in the example of FIG. 5-1.
- the 0.1% by mass NaCl solution tended to show a higher value in the anti-influenza HA IgG antibody induction value than the 0.9% by mass NaCl, although there was no significant difference.
- induration was not confirmed at the administration site in any case. From the above, it was determined that the risk of developing induration can be avoided while maintaining a high survival rate by setting the CVP concentration to 0.1 to 0.05% by mass.
- FIG. 6 shows the results of calculating the IgA antibody titer of anti-influenza HA in serum when two immunizations (day 0 and day 14) were performed under the same conditions as in Example 2.
- the test of oral administration type HA + SF-10 and transairway administration type HA + SF-10 which are known to significantly induce the IgA antibody titer of anti-influenza HA in serum, was changed to a V / A amount ratio of 10. It was also carried out.
- the dose of the antigen protein in the HA solution was 1.0 ⁇ g, which was the same as the subcutaneous administration type for both the oral administration type and the transairway administration type.
- the dose as a vaccine was changed according to the administration method, and 100 ⁇ L was inoculated in the case of subcutaneous administration, 200 ⁇ L in the case of oral administration, and 15 ⁇ L in each nose in the case of transairway administration, for a total of 30 ⁇ L.
- CVP for the subcutaneously administered vaccine, the concentrations contained in HA + SF-10 were set to 0.01%, 0.1% and 0.5% as in FIG. 2, and 0.9% NaCl and 0. The combination with 1% NaCl was examined.
- the CVP of the oral administration solution was 0.5% and 0.9% NaCl
- the CVP of the transairway administration was 0.1% and 0.1% NaCl. The results are shown in FIG.
- the IgA antibody titer of anti-influenza HA in serum did not increase in either the subcutaneously administered HA + SF-10 vaccine or the HA antigen alone, and was judged to be ineffective in inducing the IgA antibody titer. rice field.
- a clear inducing effect was confirmed between oral administration of HA + SF-10 vaccine and transairway administration of HA + SF-10 vaccine, but transairway administration was about 2.7 times higher than oral administration. Induction of high IgA antibody titers was observed.
- the vaccine of the present invention is very useful in the medical field.
- the dose to humans is administered by using various known methods such as a HED conversion method for estimating the dose at which the same effect is exhibited in humans from the body surface area of a test animal such as a mouse. It is a common practice to estimate and accumulate experimental data to promote practical use.
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Abstract
L'invention concerne un vaccin pour une administration sous-cutanée qui utilise une protéine antigénique dans une quantité moindre que celles des vaccins classiques, qui présente l'effet supérieur d'induction d'un anticorps IgG sanguin spécifique d'un antigène, et qui est exempt de problèmes tels que la formation d'une grosseur douloureuse au niveau du site d'administration. Le vaccin pour une administration sous-cutanée a été produit, le vaccin contenant une protéine antigénique, un peptide synthétique comprenant une séquence d'acides aminés de KnLm, un liquide contenant des phospholipides et un polymère vinylé à carboxyles.
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JP2002521460A (ja) * | 1998-07-30 | 2002-07-16 | イーデー−レーリスタット,インスティチュート フォール ディールハウデレイ エン ディールゲゾントヘイト ベー.フェー. | 肺サーファクタントを含むアジュバント |
WO2005097182A1 (fr) * | 2004-04-05 | 2005-10-20 | The University Of Tokushima | Vehicule de medicament antigenique permettant l'administration transmuqueuse et transdermqiue et procédé d'induction d'immunité muquese, vaccins par voie muqueuse et srm |
WO2011108521A1 (fr) * | 2010-03-02 | 2011-09-09 | 国立大学法人徳島大学 | Vaccin muqueux |
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JP2002521460A (ja) * | 1998-07-30 | 2002-07-16 | イーデー−レーリスタット,インスティチュート フォール ディールハウデレイ エン ディールゲゾントヘイト ベー.フェー. | 肺サーファクタントを含むアジュバント |
WO2005097182A1 (fr) * | 2004-04-05 | 2005-10-20 | The University Of Tokushima | Vehicule de medicament antigenique permettant l'administration transmuqueuse et transdermqiue et procédé d'induction d'immunité muquese, vaccins par voie muqueuse et srm |
WO2011108521A1 (fr) * | 2010-03-02 | 2011-09-09 | 国立大学法人徳島大学 | Vaccin muqueux |
Non-Patent Citations (1)
Title |
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KIMOTO, T ET AL.: "Intranasal influenza vaccination using a new synthetic mucosal adjuvant SF-10: induction of potent local and systemic immunity with balanced Th1 and Th2 responses", INFLUENZA OTHER RESPIR. VIRUSES, vol. 7, no. 6, 2013, pages 1218 - 1226, XP055175754, DOI: 10.1111/irv.12124 * |
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