JPH059130A - Vaccine preparation containing immunoglobulin - Google Patents

Abstract

PURPOSE:To provide a vaccine preparation comprising an antigen blended with, an immunoglobulin non-specific to the antigen and an adjuvant absorbing the antigen and the immunoglobulin, having an increased antigenic vaccine effect, and exhibiting a sufficient effect in a small dosage. CONSTITUTION:A vaccine preparation comprises an antigen (e.g. an antigen originated from virus, bacterium, rickettsia, protozoa, etc.), an immunoglobulin non-specific to the antigen, and an adjuvant absorbing the antigen and the immunoglobulin. The preparation is useful for preventing or treating infectious diseases caused by the viruses, bacteria, protozoa, etc., of avian and mammalian sources (such as human) and can produce immune antibodies against the infectious diseases, and the preparation contains the immunoglobulin which is originated from the mammalians of birds to be the immunization targets and which does not have any specificity to the vaccine antigen.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is intended for the purpose of preventing or treating infectious diseases of mammals such as humans and birds, such as viruses, bacteria and protozoa, or for producing immune antibodies against the infectious diseases, and is targeted for immunization. The present invention relates to a vaccine preparation containing immunoglobulin which is derived from animals or birds and has no specificity with a vaccine antigen.

[0002]

2. Description of the Related Art In mammals such as human beings, infectious diseases such as viruses and bacteria are treated with antibiotics, the resistance of the host is enhanced with nutritional supplements, and symptomatic treatment against diseases is performed. However, as essential medical treatment, it is preferable to improve the conditions on the host side so that the above-mentioned infectious diseases will not occur, or that symptoms will not appear strongly even if infected. In that respect, it is no exaggeration to say that the administration of vaccines is a fundamental medical treatment. Vaccines are made from infectious disease bacterial or viral antigens, but when administered to humans or animals,
With respect to these infections, or against infections of bacteria and viruses related thereto, it is possible to enhance the immunity in the human or animal body, and protect or treat. Current,
Known target diseases of human vaccines are tuberculosis, pertussis, cholera, meningitis, typhoid fever, paratyphoid fever,
Hepatitis A, hepatitis B, hepatitis C, non-A non-B hepatitis, acute grey-myelitis, Japanese encephalitis, mumps, measles, influenza, meningitis, yellow fever, smallpox, chickenpox , Herpes,
Examples thereof include AIDS, tetanus, diphtheria, scrub typhus, rotavirus infection, vaccinia virus infection, leptospirosis, malaria and the like.

Examples of infectious diseases to livestock and poultry such as mammals and birds include swine fever, swine erysipelas, mycoplasma galisepticum infection, and chicken infectious coryza type A bacteria.
(Hemophilis paragarinum type A) infection, chicken infectious coryza type C (hemophilis paragarinum type C) infection, swine Japanese encephalitis, equine influenza, equine rhinitis, equine getah virus infection, bovine infectious rhinotracheitis , Ibaraki virus infection, Akabane virus infection, bovine epidemic fever, dog distemper, dog parvovirus infection, canine infectious hepatitis, chicken Newcastle disease, bovine adenovirus infection, parainfluenza, chicken infectious pharyngeal tracheitis, chicken Infectious bronchitis,
Examples include fowlpox, bursal disease of Fabricius, herpes turkey (Marek's disease), myelocystitis, and pork infectious gastroenteritis.
The present situation of the vaccine will be described below using hepatitis B as an example. Hepatitis B is transmitted by blood transfusions from carriers, mother-to-child transmission at birth, and misplaced injection needles at medical institutions.

Although there are many carriers of hepatitis virus in Japan and the like, most of them end their lives asymptomatic, but it is said that some of them transfer from chronic hepatitis to liver cancer through cirrhosis. Therefore, it is said that cutting off the persistent infection of this hepatitis virus is the first purpose of treatment.
However, to date, there is still no drug or treatment that can eliminate this disease and safely and surely eliminate the virus from the living body.

The most effective preventive method is B
It is a method of inducing an antibody (anti-HBs antibody) against hepatitis B virus surface antigen (HBs antigen) by administering hepatitis B vaccine in advance, and it is highly effective in case of emergency such as childbirth with suspected mother-child infection or accident. High-valent anti-HBs human immunoglobulin and hepatitis B vaccine. Co-administration significantly reduces infection after 12 months compared to immunoglobulin alone. (Hep
atology, 10 , 324-327 (1989), Takehiro M
itsui et al., Combined Hepatitis B Immune Globulin
and Vaccine for Postexposure Prophylaxis of Accid
ental Hepatitis B Virus Infectionin Hemodialysis S
taff Members: Comparison with Immune Globulin wit
houtVaccine in Historical Controls]. B like this
Hepatitis V vaccine is widely used, but there are 3 problems.
It is necessary to raise the seroconversion rate and antibody titer because it is always the case that some people do not have sufficiently high antibody production even after vaccination.

Recently, most of the current hepatitis B vaccines are obtained by inactivating HBs antigen purified from carrier plasma by heating and formalin treatment. The problem is that it is difficult to ensure quality and quantity because it is a carrier plasma. Therefore, gene recombinant hepatitis B vaccine, which is produced in large quantities by yeast and the like, has been supplied. [Pharmacy and Treatment, 15 (6), 79 (198)
7)]. Furthermore, the importance of the pre-S2 region has been discussed, and the M protein that also has the pre-S2 region as an antigen and is stable against protease-like action, that is, the modified M protein M-P3.
1c came to be made [JP-A-63-1097]
No. 95, Example 19]. M-P31c is adr type HBs antigen M
A particle consisting of M protein lacking 6 amino acid residues 44 to 49 from the N-terminal of the protein, which comprises Saccharomyce
s cerevisiaeAH22R ^- / pGLD P31-RcT
(IFO: IFO 10206; FRI: FERM BP
-1059) can be used. Hereinafter, the particles of M-P31c are referred to as TGP-943. Although the vaccines have been improved as described above, the antibody titer and seroconversion rate showing the antibody-producing ability by the vaccination described above are not always satisfactory.

[0007] Immunoglobulins are said to have an action of specifically forming an immune complex with respect to an antigen and eliminating the antigen. Therefore, it is generally pointed out that administration of an immunoglobulin having specificity to an antigen together with a vaccine (antigen) reduces an immune response due to the vaccine. [DICP The Annales of Pharmacy,
24 , 67 (1990) (Drug Interactions Involving Immu
nologic Agents. Part.1; John D. Grabe-nstei
n)]. US The Center for Disease Control (CDC)
Except when there is no effect on antibody production, avoid co-administration and administer at an appropriate time, or if co-administration is unavoidable, instruct to re-administer the vaccine after an appropriate period. There is. The following shows an example in which there was no or little suppression of antibody production. In the case of oral polio vaccine (OPV), there is no effect of immunoglobulin, but the manufacturer recommends re-administration immediately after administration of immunoglobulin and, if oral polio vaccine is administered, after 3 months. The yellow fever vaccine did not change its effect even when co-administered or pre-administered with immunoglobulin containing anti-yellow fever antibody.

When the tetanus immunoglobulin and the tetanus vaccine were simultaneously administered to different sites, the effect was not different from the case of single administration. However, there is also a report that a two-week delay was observed in immunization in the case of simultaneous administration. Anti-HBs human immunoglobulin and B
The effect of immunity when co-administered with hepatitis B vaccine is B
It is known that the production of anti-HBs antibody by administration of the hepatitis B vaccine is the same as that when the hepatitis B vaccine is administered alone. CDC recommends simultaneous administration from the viewpoint of infection prevention and treatment. However, there is no case where the antibody production ability by the vaccine is enhanced by such co-administration.

As described above, with a few exceptions, it is considered that the effect as a vaccine is reduced or does not change even when an immunoglobulin having specificity for an antigen is administered simultaneously with the antigen. It is considered. Alternatively, it is considered that the effect as a vaccine does not change even if an immunoglobulin having no specificity to the antigen is administered at the same time as the antigen.

The immune complex comprises (1) an antigen / antibody ratio, (2)
Depending on various conditions such as the type of antibody, subclass, (3) immunological state of host or lymphocyte, and (4) presence or absence of Fc portion of antibody, lymphocytic function is regulated through Fc receptor to promote or enhance immunity. It was said to contribute to the suppression. Furthermore, it has been recently reported that a part of the Fc portion of the immune complex bound to the Fc receptor is enzymatically cleaved by the action of macrophages or monocytes to obtain a peptide that acts on lymphocyte activation and immunoregulation. The importance of immune complexes is said to be important. [Advances in Immunology, 40 , 61-134 (1
987) (BiologicalActivities Residing in the
Fc Region of Immunoglobulin ； Edward L. Morgan
and William O. Weigle)). However, there are no examples of mentioning such effects other than immune complexes, and no example of a vaccine containing an antigen and an immunoglobulin having no specificity for the antigen has not been reported yet. There have been no reports of improved cases.

[0011]

[Problems to be Solved by the Invention] If a formulation that enhances the effect of a vaccine can be prepared, the antibody titer in the administered animal can be increased,
The conversion rate can be improved. Alternatively, since a small amount of administration can provide sufficient immunity, side effects can be reduced.

[0012]

[Means for Solving the Problems] When a vaccine containing an antigen was mixed with an immunoglobulin having no specificity to the antigen, it was found that the effect of the vaccine antigen can be enhanced. As a result of research,
The present invention has been completed. The present invention provides a vaccine preparation in which an antigen is mixed with an immunoglobulin having no specificity to the antigen and an adjuvant that adsorbs the antigen and the immunoglobulin. Since the purpose of vaccines is to prevent and treat infectious diseases, antigens are derived from viruses, bacteria, rickettsia, protozoa, etc. that cause infectious diseases in hosts such as humans and other mammals and birds. Use one. Examples of the above host include humans,
Cow, sheep, pig, chicken, horse, goat, rabbit,
Examples include livestock and poultry such as turkeys, cats, dogs, guinea pigs, hamsters, monkeys, mice, and rats.

The above viruses include hepatitis A virus, hepatitis B virus, hepatitis C virus, non-A non-B
Hepatitis B virus, acute poliomyelitis virus, Japanese encephalitis virus, mumps virus, measles virus, influenza virus, meningitis virus, yellow fever virus,
Human smallpox virus, chickenpox virus, herpes virus, AIDS virus, rotavirus, vaccinia virus, and other viruses that infect humans, swine erysipelas virus, swine Japanese encephalitis virus, equine influenza virus, equine rhinitis virus, equine getavirus , Bovine infectious rhinotracheitis virus, Ibaraki virus, Akabane virus, bovine epidemic virus, canine parvovirus, canine distemper virus, canine infectious hepatitis virus, chicken Newcastle disease virus, bovine adenovirus, parainfluenza virus,
Infects domestic animals and poultry such as chicken infectious pharyngeal tracheitis virus, chicken infectious bronchitis virus, fowlpox virus, bursal disease virus, turkey herpes virus (Marek's disease), poultry myelitis virus, swine infectious gastroenteritis virus The virus that does. Examples of the above-mentioned bacteria include Mycobacterium tuberculosis, Bordetella pertussis, Cholera, Neisseria meningitidis, Salmonella typhi, Paratyphi, and Leptospira.

A toxin may be used as the antigen, and examples of the toxin include tetanus toxin and diphtheria toxin. Examples of the above-mentioned rickettsia include tsutsugamushi disease rickettsia. Examples of the above-mentioned protozoa include malaria parasite. These viruses, bacteria, rickettsia, protozoa, etc. can be used as an antigen by a usual method. Of these viruses, bacteria, rickettsia, and protozoa, those with low toxicity can be used as they are as antigens. Highly toxic ones may be used as antigens in the form of treated bacteria, killed bacteria, toxins produced by bacteria, viruses inactivated by formalin, etc. Further, virus surface antigens such as virus surface glycoproteins can be used. Those antigens produced by genetic engineering can also be used.

As the immunoglobulin having no specificity to the antigen, immunoglobulin G or immunoglobulin M derived from an animal to be immunized is preferably used. These immunoglobulins can be obtained as natural ones by fractionating from animal blood by a method known in the literature, but those obtained from hybridomas using gene recombination technology can also be used. Commercially available immunoglobulins and immunoglobulin preparations can also be used. Instead of these immunoglobulins, a compound having a partial structure thereof, such as the Fc portion, can be incorporated into the vaccine of the present invention. As the adjuvant, aluminum compounds (gel) such as aluminum hydroxide and aluminum phosphate, Freund's adjuvant and the like are used. An aluminum compound is preferably used. Aluminum hydroxide and aluminum phosphate can be obtained by adding sodium hydroxide, phosphate and the like to an aqueous solution of aluminum chloride and adjusting the pH.

The dose of the antigen varies depending on the kind of the antigen and the kind of the animal, but in the case of human, about 100 ng to 100 μg is used. Preferably 1 to 100 μg is used. The amount of immunoglobulin added is preferably 5 to 5000% by weight of the antigen. More preferably, it is 10 to 500%. The amount of the adjuvant to be added varies depending on the type of the adjuvant and the animal to which it is administered. When an aluminum compound is used and administered to humans, an aluminum content of 10 μg to 1 mg is used. It is preferably 50 μg to 500 μg.

The above formulation is added to water at 0 ° C. to room temperature and gently mixed to give an aqueous solution or suspension of 0.1 to 5 ml. In some cases, either or both of the above antigens and immunoglobulins may be added before preparing the aluminum hydroxide gel or aluminum phosphate gel. The above aqueous solution or suspension is usually a human or animal-acceptable amount of monosodium phosphate, dipotassium phosphate, disodium phosphate, monopotassium phosphate, sodium hydroxide, pH adjusting agents such as hydrochloric acid, thimerosal, etc. Preservatives, kanamycin sulfate, erythromycin lactobionate, antibiotics such as potassium penicillin G, lactose, potassium glutamate, stabilizers such as D-sorbitol, aminoacetic acid, human serum albumin, coloring agents such as phenol red, sodium chloride, etc. Tonicity agents may be added. The final aqueous solution or suspension having a pH of 6 to 9.2 is used. This preparation may be stored in the form of an aqueous solution or suspension, but it may be stored in a freeze-dried state and dissolved or suspended in distilled water for injection before administration. The storage temperature may be room temperature or lower, but is preferably 10 ° C. or lower under light shielding conditions. The administration method is subcutaneous or
An intramuscular injection method is used.

[0018]

[Function] Vaccine antigens are combined with immunoglobulins that have no specificity to the antigens and adjuvants that adsorb the antigens and immunoglobulins, and this new formulation enhances the antibody titer in the treated animals and improves the seroconversion rate. The effect of can be enhanced. Further, since a small amount of administration provides sufficient immunity, side effects can be reduced. This vaccine formulation not only enables more effective prevention and treatment of diseases, but also provides efficient antibody production in immunization experiments.

[0019]

EXAMPLES The present invention will be described in more detail with reference to Examples and Experimental Examples, but the present invention should not be limited thereto. Example 1 20 μg of TGP-943, aluminum chloride hexahydrate 2.
235 mg, disodium phosphate hexahydrate 0.373 mg, potassium phosphate monobasic 0.489 mg, sodium hydroxide for adjusting pH, hydrochloric acid, and salt for adjusting osmotic pressure.
7 μg of human immunoglobulin G (Nippon Pharmaceutical Co., Ltd .: gamma globulin Nichiyaku) in 5 ml of TGP-943 gel preparation
Add 10 μl saline solution and gently stir,
A vaccine formulation was obtained.

Example 2 20 μg of TGP-943, aluminum chloride hexahydrate 1.
0.1 mg obtained by using 118 mg, disodium phosphate hexahydrate 0.373 mg, potassium monopotassium 0.489 mg, sodium hydroxide for adjusting pH, hydrochloric acid, and salt for adjusting osmotic pressure.
5 μg of TGP-943 gel preparation, human immunoglobulin G (Nippon Pharmaceutical Co., Ltd .: gamma globulin Nichiyaku) 7 μg /
Add 10 μl saline solution and gently stir,
A vaccine formulation was obtained.

Example 3 20 μg of TGP-943, aluminum chloride hexahydrate
0.47 mg, disodium phosphate hexahydrate 0.373 mg, potassium monopotassium 0.489 mg, sodium hydroxide for adjusting pH, hydrochloric acid, and salt for adjusting osmotic pressure.
5 μg of TGP-943 gel preparation, human immunoglobulin G (Nippon Pharmaceutical Co., Ltd .: gamma globulin Nichiyaku) 7 μg /
A 10 μl physiological saline solution was added and gently stirred to obtain a vaccine preparation.

Example 4 20 μg of TGP-943, aluminum chloride hexahydrate 2.
235 mg, disodium phosphate hexahydrate 0.187 mg, potassium monopotassium 0.245 mg, sodium hydroxide for adjusting pH, hydrochloric acid, and salt for adjusting osmotic pressure.
5 μg of TGP-943 gel preparation, human immunoglobulin G (Nippon Pharmaceutical Co., Ltd .: gamma globulin Nichiyaku) 7 μg /
Add 10 μl saline solution and gently stir,
A vaccine formulation was obtained.

Example 5 20 μg of TGP-943, aluminum chloride hexahydrate 2.
It was obtained using 235 mg, disodium phosphate hexahydrate 0.933 mg, potassium monophosphate 1.223 mg, sodium hydroxide for adjusting pH, hydrochloric acid, and salt for adjusting osmotic pressure.
5 μg of TGP-943 gel preparation, human immunoglobulin G (Nippon Pharmaceutical Co., Ltd .: gamma globulin Nichiyaku) 7 μg /
Add 10 μl saline solution and gently stir,
A vaccine formulation was obtained.

Example 6 Gel formulation 20 of TGP-943 described in Example 1
Human immunoglobulin G (manufactured by Nippon Pharmaceutical Co., Ltd.) in μg / 0.5 ml:
70 μg / 10 μl physiological saline solution of (Gamma globulin) was added and gently stirred to obtain a vaccine preparation.

Example 7 TGP-943 Gel Formulation 20 Described in Example 1
Human immunoglobulin G (manufactured by Nippon Pharmaceutical Co., Ltd.) in μg / 0.5 ml:
20 μg / 10 μl physiological saline solution of gamma globulin) was added and gently stirred to obtain a vaccine preparation.

Example 8 Recombinant Precipitated Hepatitis B Vaccine (20 ml of HBsAg in 1 ml)
Containing μg and aluminum hydroxide 0.5 mg; Beamgen manufactured by Institute of Chemistry and Serum Therapy 10 μg / 0.
A human immunoglobulin G (Nippon Pharmaceutical Co., Ltd .: gamma globulin Nichiyaku) 3.5 μg / 10 μl physiological saline solution was added to 5 ml of the formulation, and the mixture was gently stirred to obtain a vaccine formulation.

Example 9 30 μg / 10 μl of human immunoglobulin G (manufactured by Nippon Pharmaceutical Co., Ltd .: gamma) in the Japanese Pharmacopoeia “precipitated tetanus toxoid” (containing about 10 Lf of tetanus toxoid adsorbed on an aluminum salt in 1 ml, Takeda Pharmaceutical Co., Ltd.) (Globulin NIPPON) was added and gently stirred to obtain a vaccine preparation.

Example 10 Japanese Pharmacopoeia "Settling Diphtheria Tetanus Toxoid" (1 ml
140 μg / 10 μl of human immunoglobulin G (Nippon Pharmaceutical Co., Ltd .: gamma globulin Nichiyaku) was added to diphtheria toxoid about 50 Lf and tetanus toxoid about 10 Lf adsorbed on aluminum salt, and gently stirred. , A vaccine preparation was obtained.

Example 11 Japanese Pharmacopoeia “Precipitation Pertussis Diphtheria Tetanus Toxoid”
65 μg / 10 μl of human immunoglobulin G (Japan Takeda Pharmaceutical Co., containing 8 international units of pertussis protective antigen depleted with formalin adsorbed on aluminum salt, about 30 Lf of diphtheria toxoid and about 5 Lf of tetanus toxoid in 1 ml) (Japan) (Manufactured by Pharmaceutical Co., Ltd .: gammaglobulin Nichiyaku) was added and gently stirred to obtain a vaccine preparation.

Example 12 Porcine Volvodetella Infectious Disease Prevention Solution (Volvodetella bronchiseptica Phase I inactivated in 1 ml (pre-inactivated inoculum: 10)
¹⁰ or more) and about 7 mg of aluminum hydroxide gel; Nisseiken Co., Ltd. Porcine AR vaccine) 10 μg / 0.5 ml
10 μm of Cappel's Butynoglobulin G
g / 10 μl was added and gently stirred to obtain a vaccine preparation.

Example 13 Newcastle disease / chicken infectious bronchitis mixed inactivation preventive solution
(In 1 ml, inactivated Newcastle disease virus (pre-inactivation virus amount: 10 ⁸ EID ₅₀ or more), inactivated chicken infectious bronchitis virus (pre-inactivation virus amount: 10 ⁷ EID ₅₀ or more) and aluminum hydroxide gel) Contain about 6 mg;
Nissei Ken's NB inactivated vaccine) 10 μg / 0.5 ml formulation with 10 μl of Cappel chicken immunoglobulin G
g / 10 μl was added and gently stirred to obtain a vaccine preparation.

[0032] EXAMPLE 14 Bovine ephemeral fever tissue culture inactivated preventing fluid (in 1 ml, inactivated attenuated bovine ephemeral fever virus (inactivated before viral load: 10 4 ^{· 8} TCI
D ₅₀ or more) and 5 mg of aluminum hydroxide gel;
Nisseiken Co., Ltd. bovine epidemic heat inactivated vaccine) 10 μg / 0.
1 ml of Kappel Bovine Immunoglobulin G in 5 ml formulation
0 μg / 10 μl was added and gently stirred to obtain a vaccine preparation.

Example 15 Equine rhinitis pneumonia inactivation preventive solution (containing 1 mg of inactivated equine rhinitis pneumonia virus (pre-inactivation virus epidemic: 10 ⁸ .5 TCID ₅₀ or more) and 5 mg of aluminum chloride in 1 ml; manufactured by Nisseiken Co., Ltd.) Equine insufficiency inactivating vaccine "Nisseiken") 10 μg / 0.5 ml formulation with 10 μg / 1 of Kappel's Umimunoglobulin G
0 μl was added and gently stirred to obtain a vaccine preparation.

Example 16 The gel formulation of TGP-943 described in Example 1 was added to mouse immunoglobulin G (Jackson ImmunoResearch La).
b. Company: ChromPure IgG, Whole molecule) 7 μg /
10 μl was added and gently stirred to obtain a vaccine preparation.

Example 17 The gel preparation of TGP-943 described in Example 1 was supplemented with mouse immunoglobulin G (Jackson ImmunoResearch La).
b. Made by: ChromPure IgG, Whole molecule) 70μ
g / 10 μl was added and gently stirred to obtain a vaccine preparation.

Example 18 The TGP-943 gel formulation described in Example 1 was added to mouse immunoglobulin G (Jackson ImmunoResearch La).
b. Company: ChromPure IgG, Whole molecule) 20μg
/ 10 μl was added and gently stirred to obtain a vaccine preparation.

Example 19 Recombinant Precipitated Hepatitis B Vaccine (Beamgen manufactured by the Institute of Chemistry and Serum Therapy) 10 μg / 0.5 ml of mouse immunoglobulin G (Jackson ImmunoResearch La)
b. Company: ChromPure IgG, Whole molecule) 3.5μ
g / 10 μl was added and gently stirred to obtain a vaccine preparation.

Example 20 The gel formulation of TGP-943 described in Example 1 was added to the mouse hybridoma HRL 1-52 (IFO: IFO).
50222; FRI: FERM BP-2747) produced anti-interleukin 2 monoclonal antibody (IgG ₁ ).
Was added at a ratio of 7 μg / 10 μl and gently stirred to obtain a vaccine preparation.

Example 21 Japanese Pharmacopoeia "Precipitation Pertussis Diphtheria Tetanus Toxoid"
65 μg / 10 μl of mouse immunoglobulin (Jackson ImmunoResearch Lab .; Chrompure IgG,
Whole molecule) was added and gently stirred to obtain a vaccine preparation.

Experimental Example 1 In the preparations of Examples 1, 16 and 17, 1 μg of TGP-943 was given to mice (Balb / c, 6W, ♀, n = 9-10).
After 6 weeks, the anti-HBs antibody production was quantified with an anti-HBs antibody detection kit "OSAB EIA" (Dynabot). In the formulation of Example 16, the average antibody titer increased by 5.3-fold as compared with that of the gel formulation of TGP-943 described in Example 1 (without addition of immunoglobulin).
It was found that the addition of 0 ng of mouse immunoglobulin increased the antibody titer. Further, the 2.1 times value of the negative control (mouse plasma) was used as a cutoff value as a criterion for antibody positive judgment, and the conversion rate of the preparation of Example 16 was determined. The conversion rate increased from 67% to 100%. did.
Similarly, in the formulation of Example 17, the average antibody titer increased about 2.3 times as compared with that of the gel formulation described in Example 1 (without addition of immunoglobulin), and the antibody was added by the addition of 35 μg of immunoglobulin. It was found that the price increased.
On the other hand, administration of mouse globulin alone produces anti-HB
s No antibody production is observed. When the formulation of Example 1 was administered to mice, Example 1
The average antibody titer of the preparation of No. 2 was the same as that of the TGP-943 gel preparation. That is, it was found that the addition of human immunoglobulin did not enhance the antibody-producing ability in mice. That is, it was shown that it is preferable to add an immunoglobulin of the same species as the host to the preparation. In other words, in order to administer to humans and improve antibody production ability,
It is believed that human immunoglobulin is required.

[Table 1]

Experimental Example 2 Gel formulation of TGP-943 described in Example 1 (T
1 μg of GP-943 (immunoglobulin not added) was intraperitoneally administered to a mouse, and immediately after administration of mouse immunoglobulin from the tail vein of the mouse, the average antibody titer was TGP.
Almost unchanged at 0.79 times that of the -943 gel formulation. It was found that the mouse immunoglobulin did not have the ability to enhance antibody production when the administration route was divided.

Experimental Example 3 In the same manner as in Experimental Example 1, 0.25 μg of the recombinant precipitated hepatitis B vaccine (Beamgen manufactured by the Institute for Chemo-Serum Therapy) as a control of Example 19 was intraperitoneally administered to mice, The antibody seroconversion rate after 6 weeks was examined.

[Table 2] It was also found that immunoglobulin also improves the antibody-producing ability in the recombinant precipitated hepatitis B vaccine.

Experimental Example 4 The vaccine preparation of Example 21 was diluted 5 times and 25 times with physiological saline, and the mouse (DD SPF, 4-5W, ♀, n =
Into the abdominal cavity of 10), 0.5 ml each was administered. After 4 weeks, the pertussis antibody titer was measured by the ELSA method. The titer of the vaccine preparation of Example 21 was about 1.5 times higher than that of the Japanese Pharmacopoeia “precipitated pertussis diphtheria tetanus toxoid”.

[0044]

EFFECT OF THE INVENTION This new preparation, in which an antigen having no specificity for the antigen and an adjuvant for adsorbing the antigen and the immunoglobulin is added to the antigen, enhances the antibody titer in the administered animal and improves the seroconversion rate, The effect of vaccine antigen can be enhanced. Further, since a small amount of administration provides sufficient immunity, side effects can be reduced. This vaccine formulation not only enables more effective prevention and treatment of diseases, but also provides efficient antibody production in immunization experiments.

Claims (1)

Claims: 1. A vaccine preparation comprising a vaccine antigen, an immunoglobulin having no specificity for the vaccine antigen, and an adjuvant that adsorbs the vaccine antigen and the immunoglobulin.