TW201008577A - Vaccine composition - Google Patents

Abstract

The present invention relates to new, advantageous DTP-based combination vaccine formulations, and concomitantly administered combination vaccine kits. Methods of administration of these vaccines and kits are also provided.

Description

201008577 VI. Description of the Invention: • Technical Field to Which the Invention pertains The present invention relates to novel combination vaccine formulations. In order to reduce the number of vaccinations that can protect against several pathogens, reduce the cost of administration, and increase the acceptance and vaccination rate (providing protection against several pathogens), a combination vaccine is very necessary. The antigenic competition (or interference) phenomenon listed in the literature makes the development of complex vaccines more complicated. Antigen interference means that the immune response against an antigen obtained by administering a complex antigen is often lower than that of an individual ® administered with a particular antigen. [Prior Art] It is known that a combination vaccine can prevent B〇rdete Ua pertussis, Clostridium tetani, and Corynebacterium diphtheriae, and can prevent hepatitis B virus and Haemophilus typhimurium type 1 as appropriate ( Reference is made, for example, to WO 93/24148 and WO 97/00697). The present invention relates to the manufacture of the most desirable multivalent vaccines to date, and the use of such φ vaccines can prevent or treat infections of B. pertussis, tetanus, diphtheria, hepatitis B virus and meningococcus, preferably The infection of Haemophilus influenzae, Streptococcus pneumoniae, Hepatitis A virus and/or poliovirus can be prevented or treated, wherein the vaccine component does not significantly interfere with the immune performance of any of the components of the vaccine. SUMMARY OF THE INVENTION Therefore, 'the present invention is to provide a complex immune composition, to host against the disease of B. pertussis, tetanus, diphtheria, hepatitis B virus, poliovirus and occupational inflammation (four) disease 143906 Protection of .doc 201008577, which includes: (a) Not the entire death of C. pertussis cells (pw), two or more acellular pertussis components (Pa) [preferably the latter], (b) Tetanus toxoid (TT or T), 0) diphtheria toxoid (DT or D), (d) hepatitis B surface antigen (HepB or HB), (e) deactivated poliovirus (IP v), and (f) a carrier protein and a co-plant of one or both of the capsular polysaccharides selected from the group consisting of Y-type meningococcus (MenY) and type C meningococcus (MenC), and (g) optionally carrier protein And a conjugate of the type B polychaete of the B. sinensis. The aforementioned immunological composition may additionally comprise one, two, three, four, five, or six components selected from the group consisting of type A meningococcus polysaccharides [MenA] (preferably conjugated), ... meningitis Diplococcus polysaccharide [MenW] (preferably via a total vehicle), Salmonella typhimurium Vi polysaccharide, meningococcus (preferably B clear type) outer membrane cyst, one or more meningococcus (preferably B serotype) outer membrane (surface exposed) protein, and death-attenuated hepatitis A virus are preferably known as HavrixTM, a product [SmithKUne Beecham

Bi〇1〇giCals]) 'These do not have the problem of substantially interfering with the antigen in any composition. A second object of the present invention is to provide various beneficial kits comprising two, three or four complex immunological compositions capable of conferring host resistance to B. pertussis, tetanus, diphtheria, hepatitis B virus, : 儿 143906.doc 201008577 :::: Toxic and Streptococcus pneumoniae, and the protective effect of diseases caused by Bacillus licheniformis infection. A first specific example of the first subject of the present invention provides a kit comprising a two-valency immunological composition which confers on the host against tetanus tetanus (four), diphtheria rod g, B brix virus, Pediatric pruritus and Streptococcus pneumoniae, and the protective effects of diseases caused by meningococcal and flu.

The first container in the set includes: (4) not the entire dead B. pertussis cells (Pw), two or more non-cellular pertussis components (Pa) [preferably the latter], (b) tetanus toxoid ( Ττ or τ), (c) diphtheria toxoid (DT or D), (d) hepatitis B surface antigen (10) or y), and (e) deactivated poliovirus (Ipv), and a second container The method includes: (a) one or more carrier proteins and a Streptococcus pneumoniae sac polysaccharide [wherein the pain vesicles are preferably selected from 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, A total of 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F pneumonia serotypes. In another advantageous embodiment of the aforementioned kit of the present invention, the first container may additionally comprise (f) a carrier protein and a type selected from the group consisting of Y-type meningococcus (MenY) and type C meningococcus (MenC). a co-injection of one or both of the bactericidal polysaccharides, and (g) a carrier protein and a type B Haemophilus influenzae (Hib) sac. 143906.doc 201008577 a co-injection of a cool body; or a second container Further comprising: (b) a carrier protein and a conjugate selected from one or both of Y-type meningococcus (MenY) and c-type meningococcus (MenC) capsular polysaccharide, and (4) a carrier protein And a conjugate of the type B Haemophilus influenzae (Hib) capsular polysaccharide; or the first trough additionally includes (f) a carrier protein and is selected from the group consisting of γ-type meningococcus (MenY) and type C meningitis One or both of the Mycobacterium capsular polysaccharides and the second container additionally includes (b) a carrier protein and a conjugate of a type B Haemophilus influenzae (Hib) capsular polysaccharide; Or the first container additionally includes (f) a carrier protein and a conjugate of the type B genus Haeophilus capsular polysaccharide, and the second container Comprising an outer (b) and the carrier protein is selected from Neisseria meningitidis type γ (of MenY) and type C meningococcal (the MenC) or both of a bacterial capsular polysaccharide conjugate of the body. A second specific example of the second subject of the present invention provides a kit comprising two complex immunological compositions which confers resistance to a host against B. pertussis, tetanus, diphtheria, hepatitis B virus, polio The protective effect of diseases caused by viral, meningococcal and Haemophilus infections. The first container of the kit includes: (a) Not the entire dead B. pertussis cell (pw), which is two or more non-cellular pertussis components (Pa) [preferably the latter], (b) tetanus toxoid (TT or T), (c) diphtheria toxoid (DT or d), (d) hepatitis B surface antigen (HepB or hB), and (e) deactivated poliovirus (Ipv), 143906.doc 201008577 and the second container include: (a) a carrier protein and a conjugate selected from one or both of Y-type meningococcus (MenY) and type C meningococcus (MenC) capsular polysaccharide, And (b) a co-consumer of the carrier protein and the bacterium cysticercosis. A third specific example of the second subject of the present invention is to provide a kit comprising three complex immunological compositions which can confer to a host against Z. pertussis, tetanus, diphtheria, hepatitis B virus, poliomyelitis The protective effect of viruses and diseases caused by meningococcal, haemaophilus and pneumococcal infections. The first container of the kit includes: (a) Not the entire dead B. pertussis cell (Pw), which is two or more non-cellular C. sinensis components (Pa)|; preferably the latter], (b) Tetanus toxoid (ΤΤ or T), (c) diphtheria toxoid (DT or D), φ (4) hepatitis 8 surface antigen (HepB or HB), (e) — or more de-active poliovirus (IPV), And the second container comprises: (a) one or more carrier proteins and a Streptococcus pneumoniae sac polysaccharide [wherein the capsular polysaccharide is preferably selected from the group consisting of 1, 2, 3, 4, 5, 6A, 6B, Conjugates of pneumonia serotypes of 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F, and in the third container : 143906.doc 201008577 (a) carrier protein and one or both conjugates of the bacteriocosin selected from γ-type meningococcus (MenY) and c-type meningococcus (MenC), and (b) A carrier protein and a mixture of a bacterium of the genus A. sinensis. Any of the foregoing kits or kits of the present invention may additionally comprise one, two, three, four, five, six or seven components selected from the group consisting of type A meningococcus polysaccharide [MenA] (preferably A total of (6), meningococcal polysaccharides [MenW] (preferably by a total vehicle), Salmonella typhimurium% polysaccharide, meningococcus (preferably B serotype) outer membrane cyst, or a variety of meningitis Diacobacter (preferably B serotype) outer membrane (surface exposed) protein, sputum - (as mentioned above), and / or a variety of pneumococcal proteins (preferably surface exposed), these do not substantially interfere The problem of the antigen in any composition. The container of the kit may be packaged separately, but is preferably packaged. It is preferred to provide a list of two or three container vaccine lists in the kit. The kits provided by the foregoing methods allow various antigens to be presented to the host immune system in an optimal manner. The kit provides the following - or more (preferably 2 or 3, preferably the owner) of the medical personnel. The best way to benefit the host: for all The original protective effect 'immunizes with minimal side effects, minimal carrier inhibition, minimal adjuvant/antigen interference, or minimal antigen/antigen interference. In this way, the least number of times (twice) is used for administration (more) At the same time, visiting the medical staff can achieve these goals. Although in the first and second (and third) containers 143906.doc 201008577 of the preferred embodiment, the vaccine is vaccinated at different locations at the same time. (As described later), but in another embodiment, the present invention contemplates mixing the first and second containers (preferably in an immediate manner) as a single vaccine prior to administration. Methods] Vaccine antigen preparation of tetanus toxoid (ττ) is a well-known method in the art. For example, TT is preferably prepared by chemical Φ detoxification after purification of toxin from culture medium of tetanus bacillus, but another The method is to purify a recombinant or genetically engineered toxin analog of a toxin (for example, as described in European Patent No. 209,281). 'Tetratoxin It also has an immunological fragment of the full-length protein (e.g., fragment c-reference European Patent No. 4786-2). Preparation of diphtheria toxoid (DT) is also a well-known method in the art, for example, DT is preferably cultured from diphtheria bacilli The toxin is purified from the liquid and then prepared by chemical detoxification, but the other way is to purify the recombinant or genetically engineered detoxified analog of the toxin (for example, CRM197, Japanese Patent No. 4,709,017, US Patent Case 5 843 711, U.S. Patent No. 5,601,827, and U.S. Patent 5,917,017) » 'Acellular Cough (Pa) is well known in the art, and examples include coughaceous toxin (PT), filamentous hemagglutinin ( FHA), pertussis protein (PR) and agglutinogens 2 and 3. These antigens are partially purified or highly purified, preferably two or more non-cellular pertussis components are used in the vaccine, and more preferably, two, three, four or all five non-cellular pertussis components are incorporated into the vaccine. The best include PT, FHA and PRN. The ρτ can be prepared in any manner, for example, by purifying the toxin from the culture solution of bacillus bacillus, followed by chemical detoxification, as 143906.doc 201008577 Another way is to purify the genetically engineered detoxified analog of PT (for example, US Patent 5,085,862). The preparation of cells (Pw) for the entire B. pertussis bacterium suitable for the present invention is disclosed in WO 93/24148, which is the preparation of DT-TT-Pw-HepB and DT-TT-Pa·

A suitable formulation of the HepB vaccine. Deactivation of poliovirus (IPV) preferably includes Type 1, 2 and 3 of the vaccine art standard, the best being the Shak polio vaccine. The main Streptococcus pneumoniae vaccine of the present invention comprises a polysaccharide antigen (preferably via a common vehicle), wherein the polyglyth is derived from at least four selected from the group consisting of 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N , 9V, l〇A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F pneumococcal serotype, preferably four serotypes including 6B, 14, 191? And 23?, preferably, the composition includes at least seven serotypes, such as those derived from 4, 6B, 9V, 14, 18C, 19F, and 23F. More preferably, the composition includes more than seven serotypes. , for example, at least 1 serotype, such as in a composition in a specific example, including! j species of vesicles derived from i, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (preferably conjugated). In a preferred embodiment of the invention, at least 13 polysaccharide antigens (preferably conjugated) are included. The invention may additionally comprise a polysaccharide antigen, such as 23 valence (such as serum 1, 2, 3, 4, 5, 6B). , 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 2〇, 22F, 23F and 33F serotypes). In the case of vaccination for the elderly (for example, prevention of pneumonia), it is advantageous to include 8 and 121 serotypes in the preferred preferred 11-valent antigen composition (and preferably 143906.doc • 10-201008577 containing 15 and 22) To constitute a 13/15 valency vaccine, and for infants or toddlers (prevent otitis media), it is preferred to include the 6A and 19A serotypes to constitute a 13-valent vaccine. Co-consumer Bacterial sac multi-female co-plants include any vector 3., poly 3. or protein containing at least one tau-helper cell determinant. Preferably, the carrier protein used is selected from the group consisting of tetanus toxoid, diphtheria toxoid, CRM197, heavy

Group of diphtheria toxins (as described in any of U.S. Patent Nos. 4,709,017, WO 93/25210, W〇95/33481 or |〇00/48638), pneumonia lysin derived from Streptococcus pneumoniae (preferably by chemistry) Methods Detoxification, or detoxification of mutants), 0 MPC derived from meningococcus, and protein D derived from Haemophilus influenzae (European Patent No. 594610). Because of the known carrier inhibiting action, it is more advantageous if each of the compositions of the present invention contains such polysaccharide antigens & antigens, and the yoke is more than one carrier. Thus, one type of carrier protein can (respectively) contain (5) a polysaccharide, and one carrier protein carries one polysaccharide, or (n_2) a polysaccharide is carried on _ while the object is carried on another carrier protein. For example, in the vaccine of the somatic Bacterial multi-breast co-plant, the benefit of the two or all of the multi-cooled bodies can be shared with different proteins on the different proteins of the dragon protein is the carrier protein of the composition of the present invention. Because it can be used in various (2, 3, 4 or more) poly-hearings in the composition without significant vector inhibitory effects. The optimal T is the TT conjugate 'pneumococcal polysaccharide is peptone, π or (10) Π97 conjugate' and MeNA, MenC, and π or (10) conjugate, protein D may also be a carrier carrier egg*, Because it provides another 143906.doc 201008577 an antigen that protects against the protection of Haemophilus influenzae. The polysaccharide can be attached to the carrier protein by any known method (e.g., U.S. Patent No. 4,372,945, issued to A.S. Pat. (WO 95/08348) In CDAP, the cyanating agent cyano-didecylaminoindole indole (CDAP) is preferably used to synthesize a polysaccharide-protein conjugate. The cyanation reaction is carried out under relatively mild conditions to avoid hydrolysis of the alkali-sensitive polysaccharide. This synthesis can be coupled directly to the carrier protein. Characteristics of the immunological composition of the present invention The immunological composition of the present invention is preferably formulated into a vaccine which is administered to a host by in vivo administration. The immunity of individual components in the composition formulated by this method is substantially not affected by other The individual components in the composition are destroyed. The term "substantially not destroyed" means that after inoculation, the antibody titer against each component is higher than 60% of the titer obtained by a single antigen, preferably 70% higher. More than 80%, better than 90%, and the best is 95-100% higher. Interestingly, if it is possible to inoculate with the aforementioned kit combination, the antibody titer against Heb capsular polysaccharide or a pneumonia polysaccharide is close to that of ι〇〇0/〇 individual single antigen. Or higher than the potency obtained by individual administration of a single antigen. Vaccine Formulation The immunological composition of the present invention is preferably formulated into a vaccine which is administered to a host by in vivo administration, and the antibody titer conferred by the antibody is superior to that of the human body receptor. 143906.doc •12· 201008577 The seroprotective effect of each antigenic component is regulated, which is a test that evaluates the effectiveness of the entire population on vaccines. Antigens that are considered by the host to convert to anti-antigens and have the above-mentioned related antibody valency are well known. Some organizations have published such titers, such as WHO. Preferably, more than 80% of the host statistics show that the sample is converted, preferably more than 9%, more preferably more than 93%, and the best is 96-100%.

The immunological compositions of the invention are preferably adjuvanted. Suitable adjuvants include salt, such as alumina gel (aluminum gel) or aluminum phosphate, but may also be calcium, iron or salt, or acetaminophen, acetamidine, anion or cation derivatization. An insoluble suspension of vinegar' or polyphosphazenes. The adjuvant of choice may also be a preferred reaction-derived elicitor to aid in the cellular mediator response in the immune response. High levels of TM-type cytokines help induce a cellular immune response against a particular antigen. High levels of Th2• cytokines help induce a liquid immune response against the antigen.

A suitable adjuvant system that promotes a significant addition reaction comprises a mono(10)-based lipid a or a derivative thereof, a special (5) is a 3-de-indolizine single-acid lipid-based lipid a, and a single-loaded acid-based lipid A combination is preferably Mixed with salt of 3_de_〇_B, a single acid-filled lipid A (3D-MPL). The combination of single-disc acid esters in combination with QS21 and 3D-MPL), 94/00153, or a combination of lower side-effect reactivity, cholesterol termination activity, is disclosed in WO 96/33739.

Qualitative A and saponin derivatives (the special enhancement system disclosed in WO QS21, 3D-MPL and tocopherols have specific potentials as shown in WO 95/17210, which may additionally include sputum (where QS21 is soluble in Oil-in-water adjuvant formulation, keratin, better 143906.doc •13· 201008577 is QS21. Formulations may also include oil-in-water emulsions and tocopherols (WO 95/17210). Containing oligonucleosides Acidic unpurified CpG (WO 96/02555) is also a preferred elicitor of the TH1 reaction and is suitable for use in the present invention. Aluminium salts are preferred adjuvants in the aforementioned immunological compositions, specifically, Before mixing with other ingredients, HepB should preferably be adsorbed by aluminum phosphate. Before mixing with other ingredients, pertactin should preferably be adsorbed by hydroxide. In order to reduce the content of adjuvant (especially aluminum salt) in the combination of the present invention, polysaccharide The body complex is unadjuvanted. The invention also provides a method comprising the steps of mixing a vaccine component with a pharmaceutically acceptable excipient to prepare a vaccine formulation. The invention is particularly preferred for DTPa compositions (alone or for use) The first of the aforementioned sets The components in the container include: TT, DT, Pa (preferably including PT, FHA and PRN - preferably PRN adsorbed by aluminum hydroxide), HepB (preferably filled with acid), IPV, MenC (better total The protein D, TT, DT or CRM197), and optionally MenY (preferred conjugated protein D, TT, DT or CRM197), the composition also includes Hib (preferably conjugated TT and / or no adsorption) Adjuvant). The preferred vaccine is packaged in 2 vials, the first bottle comprising the liquid DTPa-IP V-HepB, and the second bottle comprising the freeze-dried version of MenC (as appropriate, MenY and/or Hib), preferably Freeze-dried in the case of anti-clotting agents (such as sucrose or lactose). The ingredients in the bottle can be mixed in a container before being administered to the host, and administered in a single administration/injection. The composition can also be used in the aforementioned set. In the group (ingredients in the first container), including one or both of Hib (preferably conjugated TT and/or unadjuvanted adsorption) and/or MenC and MenY (preferably conjugated protein D, TT, DT or 143906.doc -14· 201008577. For the purpose of the set of 97 and/or unadsorbed containers, this combination Preferably, it is stored in a cold-drying form, preferably in the presence of an anti-caking agent such as sucrose or lactose. The invention comprises DTPa and Hib and/or MenC^ Mer^ or both. In the case of the DTPa composition (individually used or as a component in the first container of one of the aforementioned kits), wherein the Hib and/or Men components are conjugated to ττ, preferably the sputum component of the vaccine is maintained in equilibrium. The total enthalpy content of ττ in a single container does not exceed a critical threshold (such as 40, 45, 50, 60, 70 or 80 micrograms ττ) to reduce, reduce or pre-kappa immune interference or carrier inhibition of ττ conjugated polysaccharides. The preferred threshold is about 5 micrograms. The present inventors have found that the ratio of the polysaccharide in the conjugate: ττ is reduced to 1: 〇 5 - 15 by weight (preferably 1: 0.6-1.2, preferably about U), which is advantageous in this respect. For example, the T content of DTPa in the DTPa-HB-IPV-Hib(TT)-MenC(TT) vaccine should preferably be lower than the standard value (for example, 24 μg) (preferably about a quarter to two of the normal amount). About half of the total TT will be about 41 micrograms, and the total TT will be about 12 micrograms for a total of TT to 乂(3)0 of about 5 micrograms TT'. Particularly preferred Hib/Pneumococcal polysaccharide compositions (individually used or as a component of the second container of one of the aforementioned kits) include: Hib (preferably a total of τΤ and/or unadsorbed) and a variety of For example, more than 1, 2, 3, 4, 5, 6 '7, 8, 9, 10 or π) pneumococcal polysaccharide conjugates (such as the compositions described in the Streptococcus pneumoniae segment of the invention), preferably Including 11 polysaccharides (serotype 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C '19F and 23F), preferably pneumococcal polysaccharide conjugated PD, DT, CRM197 or TT, It can also be adsorbed without adjuvant, in particular aluminum salt ◎ In a particularly preferred embodiment of 143906.doc -15-201008577, there is no adjuvant aluminum salt in the composition. An antigen may additionally be included in the composition of the invention (e.g., a type C meningococcus capsular polysaccharide conjugate [preferably conjugated protein D, TT, DT or CRM197 and/or unadjuvanted adsorption]), however, In another embodiment, the composition contains only Hib and pneumococcal polysaccharide co-hosts, and in a particular embodiment of another of the foregoing formulations,

Hib and pneumococcal polysaccharides do not co-locate to the same carrier protein (especially when CRM197 is a carrier protein). The vaccine can be contained in a container (the composition is not liquid or lyophilized), or the first of the two vials contains Hib (preferably freeze-dried). The second contains pneumococcal antigen (preferably liquid type). Preferably, the lyophilized composition of the composition is provided with an anti-clotting agent, such as sucrose or lactose. The ingredients in the vial may be mixed in a container immediately prior to administration to the host in a single administration/injection mode. 'Inoculation of such a formulation may result in proximity or Often more than 100% of the anti-Hib capsular polysaccharide antibody titer obtained when the antigen is administered alone. In a preferred embodiment, the pneumococcal polysaccharide conjugate in the composition is compared to the separate administration, and No significant adverse effects (in terms of protection efficiency) 'This assay measures the last major vaccination (primary vaccination is the initial administration - usually three months in the first year of life) one month after the determination of anti-polysaccharide The main geometric mean concentration of the antibody (GMC). The vaccine GMC (micrograms/ml) of the present invention should preferably exceed 55 °/ of the GMC obtained by administering the pneumococcal polysaccharide without the Hib conjugate. (more preferably, more than 60, 70, 80, or 90%), and finally the main method of investing in the vaccine of the present invention is compared with the vaccine containing no Hib after 1 month. 'If the antibody concentration is not lower than that of 〇乃微克/ The percentage of acceptors in milliliters does not exceed 10 ° / (preferably less than 9, 7, 5, 3 or 1%), then there is no adverse 143906.doc • 16- 201008577 effect. Although the above refers to Hib, Pneumococcal and meningococcal 'polysaccharide body, only the invention can be extended to Hib and pneumococcal, size range polysaccharides, and oligosaccharides' (treatment of multi-body will have less size, it still has induced host protection These are well known in the art of vaccination (see, for example, European Patent No. 497525). [Beneficially, MenY can be 0.1, 〇.2, 0.3, 0.4, 〇·5, 〇·6, 〇·7, 〇· 8 or 9 times the oligosaccharide conjugate of the original polysaccharide. Another object of the invention is to provide an immunological composition or vaccine which can be used as a remedy for use in this patent specification. Another object of the present invention is to provide the present invention. In preparation for the treatment or prevention of pertussis, tetanus An immunological composition of a disease caused by infection of Bacillus, diphtheria, sputum hepatitis virus, poliovirus, and meningitis bis (four) (and optionally Haemophilus vaginalis), and additionally provides an immunological composition of the present invention In the preparation of a set of diseases for the treatment or prevention of B. pertussis, tetanus rods, ^, diphtheria, hepatitis B virus, poliovirus, sputum bacillus, pneumococcal and meningococcal infections. In addition, this (4) also provides immunological methods for the host to fight against diseases caused by pertussis (four), tetanus, diphtheria, hepatitis B virus, poliovirus and meningococcus (and, depending on the situation). 'This method includes administering an immunoprotective dose of the present invention to an immunologically acceptable composition of the invention.>> The other main finger of the present invention provides a host against the 143906.doc •17· 201008577 B. pertussis, tetanus, diphtheria in the aforementioned kit of the present invention. Bacilli, hepatitis B virus, poliovirus and/or a variety of ▲ cold bacilli, pneumococci and meningitis Immunization diseases caused by infection, which is administered at the same time drive. Simultaneous administration schedule

The course of this procedure involves administration of an immunoprotective dose of the immunological composition in the first container of the set of different lymph nodes at the site of the host (eg, one of the sets of the invention) and is administered at a different lymphocyte collection from the anterior Preferably, the steps of the immunological composition in the second (or third) container in the set are at different limbs, preferably the vaccine is administered within 24 hours, and more preferably in the same place, The best is when the same visit to the medical staff is hosted. Preferably, the host system applies two (or all) of the epidemic fields in one or more (preferably 2) times in the same manner every 2-12 weeks (preferably about 丨), the third vaccination The drug is usually administered between 2 weeks and 7 months after the second vaccination. For example, the administration method of the aforementioned vaccine can be based on the normal administration schedule of the DTP vaccine (such as three visits, each visit interval is one month, for example, age 3). At 4 and 5 months; or 3, 5 & U months at 'or 3, 5 and 12 months', such dosing schedule can be used to counter the antigens of two (or all) containers in the kit The immune response is the highest. From the life-year to adulthood, the fork medicine can be added in the same way at any time. Although it is better to use the intramuscular route to administer the vaccine, the advantage of additional administration is that it can be administered through the mucosa, and mucus can be stored as appropriate. An adjuvant (preferably iaureth 9 or a heat-stable toxin derived from Escherichia coli fLT) or a canine thereof (or a fragment thereof) (for example, a vaccine is easy to administer a nasal vaccine) and especially when The host is administered parenterally, the method is 143906.doc -18· 201008577 is very good, the section 0 and the vaccine administration position does not need to be collected into different lymphocytes. The invention also includes the simultaneous preparation of the vaccine set immunological combination of the invention. The use of the object. , a package that includes two or more containers of ττ

Another subject of the present invention relates to a vaccine kit for simultaneous administration (as defined above) wherein the balance of the ττ components in two or more of the sputum is sufficient to effectively reduce, reduce or prevent sputum immune interference or ττ Carrier inhibition of multiple listeners. Quinoa is a fairly good carrier, however it is known that its use in vaccine compositions is limited, especially when free tau is also present. If used in excess, all antigens that are conjugated to sputum exhibit lower antibody titers, so an important topic in the art is how to use sputum in many different fields in large combinations of vaccines (eg as free antigens and as many listeners) The carrier of the bulk antigen" does not have the above disadvantages. The present inventors have found the best way to solve this problem; it is to use the kit to simultaneously administer the time course (as described above). The content of sputum in the vaccine in the first container is no more than the occurrence of immune interference or carrier inhibition. The critical threshold at which the action occurs, and the amount of sputum in the vaccine in the second container does not exceed the critical threshold at which immune interference or vector inhibition occurs, which allows the total amount of sputum to be administered simultaneously above this critical threshold' and reduces immune interference. (or carrier inhibition) (ie less than one vaccination component), preferably not at all. The critical threshold can be 40, 45, 50, 60, 70 or 80 micrograms, preferably about 50. Micrograms, therefore, the highest amount of sputum that can be dosed is equal to the amount of the number in the set of containers multiplied by the critical threshold. 143906.doc • 19· 201008577 The invention therefore provides a kit comprising two (or three) containers comprising two (or three) immunological compositions for simultaneous administration, each combination

Contains a free and/or common form of TT in which the TT content in each container does not exceed a critical threshold to prevent or reduce the production of TT immune interference (or vector inhibition) effects - but the total amount of TT in all containers Exceeding this critical threshold. Preferably at least one of the containers should comprise free (unconjugated) TT, most preferably a DTPa or DTPw reconstituted vaccine component. Although the free TT content is in the normal range of about 42 micrograms, another advantage of the present invention is that the content can be reduced (10-30 or 10-20 micrograms, for example, 1 〇, 15, 20, 25 or 30 micrograms), but still Inducing optimal anti-τττ anti-鳢 potency with minimal (or no) immune interference or vector inhibition effect. Preferably at least one of the containers (but possibly 2 or 3) should include at least one (but possible The conjugated polysaccharide of 2, 3, 4, 5, 6, 7, or more) may be any one of the patent specifications described herein, preferably one or more pneumococcal multi-enzymes (as mentioned earlier), or MenC, MenY or Hib. The car father's kit can be any set of the aforementioned invention. Preferably, one, two, three or all of the polysaccharides are contained in the set, thereby reducing the polysaccharide: TT ratio (compared to standard conjugate) to 1:0.5·1.5 weight ratio (preferably The ratio is 1:0.64.2, and the best is about 1:1). This vehicle still has immune function, but it helps to reduce or prevent the ττ immune interference or carrier inhibition effect. The invention further provides a method of immunizing a host with the aforementioned kit, the method comprising administering to the first location of the host an immunoprotective agent in the first container of the host 143906.doc -20- 201008577 an immunological composition Φ flute - in the container ^ - placed in the host with the second immunoprotective agent 1 (in the case of the host third:: placed in the third container of the host immune protection dose of the immune group The first and second (and the third stand) have different lymph nodes.

Simultaneous administration should be carried out as described above, and the first and second (and third) positions are preferably in the different limbs of the host, in the first and second (and third) containers. Preferably, the immunological composition is on the same day, preferably the host is re-administered in the same manner _ times or more in the future, each interval of 2 '12 weeks' is better twice, each interval is about 1-2 month. Kits comprising two or more containers of DT or CRM197 Another subject of the invention is a vaccine kit for simultaneous administration (as defined above), wherein the DT component (including DT and any of the two or more containers) Alien-free mutants, such as CRM197, are balanced enough to effectively potentiate DT (or CRM197) conjugated polysaccharide antibody titers and reduce post-administration reactivity (ie, when the components in the container are dosed in a single injection) It has low reactivity when used). DT and CRM197 are quite good carriers. However, it is known that DT-containing vaccines produce considerable post-dosing reactivity. The inventors of the present invention used a kit to simultaneously administer a drug schedule (as described above) to a high content (4〇). _15 〇 micrograms are preferably 60-120 micrograms, more preferably 70-100 micrograms, and most preferably about 95 micrograms. The second container includes DT- or CRM197-conjugated polysaccharides. The vaccine is administered at the same time. The benefits of the present invention are that a) although the DT content in the first container is high, it is not sufficient to induce DT immune interference or carrier inhibition effects, b) DT- or CRM- in the first container 143906.doc -21 - 201008577 The 197 polysaccharide conjugate is separate, so the side effect reactivity of the vaccine in the first container does not increase, but c) the antibody titer against the co-consumption of dt or CRM197 polysaccharide is not reduced, and may increase ( Those who administer conjugates have higher potency or lower DT content than the first container. The invention therefore provides a kit comprising two (or three) containers comprising two (or three) immunological compositions for simultaneous administration, wherein the first container comprises a high level of DT component (DT plus Upper CRM197; preferably free or unconjugated), and the second (and third) container comprises one or more polysaccharides conjugated to DT and/or CRM197. The first container preferably comprises free (unconjugated) DT, most preferably a DTPa or DTPw reconstituted vaccine. The DT/CRM197 conjugated polysaccharide may be any of the patent specifications; preferably one or more of the following: pneumococcal polysaccharides 1, 2, 3, 4, 5,

, 12F, 14, 15B, 2F, 23F or 33F, MenC, Ming, one or more of which are only suitable for immunization of the light weight itself. A preferred set of the present invention may be any of the foregoing inventions.

The best one is about 1:1) ^ -, two, three or all of the polysaccharides - DT (or so can reduce the polysaccharide: DT / CRM1 Q7 屮 you 丨, 夕 糖: DT / CrM197 ratio 1, 5 weight Ratio (preferably 1:0.6-1.2, 143906.doc 201008577) The invention further provides a method of immunizing a host with the aforementioned kit, the method comprising administering to the host the first container a dose of immunoprotective agent at the first location of the host An immunological composition, which is administered to a host at a second location in the host with an immunoprotective dose of an immunoprotective dose in the second snail (if appropriate, in the third position of the host, immunization protection in the third container of the host) The dose of the immunological composition), wherein the first and second (and third) positions are treated with different lymph nodes. ❹ Simultaneous administration should be carried out in the same manner as the first and second (and The third) position is preferably in the different limbs of the host, and the immunological composition in the first and second (and second) containers is preferably administered on the same day, preferably after the host. Re-do the drug one or more times in the same way, every interval of 2-12 weeks' The best is twice, each interval about ι_2 months. The vaccine preparation of the present invention can be administered by the systemic or mucosal route to protect or treat mammals susceptible to infection, including intramuscular and peritoneal. Injection by internal, percutaneous or subcutaneous route; or mucosal route of administration via oral/digestive tract, respiration (eg intranasal), genitourinary tract. The dose of antigen selected for each vaccine dose induces an immunoprotective response without There are significant side effects. This content depends on the particular immunogen selected and how it is presented. Generally, each dose is intended to include a polysaccharide of 〇1_丨〇〇 microgram, preferably 0.1-50 micrograms. Preferably, it is o.uo microgram, and 1 to 5 micrograms is the best range. The vaccine protein antigen component mainly ranges from 1_1 micrograms, preferably 5_5 micrograms, the most important range is 5-25 micrograms. After the vaccine is administered, the subject may receive 144906.doc -23- 201008577 to accelerate the immunization at appropriate intervals. The vaccine preparation is prepared as described in the vaccine design ("Second unit and adjuvant method" (Powell MF & Newman MJ•Published) (1995), Plenum Printed in New York), the lipid body embedding method described by Fullerton, U.S. Patent No. 4,235,877 °. The examples provided are for illustrative purposes, and are not limiting. Scope of the invention. Example 1: Preparation of a DT-TT-Pa-IPV-HepB (DTPal PVHepB) vaccine was prepared as disclosed in WO 93/24148, marketed under the trade name Infanrix-PeNTaTM (SmithKline Beecham Biologicals) ° Example 2 : Preparation of MenC or MenC-MenY vaccine

MenC: Conjugated type C meningococcal vesicles onto protein D or TT (using CDAP technique) to contain 5 micrograms of polysaccharide per 0.5 milliliter of human dose conjugate. The pH was adjusted to 6.1 and lyophilized under sucrose.

MenCMenY: Mix conjugated protein 0 or Dingding (using CDAP technology) type C meningococcus capsular polysaccharide and conjugated protein D or TT Y-type meningococcal capsular polysaccharide, so that each A 0.5 ml human dose contains 5 micrograms of polysaccharide per conjugate. The pH was adjusted to 6.1 and lyophilized under sucrose. Example 3: Preparation of DT-TT-Pa-IPV-HepB, MenC-MenY (DTPalPV HepB/MenCMenY) or DT-TT-Pa-IPV_HepB-MenC (DTPal PVHepB/MenC) vaccine 143906.doc -24- 201008577 Before use, The vaccines of Examples 1 and 2 were mixed immediately (on the same day). Example 4: Preparation of Hib-valence pneumococcal conjugate (Hib/StrepllV) vaccine Concentration in the presence of lactose, lyophilized to TT at pH 6.1 conjugated to TT bacteriophage virus B capsular polysaccharide (conjugated in each dose) 10 micrograms of polysaccharides) [HiberixTM (SmithKline Beecham Biologicals)] immediately before use (using the same sputum) dissolved in 11-valent conjugated to PD pneumococcal polysaccharides (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F serotypes) (1 microgram of polysaccharide per body in each dose) in a liquid solution, lung

A inflammatory vaccine has been adsorbed by 0.5 mg of Al3+ (such as AlP〇4) beforehand. Example 5: Clinical Trial Example 4 Vaccine Study Three doses of the German infant (3, 4, 5 months old) Example 4 vaccine and control group vaccine were administered according to the time course. The results of the immune reaction (measured one month after the last inoculation) are as follows. Anti-pneumococcal IgG antibody: GMC (micro/ml) (measured by Elisa) PS Antibody time Ν Α group s+r%i GMC Ν Group D S+r%l GMC anti-1 ΡΙΙΙ 30 100 1.23 33 100 0.99 Anti- 3 ΡΙΙΪ 30 100 2.04 33 97.0 1.20 耐-4 ΡΙΙΙ 30 100 0.98 33 100 1.03 耐-5 ΡΙΙΙ 30 100 1.33 33 100 1.34 -6 抗 ΡΙΙΙ 30 100 0.54 33 100 0.62 -7F ΡΙΙΙ 30 100 1.60 33 100 1.33 Anti- 9V ΡΙΙΙ 30 100 1.61 33 100 1.21 Anti-14 ΡΙΙΙ 30 100 2.27 33 100 2.32 Anti-18C ΡΙΙΙ 30 100 1.06 33 100 1.04 Anti-19F ΡΙΙΙ 30 100 2.05 33 100 1.92 Anti-23F ΡΙΙΙ 30 96.7 0.75 33 100 0.76 143906. Doc -25- 201008577 Eight groups = 11?11-?0 + 11^&1114乂-116乂31'1^(111£31114 parent-?61113 plus additional Hib conjugate-DTPa-HB-IPV -Hib) Group D = llPn-PD/Hib+Infanrix_PeNTaTM (DTPa_HB-IPV) + specifies concomitant (different limbs), not combined administration. The concentration of the receptor antibody is not less than the percentage of 〇.5 μg/ml. PS1 3 4 5 6B 7F 7V 14 18C 19F 23F D 84.8 87.9 87.9 90.9 51.5 90.9 93.9 97.0 81.8 97.0 72.7 A 86.7 96.7 76.7 90.0 50.0 93.3 90.0 90.0 80.0 96.7 66.7 Anti-PRP antibody: GMC (mg/ml) (determined by Elisa) Group D (N=34) η 21 μg/ml [%] GMC [μg/ml] Anti-PRP PIII 33 100 10.75 100% Receptor An anti-PRP (Hib polysaccharide) antibody of not less than 1.0 μg/ml. Approximately 6 μg/ml of GMC of Hiberix (unadsorbed Hib-TT conjugate) was administered in a similar dosing schedule. In the case of ELISA antibodies, in addition to the lower geometric mean concentrations of serotypes 1, 3 and 9V found in the llPn-PD/Hib vaccine, the immune response of infants vaccinated with 1 ιρη_PD/Hib vaccine and all serotypes inoculated 1 The ipn_PD vaccine was found to be similar, however, based on the overlap of the 95% confidence interval, these differences were not significant. The llPn-PD/Hib vaccine induces functional (adjustment of function) antibodies against all serotypes. The Hib vaccine with a combination of pneumococcal vaccines does not significantly interfere with the pneumococcal immune response, and it is surprisingly more than two registered plagues 143906.doc -26- 201008577 seedlings (Infanrix-HeXa and Hiberix) It can increase the anti-PRP reaction. Example 3 Vaccine, or Study Example 3 and Example 4 Vaccine Co-administration Study 1 : Infanrix-PeNTa for mixed MenC co-vehicle vaccine was evaluated by administering Hib vaccine or simultaneously administering an 11-valent pneumococcal vaccine mixed with Hiberix. Safety and immunity. Both the PD and TT vectors can evaluate the MenC conjugate, and the infants can administer three doses of vaccine. When visiting medical staff, they can also be vaccinated on different limbs. Study 2: The safety and immunity of Infanrix-PeNTa mixed with the MenC-MenY co-vehicle vaccine was evaluated by administering Hib vaccine or simultaneously administering an 11-valent pneumococcal vaccine mixed with Hiberix. Both the Pd and TT vectors can be used to evaluate the MenC and MenY conjugates, and the infants are administered three doses of vaccine, which can be vaccinated on different limbs while visiting medical staff. 143906.doc 27·

Claims (1)

201008577 VII. Patent Application Range: 1. A compound immunological composition for conferring protection against the diseases caused by Haemophilus influenzae and Streptococcus pneumoniae, including: (a) a carrier protein and B A conjugate of a bacterium cysteine or oligosaccharide of the type of bacterium, and (b) a mixture of a carrier protein and a S. pneumoniae saccharide or oligosaccharide. 2. The immunological composition of claim 1 wherein the composition comprises 2 or more ® carrier proteins and a conjugate of a Streptococcus pneumoniae saccharide or a saccharide. 3. The immunological composition of claim 2, wherein the composition comprises more than 7 carrier proteins and a conjugate of a Streptococcus pneumoniae saccharide or oligosaccharide. 4. The immunological composition according to any one of claims 1 to 3, wherein the S. pneumoniae capsular succulent or biliary system is obtained from the group consisting of 1, 2, 3, 4, 5, 6A, 6B, 7F The serotypes of the groups consisting of 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F. 5. The immunological composition of claim 4 which comprises a carrier protein and a bacteriophage or oligo of the S. pneumoniae serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F A total of sugar bodies. 6. The immunological composition according to any one of items 1 to 3, which additionally comprises an adjuvant. The immunological composition according to any one of claims 1 to 3, wherein the capsular polysaccharide or oligosaccharide of type B haemophilus b is not adsorbed to the aluminum salt adjuvant. 8. The immunological composition of claim 7, wherein the Streptococcus pneumoniae 143906.doc 201008577 body or oligosaccharide is adsorbed to the salt salt adjuvant. 9. An immunological composition according to the seventh embodiment of claim 7, wherein the capsular polysaccharide or oligo-tano of the type B haemophilus bacillus and the bacteriophage or oligos of the pneumococci are not adsorbed to the aluminum salt. Agent. The immunological composition according to any one of claims 1 to 3, wherein the carrier protein used is selected from the group consisting of tetanus toxoid, diphtheria toxoid, Ml 97 recombinant diphtheria toxin, and meningococcus. 〇MpC, pneumococcal pneumoniae and Haemophilus bacillus protein D. The immunological composition according to any one of claims 1 to 3, wherein the cystosome b or the oligosaccharide of the type B, and the Streptococcus pneumoniae saccharide or oligosaccharide are not conjugated to the same Carrier protein. 12. An immunological composition according to the invention, wherein the type B blood-sense bacillus sac multi-St or oligobiliary and S. pneumoniae sac multi-breast or oligosaccharide non-common to CRM197 . The immunological composition according to any one of the items 3 to 3, wherein the carrier protein of the capsular polysaccharide or the saccharide of the type B haemophilus is a tetanus toxoid. 14. The immunological composition according to any one of the items (1), wherein the carrier protein of all S. pneumoniae granules or oligosaccharides is protein 15. The immunological composition according to any one of claim (1), It is formulated as a vaccine for administration to a host in vivo 'wherein the individual components of the composition are formulated such that their immunity is not destroyed by other individual components of the composition. 16. The immunological composition of any of the items in claim (1), which is formulated into a living 143906.doc 201008577. A vaccine administered to the host, which allows an acceptable percentage of human-body's per-antigenic component Produces antibodies with potency that are superior to serum protection protocols. 17. As requested! The immunological composition according to any one of 3, which is for use as a medicament. A method of preparing a complex immunological composition according to any one of claims 1 to μ, which comprises the step of mixing the individual components together. 143906.doc 201008577 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: (none) 143906.doc