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    • 专利摘要:
    The present invention relates to a method of immunization against infection by Neisseria meningitidis, comprising the following steps a) immunizing a human patient at an early age between 0 and 11 months with a conjugate vaccine based on bacterial saccharide comprising at least one, two or three bacterial saccharides separately conjugated to a carrier protein to form at least one, two or three bacterial saccharide conjugates; and b) immunization of the human patient at a second age between 12 and 24 months with an anti-Neisseria meningitidis conjugate vaccine comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of N. meningitidis of serogroup A (MenA), a capsular saccharide of N. meningitidis serogroup C (MenC), a capsular saccharide of N. meningitidis serogroup W135 (MenWl35) and a capsular saccharide of N. meningitidis serogroup Y (MenY ), separately conjugated to a carrier protein, the anti-Neisseria meningitidis conjugate vaccine being co-administered with a vaccine comprising diphtheria toxoid and tetanus toxoid.
    公开号:BE1021934B1
    申请号:E2014/0175
    申请日:2014-03-17
    公开日:2016-01-27
    发明作者:Yaela Baine；Jacqueline Miller
    申请人:Glaxosmithkline Biologicals S.A.；
    IPC主号:
    专利说明:

    PROCESSING METHOD
    Technical area
    The present invention relates to the field of use of conjugate vaccines protecting against Neisseria meningitidis for the prevention or treatment of N. meningitidis infection. In particular, the present invention relates to the coadministration of anti-N conjugate vaccines. Meningitidis with DTP-containing vaccines to a population that has been pre-immunized with at least one conjugate vaccine. Another aspect of the invention relates to the use of additional immunization.
    Context of the invention
    An invasive Neisseria meningitidis infection causes severe illness with a mortality of approximately 10%, even when appropriate antibiotics and supportive therapy are administered [1]. In the United States, the majority of invasive meningococcal disease (IMD) is caused by serogroups B, C and Y [2], while serogroups A, W-135 and X, which are important causes of epidemics in many World regions [3, 4] are more rarely detected. Infants <1 year of age have the highest incidence of IMD in the United States (approximately 1 case for a population of 18,500, 1998-2007) [2]. Therefore, to have an impact on meningococcal disease in infants and children in the United States, meningococcal conjugate vaccines must be effective from the earliest ages [5].
    An anti-meningococcal serogroup C and Y vaccine, combined with Hib (HibMenCY-TT, MenHibrix ™, GlaxoSmithKline Vaccines), has recently been licensed in the United States for use in infants by administering a series of 4 doses at 2 months of age [6], after demonstrating its immunogenicity and safety in clinical trials in infants and young children [7-14]. A quadrivalent anti-meningococcal serogroup A, C, W-135 and Y (MenACWY) vaccine is authorized in the United States for use in children 9 to 12 months of age (Menactra ™, sanofi pasteur), two doses of which are recommended by the Advisory Committee on Immunization Practices (ACIP) for children at increased risk of IMD due to complement deficiency or exposure due to travel / stay in an endemic area [15]. Another MenACWY conjugate vaccine is authorized for use from the age of 2 years (Menveo ™, Novartis).
    GlaxoSmithKline Vaccines MenACWY vaccine, where all serogroups are conjugated to tetanus toxoid (TT) (MenACWY-TT: Nimenrix ™), is licensed in Europe for single dose administration, but remains under study in the USA. Clinical trials have shown that a dose of MenACWY-TT. is immunogenic for the four serogroups and well tolerated in infants over 12 months of age, children, adolescents and adults [16-23].
    The pediatric immunization schedule is saturated and there is still a need to evaluate the safety and immunogenicity of meningococcal conjugate vaccines when they are introduced into an immunization schedule with other pediatric vaccines. It is useful to determine whether co-administration with other vaccines causes interference problems or enhances immunogenicity.
    This study evaluates the immunogenicity and safety of meningococcal conjugate vaccines when administered as an additional dose in the second year of life. In particular, it reports the effect of co-administration with a dose of acellular diphtheria-tetanus vaccine (DTPa) during the second year of life. The study unexpectedly shows that the coadministration of a multivalent meningococcal conjugate vaccine with DTPa vaccines during the second year of life results in an increased immune response against meningococcal conjugates compared to a situation in which vaccines are administered at different times. A simpler immunization schedule, in which a meningococcal conjugate and DTPa are coadministered, provides a dual benefit of less frequent clinic visits and better immunogenicity.
    According to one aspect of the invention, there is provided a method of immunizing against Neisseria meningitidis infection, comprising the following steps: a) immunizing a human patient at a first age of between 0 and 11 months with at least a bacterial saccharide conjugated to a first carrier protein to form a bacterial saccharide conjugate; and b) immunizing the human patient at a second age between 12 and 24 months with an anti-Neisseria meningitidis conjugate vaccine comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of N. meningitidis serogroup A (MenA), capsular saccharide of N. meningitidis serogroup A, capsular saccharide N. meningitidis serogroup C (MenC), capsular saccharide N. meningitidis serogroup W135 (MenW135) and A capsular saccharide of N. meningitidis serogroup Y (MenY), conjugated separately to a second carrier protein, wherein the anti-Neisseria meningitidis conjugate vaccine is coadministered with a vaccine comprising diphtheria toxoid and tetanus toxoid.
    According to another aspect of the invention, there is provided a medical use of an anti-N multivalent conjugate vaccine. meningitidis in the prevention or treatment of N. meningitidis-induced disease, in which a human patient is immunized according to a schedule comprising steps a) and b), wherein step a) immunizes the human patient to a first age between 0 and 11 months with at least one bacterial saccharide conjugated to a first carrier protein to form a bacterial saccharide conjugate; and step b) immunizes the human patient at a second age between 12 and 24 months with an anti-Neisseria meningitidis conjugate vaccine comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of N. meningitidis serogroup A (MenA), a capsular saccharide of N. meningitidis serogroup A, a capsular saccharide N. meningitidis serogroup C (MenC), a capsular saccharide N. meningitidis serogroup W135 (MenW135) and a capsular saccharide of N. meningitidis serogroup Y (MenY), conjugated separately to a second carrier protein, wherein the anti-Neisseria meningitidis conjugate vaccine is co-administered with a vaccine comprising diphtheria toxoid and tetanus toxoid .
    Description of figures
    Figure 1: subject participating in the study.
    See Supplementary Table 3 for details on the reasons for withdrawal of certain study subjects or their removal from the protocol compliant cohort for immunogenicity in the fourth dose phase. * Subjects who did not participate in the fourth dose phase because they did not want to participate (n = 83); were lost to follow-up (n = 47) or were not eligible to participate (n = 78).
    Figure 2: Percentage of subjects with titres of hBSA ^ 1: 8 one month after vaccination with MenACWY-TT or with HibMenCY-TT at 12 to 15 months of age, with MenACWY-TT + DTaP at 15 to 18 months or with DTaP at 15 to 18 months of age (control group) (CAP cohort for immunogenicity, fourth dose phase). CAP = protocol compliant; hSBA = serum bactericidal activity using a source of human complement.
    Figure 3: TMG in hSBA one month after vaccination with MenACWY-TT or with HibMenCY-TT at 12 to 15 months of age, or with MenACWY-TT + DTaP at 15 to 18 months of age or with DTaP at an older age 15 to 18 months (control group) (CAP cohort for immunogenicity, fourth dose phase). CAP = protocol compliant; hSBA = serum bactericidal activity using a source of human complement; TMG = geometric mean title. * Represents the differences observed between the co-administration group and the other groups.
    Figure 4: Local and general requested symptoms within 8 days after vaccination with MenACWY-TT or with HibMenCY-TT at 12 to 15 months of age, or DTaP and MenACWY-TT (Coad group) at 15 to 18 months (fully vaccinated cohort, fourth dose phase).
    For all groups, local symptoms refer to the percentage of subjects with at least one local symptom at the MenACWY-TT or HibMenCY-TT injection site. Fever (any pathway)> 38.0 ° C; category 3: redness and swelling> 30 mm; pain - crying when the limb is touched / spontaneously painful; fever (any pathway)> 40 ° C; irritability / nervousness and drowsiness - normal activity impossible; loss of appetite - not feeding at all.
    detailed description
    The present invention describes a method of immunizing against Neisseria meningitidis infection, comprising the following steps: a) immunizing a human patient at a first age of between 0 and 11 months with at least one bacterial capsular saccharide conjugated to a first carrier protein to form a bacterial capsular saccharide conjugate; and b) immunizing the human patient at a second age between 12 and 24 months with an anti-Neisseria meningitidis conjugate vaccine comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of N. meningitidis serogroup A (MenA), capsular saccharide of N. meningitidis serogroup A, capsular saccharide N. meningitidis serogroup C (MenC), capsular saccharide N. meningitidis serogroup W135 (MenW135) and A capsular saccharide of N. meningitidis serogroup Y (MenY), conjugated separately to a second carrier protein, wherein the anti-Neisseria meningitidis conjugate vaccine is coadministered with a vaccine comprising diphtheria toxoid and tetanus toxoid. Step a) is an immunization in the first year of life, usually performed on human infants aged 0 to 8 months, 1 to 7 months or 2 to 6 months. In one embodiment, the immunization step a) comprises a Haemophilus influenza saccharide conjugate (Hib) and / or a N. meningitidis capsular saccharide conjugate C (MenC) and / or a saccharide conjugate. capsular N. meningitidis serogroup Y (MenY).
    In one embodiment, the conjugate or each of the conjugates administered in step a) contains a carrier protein selected from tetanus toxoid, diphtheria toxoid or CRM197. In a preferred embodiment, when more than one conjugate is administered in step a), the same type of carrier protein is independently conjugated to each saccharide. In a preferred embodiment, the first carrier protein is tetanus toxoid.
    In one embodiment, the immunization of step a) involves the administration of 2 or 3 doses of the bacterial saccharide conjugate (s), for example during the immunization of a human infant at an age of 2, 4 and 6 months.
    In one embodiment, during step a), the bacterial capsular saccharide conjugate (s), for example Hib, MenC and / or MenY, are administered simultaneously in the form of a vaccine comprising diphtheria antigens, tetanus and pertussis (DTP). The diphtheria antigen is usually diphtheria toxoid, the tetanus antigen is usually tetanus toxoid and the pertussis antigen may be a whole cell or acellular pertussis antigen, optionally comprising one or more elements selected from pertussis toxoid. , FHA or pertactin. In one embodiment, the DTP vaccine further comprises a hepatitis B surface antigen and / or IPV. In one embodiment, immunization of step a) administers a HibMenCY-TT vaccine containing 2.5 μg of tetan toxoid-conjugated Hib PRP and 5 μg of each capsular saccharide, MenC and Y, conjugated to the tetanus toxoid, with a total TT content of 5 μg to 40 μg, 10 μg to 30 μg, 15 μg to 20 μg or approximately 18 μg. Step b) involves immunization of the same human patient in the second year of life, that is, between 12 and 24 months, preferably between 13 and 20 months, between 12 and 18 months, between 14 and 18 months or between 15 and 18 months. Immunization of step b) involves coadministration of i) a multivalent capsular saccharide conjugate vaccine of N. meningitidis with ii) a vaccine comprising diphtheria toxoid and tetanus toxoid. The multivalent capsular saccharide conjugate vaccine of N. meningitidis comprises at least two capsular saccharides selected from MenA, MenC, MenWl35 and MenY; for example, conjugates of: capsular polysaccharides of serogroups C and Y (MenCY), capsular polysaccharide of serogroups C and A (MenAC), capsular polysaccharide of serogroups C and W135 (MenCW), capsular polysaccharide serogroups A and Y (MenAY) , capsular polysaccharides of serogroups A and W135 (MenAW), capsular polysaccharides of serogroups W135 and Y (Men WY), capsular polysaccharides of serogroups A, C and W135 (MenACW), capsular polysaccharides of serogroups A, C and Y (MenACY); capsular polysaccharides of serogroups A, W135 and Y (MenAWY), capsular polysaccharides of serogroups C, W135 and Y (MenCWY); or capsular polysaccharides of serogroups A, C, W135 and Y (MenACWY).
    In one embodiment, the multivalent capsular saccharide vaccine of N. meningitidis utilizes a carrier protein (second carrier protein) that is selected from the group consisting of tetanus toxoid, diphtheria toxoid, and CRM197. In one embodiment, the second carrier protein is tetanus toxoid. In a preferred embodiment, the first carrier protein and the second carrier protein are identical, preferably tetanus toxoid.
    In one embodiment, the coadministered vaccine containing diphtheria toxoid and tetanus toxoid is a DTP vaccine containing in addition pertussis components which are pertussis components of whole cell or acellular cell, for example containing pertussis toxoid, FHA or pertactin. In one embodiment, the vaccine containing diphtheria toxoid and tetanus toxoid further comprises antigens, for example HBV and / or IPV.
    In one embodiment, co-administration of the multivalent anti-ΛΖ conjugate vaccine. Meningitidis with a vaccine containing diphtheria toxoid and tetanus toxoid causes an increase in the immunogenicity of at least one meningococcal component; for example MenC, MenY, MenW135, MenC and MenY, MenC and MenW135 or MenC, MenWl35 and MenY. In one embodiment, the increase of
    immunogenicity is measured by an SBA test (possibly using a source of human complement), possibly performed on serum taken one month after vaccination with multivalent anti-N conjugate vaccine. meningitidis in the second year of life. In one embodiment, the TMG increases after co-administration with a vaccine comprising diphtheria toxoid and tetanus toxoid of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, compared with TMG after the single administration of the multivalent anti-N conjugate vaccine. meningitidis.
    In one embodiment, the carrier protein of step b) is present in the conjugate dose of Neisseria meningitidis at a total dose of 10 μg to 100 μg, 20 μg to 90 μg, 20 μg to 80 μg, 30 μg. at 70 μg, 35 μg at 60 or 40 μg at 50 μg. For example, for a tetravalent anti-N conjugate vaccine. meningitidis with TT, DT or CRM197 as a carrier protein, a total dose of carrier protein from 20 μg to 80 μg is envisioned. For a bivalent anti-N conjugate vaccine. meningitidis, a total dose of carrier protein for TT, DT or CRM197 of 20 μg to 40 μg is considered.
    The details given above in connection with an immunization method apply in the same way to the uses of a multivalent anti-N conjugate vaccine. meningitidis in the prevention or treatment of a disease induced by N. meningitidis.
    In one embodiment, the average size (or molecular weight) of at least one, two, three, four, or each N. meningitidis polysaccharide is from 50 kDa to 1500 kDa, 50 kDa to 500 kDa, 50 kDa to 300 kDa, 101 kDa at 1500 kDa, 101 kDa at 500 kDa or 101 kDa at 300 kDa as determined by MALLS.
    In one embodiment, the MenA polysaccharide, when present, has a molecular weight of 50 kDa to 500 kDa, 50 kDa to 100 kDa, 100 kDa to 500 kDa, 55 kDa to 90 kDa, 60 kDa to 70 kDa or 70 kDa at 80 kDa or 60 kDa at 80 kDa as determined by MALLS.
    In one embodiment, the MenC polysaccharide, when present, has a molecular weight of 100 kDa to 200 kDa, 50 kDa to 100 kDa, 100 kDa to 150 kDa, 101 kDa to 130 kDa, 150 kDa to 210 kDa or 180 kDa at 210 kDa as determined by MALLS.
    In one embodiment, the MenY polysaccharide, when present, has a molecular weight of 60 kDa to 190 kDa, 70 kDa to 180 kDa, 80 kDa to 170 kDa, 90 kDa to 160 kDa, 100 kDa to 150 kDa or 110 kDa at 140 kDa, 50 kDa at 100 kDa, 100 kDa at 140 kDa, 140 kDa at 170 kDa or 150 kDa at 160 kDa, as determined by MALLS.
    In one embodiment, the MenA polysaccharide, when present, has a molecular weight of 60 kDa to 190 kDa, 70 kDa to 180 kDa, 80 kDa to 170 kDa, 90 kDa to 160 kDa, 100 kDa to 150 kDa, 110 kDa at 140 kDa, 50 kDa at 100 kDa or 120 kDa at 140 kDa as determined by MALLS.
    The molecular weight or average molecular weight of a polysaccharide herein refers to the weight average molecular weight (Mw) of the polysaccharide measured before conjugation, and is measured by MALLS.
    The MALLS technique is well known in the art and is usually performed as described in Example 2. For MALLS analysis of meningococcal saccharides, two columns (TSKG6000 and 5000PWx1 TOSOH Bioscience) can be used in combination and the saccharides are eluted with water. The saccharides are detected by means of a light scattering detector (for example, the Wyatt Dawn DSP equipped with an argon laser of 10 mW at 488 nm) and an interferometric refractometer (for example, the Wyatt Otilab DSP equipped with a P100 cell and a red filter at 498 nm).
    In one embodiment, N. meningitidis polysaccharides are native polysaccharides or native polysaccharides whose size has been reduced in a normal extraction process.
    In one embodiment, the polysaccharides of N. meningitidis are dimensioned by mechanical cleavage, for example by microfluidization or sonification. Microfluidization and sonication have the advantage of effectively reducing the size of the largest native polysaccharides to provide a filterable conjugate. The sizing is by a factor of at most x20, x10, x8, x6, x5, x4, x3, x2 or xl, 5.
    In one embodiment, the immunogenic composition comprises N. meningitidis conjugates which are prepared from a mixture of native polysaccharides and polysaccharides which are sized by a factor of at most x20. For example, polysaccharides from MenC and / or MenA are native. For example, polysaccharides from MenY and / or MenW are sized by a factor of at most x20, x10, x8, x6, x5, x4, x3, x2 or xl, 5. For example, an immunogenic composition contains a conjugate prepared from MenY and / or MenW and / or MenC and / or MenA that are sized by a factor of at most x20, x10, x8, x6, x5, x4. , x3, x2 or xl, and / or which are microfluidized. For example, an immunogenic composition contains a conjugate prepared from native MenA and / or native MenC and / or native MenW and / or native MenY. For example, an immunogenic composition comprises a conjugate prepared from native MenC. For example, an immunogenic composition comprises a conjugate prepared from native MenC and MenA that are sized by a factor of at most x20, x10, x8, x6, x5, x4, x3, x2 or xl, and / or are microfluidized. For example, an immunogenic composition comprises a conjugate prepared from native MenC and MenY that are sized by a factor of at most x20, x10, x8, x6, x5, x4, x3, x2 or xl, and / or are microfluidized.
    In one embodiment, the polysaccharide polydispersity is 1 to 1.5, 1 to 1.3, 1 to 1.2, there 1.1 or 1 to 1.05, and after conjugation to a carrier protein, polydispersity conjugate is 1.0 to 2.5, 1.0 to 2.0, 1.0 to 1.5, 1.0 to 1.2, 1.5 to 2.5, 1.7 to 2.2 or 1.5 to 2.0. All polydispersity measurements are made by MALLS.
    The polysaccharides are optionally sized up to 1.5, 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20 times with respect to the size of the polysaccharides isolated from the bacteria.
    In one embodiment, the multivalent anti-AL meningitidis conjugate vaccine further comprises a N. meningitidis serogroup B antigen. The antigen is optionally a N. meningitidis serogroup B capsular polysaccharide (MenB) or a polysaccharide or oligosaccharide. dimensioned by drifting. The antigen is optionally an outer membrane vesicle preparation of N. meningitidis serogroup B, as described in EP 301 992, WO 01/09 350, WO 04/14 417, WO 04/14 418 and WO 04 / 14,419.
    In one embodiment, the anti-N multivalent conjugate vaccine. meningitidis further comprises a capsular saccharide of H. influenzae b (Hib) conjugated to a carrier protein.
    The N. meningitidis polysaccharide (s) (and optionally the Hib capsular saccharide) included in the pharmaceutical compositions of the invention are conjugated to a carrier protein, such as tetanus toxoid, tetanus toxoid fragment C, mutants. non-toxic tetanus toxin, diphtheria toxoid, CRM197, other nontoxic mutants of diphtheria toxin [such as CRM176, CRM197, CRM228, CRM45 (Uchida et al J. Biol Chem 218, 3838-3844, 1973); CRM9, CRM45, CRM102, CRM103 and CRM107 and the other mutations described by Nicholls and Youle in Genetically Engineered Toxins, Ed .: Frankel, Maecel Dekker Inc, 1992; a deletion or mutation of Glu-148 to Asp, Gin to Ser and / or Ala 158 to Gly and the other mutations described in US 4,709,017 or US 4,950,740; mutation of at least one or more residues Lys 516, Lys 526, Phe 530 and / or Lys 534 and the other mutations described in US 5,917,017 or US 6,455,673; or a fragment described in US 5,843,711].
    In one embodiment, the anti-N multivalent conjugate vaccine. Meningitidis of the invention utilizes the same carrier protein (independently) in at least two, three, four or each of N. meningitidis polysaccharides. In one embodiment, when Hib is present, Hib can be conjugated to the same carrier protein as the at least one, two, three, four or each of the N. meningitidis polysaccharides. For example, 1, 2, 3 or 4 N. meningitidis polysaccharides are conjugated independently to tetanus toxoid to prepare 1, 2, 3 or 4 conjugates.
    In one embodiment, a single carrier protein may carry multiple saccharide antigens (WO 04/083251). For example, a single carrier protein could be conjugated to MenA and MenC; MenA and MenW; MenA and MenY; MenC and MenW; MenC and MenY; MenW and MenY; MenA, MenC and MenW; MenA, MenC and MenY; MenA, MenW and MenY; MenC, MenW and MenY; MenA, MenC, MenW and MenY; Hib and MenA; Hib and MenC; Hib and MenW; or Hib and MenY.
    The anti-N multivalent conjugate vaccine meningitidis optionally comprises at least one meningococcal saccharide conjugate (e.g., MenA, MenC, MenW, MenY, MenA and MenC, MenA and
    MenW; MenA and MenY; MenC and Men W; Men C and MenY;
    Men W and MenY; MenA, MenC and MenW; MenA, MenC and
    MenY; MenA, MenW and MenY; MenC, MenW and MenY or MenA,
    MenC, MenW and MenY) having a ratio of saccharide Men to carrier protein (particularly tetanus toxoid) of 1: 5 to 5: 1, 1: 2 and 5: 1, 1: 0.5 at 1: 2.5 or 1: 1.25 to 1: 2.5 (w / w).
    The ratio of saccharide to carrier protein (w / w) in a conjugate can be determined in. using the sterilized conjugate. The amount of protein is determined by means of a Lowry assay (e.g., Lowry et al (1951) J. Biol Chem 193, 265-275 or Peterson et al Analytical
    Biochemistry 100, 201-220 (1979)) and the amount of saccharide is determined by ICP-OES (inductively coupled plasma optical emission spectroscopy) for MenA, a DMAP assay for MenC and a resorcinol assay for MenW and MenY (Monsigny et al (1988) Anal Biochem 175, 525-530).
    In one embodiment, the capsular saccharide (s) of N. meningitidis and / or the Hib saccharide are conjugated to the carrier protein via a linker, for example a bifunctional linker. The linker is optionally hetero-functional or homofunctional, for example containing a reactive amino group and a reactive carboxylic acid group, two reactive amino groups or two reactive carboxylic acid groups. For example, the linker contains between 4 and 20, 4 and 12, 5 and 10 carbon atoms. A possible linker is ADH. Other linkers include β-propionamido (WO 00/10 599), nitrophenyl-ethylamine (Gever et al (1979) Med., Microbiol Immunol 165, 171-288), haloalkyl halides (US 4,057,685), glycosidic linkages (US 4,673,574, US4808700), hexane diamine, and 6-aminocaproic acid (US 4,459,286).
    The polysaccharide conjugates used in the invention can be prepared by any coupling technique. The conjugation method may include activating the saccharide with 1-cyano-4-dimethylamino pyridinium tetrafluoroborate (CDAP) to form a cyanate ester. The activated saccharide can then be coupled directly or via a spacer group (linker) to an amino group on the carrier protein. For example, the spacer may be cystamine or cysteamine to give a thiolated polysaccharide that can be coupled to the carrier protein via a thioether linkage obtained after reaction with a maleimide-activated carrier protein (e.g. using GMBS) or a holoacetylated carrier protein (e.g., using iodoacetimide or N-succinimidyl bromoacetatebromoacetate). Optionally, the cyanate ester (optionally prepared by CDAP chemistry) is coupled to hexane diamine or ADH and the amino-derivatized saccharide is conjugated to the carrier protein using carbodiimide chemistry (e.g. EDAC or EDC). Such conjugates are described in published PCT application WO 93/15760 Uniformed Services University and WO 95/08348 and WO 96/29 094. Other suitable techniques utilize carbinides, hydrazides, active esters, and the like. norborane, p-nitrobenzoic acid, N-hydroxy-succinimide, S-NHS, EDC, TSTU. Many techniques are described in WO 98/42 721. The conjugation may involve a carbonyl linker which may be formed by the reaction of a free hydroxyl group of the saccharide with CDI (Bethell et al J. Biol Chem 1979 254, 2572-4, Hearn et al., J. Chromatogr 1981. 218, 509-18), followed by reaction with a protein to form a carbamate linkage. This may involve reduction of the anomeric terminal end to obtain a primary hydroxyl group, possibly protection / deprotection of the primary hydroxyl group, reaction of the primary hydroxyl group with CDI to form a CDI carbamate intermediate and coupling of the intermediate CDI carbamate with an amino group found on a protein.
    The conjugates can also be prepared by direct reductive amination methods as described in US 4,365,170 (Jennings) and US 4,673,574 (Anderson). Other methods are described in EP-0-161-188, EP-208 375 and EP-0-477 508.
    Another method involves coupling a cyanogen bromide (or CDAP) activated saccharide, derivatized with adipic acid hydrazide (ADH), to the carbodiimide condensation carrier protein (Chu C. et al Infect). Immunity, 1983 245 256), for example using EDAC.
    In one embodiment, a hydroxyl group (optionally, an activated hydroxyl group, e.g., an activated cyanate ester hydroxyl group) on a saccharide is directly or indirectly linked (via a linker) to a amino or carboxylic group on a protein. When a linker is present, a hydroxyl group on a saccharide is optionally attached to an amino group on a linker, for example using CDAP conjugation. Another amino group on the linker (e.g., ADH) can be conjugated to a carboxylic acid group on a protein, for example using carbodiimide chemistry, for example using EDAC. In one embodiment, the Hib saccharide or the N. meningitidis capsular polysaccharide are conjugated first to the linker prior to conjugation of the linker to the carrier protein.
    In one embodiment, the Hib saccharide, when present, is conjugated to the carrier protein using CNBr or CDAP, or a combination of CDAP and carbodiimide chemistry (such as EDAC), or a combination of CNBr and carbodiimide chemistry (such as EDAC). Hib is optionally conjugated using CNBr and carbodiimide chemistry, possibly with EDAC. For example, CNBr is used to link the saccharide and the linker, and then carbodiimide chemistry is used to link the linker to the carrier protein.
    In one embodiment, at least one of N. meningitidis capsular polysaccharide is conjugated directly to the carrier protein; optionally, Men W saccharide and / or MenY saccharide and / or MenC saccharide are conjugated directly to the carrier protein. For example, MenW; MenY; MenC; MenW and MenY; MenW and MenC; MenY and MenC; or MenW, MenY and MenC are directly related to the carrier protein. Optionally, the at least one capsular polysaccharide of N. meningitidis capsular polysaccharides is conjugated directly by CDAP. For example, MenW; MenY; MenC; MenW and MenY; MenW and MenC; MenY and MenC; or MenW, MenY and MenC are directly linked to the carrier protein by CDAP (see, WO 95/08348 and WO 96/29,094). In one embodiment, all capsular polysaccharides of N. meningitidis are conjugated to tetanus toxoid.
    Optionally, the ratio of Men W saccharide and / or Men Y saccharide to the carrier protein is between 1: 0.5 and 1: 2 (w / w) and / or the ratio of MenC saccharide to carrier protein is between 1: 0.5 and 1: 4 or 1: 1.25 and 1: 1.5 or 1: 0.5 and 1: 1.5 (w / w), especially when these saccharides are directly bound to the protein, possibly using CDAP.
    In one embodiment, at least one of N. meningitidis capsular polysaccharide is conjugated to the carrier protein via a linker, for example a bifunctional linker. The linker is optionally heterofunctional or homo-functional, for example containing a reactive amine group and a reactive carboxylic acid group, two reactive amine groups or two reactive carboxylic acid groups. For example, the linker contains between 4 and 20, 4 and 12, 5 and 10 carbon atoms. A possible linker is ADH.
    In one embodiment, MenA; MenC; or MenA and MenC are conjugated to a carrier protein (eg, tetanus toxoid) via a linker.
    In one embodiment, at least one N. meningitidis polysaccharide is conjugated to a carrier protein via a linker using CDAP and EDAC. For example, MenA; MenC; or MenA and MenC are conjugated to a protein via a linker (for example, those having two hydrozino groups at their end, such as ADH) using CDAP and EDAC, as described above. For example, CDAP is used to conjugate the saccharide to a linker and EDAC is used to conjugate the linker to a protein. Optionally, conjugation via a linker gives a ratio between the polysaccharide and the carrier protein between 1: 0.5 and 1: 6; 1: 1 and 1: 5 or 1: 2 and 1: 4, for MenA; MenC; or MenA and MenC.
    In one embodiment, the MenA capsular polysaccharide, when present, is at least partially O-acetylated, such that at least 50%, 60%, 70%, 80%, 90%, 95% or 98% repeating units are O-acetylated at at least one position. For example, O-acetylation is present at least at the 0-3 position of at least 50%, 60%, 70%, 80%, 90%, 95% or 98% of the repeating units.
    In one embodiment, the MenC capsular polysaccharide, when present, is at least partially O-acetylated, so that at least 30%, 40%, 50%, 60%, 70%, 80%, 90% 95% or 98% of the (2-> 9) NeuNac repeat units are O-acetylated in at least one or two positions. For example, 0-acetylation is present at position 0-7 and / or at position 0-8 of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 98% of repeating patterns.
    In one embodiment, the MenW capsular polysaccharide, when present, is at least partially O-acetylated, so that at least 30%, 40%, 50%, 60%, 70%, 80%, 90% 95% or 98% of the repeating units are O-acetylated in at least one or two positions. For example, 0-acetylation is present at position 0-7 and / or position 0-9 of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 98% of repeating patterns.
    In one embodiment, the MenY capsular polysaccharide, when present, is at least partially O-acetylated, so that at least 20%, 30%, 40%, 50%, 60%, 70%, 80% 90%, 95% or 98% of the repeating units are O-acetylated in at least one or two positions. O-acetylation is present at position 7 and / or position 9 by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 98% of the repeated reasons.
    The percentage of O-acetylation refers to the percentage of repeat units containing O-acetylation. This can be measured in the polysaccharide before conjugation and / or after conjugation.
    The term "saccharide" includes polysaccharides or oligosaccharides. The polysaccharides are isolated from the bacteria or isolated from the bacteria and sized to a certain extent by known methods (see, for example, EP 497,524 and EP 497,525) and, optionally, by microfluidization. The polysaccharides may be sized to reduce the viscosity in the polysaccharide samples and / or to improve the filterability of the conjugates. Oligosaccharides are characterized in that they are usually hydrolysed polysaccharides containing a small number of repeating units (usually 5 to 30 repeating units).
    The average dose is determined by adding doses of all additional polysaccharides and dividing by the number of additional polysaccharides. Additional polysaccharides are polysaccharides within the immunogenic composition other than Hib and may include capsular polysaccharides of N. meningitidis. The "dose" is in the amount of immunogenic composition or vaccine that is administered to a human.
    A Hib saccharide is the capsular polysaccharide polyribosyl phosphate (PRP) of Haemophilus influenzae type b or an oligosaccharide derived therefrom.
    In one embodiment, the anti-N multivalent conjugate vaccine. meningitidis contains each capsular saccharide of N. meningitidis at a dose of between 0.1 μg and 20 μg; 1 μg and 10 μg; 2 μg and 10 μg, 2.5 μg and 5 μg, approximately or exactly 5 μg; or about or exactly 2.5 μg.
    The terms "approximately" and "approximately" indicate a variation of plus or minus 10% with respect to the figure given in the context of the invention.
    In one embodiment of the invention, the saccharide dose of each of the at least two, three, four, or each of the N. meningitidis saccharide conjugates is optionally the same or approximately the same.
    The anti-N multivalent conjugate vaccine Meningitidis may contain MenA, MenC, MenW135 and MenY at saccharide dose ratios of 1: 1: 1: 1 or 2: 1: 1: 1 or 1: 2: 1: 1 or 2: 2: 1: 1 or 1: 3: 1: 1 or 1: 4: 1: 1 (w / w).
    A vaccine used in the process or in the use of the invention optionally contains a pharmaceutically acceptable excipient.
    In one embodiment, the anti-N multivalent conjugate vaccine. Meningitidis is buffered at or adjusted to a pH of between 7.0 and 8.0 or between 7.2 and 7.6, or the pH is approximately or exactly 7.4.
    The anti-N multivalent conjugate vaccine meningitidis is optionally lyophilized in the presence of a stabilizing agent, for example a polyol, such as sucrose or trehalose.
    Optionally, the anti-N multivalent conjugate vaccine. meningitidis contains an amount of adjuvant sufficient to enhance the immune response to the immunogen. Suitable adjuvants include, but are not limited to, aluminum salts (aluminum phosphate or aluminum hydroxide), squalene mixtures (SAF-1), muramyl peptide, saponin derivatives, preparations Mycobacterium cell wall, monophosphoryl lipid A, mycolic acid derivatives, block copolymer nonionic surfactants, Quil A, cholera toxin subunit B, polyphosphazene and its derivatives, and immunostimulatory complexes (ISCOMs), such as those described by Takahashi et al. (1990) Nature 344: 873-875.
    For the combinations of N. meningitidis or HibMen described above, it may be advantageous not to use an aluminum salt adjuvant or even not to use any adjuvant at all.
    As with all immunogenic compositions or vaccines, the immunologically effective amounts of the immunogens must be determined empirically. Factors to be considered include immunogenicity whether or not the immunogen is complexed with or covalently bound to an adjuvant or a carrier protein or other carrier, the route of administration, and the number of doses of immunization to administer. These factors are known in the art of vaccines and immunologists are quite capable of making such determinations without undue experimentation. The active agent may be present at various concentrations in the pharmaceutical composition or vaccine of the invention. Usually, the minimum concentration of the substance is an amount necessary to achieve its intended use, while the maximum concentration is a maximum amount that will remain in solution or homogeneous suspension within the initial mixture. For example, the minimal amount of a therapeutic agent is optionally an amount that will provide a single therapeutically effective dose. For bioactive substances, the minimum concentration is a quantity necessary for the bioactivity during reconstitution and the maximum concentration is reached when a homogeneous suspension can not be maintained. In the case of single dose units, the amount is that of a single therapeutic application. Generally, it is expected that each dose will comprise 1 μl to 100 μg of protein antigen, optionally 5 μg to 50 μg or 5 μg to 25 μg. Examples of doses of bacterial saccharin are 10 μg to 20 μg, 5 μg to 10 μg, 2.5 μg to 5 μg or 1 μg to 2.5 μg. The preferred amount of the substance varies depending on the substance, but it can easily be determined by those skilled in the art.
    The vaccine preparations of the present invention can be used to protect or treat a human patient susceptible to developing an infection by administering said vaccine systemically or mucosally. The human patient is possibly an infant (less than 12 months old) or an infant (12 to 24 months, 12 to 16 months or 12 to 14 months). Such administrations may include intramuscular, intraperitoneal, intradermal or subcutaneous injection; or mucosal administration by the oral / alimentary, respiratory, genitourinary route. In addition to a single route of administration, 2 different administrations can be used. For example, viral antigens can be administered ID (intradermally), while bacterial proteins can be administered IM (intramuscular) or IN (intranasal). If saccharides are present, they can be administered IM (or ID) and bacterial proteins can be administered by IN (or ID). In addition, the vaccines of the invention may be administered IM for the primary vaccination doses and IN for the booster doses.
    The inventors further determined that a later booster dose of an anti-N conjugate vaccine. meningitidis comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of N. meningitidis serogroup A (MenA), a capsular saccharide of N. meningitidis serogroup C (MenC), a capsular saccharide of N. meningitidis serogroup W135 (MenW135) and a capsular saccharide of N. meningitidis serogroup Y (MenY) can produce an even stronger immune response against capsular saccharide antigens. The data provided in Example 3 show that a booster immunization given several years after the initial immunization gives a much higher GMT, as determined by an SBA assay. Other booster doses of meningococcal conjugate vaccines may prolong the duration of protection induced by the vaccine. Additional booster doses may be considered to be both an independent aspect of the invention or an additional step in the co-administration aspect of the invention.
    Therefore, there is provided a method of immunizing against Neisseria meningitidis infection, comprising the steps of immunizing a human patient at an age of between 12 and 24 months with a multivalent anti-N conjugate vaccine. meningitidis comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of N. meningitidis serogroup A (MenA), a capsular saccharide of N. meningitidis serogroup C (MenC), a capsular saccharide of N. meningitidis serogroup W135 (MenW135) and a capsular saccharide N. meningitidis serogroup Y (MenY), separately conjugated to a carrier protein, and reimmunization of the human patient at an age between 4 and 20, 5 and 15, 5 and 11, 5 and 9 or 5 and 6 years with an anti-N conjugate vaccine. recall meningitidis comprising at least two capsular saccharides selected from MenA, MenC, MenW135 and MenY, each being separately conjugated to a carrier protein.
    In one embodiment, the anti-W multivalent conjugate vaccine. meningitidis includes conjugates of MenC and MenY and / or conjugate anti-N vaccines. Reminder meningitidis include MenC and MenY conjugates.
    In one embodiment, the anti-N multivalent conjugate vaccine. meningitidis comprises conjugates of MenA, MenC, MenW135 and MenY and / or the conjugate anti-meningitidis conjugate vaccine comprises conjugates of MenA, MenC, MenW135 and MenY.
    In one embodiment, each capsular saccharide of the booster anti-meningitidis conjugate vaccine is conjugated to a carrier protein selected from the group consisting of tetanus toxoid, diphtheria toxoid and CRM197, preferably the carrier protein is tetanus toxoid or CRM197, and more preferably the carrier protein is tetanus toxoid.
    In one embodiment, each capsular saccharide of the anti-N multivalent conjugate vaccine. meningitidis is conjugated to a carrier protein selected from the group consisting of tetanus toxoid, diphtheria toxoid and CRM197, preferably the carrier protein is tetanus toxoid or CRM197, and more preferably the carrier protein is tetanus toxoid.
    It is understood that the aforementioned attributes of the saccharides and meningococcal conjugates for the initial aspects of the invention are equally applicable to the second aspect of the invention. Therefore, the descriptions of the meningococcal saccharides and conjugates mentioned above are possibly present in the multivalent conjugate vaccine against Ab meningitidis and the anti-N conjugate vaccine. recall meningitidis.
    Vaccine preparation is generally described in Vaccine Design ("The Subunit and Adjuvant Approach" (eds Powell M.F. & Newman M.J.) (1995) Plenum Press New York). The encapsulation within liposomes is described by Fullerton, U.S. Patent 4,235,877.
    The inventors contemplate in this document that the terms "including", "understand" and "include" may be optionally substituted, respectively, by the terms "consisting of", "consisting of" and "consisting of" in each case.
    All references or patent applications cited in this patent application are hereby incorporated by reference.
    In order to better understand the present invention, the following examples are given. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way whatsoever.
    Examples
    Example 1
    Study plan
    This randomized, controlled phase III study was conducted in 59 centers in the United States according to good clinical practice and the Helsinki Declaration (1996 Somerset West). Written informed consent was obtained from each parent / guardian of the children prior to enrollment.
    Healthy children were enrolled and randomized 5: 1 for vaccination at 2, 4 and 6 months of age with HibMenCY-TT and DTaP-HBV-IPV, or Hib-TT + DTaP-HBV-IPV (table 1, Figure 1). At the age of 12 to 15 months (fourth dose phase), children immunized with HibMenCY-TT + DTaP-HBV-IPV were randomized again (2: 2: 1) to receive MenACWY-TT at age from 12 to 15 months, then DTaP at the age of 15 to 18 months (MenACWY-TT group); MenACWY-TT co-administered with DTaP at 15 to 18 months of age (Coad group); or HibMenCY-TT at the age of 12 to 15 months, then DTaP at the age of 15 to 18 (HibMenCY-TT group). Children primed with Hib-TT + DTaP-HBV-IPV were not re-randomized and received DTaP at age 15-18 (control group). Subjects in the Coad, MenACWT-TT and control groups did not receive a booster Hib vaccination because of a continuing shortage of Hib conjugate vaccine in the United States at the time of the study. Hib booster vaccinations have been postponed until the Hib conjugate vaccine is available again [25]. The study was conducted prior to the availability of a meningococcal conjugate vaccine licensed in the United States for use in children under 2 years of age; therefore, the control group did not receive meningococcal vaccination during the study. All subjects were allowed to receive routine vaccines recommended by ACIP. The study was single-blind in the primary phase because of the different appearance of the vaccines. Before the fourth dose, parents / guardians were informed of what type of vaccine their child had received in the primary phase, and knew their treatment group in the fourth dose phase, because of the different number of vaccine and the timing of serum collection for the various treatment groups.
    A randomization list was used to number the vaccines. Random assignment for each phase of the study was performed using a central Internet system that included a minimization procedure to ensure a balanced allocation between groups at the individual centers.
    Study subjects and vaccines
    The participants were healthy infants aged 6 to 12 weeks, born after at least 36 weeks of gestation. Exclusion criteria included prior injection of blood products from the birth or injection of different vaccines from a pneumococcal conjugate vaccine or human rotavirus vaccine within 30 days of the first dose. A birth dose of hepatitis B vaccine was allowed. A history of N. meningitidis, Hib, diphtheria, tetanus, whooping cough, hepatitis B or polio, or vaccination against any of these diseases during the study resulted in exclusion of the primary phase and the fourth dose phase. To be admitted to the fourth dose phase, the subjects had to have received all three primary vaccination doses.
    A 0.5 ml dose of HibMenCY-TT containing 2.5 μg TT conjugated Hib polyribosylribitol phosphate (PRP) and 5 μg MenC polysaccharide and TT-conjugated MenY polysaccharide (total TT content ~ 18 μg) . A 0.5 ml dose of MenACWY-TT each containing 5 μg of meningococcal polysaccharide serogroups A, C, W-135 and Y conjugated to TT (total TT content ~ 44 μg). The lyophilized meningococcal vaccines were reconstituted with sterile saline for injection and administered intramuscularly into the left arm or thigh.
    The composition of authorized DTaP-HBV-IPV (Pediarix ™, GlaxoSmithKline Vaccines) and Hib-TT (ActHIB ™, Sanofi Pasteur) vaccines is described elsewhere [10]. The composition of DTaP (Infanrix ™, GlaxoSmithKline Vaccines) is identical to DTaP component of DTaP-HBV-IPV.
    Objectives of the study
    The main objectives were 1) to demonstrate the non-inferiority of MenACWY-TT with or without coadministration of DTaP at a fourth dose of
    HibMenCY-TT in terms of percentage of subjects with serum bactericidal activity (using a human complement source: hSBA) ^ 1: 8 and geometric mean titres (GMT) for serogroups C and Y; 2) to demonstrate the immunogenicity of a single dose of MenACWY-TT with or without coadministration of DTaP in terms of the percentage of subjects with hSBA titres 1: 8 for serogroups A and W-135; and 3) demonstrate the non-inferiority of DTaP co-administered with MenACWY-TT compared to DTaP alone in terms of the percentage of subjects with diphtheria and tetanus antibody concentrations of 1.0 IU / ml and mean concentrations. geometric anti-pertussis. This document describes the criteria for meningococcal evaluation according to the predefined statistical criteria. The endpoints and immune responses are presented in Table 2. The endpoints for DTaP reminder vaccine are presented elsewhere [24].
    Evaluation of immunogenicity
    Blood samples were taken from the subjects one month after vaccination (Table 1) and before vaccination in the Coad group at 15-18 months of age (to assess the persistence of hSBA at 15-18 months of age). month after vaccination of infants with 3 doses of HibMenCY-TT).
    Evaluation of safety and reactogenicity
    Specific local and general symptoms were recorded by the parents on reminder cards for 8 days (days 0 to 7) after vaccination with the fourth dose. All other adverse events (AEs) were recorded
    for 31 days after vaccination. Serious adverse events (SAEs) and the occurrence of specific AEs indicating a new onset of chronic disease, and states inciting emergency room (ER) visits have been reported from dose 1 to 6 months after the last vaccination via a standardized telephone script. The occurrence of rashes was recorded during the fourth dose phase. An SAE was defined as an event causing death or endangering the patient's life; an event requiring hospitalization or an extension of an existing hospitalization; an event leading to disability or disability in the subject; or any other event considered serious by the investigator.
    Statistical Analyzes The immunogenicity analysis was conducted on the protocol compliant cohort (CAP) for immunogenicity that included all vaccinated subjects who adhered to the procedures defined by the protocol. The main objectives were assessed in a hierarchical manner; that is, it could only be considered that a goal was formally fulfilled only after all previous objectives were fulfilled.
    Collection of a pre-vaccination blood sample in the Coad group (Table 1) allowed calculation of vaccine response levels and pre- and post-vaccination GMT reports in this group. A response to the vaccine was defined as an antibody titre> 1: 8 post-vaccination in initially seronegative subjects, and a> 4-fold increase in antibody titre prevaccination and initially seropositive subjects.
    Potential differences between the groups were highlighted in the exploratory analyzes if the asymptomatic standardized 95% confidence interval (CI) for the difference between 2 groups in terms of percentage of subjects reaching specified cuts did not include 0, or if the 95% CI for the GMT ratio between the groups did not include 1. These exploratory analyzes should be interpreted with caution if one takes into account that there was no adjustment for multiplicity. The safety analysis was performed on the entire vaccinated cohort that included all vaccinated subjects. The incidence and intensity of symptoms were calculated with an exact CI of 95% for each group.
    The analyzes were performed using SAS® Version 9.1 software (SAS Institute Inc., Cary, NC, USA) and ProcStatXact 7.0. Results Study subjects A total of 1554 subjects were enrolled and vaccinated during the primary vaccination phase, of which 1447 completed this phase of the study. For the fourth dose phase, 1303 infants were enrolled and vaccinated (Figure 1), of whom 1238 completed the vaccination phase with the fourth dose of the study and 1209 completed the extended phase of follow-up. security. A summary of the reasons for the withdrawal of some study subjects or their removal from CAP cohorts is presented in Table 3 (additional). Two subjects, one belonging to the MenACWY-TT group and one belonging to the HibMenCY-TT group, withdrew during the vaccination phase with the fourth dose because of an AE. Both subjects experienced a febrile seizure prior to the fifth scheduled dose of DTaP: one with onset 38 days after the fourth dose and one with onset 43 days after the fourth dose. The investigator considered that no event was associated with vaccination. There were 955 subjects in the CAP cohort for immunogenicity. There were more boys than girls in the Co-ad group (165 versus 138 respectively) and more girls than boys in the control group (97 vs. 78 respectively). The study groups were otherwise comparable in terms of demographic characteristics (Table 4: additional).
    immunogenicity
    After immunization with HibMenCY-TT or MenACWY-TT at 12 to 15 months of age or MenACWY-TT + DTaP at 15 to 18 months of age, 100% had hSBA titers> 1: 8 for serogroups C and Y (Figure 2), against which they had previously been primovaccinated. At least 96.1% of subjects vaccinated with MenACWY-TT also had hSBA titers> 1: 8 for serogroups A and W-135 (Figure 2). Very few subjects (<7.8%) in the control group had hSBA titers> 1: 8 for any of the serogroups.
    Exploratory analyzes failed to detect differences between the MenACWY-TT group and the Coad group compared to the HibMenCY-TT group for serogroups C and Y in terms of the percentage of subjects with hSBA titers> 1: 8 , one month after vaccination. However, the results suggest higher post-vaccination GMTs: 1) for serogroups C and Y in MenACWY-TT and Coad compared to HibMenCY-TT and 2) for serogroups C, W-135 and Y in the Coad group compared to the MenACWY-TT group (Figure 3).
    The percentage of subjects in the Coad group with a response to the vaccine was 95.9% (95% CI 92.3%, 98.1%) for serogroup A, 99.2% (97.3%; 9%) for serogroup C, 97.7% (94.8%, 99.3%) for serogroup W-135 and 98.9% (96.8%, 99.8%) for serogroup Y. At least 96.1% of the initially seronegative subjects had a response to the vaccine relative to one or more serogroups.
    Before vaccination in the Coad group, 90.7% and 96.3% of subjects maintained seropositive titres in hSBA 1: 4) against serogroups C and Y after a primary vaccination with 3 doses of HibMenCY-TT. In the Coad group, GMTs increased from pre-vaccination to post-vaccination by 107-fold for serogroup C and 53-fold for serogroup Y, indicating a booster response after primary vaccination with HibMenCY-TT; and 4-fold for serogroup A and 244-fold for serogroup W-135, which shows good immunogenicity for first exposure to these vaccine antigens.
    Seroprotection levels and post-dose 4 GMT for serogroup W-135 were high in MenACWY-TT and Coad, as well as in subjects who received HibMenCY-TT but did not receive antigen. W-135 vaccine at dose 4. No response to serogroup W-135 was observed in controls. reactogenicity
    Percentages of subjects reporting local and general symptoms were in the same range across the three study groups (Figure 4). Percentage of subjects reporting CAS, new onset of chronic disease, and AEs receiving an ER visit from the start of primary vaccination to 6 months after the fourth dose were similar for all three groups (Table 5). Three SAEs reported in two subjects were considered to be associated with the vaccine. There was one case of hypotonic infants that occurred 47 days after dose 4 (Coad group), which ended after 2 days. In addition, there was one reported case of convulsion 65 days after the first primary vaccination dose (HibMenCY-TT group), which occurred in one child who later died of a second SAE (death syndrome). 89 days post-dose 1. Three other deaths were observed in the study (all during the primary phase), but none were considered to be associated with the vaccine: one subject is died because of Sudden Infant Death Syndrome, 33 days post-dose 1; one subject died from dehydration, hemolytic uremic syndrome and septic shock 43 days post-dose 1; and one subject died from leukemia (onset 57 days post-dose 3) and resulting respiratory failure.
    Example 2 Determination of Molecular Weight by MALLS
    The detectors were coupled to a size exclusion HPLC column from which the samples were eluted. On the one hand, the laser light scattering detector measured the light intensity scattered at 16 angles by the macromolecular solution and, on the other hand, an interferometric refractometer placed in line allowed the determination of the amount of eluted sample. From these intensities, the size and shape of the macromolecules in solution can be determined.
    The weight average molecular weight (Mw) is defined as the sum of the weights of all species multiplied by their respective molecular weights and divided by the sum of the weights of all species. a) Weight average molecular weight: -Mw-
    b) Average molecular weight in number: -Mn-
    (c) Mean quadratic radius: -Rw- and R2w is the quadratic radius defined by:
    (-mi- is the threat of the diffusion center i and -ri- is the distance between the diffusion center i and the center of gravity of the macromolecule). d) Polydispersity is defined as the ratio -Mw / Mn-.
    The meningococcal polysaccharides were analyzed by MALLS by loading on two HPLC columns (TSKG6000 and 5000PWx1) used in combination. 25 μl of the polysaccharide were loaded onto the column and eluted with 0.75 ml of distilled water. The polysaccharides are detected using a light scattering detector (Wyatt Dawn DSP equipped with an argon laser of 10 mW at 488 nm) and an interferometric refractometer (Wyatt Otilab DSP equipped with a P100 cell and a red filter at 498 nm).
    Molecular weight polydispersities and recoveries of all samples were calculated by the Debye method using a polynomial fit of 1 in the software Astra 4.72 software.
    Example 3 - Effect of booster immunization
    A further study evaluated the persistence of antibodies 12 months after booster vaccination with a meningococcal conjugate vaccine of serogroups A, C, W-135, Y (MenACWY-TT, GlaxoSmithKline Vaccines), compared with a meningococcal serogroup C conjugate vaccine (MenC-CRM197, Wyeth LLC), in healthy children. Methods. In Phase III, a multi-center, controlled, unblinded study in Finland (NCT00955682), previously randomized (3: 1) children who received primary vaccination with a single dose of MenACWY-TT or MenC-CRMi97 at 12 to 23 months of age (NCT00474266) received a booster dose of the same vaccine 48 months after primary vaccination. Immunogenicity was assessed at month (M) 60 (12 months post-boost) with spherical bactericidal antibody assays using rabbit complement (rSBA; cut 1: 8) and human (hSBA; cut 1: 4 ). Serious adverse events associated with the vaccine (SAE) were recorded up to M60. Results. Of the 293 children who received the recall, 286 returned to M60, with 277 included in the protocol cohort for persistence at M60 (MenACWY-TT: N = 231, MenC-CRM197: N = 46). At M60, all MenACWY-TT subjects retained 2: 8 rSBA titres (except for MenC, 97.4%) and 2 1: 4 hSBA titres (except for MenA, 95.5%). (board). The geometric mean titres of hSBA (TMG) to M60 had dropped from M49 (1 month after the boost), but were higher than after the primary vaccination. MenC seropositivity levels and TMGs (rSBA, hSBA) were comparable among the groups. No SAE associated with the vaccine has been reported.
    Conclusion. Antibodies evaluated by rSBA and hSBA tests persisted for each serogroup in more than 97% of children 12 months after Menacwy-TT booster vaccination. These data indicate that additional booster doses of MenACWY-TT may prolong the duration of protection induced by the vaccine.
    References [1] NE Rosenstein, Perkins BA, DS Stephens, Popovic T, Hughes JM. Meningococcal disease. N Engl J Med 2001; 344: 1378-1388.
    [2] Cohn AC, MacNeil JR, Harrison LH, et al. Changes in
    Neisseria meningitidis disease epidemiology in the United States, 1998-2007: implications for prevention of meningococcal disease. Clin Infect
    Say 2010; 50: 184-191.
    [3] Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. Vaccine 2009; 27: B51-63.
    [4] Pollard AJ. Global epidemiology of meningococcal disease and vaccine efficacy. Pediatr Infect Dis J 2004; 23: S274-279.
    [5] JR Lingappa, Rosenstein N, Zell ER, Shutt KA,
    Schuchat A, Perkins BA. Surveillance for meningococcal disease and strategies for meningococcal conjugate vaccines in the United States. Vaccine 2001; 19: 4566-4575.
    [6] Press Release - FDA clears new combination vaccine that protects children against two bacterial diseases. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements / ucm308350.htm. Accessed July 30, 2012.
    [7] Bryant KA, Marshall GS, Marchant CD, et al. Immunogenicity and safety of H influenzae type b-N meningitidis C / Y conjugate vaccine in infants. Pediatrics 2011; 127: el375-1385.
    [8] Nolan T, Lambert S, Roberton D, et al. A novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus-toxoid conjugate vaccine is immunogenic and immune-induces when co-administered with DTPa-HBV-IPV and pneumococcal conjugate vaccines in infants. Vaccine 2007; 25: 8487-8499.
    [9] Habermehl P, Leroux-Roels G, Sänger R, Mächler G, Boutriau D. Combined Haemophilus influenzae type b and Neisseria meningitidis serogroup C (HibMenC) or serogroup C and Y-tetanus toxoid conjugate (and HibMenCY) vaccines are well- tolerated and immunogenic when administered according to the 2, 3, 4 months schedule with a fourth dose at 12-18 months of age. Hum Vaccine 2010; 6: 640-651.
    [10] Marshall GS, Marchant CD, Blatter M, Friedland LR, Aris E, Miller JM. Co-administration of a novel Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine does not interfere with the immune response to antigens contained in infant vaccines routinely used in the United States. Hum Vaccine 2011; 7: 258-264.
    [11] Marchant CD, Miller JM, Marshall GS, et al.
    Randomized trial to assess immunogenicity and safety of Haemophilus influenzae type b
    Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine in infants. Pediatr
    Infect Dis J 2010; 29: 48-52.
    [12] Rinderknecht S, Bryant K, Nolan T, et al. The safety profile of hemophilus influenzae type b
    Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine (HibMenCY). Hum Vaccine Immunother 2012; 8 (3). Available at: http: //www.ncbi.nlm.nih.gov/pubmed/22 32 7 4 93. Accessed February 29, 2012.
    [13] Marshall GS, Marchant CD, Blatter M, et al. Immune response and one-year antibody persistence after a fourth dose of a novel Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY) at 12 to 15 months of age. Pediatr Infect Dis J 2010; 29: 469-471.
    [14] Nolan T, Richmond P, Marshall H, et al. Immunogenicity and safety of an investigational combined Haemophilus influenzae type B-Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine. Pediatr Infect Dis J 2011; 30: 190-196.
    [15] ACIP recommendation for the use of a meningococcal quadrivalent conjugate vaccine (MenACWY-D) in children 9 to 23 months of age with increased risk of invasive meningococcal disease. Available at: http: //www.cdc.gov/mmwr/preview/mmwrhtml/mm6040a4 .htm S_cid = mm6040a4_e% 0d% 0a. Accessed January 13, 2012.
    [16] Ostergaard L, Lebacq E, Poolman J, Maechler G, Boutriau D. Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15 -25 years. Vaccine 2009; 27: 161-168.
    [17] Knuf M, Kieninger-Baum D, Habermehl P, et al. A dose-range study assessing the immunogenicity and safety of a new candidate meningococcal serogroups A, C, W-135, and tetanus toxoid conjugate (MenACWY-TT) vaccine administered in the second year of life and in young children. Vaccine 2010; 28: 744-753.
    [18] Baxter R, B Y, Ensor K, Bianco V, Friedland LR,
    Miller JM. Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age. Pediatr Infect Dis J 2011; 30: e41-48.
    [19] Vesikari T, Karvonen A, V Bianco, Van der Wielen Μ,
    Miller J. Tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine is well tolerated and immunogenic when co-administered with measles-mumps-rubella-varicella vaccine during the second year of life: an open, randomized controlled trial. Vaccine 2011; 29: 4274-4284.
    [20] Memish ZA, Dbaibo G, Montellano M, et al. Immunogenicity of a single dose of tetravalent meningococcal serogroups A, C, W-135, and conjugate Y conjugate to 2- to 10-year-olds is noninferior to a licensed-ACWY polysaccharide vaccine with an acceptable safety profile. Pediatr Infect Dis J 2011; 30: e56-62.
    [21] Knuf M, Pantazi-Chatzikonstantinou A,
    Pfletschinger U, et al. An investigational tetravalent meningococcal serogroups A, C, W-135 and Y-tetanus toxoid conjugate vaccine co-administered with Infanrix ™ hexa is immunogenic, with an acceptable safety profile in 12-23-month-old children. Vaccine 2011; 29: 4264-4273.
    [22] Bermal N, Huang L-M, Dubey A, et al. Safety and immunogenicity of meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults. Hum Vaccine 2011; 7: 239-247.
    [23] Dbaibo G, Macalalad N, Reyes MRA-DL, et al. The immunogenicity and safety of an investigational meningococcal serogroups A, C, W-135, and tetanus toxoid conjugate (ACWY-TT) compared with a meningococcal tetravalent polysaccharide vaccine: A randomized, controlled non-inferiority study. Hum Vaccine Immunother 2012; 8. Available at: http: //www.ncbi.nlm.nih.gov/pubmed/22485050. Accessed June 22, 2012.
    [24] Leonardi M, Latiolais T, Sarpong K, et al. Immunogenicity and reactogenicity of coadministration of InfanrixTM with meningococcal MenACWY-TT conjugate vaccine in toddlers primed with MenHibrixTM and PediarixTM.
    [25] Interim recommendations for the use of Haemophilus influenzae type b (Hib) conjugate vaccines related to the recall of certain lots of Hib-containing vaccines (PedvaxHIB and Comvax). MMWR 2007; 56: 1318-1320.
    [26] Schmitt H-J, Maechler G, Habermehl P, et al. Immunogenicity, reactogenicity, and immune memory after a novel Haemophilus influenzae-Neisseria meningitidis serogroup C conjugate vaccine. Clin. Vaccine Immunol 2007; 14: 426-434.
    [27] Kitchin NRE, Southern J, Morris R, et al.
    Evaluation of a diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b vaccine given concurrently with meningococcal C conjugate vaccine group at 2, 3 and 4 months of age. ArchDis Child 2007; 92: 11-16.
    [28] Diez-Domingo J, Cantarino MVP, Torrent! JMB, et al. A randomized, multicenter, open-label clinical trial to assess the immunogenicity of a meningococcal C vaccine booster dose administered to children aged 14 to 18 months. Pediatr Infect Dis J 2010; 29: 148-152.
    [29] Khatami A, Snape MD, John T, et al. Persistence of
    immunostaining following a booster dose of Haemophilus influenzae type B-Meningococcal serogroup C glycoconjugate vaccine: follow-up of a randomized controlled trial. Pediatr Infect Dis J 2011; 30: 197-202.
    [30] AK Bhattacharjee, Jennings HJ, CP Kenny, Martin A, Smith IC. Structural determination of the polysaccharide antigens of Neisseria meningitidis serogroups Y, W-135, and BOI. Can J Biochem 1976; 54: 1-8.
    权利要求:
    Claims (96)
    [1]
    A method of immunizing against Neisseria meningitidis infection, comprising the following steps: a) immunizing a human patient at a first age of between 0 and 11 months with a bacterial saccharide conjugate vaccine comprising at least one two or three bacterial saccharides separately conjugated to a carrier protein to form at least one, two or three bacterial saccharide conjugates; and b) immunizing the human patient at a second age between 12 and 24 months with an anti-Neisseria meningitidis conjugate vaccine comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of N. meningitidis serogroup A (MenA), capsular saccharide of N. meningitidis serogroup C (MenC), capsular saccharide N. meningitidis serogroup W135 (MenWl35) and capsular saccharide N. meningitidis serogroup Y (MenY) ), conjugated separately to a carrier protein, wherein the Neisseria meningitidis conjugate vaccine is coadministered with a vaccine comprising diphtheria toxoid and tetanus toxoid.
    [2]
    The method of claim 1, wherein the at least one, two, or three bacterial saccharides of step a) comprise a Haemophilus influenza (Hib) saccharide.
    [3]
    The method of claim 1 or 2, wherein the at least one, two or three bacterial saccharides of step a) comprises a capsular saccharide of N. meningitidis serogroup C (MenC).
    [4]
    The method according to any one of claims 1 to 3, wherein the at least one, two or three bacterial saccharides of step a) comprise a capsular saccharide of N. meningitidis serogroup Y (MenY).
    [5]
    The method according to any one of claims 1 to 4, wherein the carrier protein of step a) is tetanus toxoid, diphtheria toxoid or CRM197.
    [6]
    The method of claim 5, wherein the carrier protein of step a) is tetanus toxoid, optionally at a total TT content of 5 μg to 40 μg, from 10 μg to 30 μg, from 15 μg to 20 μg or about 18 μg per dose.
    [7]
    The method according to any one of claims 1 to 6, wherein the immunization of step a) involves the administration of 2 or 3 doses of the bacterial saccharide conjugate, optionally at an age of 2, 4 and 6. month.
    [8]
    The method of any one of claims 1 to 7, wherein the co-administration of the Neisseria meningitidis conjugate vaccine with the vaccine comprising diphtheria toxin and tetanus toxin in step b) results in an increase of less than 10% of the immunogenicity against MenA and / or MenC and / or MenWl35 and / or MenY compared to the administration of the single anti-Neisseria meningitidis conjugate vaccine, possibly measured with an SBA test.
    [9]
    The method of any one of claims 1 to 8, wherein during step a), the bacterial saccharide conjugate vaccine is administered concurrently with a vaccine comprising DTP.
    [10]
    The method of claim 9, wherein the vaccine comprising DTP contains a hepatitis B antigen.
    [11]
    The method of claim 9 or 10, wherein the vaccine comprising DTP contains IPV.
    [12]
    The method of any one of claims 1 to 11, wherein the anti-N conjugate vaccine. meningitidis of step b) includes MenA.
    [13]
    The method of any one of claims 1 to 12, wherein the anti-AI conjugate vaccine. meningitidis from step b) includes MenC.
    [14]
    The method of any one of claims 1 to 13, wherein the anti-N conjugate vaccine. meningitidis of step b) includes MenW135.
    [15]
    The method of any one of claims 1 to 14, wherein the anti-meningitidis conjugate vaccine of step b) comprises MenY.
    [16]
    The method according to any one of claims 1 to 15, wherein the carrier protein of step b) is selected from the group consisting of tetanus toxoid, diphtheria toxoid and CRMI 97.
    [17]
    The method of claim 16, wherein the carrier protein of step b) is tetanus toxoid.
    [18]
    The method of any one of claims 1 to 17, wherein the carrier protein of step a) and the carrier protein of step b) are identical.
    [19]
    The method of any one of claims 1 to 18, wherein the vaccine comprising diphtheria toxoid and tetanus toxoid is a DTPa vaccine.
    [20]
    The method of any one of claims 1 to 19, wherein step b) immunizes the human patient at an age of between 12 and 18 months.
    [21]
    The method of claim 20, wherein step b) immunizes the human patient at an age of between 15 and 18 months.
    [22]
    22. A method according to any one of claims 1 to 21, comprising a step c) additional immunization of the human patient at a senior age between 4 and 20 years, 5 and 15 years or 5 and 11 years with a conjugate vaccine anti-N. meningitidis comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of N. meningitidis serogroup A (MenA), a capsular saccharide of N. meningitidis serogroup C (MenC), a capsular saccharide of N. meningitidis serogroup W135 (MenW135) and a capsular saccharide N. meningitidis serogroup Y (MenY), separately conjugated to a carrier protein.
    [23]
    The method of claim 22, wherein the anti-meningitidis conjugate vaccine is identical to the anti-W conjugate vaccine. meningitidis according to any one of claims 1 to 18.
    [24]
    24. The method of claim 22, wherein the anti-W conjugate vaccine. meningitidis contains capsular saccharides of MenA, MenC, MenW135 and MenY, each of which is separately conjugated to a tetanus toxoid-carrying protein.
    [25]
    25. Conjugated anti-AA meningitidis vaccine for use in the prevention or treatment of AA meningitidis-induced disease, in which a human patient is immunized according to a schedule comprising steps a) and b), wherein the step a) immunizes the human patient at a first age of between 0 and 11 months with a bacterial saccharide conjugate vaccine comprising at least one, two or three bacterial saccharides conjugated to a carrier protein to form at least one, two or three conjugates bacterial saccharide; and step b) immunizes the human patient at a second age between 12 and 24 months with an anti-Neisseria meningitidis conjugate vaccine comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of AA meningitidis serogroup A (MenA), capsular saccharide of serogroup C meningitidis C (MenC), capsular saccharide of serogroup W135 (MenWl35) meningitidis and capsular saccharide of serogroup Y (MenY) AA meningitidis conjugates separately to a carrier protein, wherein the anti-Neisseria meningitidis conjugate vaccine is coadministered with a vaccine comprising diphtheria toxoid and tetanus toxoid.
    [26]
    An anti-AA meningitidis conjugate vaccine for use according to claim 25, wherein the at least one, two or three bacterial saccharides of step a) comprise a Haemophilus influenza (Hib) saccharide.
    [27]
    27. 27-conjugated vaccine. meningitidis for use according to claim 25 or 26, wherein the at least one, two or three bacterial saccharides of step a) comprise a capsular saccharide of N. meningitidis serogroup C (MenC).
    [28]
    28. 27-conjugated vaccine. meningitidis for use according to any one of claims 25 to 27, wherein the at least one, two or three bacterial saccharides of step a) comprises a capsular saccharide of N. meningitidis serogroup Y (MenY).
    [29]
    29. 27-conjugated vaccine. meningitidis for use according to any one of claims 25 to 28, wherein the carrier protein of step a) is tetanus toxoid, diphtheria toxoid or CRMI 97.
    [30]
    30. Conjugate anti-27 vaccine. meningitidis for use according to claim 29, wherein the carrier protein of step a) is tetanus toxoid, optionally at a total TT content of 5 μg to 40 μg, 10 μg to 30 μg, 15 μg at 20 μg or about 18 μg per dose.
    [31]
    31. Conjugate anti-27 vaccine. meningitidis for use according to any one of claims 25 to 30, wherein the immunization of step a) involves the administration of 2 or 3 doses of the bacterial saccharide conjugate, optionally at an age of 2, 4 and 6 months.
    [32]
    32. Conjugate anti-N vaccine. meningitidis for use according to any one of claims 25 to 31, wherein the co-administration of the anti-Neisseria meningitidis conjugate vaccine and the vaccine comprising diphtheria toxin and tetanus toxin in step b) results in an increase of at least 10% of the immunogenicity against MenA and / or MenC and / or MenW135 and / or MenY compared to the administration of the single anti-Neisseria meningitidis conjugate vaccine, possibly measured with an SBA test.
    [33]
    33. Conjugate Vaccine Anti-JV. meningitidis for use according to any one of claims 25 to 32, wherein during step a), the bacterial saccharide conjugate vaccine is administered together with a vaccine comprising DTP.
    [34]
    34. An anti-AA meningitidis conjugate vaccine for use according to claim 33, wherein the vaccine comprising DTP contains a hepatitis B antigen.
    [35]
    35. W conjugate vaccine. meningitidis for use according to claim 33 or 34, wherein the vaccine comprising DTP contains IPV.
    [36]
    36. Anti-N conjugate vaccine meningitidis for use according to any one of claims 25 to 35, wherein the anti-N conjugate vaccine. meningitidis of step b) includes MenA.
    [37]
    37. Anti-N conjugate vaccine meningitidis for use according to any one of claims 25 to 36, wherein the anti-N conjugate vaccine. meningitidis from step b) includes MenC.
    [38]
    38. Conjugate anti-IV vaccine. meningitidis for use according to any one of claims 25 to 37, wherein the anti-meningitidis conjugate vaccine of step b) comprises MenWl35.
    [39]
    39. The conjugated anti-meningitidis vaccine for use according to any of claims 25 to 38, wherein the anti-meningitidis conjugate vaccine of step b) comprises MenY.
    [40]
    40. The conjugated anti-AL meningitidis vaccine for use according to any one of claims 25 to 39, wherein the carrier protein of step b) is selected from the group consisting of tetanus toxoid, diphtheria toxoid and CRM197.
    [41]
    41. The conjugated anti-meningitidis vaccine for use according to claim 40, wherein the carrier protein of step b) is tetanus toxoid.
    [42]
    42. The conjugated anti-AL meningitidis vaccine for use according to any one of claims 25 to 41, wherein the carrier protein of step a) and the carrier protein of step b) are identical.
    [43]
    43. The conjugated anti-AL meningitidis vaccine for use according to any one of claims 25 to 42, wherein the vaccine comprising diphtheria toxoid and tetanus toxoid is a DTP vaccine.
    [44]
    44. The conjugated anti-AL meningitidis vaccine for use according to any one of claims 25 to 43, wherein step b) immunizes the human patient at an age of between 12 and 18 months.
    [45]
    45. The conjugated anti-meningitidis vaccine for use according to claim 44, wherein step b) immunizes the human patient at an age of between 15 and 18 months.
    [46]
    46. An anti-meningitidis conjugate vaccine for use according to any one of claims 25 to 45, comprising a further step c) of immunizing the human patient at a senior age of between 4 and 20 years, 5 and 15 years or 5 and 11 years with an anti-N conjugate vaccine. meningitidis comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of AA meningitidis serogroup A (MenA), a capsular saccharide of AA meningitidis serogroup C (MenC), a capsular saccharide of AA meningitidis serogroup W135 (MenWl35) and a capsular saccharide of Y meningitidis serogroup Y (MenY), separately conjugated to a carrier protein.
    [47]
    47. An anti-AA meningitidis conjugate vaccine for use according to claim 46, wherein the anti-AA meningitidis conjugate vaccine is identical to the anti-AA meningitidis conjugate vaccine according to any one of claims 25 to 42.
    [48]
    48. An anti-AA meningitidis conjugate vaccine for use according to claim 46, wherein the anti-AA meningitidis conjugate vaccine contains menA, MenC, MenW135 and MenY capsular saccharides, each separately conjugated to a tetanus toxoid carrier protein. .
    [49]
    49. An anti-AA meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-Neisseria meningitidis conjugate vaccine of step b) and / or step c) contains capsular saccharides of AA meningitidis with an average size of more than 50 kDa, 75 kDa, 100 kDa, 110 kDa, 120 kDa or 130 kDa.
    [50]
    50. An anti-meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-Neisseria meningitidis conjugate vaccine of step b) and / or step c) contains capsular saccharides. N. meningitidis which are each a native polysaccharide or whose average size is reduced compared to that of a native polysaccharide by a factor of at most 10.
    [51]
    51. An anti-meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-Ah meningitidis conjugate vaccine of step b) and / or step c) contains at least one capsular saccharide of N. meningitidis which is a native polysaccharide.
    [52]
    52. An anti-meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-Ah meningitidis conjugate vaccine of step b) and / or step c) contains at least a capsular saccharide of N. meningitidis whose size is reduced by microfluidization.
    [53]
    53. An anti-meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-meningitidis conjugate vaccine of step b) and / or step c) contains at least one N. meningitidis capsular saccharide selected from the group consisting of MenY and MenW135 which are microfluidized, optionally to reduce the average size by at most 10-fold over that of the native capsular polysaccharide.
    [54]
    54. An anti-meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-N conjugate vaccine. meningitidis of step b) and / or step c) contains at least one capsular saccharide of N. meningitidis selected from the group consisting of MenA and MenC which are native polysaccharides.
    [55]
    55. An anti-meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-meningitidis conjugate vaccine of step b) and / or step c) contains a capsular saccharide. of MenA having an average size of more than 50 kDa, 75 kDa, 100 kDa or an average size of between 50 kDa and 100 kDa or 55 kDa and 90 KDa or 60 kDa and 80 kDa.
    [56]
    56. An anti-meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-A, meningitidis conjugate vaccine of step b) and / or step c) contains a MenC capsular saccharide having an average size of greater than 50 kDa, 75 kDa, 100 kDa or between 100 kDa and 200 kDa, 100 kDa and 150 kDa, 80 kDa and 120 kDa, 90 kDa and 110 kDa, 150 kDa and 200 kDa kDa, 120 kDa and 240 kDa, 140 kDa and 220 kDa, 160 kDa and 200 kDa or 190 kDa and 200 kDa.
    [57]
    57. An anti-meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-W conjugate vaccine. meningitidis of step b) and / or step c) contains a MenY capsular saccharide having an average size of more than 50 kDa, 75 kDa, 100 kDa or between 60 kDa and 190 kDa or 70 kDa and 180 kDa or 80 kDa and 170 kDa or 90 kDa and 160 kDa or 100 kDa and 150 kDa, 110 kDa and 145 kDa or 120 kDa and 140 kDa.
    [58]
    58. An anti-meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-I7 conjugate vaccine. meningitidis of step b) and / or step c) contains a MenW135 capsular saccharide having an average size of more than 50 kDa, 75 kDa, 100 kDa or between 60 kDa and 190 kDa or 70 kDa and 180 kDa or 80 kDa and 170 kDa or 90 kDa and 160 kDa or 100 kDa and 150 kDa, 140 kDa and 180 kDa, 150 kDa and 170 kDa or 110 kDa and 140 kDa.
    [59]
    59. An anti-meningitidis conjugate method or vaccine for use according to any one of the preceding claims, wherein the anti-W conjugate vaccine. meningitidis of step b) and / or step c) contains N. meningitidis capsular saccharide conjugates, each having a polysaccharide: carrier ratio of 1: 5 to 5: 1 or 1: 1 to 1: 4 (in weight / weight).
    [60]
    60. Anti-N conjugate method or vaccine. meningitidis for use according to any one of the preceding claims, wherein the anti-N conjugate vaccine. meningitidis of step b) and / or step c) contains at least one N. meningitidis capsular polysaccharide conjugate which is directly conjugated to the second carrier protein.
    [61]
    61. Anti-N conjugate method or vaccine. meningitidis for use according to claim 60, wherein the anti-N conjugate vaccine. meningitidis of step b) and / or step c) contains MenW and / or MenY, MenW and / or MenC, MenY and / or MenC, or MenW and MenC and MenY that are directly conjugated to the second carrier protein.
    [62]
    62. Anti-N conjugate method or vaccine. meningitidis for use according to claim 60 or 61, wherein the anti-N conjugate vaccine. meningitidis of step b) and / or step c) contains at least one conjugate of N. meningitidis capsular saccharide directly conjugated using a CDAP chemistry.
    [63]
    63. Anti-N conjugate method or vaccine. meningitidis for use according to any one of claims 60 to 62, wherein the anti-N conjugate vaccine. meningitidis of step b) and / or step c) contains conjugates in which the ratio of MenW and / or Y capsular saccharide on the second carrier protein is between 1: 0.5 and 1: 2.
    [64]
    64. Anti-N conjugate method or vaccine. meningitidis for use according to any one of claims 60 to 63, wherein the anti-N conjugate vaccine. meningitidis of step b) and / or step c) contains a MenC conjugate in which the ratio of the MenC polysaccharide to the carrier protein is between 1: 0.5 and 1: 2.
    [65]
    65. Anti-N conjugate method or vaccine. meningitidis for use according to any one of the preceding claims, wherein the anti-N conjugate vaccine. meningitidis of step b) and / or step c) contains one or more capsular saccharides of N. meningitidis conjugated to the carrier protein via a linker.
    [66]
    66. Anti-N conjugate method or vaccine. meningitidis for use according to claim 65, wherein the linker is bifunctional.
    [67]
    67. Anti-N conjugate method or vaccine. meningitidis for use according to claim 65 or 66, wherein the linker contains two reactive amino groups.
    [68]
    68. Anti-N conjugate method or vaccine. meningitidis for use according to any one of claims 65 to 67, wherein the linker contains between 4 and 12 carbon atoms.
    [69]
    69. Anti-N conjugate method or vaccine. meningitidis for use according to any one of claims 65 to 68, wherein the linker is ADH.
    [70]
    70. Anti-N conjugate method or vaccine. meningitidis for use according to any one of claims 65 to 69, wherein the capsular saccharide of N. meningitidis is conjugated to the linker using CDAP chemistry.
    [71]
    71. Anti-N conjugate method or vaccine. meningitidis for use according to any one of claims 65 to 70, wherein the carrier protein is conjugated to the linker using carbodiimide chemistry, optionally using EDAC.
    [72]
    72. Anti-N conjugate method or vaccine. meningitidis for use according to any one of claims 65 to 71, wherein MenA is conjugated to the carrier protein via a linker.
    [73]
    73. Anti-N conjugate method or vaccine. meningitidis for use according to claim 72, wherein the ratio of the MenA polysaccharide to the carrier protein is between 1: 2 and 1: 5.
    [74]
    74. Anti-N conjugate method or vaccine. meningitidis for use according to any one of claims 65 to 73, wherein MenC is conjugated to the carrier protein via a linker.
    [75]
    75. Anti-N conjugate method or vaccine. meningitidis for use according to claim 74, wherein the ratio of the MenC polysaccharide to the carrier protein is between 1: 2 and 1: 5.
    [76]
    76. Anti-N conjugate method or vaccine. meningitidis for use according to any one of the preceding claims, wherein the anti-meningitidis conjugate vaccine of step b) and / or step c) further contains a capsular saccharide of H. influenzae conjugated to a carrier protein.
    [77]
    77. Anti-N conjugate method or vaccine. meningitidis for use according to any one of the preceding claims, wherein the anti-meningitidis conjugate vaccine of step b) and / or step c) contains a N. meningitidis serogroup B antigen, a N. meningitidis outer membrane vesicle serogroup B and / or serogroup B N. meningitidis protein
    [78]
    78. Anti-N conjugate method or vaccine. meningitidis for use according to any one of the preceding claims, wherein the carrier protein of step b) and / or step c) is present in the conjugate dose of N. meningitidis at a total dose of 10 μg. at 100 μg, 20 μg at 90 μg, 30 μg at 80 μg, 30 μg at 70 μg, 35 μg at 60 or 40 μg at 50 μg.
    [79]
    79. A method of immunizing against Neisseria meningitidis infection, comprising the steps of immunizing a human patient at an age of between 12 and 24 months with a multivalent anti-N conjugate vaccine. meningitidis comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of N. meningitidis serogroup A (MenA), a capsular saccharide of N. meningitidis serogroup C (MenC), a capsular saccharide of N. meningitidis serogroup W135 (MenW135) and a capsular saccharide N. meningitidis serogroup Y (MenY), separately conjugated to a carrier protein, and reimmunization of the human patient at an age between 4 and 20, 5 and 15, 5 and 11, 5 and 9 or 5 and 6 years with an anti-AA meningitidis conjugate vaccine comprising at least two capsular saccharides selected from MenA, MenC, MenW135 and MenY, each being separately conjugated to a carrier protein.
    [80]
    The method of claim 79, wherein the multivalent anti-AA meningitidis conjugate vaccine comprises conjugates of MenC and MenY.
    [81]
    81. The method of claim 79 or 80, wherein the anti-AA meningitidis conjugate vaccine comprises MenC and MenY conjugates.
    [82]
    82. The method according to any one of claims 79 to 81, wherein the multivalent anti-AA meningitidis conjugate vaccine comprises conjugates of MenA, MenC, MenW135 and MenY.
    [83]
    The method of any of claims 79 to 82, wherein the booster anti-AA meningitidis conjugate vaccine comprises MenA, MenC, MenW135 and MenY conjugates.
    [84]
    The method according to any one of claims 79 to 83, wherein each capsular saccharide of the conjugate anti-AA meningitidis conjugate vaccine is conjugated to a carrier protein selected from the group consisting of tetanus toxoid, diphtheria toxoid. and CRM197.
    [85]
    The method of claim 84, wherein the carrier protein is tetanus toxoid.
    [86]
    The method of any of claims 79 to 85, wherein each capsular saccharide of the anti-N multivalent conjugate vaccine. meningitidis is conjugated to a carrier protein selected from the group consisting of tetanus toxoid, diphtheria toxoid and CRM197.
    [87]
    The method of claim 86, wherein the carrier protein is tetanus toxoid.
    [88]
    88. Anti-N conjugate vaccine meningitidis for use in immunization against Neisseria meningitidis infection, wherein a human patient is immunized at 12 to 24 months of age with a multivalent anti-N conjugate vaccine. meningitidis comprising at least two capsular saccharides selected from the group consisting of a capsular saccharide of N. meningitidis serogroup A (MenA), a capsular saccharide of N. meningitidis serogroup C (MenC), a capsular saccharide of N. meningitidis serogroup W135 (MenW135) and a capsular saccharide N. meningitidis serogroup Y (MenY), separately conjugated to a carrier protein, and the human patient is reimmunized at an age between 4 and 20, 5 and 15, 5 and 11, 5 and 9 or 5 and 6 years with an anti-N conjugate vaccine. recall meningitidis comprising at least two capsular saccharides selected from MenA, MenC, MenW135 and MenY, each being separately conjugated to a carrier protein.
    [89]
    89. Conjugate vaccine against 2V. meningitidis for use according to claim 88, wherein the multivalent anti-A /. meningitidis includes conjugates of MenC and MenY.
    [90]
    90. Anti-N conjugate vaccine meningitidis for use according to claim 88 or 89, wherein the anti-AA meningoidid conjugate vaccine comprises MenC and MenY conjugates.
    [91]
    91. An anti-AA meningitidis conjugate vaccine for use according to any one of claims 88 to 90, wherein the multivalent anti-AA meningitidis conjugate vaccine comprises conjugates of MenA, MenC, MenW135 and MenY.
    [92]
    92. An anti-AA meningitidis conjugate vaccine for use according to any one of claims 88 to 91, wherein the booster anti-AA meningitidis conjugate vaccine comprises conjugates of MenA, MenC, MenW135 and MenY.
    [93]
    An anti-AA meningitidis conjugate vaccine for use according to any one of claims 88 to 92, wherein each capsular saccharide of the anti-AA meningitidis conjugate vaccine is conjugated to a carrier protein selected from the group consisting of tetanus toxoid, diphtheria toxoid and CRM197.
    [94]
    The method of claim 84, wherein the carrier protein is tetanus toxoid.
    [95]
    95. An anti-AA meningitidis conjugate vaccine for use according to any one of claims 88 to 94, wherein each capsular saccharide of the anti-AA meningitidis multivalent conjugate vaccine is conjugated to a carrier protein selected from the group consisting of toxoid tetanus, diphtheria toxoid and CRM197.
    [96]
    96. An anti-AA meningitidis conjugate vaccine for use according to claim 95, wherein the carrier protein is tetanus toxoid.
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    JP2019142898A|2019-08-29|Method of treatment
    Xu et al.2019|Development of meningococcal polysaccharide conjugate vaccine that can elicit long-lasting and strong cellular immune response with hepatitis B core antigen virus-like particles as a novel carrier protein
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    同族专利:
    公开号 | 公开日
    IL241096D0|2015-11-30|
    CA2903322A1|2014-09-25|
    IL241096A|2021-05-31|
    PL2976101T3|2021-03-08|
    EP2976101B1|2020-08-19|
    WO2014147044A1|2014-09-25|
    ES2830035T3|2021-06-02|
    AU2014234408B2|2017-04-20|
    DK2976101T3|2020-11-23|
    PT2976101T|2020-11-12|
    EP2976101A1|2016-01-27|
    JP2019142898A|2019-08-29|
    US20160279225A1|2016-09-29|
    SG10201710137QA|2018-01-30|
    AU2014234408A1|2015-10-22|
    HUE051592T2|2021-03-01|
    JP6747968B2|2020-08-26|
    SG11201506810RA|2015-10-29|
    SI2976101T1|2021-01-29|
    JP2016515539A|2016-05-30|
    MX2015013401A|2016-01-08|
    KR20150121265A|2015-10-28|
    EA034380B1|2020-01-31|
    BR112015024014A2|2017-07-18|
    CN105188743A|2015-12-23|
    EA201591468A1|2016-04-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    AU2012203419A1|2005-06-27|2012-07-05|Glaxosmithkline Biologicals S.A.|Immunogenic composition|
    EA012528B1|2005-06-27|2009-10-30|Глаксосмитклайн Байолоджикалс С.А.|Immunogenic composition|
    US20080305127A1|2005-12-23|2008-12-11|Glaxosmithkline Biologicals S.A.|Conjugate Vaccines|WO2018045286A1|2016-09-02|2018-03-08|Sanofi Pasteur, Inc.|Neisseria meningitidis vaccine|
    WO2021099982A1|2019-11-22|2021-05-27|Glaxosmithkline Biologicals Sa|Dosage and administration of a bacterial saccharide glycoconjugate vaccine|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US201361802918P| true| 2013-03-18|2013-03-18|
    US61/802918|2013-03-18|
    US201361874008P| true| 2013-09-05|2013-09-05|
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