Confidential/Proprietary Information Page 1 of 34
Hib Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) ActHIB®DESCRIPTION ActHIB®, Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), produced by Sanofi Pasteur SA, is a sterile, lyophilized powder which is reconstituted at the time of use with either saline diluent (0.4% Sodium Chloride) or Sanofi Pasteur Inc. Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed (whole-cell pertussis vaccine DTP) or Tripedia®, Sanofi Pasteur Inc. Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) (when reconstituted known as TriHIBit®) for intramuscular use only.
The vaccine consists of the Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate, PRP), a high molecular weight polymer prepared from the Haemophilus influenzae type b (HiB) strain 1482 grown in a semi-synthetic medium, covalently bound to tetanus toxoid. (1) The lyophilized ActHIB vaccine powder and saline diluent contain no preservative. The tetanus toxoid is prepared by extraction, ammonium sulfate purification, and formalin inactivation of the toxin from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium. (2) Further Confidential/Proprietary Information Page 2 of 34 manufacturing process steps reduce residual formaldehyde to levels below 0.5 micrograms (mcg) per dose by calculation.
The toxoid is filter sterilized prior to the conjugation process. Potency of ActHIB vaccine is specified on each lot by limits on the content of PRP polysaccharide and protein in each dose and the proportion of polysaccharide and protein in the vaccine which is characterized as high molecular weight conjugate. When ActHIB vaccine is reconstituted with saline diluent, each single dose of 0.5 mL is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, and 8.5% of sucrose. When ActHIB vaccine is combined with Sanofi Pasteur Inc. DTP vaccine by reconstitution, each single dose (0.5 mL) is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, 8.5% of sucrose, 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid and an estimate of 4 protective units of pertussis vaccine.
Thimerosal (mercury derivative) 1:10,000 is added as a preservative to Sanofi Pasteur Inc. DTP vaccine. (Refer to product insert for Sanofi Pasteur Inc. whole-cell DTP.) When ActHIB vaccine is combined with Tripedia vaccine (TriHIBit vaccine) by reconstitution for booster dose, each single dose (0.5 mL) is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, 8.5% of sucrose, 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid and 46.8 mcg of pertussis antigens.
The 0.6 mL vial of Tripedia vaccine is formulated without preservatives but contains a trace amount of thimerosal Confidential/Proprietary Information Page 3 of 34 [(mercury derivative), (≤0.3 mcg mercury/dose)] from the manufacturing process. (Refer to product insert for Tripedia vaccine.) The reconstituted vaccine, using saline diluent, appears clear and colorless. The reconstituted vaccine, using Sanofi Pasteur Inc. DTP vaccine, appears whitish in color. TriHIBit vaccine, the reconstituted vaccine, using Tripedia vaccine, is a homogenous white suspension.CLINICAL PHARMACOLOGYH influenzae type b was the leading cause of invasive bacterial disease among children in the United States prior to licensing of Haemophilus b conjugate vaccines.
Based on its active surveillance areas, the Centers for Disease Control and Prevention (CDC) now estimate that H influenzae type b disease in children under the age of 5 years has been reduced by 95%. (3) Before effective vaccines were introduced, it was estimated that one in 200 children developed invasive H influenzae type b disease by the age of 5 years. In children less than 5 years of age, the mortality rate for invasive H influenzae type b disease ranged between 3% and 6%. (3) In more than 60% of these children, meningitis was the clinical syndrome and permanent sequelae ranging from mild hearing loss to mental retardation affecting 20% to 30% of all survivors. (3) Ninety-five percent of the cases of invasive H influenzae disease among children <5 years of age were caused by organisms with the type b polysaccharide capsule.
Approximately two-thirds of all cases of invasive H influenzae type b disease affected infants and children <15 months of age, a group for which a vaccine was not available until late 1990. (4) (5) Confidential/Proprietary Information
Page 4 of 34 Incidence rates of invasive H influenzae type b disease have been shown to be increased in certain high-risk groups, such as native Americans (both American Indians and Eskimos), blacks, individuals of lower socioeconomic status, and patients with asplenia, sickle cell disease, Hodgkin’s disease, and antibody deficiency syndromes. (5) (6) Studies also have suggested that the risk of acquiring primary invasive H influenzae type b disease for children under 5 years of age appears to be greater for those who attend day-care facilities. (7) (8) (9) (10) The potential for person to person transmission of the organism among susceptible individuals has been recognized. Studies of secondary spread of disease in household contacts of index patients have shown a substantially increased risk among exposed household contacts under 4 years of age.
(11) Adults can be colonized with H influenzae type b from children infected with the organism. (12) The response to ActHIB vaccine is typical of a T-dependent immune response to antigen. The prominent isotype of anti-capsular PRP antibody induced by ActHIB vaccine is IgG. (13) A substantial booster response has been demonstrated in children 12 months of age or older who previously received two or three doses. Bactericidal activity against H influenzae type b is demonstrated in serum after immunization and statistically correlates with the anti-PRP antibody response induced by ActHIB vaccine. (14) Antibody to H influenzae capsular polysaccharide (anti-PRP) titers of >1.0 mcg/mL following vaccination with unconjugated PRP vaccine correlated with long-term protection against invasive H influenzae type b disease in children older than 24 months of age. (15) Although the relevance Confidential/Proprietary Information Page 5 of 34 of this threshold to clinical protection after immunization with conjugate vaccines is not known, particularly in light of the induced, immunologic memory, this level continues to be considered as indicative of long-term protection. (4) The immunogenicity and safety of ActHIB vaccine has been demonstrated in the United States and worldwide. ActHIB vaccine induced, on average anti-PRP levels ≥1.0 mcg/mL in 90% of infants after the primary series and in more than 98% of infants after a booster dose. (14) Two clinical trials supported by the National Institutes of Health (NIH) have compared the anti-PRP antibody responses to three Haemophilus b conjugate vaccines in racially mixed populations of children. These studies were done in Tennessee (16) (TABLE 1) and in Minnesota, Missouri and Texas (17) (TABLE 2) in infants immunized with ActHIB vaccine and other Haemophilus b conjugate vaccines at 2, 4 and 6 months of age. All Haemophilus b conjugate vaccines were administered concomitantly with Poliovirus Vaccine Live Oral and DTP vaccines at separate sites. Confidential/Proprietary Information
Page 6 of 34 TABLE 1 (16) ANTI-PRP ANTIBODY RESPONSES IN 2-MONTH-OLD INFANTS NIH TRIAL IN TENNESSEE VACCINE N* GEOMETRIC MEAN TITER (GMT) (mcg/mL) Post Third Immunization % 1.0 mcg/mL Pre ImmunizationPost Second ImmunizationPost Third Immunization PRP-T†(ActHIBvaccine) 65 0.10 0.30 3.64 83% PRP-OMP¶(PedvaxHIB®) 64 0.11 0.84 N/A 50%** HbOC‡(HibTITER®) 61 0.07 0.13 3.08 75% TABLE 2 (17) ANTI-PRP ANTIBODY RESPONSES IN 2-MONTH-OLD INFANTS NIH TRIAL IN MINNESOTA, MISSOURI AND TEXAS VACCINE N* GEOMETRIC MEAN TITER (GMT) (mcg/mL) Post Third§ Immunization % 1.0 mcg/mL Pre Immunization Post Second Immunization Post Third§ Immunization PRP-T†(ActHIBvaccine) 142 0.25 1.25 6.37 97% PRP-OMP¶(PedvaxHIB®) 149 0.18 4.00 N/A 85%** HbOC‡(HibTITER®) 167 0.17 0.45 6.31 90% * N = Number of Children § Sera were obtained after the third dose from 86 and 110 infants, in PRP-T and HbOC vaccine groups, respectively. † Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) ¶ Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) ** Seroconversion after the recommended 2-dose primary immunization series is shown. ‡ Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) N/A Not applicable in this comparison trial although third dose data have been published. (16) (17) Confidential/Proprietary Information
Page 7 of 34 Native American populations have had high rates of H influenzae type b disease and have been observed to have low immune responses to Haemophilus b conjugate vaccines. Following three doses of ActHIB vaccine at six weeks, four and six months of age, 75% of Native Americans in Alaska showed an anti-PRP antibody titer of ≥1.0 mcg/mL. (18) Children 12 to 24 months of age who had not previously received Haemophilus b conjugate vaccination were immunized with a single dose of ActHIB vaccine. GMT anti-PRP antibody responses were 5.12 mcg/mL (90% responding with ≥1.0 mcg/mL) for children 12 to 15 months of age and 4.4 mcg/mL (82% responding with ≥1.0 mcg/mL) for children 17 to 24 months of age. (18) These trials demonstrated that ActHIB vaccine consistently conferred an anti-PRP antibody response previously shown to correlate with protection, when administered either as a regimen of three doses at least four to eight weeks apart in infants 2 to 6 months of age or as a single dose in children 12 months of age and older. (18) ActHIB vaccine has been found to be immunogenic in children with sickle cell anemia, a condition which may cause increased susceptibility to Haemophilus b disease. Two doses of ActHIB vaccine given at two-month intervals induced anti-PRP antibody titers of ≥1.0 mcg/mL in 89% of these children with a mean age of 11 months. This is comparable to anti-PRP antibody levels demonstrated in normal children of similar age following two doses of ActHIB vaccine. (19) Confidential/Proprietary Information
Page 8 of 34 ActHIB VACCINE COMBINED WITH WHOLE-CELL PERTUSSIS VACCINE (DTP) BY RECONSTITUTION FOR PRIMARY IMMUNIZATION Comparative clinical trials demonstrated that a similar anti-PRP response was achieved in infants as young as 2 months old when one dose of Sanofi Pasteur Inc. whole-cell DTP vaccine was used to reconstitute lyophilized ActHIB vaccine (TABLE 3). (14) (18) TABLE 3 (18) ANTI-PRP RESPONSES IN 2-MONTH-OLD INFANTS FOLLOWING IMMUNIZATION WITH ActHIB VACCINE COMBINED WITH SANOFI PASTEUR INC. DTP BY RECONSTITUTION STUDY SITE N* GEOMETRIC MEAN TITER (GMT) (mcg/mL) Post Third Immunization % 1.0 mcg/mL Pre ImmunizationPost Second Immunization Post Third Immunization US 45 0.13 0.55 4.49 91 US 135 0.12 0.43 4.46 85 Chile 94 0.09 4.31 6.94 96 *N = Number of Children Antibody responses to diphtheria, tetanus and pertussis antigens were also measured in this trial. Post dose three antibody responses to all measured vaccine antigens were similar, within each study, when infants who received the combined vaccine were compared to infants who received whole-cell DTP and ActHIB vaccine separately. Interference with the antibody response to the pertussis component has been suggested with a DTP vaccine unlicensed in the US. (20) Percentages of subjects achieving antibody titers over 1 mcg/mL and GMT to PRP in 2-month-old infants following immunization with ActHIB vaccine combined with Sanofi Pasteur Inc. DTP by Confidential/Proprietary Information
Page 9 of 34 reconstitution was similar when compared to infants who received DTP and ActHIB vaccine separately (84% versus 85% and 4.3 mcg/mL versus 4.8 mcg/mL). (14) (18) TriHIBit VACCINE, ActHIB VACCINE COMBINED WITH TRIPEDIA VACCINE BY RECONSTITUTION FOR BOOSTER DOSE Randomized comparative clinical trials demonstrated that the anti-PRP response achieved in 15 to 20-month-old children after one dose of TriHIBit vaccine, Tripedia vaccine and ActHIB vaccine combination vaccine, was similar to that achieved when the two vaccines were given concomitantly at different sites with separate needles and syringes (TABLE 4). (18) All children had received three doses of a Haemophilus b conjugate vaccine (HibTITER or ActHIB vaccine) and three doses of a whole-cell DTP vaccine prior to entry into this clinical trial. TABLE 4 (18) ANTI-PRP RESPONSES IN 15 TO 20-MONTH-OLD CHILDREN FOLLOWING IMMUNIZATION WITH TriHIBit VACCINE COMPARED TO ActHIB VACCINE AND TRIPEDIA VACCINE GIVEN CONCOMITANTLY AT SEPARATE SITES IMMUNOGENICITY Pre-Dose Post-Dose TriHIBit vaccine Separate Injections TriHIBit vaccine Separate Injections N* 88 94 93 98 Anti-PRP (mcg/mL) 0.89 1.15 90.30 80.90 % >1 mcg/mL 45.50 53.20 100.00 100.00 *N = Number of Children Geometric mean titers in response to diphtheria, tetanus and pertussis (PT and FHA) were also similar between groups. (Refer to product insert for Tripedia vaccine.) A difference in four-fold Confidential/Proprietary Information
Page 10 of 34 antibody response to FHA was noted in this trial. However, theclinical significance of this difference is not known at present.INDICATIONS AND USAGE ActHIB vaccine or ActHIB vaccine combined with Sanofi Pasteur Inc. DTP vaccine by reconstitution is indicated for the active immunization of infants and children 2 through 18 months of age for the prevention of invasive disease caused by H influenzae type b and/or diphtheria, tetanus and pertussis. TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, is indicated for the active immunization of children 15 to 18 months of age for prevention of invasive disease caused by H influenzae type b and diphtheria, tetanus and pertussis. Antibody levels associated with protection may not be achieved earlier than two weeks following the last recommended dose. Only Sanofi Pasteur Inc. whole-cell DTP, Tripedia vaccine or 0.4% Sodium Chloride diluent may be used for reconstitution of lyophilized ActHIB vaccine. TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, should not be administered to infants younger than 15 months of age.
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Hib Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) ActHIB®DESCRIPTION ActHIB®, Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), produced by Sanofi Pasteur SA, is a sterile, lyophilized powder which is reconstituted at the time of use with either saline diluent (0.4% Sodium Chloride) or Sanofi Pasteur Inc. Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed (whole-cell pertussis vaccine DTP) or Tripedia®, Sanofi Pasteur Inc. Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) (when reconstituted known as TriHIBit®) for intramuscular use only.
The vaccine consists of the Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate, PRP), a high molecular weight polymer prepared from the Haemophilus influenzae type b (HiB) strain 1482 grown in a semi-synthetic medium, covalently bound to tetanus toxoid. (1) The lyophilized ActHIB vaccine powder and saline diluent contain no preservative. The tetanus toxoid is prepared by extraction, ammonium sulfate purification, and formalin inactivation of the toxin from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium. (2) Further Confidential/Proprietary Information Page 2 of 34 manufacturing process steps reduce residual formaldehyde to levels below 0.5 micrograms (mcg) per dose by calculation.
The toxoid is filter sterilized prior to the conjugation process. Potency of ActHIB vaccine is specified on each lot by limits on the content of PRP polysaccharide and protein in each dose and the proportion of polysaccharide and protein in the vaccine which is characterized as high molecular weight conjugate. When ActHIB vaccine is reconstituted with saline diluent, each single dose of 0.5 mL is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, and 8.5% of sucrose. When ActHIB vaccine is combined with Sanofi Pasteur Inc. DTP vaccine by reconstitution, each single dose (0.5 mL) is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, 8.5% of sucrose, 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid and an estimate of 4 protective units of pertussis vaccine.
Thimerosal (mercury derivative) 1:10,000 is added as a preservative to Sanofi Pasteur Inc. DTP vaccine. (Refer to product insert for Sanofi Pasteur Inc. whole-cell DTP.) When ActHIB vaccine is combined with Tripedia vaccine (TriHIBit vaccine) by reconstitution for booster dose, each single dose (0.5 mL) is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, 8.5% of sucrose, 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid and 46.8 mcg of pertussis antigens.
The 0.6 mL vial of Tripedia vaccine is formulated without preservatives but contains a trace amount of thimerosal Confidential/Proprietary Information Page 3 of 34 [(mercury derivative), (≤0.3 mcg mercury/dose)] from the manufacturing process. (Refer to product insert for Tripedia vaccine.) The reconstituted vaccine, using saline diluent, appears clear and colorless. The reconstituted vaccine, using Sanofi Pasteur Inc. DTP vaccine, appears whitish in color. TriHIBit vaccine, the reconstituted vaccine, using Tripedia vaccine, is a homogenous white suspension.CLINICAL PHARMACOLOGYH influenzae type b was the leading cause of invasive bacterial disease among children in the United States prior to licensing of Haemophilus b conjugate vaccines.
Based on its active surveillance areas, the Centers for Disease Control and Prevention (CDC) now estimate that H influenzae type b disease in children under the age of 5 years has been reduced by 95%. (3) Before effective vaccines were introduced, it was estimated that one in 200 children developed invasive H influenzae type b disease by the age of 5 years. In children less than 5 years of age, the mortality rate for invasive H influenzae type b disease ranged between 3% and 6%. (3) In more than 60% of these children, meningitis was the clinical syndrome and permanent sequelae ranging from mild hearing loss to mental retardation affecting 20% to 30% of all survivors. (3) Ninety-five percent of the cases of invasive H influenzae disease among children <5 years of age were caused by organisms with the type b polysaccharide capsule.
Approximately two-thirds of all cases of invasive H influenzae type b disease affected infants and children <15 months of age, a group for which a vaccine was not available until late 1990. (4) (5) Confidential/Proprietary Information
Page 4 of 34 Incidence rates of invasive H influenzae type b disease have been shown to be increased in certain high-risk groups, such as native Americans (both American Indians and Eskimos), blacks, individuals of lower socioeconomic status, and patients with asplenia, sickle cell disease, Hodgkin’s disease, and antibody deficiency syndromes. (5) (6) Studies also have suggested that the risk of acquiring primary invasive H influenzae type b disease for children under 5 years of age appears to be greater for those who attend day-care facilities. (7) (8) (9) (10) The potential for person to person transmission of the organism among susceptible individuals has been recognized. Studies of secondary spread of disease in household contacts of index patients have shown a substantially increased risk among exposed household contacts under 4 years of age.
(11) Adults can be colonized with H influenzae type b from children infected with the organism. (12) The response to ActHIB vaccine is typical of a T-dependent immune response to antigen. The prominent isotype of anti-capsular PRP antibody induced by ActHIB vaccine is IgG. (13) A substantial booster response has been demonstrated in children 12 months of age or older who previously received two or three doses. Bactericidal activity against H influenzae type b is demonstrated in serum after immunization and statistically correlates with the anti-PRP antibody response induced by ActHIB vaccine. (14) Antibody to H influenzae capsular polysaccharide (anti-PRP) titers of >1.0 mcg/mL following vaccination with unconjugated PRP vaccine correlated with long-term protection against invasive H influenzae type b disease in children older than 24 months of age. (15) Although the relevance Confidential/Proprietary Information Page 5 of 34 of this threshold to clinical protection after immunization with conjugate vaccines is not known, particularly in light of the induced, immunologic memory, this level continues to be considered as indicative of long-term protection. (4) The immunogenicity and safety of ActHIB vaccine has been demonstrated in the United States and worldwide. ActHIB vaccine induced, on average anti-PRP levels ≥1.0 mcg/mL in 90% of infants after the primary series and in more than 98% of infants after a booster dose. (14) Two clinical trials supported by the National Institutes of Health (NIH) have compared the anti-PRP antibody responses to three Haemophilus b conjugate vaccines in racially mixed populations of children. These studies were done in Tennessee (16) (TABLE 1) and in Minnesota, Missouri and Texas (17) (TABLE 2) in infants immunized with ActHIB vaccine and other Haemophilus b conjugate vaccines at 2, 4 and 6 months of age. All Haemophilus b conjugate vaccines were administered concomitantly with Poliovirus Vaccine Live Oral and DTP vaccines at separate sites. Confidential/Proprietary Information
Page 6 of 34 TABLE 1 (16) ANTI-PRP ANTIBODY RESPONSES IN 2-MONTH-OLD INFANTS NIH TRIAL IN TENNESSEE VACCINE N* GEOMETRIC MEAN TITER (GMT) (mcg/mL) Post Third Immunization % 1.0 mcg/mL Pre ImmunizationPost Second ImmunizationPost Third Immunization PRP-T†(ActHIBvaccine) 65 0.10 0.30 3.64 83% PRP-OMP¶(PedvaxHIB®) 64 0.11 0.84 N/A 50%** HbOC‡(HibTITER®) 61 0.07 0.13 3.08 75% TABLE 2 (17) ANTI-PRP ANTIBODY RESPONSES IN 2-MONTH-OLD INFANTS NIH TRIAL IN MINNESOTA, MISSOURI AND TEXAS VACCINE N* GEOMETRIC MEAN TITER (GMT) (mcg/mL) Post Third§ Immunization % 1.0 mcg/mL Pre Immunization Post Second Immunization Post Third§ Immunization PRP-T†(ActHIBvaccine) 142 0.25 1.25 6.37 97% PRP-OMP¶(PedvaxHIB®) 149 0.18 4.00 N/A 85%** HbOC‡(HibTITER®) 167 0.17 0.45 6.31 90% * N = Number of Children § Sera were obtained after the third dose from 86 and 110 infants, in PRP-T and HbOC vaccine groups, respectively. † Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) ¶ Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) ** Seroconversion after the recommended 2-dose primary immunization series is shown. ‡ Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) N/A Not applicable in this comparison trial although third dose data have been published. (16) (17) Confidential/Proprietary Information
Page 7 of 34 Native American populations have had high rates of H influenzae type b disease and have been observed to have low immune responses to Haemophilus b conjugate vaccines. Following three doses of ActHIB vaccine at six weeks, four and six months of age, 75% of Native Americans in Alaska showed an anti-PRP antibody titer of ≥1.0 mcg/mL. (18) Children 12 to 24 months of age who had not previously received Haemophilus b conjugate vaccination were immunized with a single dose of ActHIB vaccine. GMT anti-PRP antibody responses were 5.12 mcg/mL (90% responding with ≥1.0 mcg/mL) for children 12 to 15 months of age and 4.4 mcg/mL (82% responding with ≥1.0 mcg/mL) for children 17 to 24 months of age. (18) These trials demonstrated that ActHIB vaccine consistently conferred an anti-PRP antibody response previously shown to correlate with protection, when administered either as a regimen of three doses at least four to eight weeks apart in infants 2 to 6 months of age or as a single dose in children 12 months of age and older. (18) ActHIB vaccine has been found to be immunogenic in children with sickle cell anemia, a condition which may cause increased susceptibility to Haemophilus b disease. Two doses of ActHIB vaccine given at two-month intervals induced anti-PRP antibody titers of ≥1.0 mcg/mL in 89% of these children with a mean age of 11 months. This is comparable to anti-PRP antibody levels demonstrated in normal children of similar age following two doses of ActHIB vaccine. (19) Confidential/Proprietary Information
Page 8 of 34 ActHIB VACCINE COMBINED WITH WHOLE-CELL PERTUSSIS VACCINE (DTP) BY RECONSTITUTION FOR PRIMARY IMMUNIZATION Comparative clinical trials demonstrated that a similar anti-PRP response was achieved in infants as young as 2 months old when one dose of Sanofi Pasteur Inc. whole-cell DTP vaccine was used to reconstitute lyophilized ActHIB vaccine (TABLE 3). (14) (18) TABLE 3 (18) ANTI-PRP RESPONSES IN 2-MONTH-OLD INFANTS FOLLOWING IMMUNIZATION WITH ActHIB VACCINE COMBINED WITH SANOFI PASTEUR INC. DTP BY RECONSTITUTION STUDY SITE N* GEOMETRIC MEAN TITER (GMT) (mcg/mL) Post Third Immunization % 1.0 mcg/mL Pre ImmunizationPost Second Immunization Post Third Immunization US 45 0.13 0.55 4.49 91 US 135 0.12 0.43 4.46 85 Chile 94 0.09 4.31 6.94 96 *N = Number of Children Antibody responses to diphtheria, tetanus and pertussis antigens were also measured in this trial. Post dose three antibody responses to all measured vaccine antigens were similar, within each study, when infants who received the combined vaccine were compared to infants who received whole-cell DTP and ActHIB vaccine separately. Interference with the antibody response to the pertussis component has been suggested with a DTP vaccine unlicensed in the US. (20) Percentages of subjects achieving antibody titers over 1 mcg/mL and GMT to PRP in 2-month-old infants following immunization with ActHIB vaccine combined with Sanofi Pasteur Inc. DTP by Confidential/Proprietary Information
Page 9 of 34 reconstitution was similar when compared to infants who received DTP and ActHIB vaccine separately (84% versus 85% and 4.3 mcg/mL versus 4.8 mcg/mL). (14) (18) TriHIBit VACCINE, ActHIB VACCINE COMBINED WITH TRIPEDIA VACCINE BY RECONSTITUTION FOR BOOSTER DOSE Randomized comparative clinical trials demonstrated that the anti-PRP response achieved in 15 to 20-month-old children after one dose of TriHIBit vaccine, Tripedia vaccine and ActHIB vaccine combination vaccine, was similar to that achieved when the two vaccines were given concomitantly at different sites with separate needles and syringes (TABLE 4). (18) All children had received three doses of a Haemophilus b conjugate vaccine (HibTITER or ActHIB vaccine) and three doses of a whole-cell DTP vaccine prior to entry into this clinical trial. TABLE 4 (18) ANTI-PRP RESPONSES IN 15 TO 20-MONTH-OLD CHILDREN FOLLOWING IMMUNIZATION WITH TriHIBit VACCINE COMPARED TO ActHIB VACCINE AND TRIPEDIA VACCINE GIVEN CONCOMITANTLY AT SEPARATE SITES IMMUNOGENICITY Pre-Dose Post-Dose TriHIBit vaccine Separate Injections TriHIBit vaccine Separate Injections N* 88 94 93 98 Anti-PRP (mcg/mL) 0.89 1.15 90.30 80.90 % >1 mcg/mL 45.50 53.20 100.00 100.00 *N = Number of Children Geometric mean titers in response to diphtheria, tetanus and pertussis (PT and FHA) were also similar between groups. (Refer to product insert for Tripedia vaccine.) A difference in four-fold Confidential/Proprietary Information
Page 10 of 34 antibody response to FHA was noted in this trial. However, theclinical significance of this difference is not known at present.INDICATIONS AND USAGE ActHIB vaccine or ActHIB vaccine combined with Sanofi Pasteur Inc. DTP vaccine by reconstitution is indicated for the active immunization of infants and children 2 through 18 months of age for the prevention of invasive disease caused by H influenzae type b and/or diphtheria, tetanus and pertussis. TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, is indicated for the active immunization of children 15 to 18 months of age for prevention of invasive disease caused by H influenzae type b and diphtheria, tetanus and pertussis. Antibody levels associated with protection may not be achieved earlier than two weeks following the last recommended dose. Only Sanofi Pasteur Inc. whole-cell DTP, Tripedia vaccine or 0.4% Sodium Chloride diluent may be used for reconstitution of lyophilized ActHIB vaccine. TriHIBit vaccine, ActHIB vaccine combined with Tripedia vaccine by reconstitution, should not be administered to infants younger than 15 months of age.
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