Study of the Booster Effect of DTaP-IPV-Hep B-PRP~T Combined Vaccine or Infanrix Hexa™ and Prevenar™ in Healthy Infants

All participants who completed trial A3L24 (NCT01177722) will be recruited to participate in this trial. Those who received DTaP-IPV-Hep B-PRP-T combined vaccine will be randomized to receive either a booster dose of DTaP-IPV-Hep B-PRP-T or Infanrix hexa™ vaccine.

Those who received Infanrix hexa™ will receive a booster dose of DTaP-IPV-Hep B-PRP-T combined vaccine. All participants will receive a booster dose of Prevenar™ concomitantly.

• DTaP-IPV-Hep B-PRP~T combined vaccine + Pneumococcal polysaccharide (Biological), also known as DTaP-IPV-Hep B-PRP~T vaccine, Prevenar™: 0.5 mL, Intramuscular each into the right and left deltoid muscle
• DTaP-Hep B-IPV // Hib Vaccine + Pneumococcal polysaccharide (Biological), also known as Infanrix hexa™, Prevenar™: 0.5 mL, Intramuscular each into the right and left deltoid muscle
• DTaP-IPV-Hep B-PRP~T + Pneumococcal polysaccharide vaccine (Biological), also known as DTaP-IPV-Hep B-PRP~T combined vaccine, Prevenar™: 0.5 mL (each), Intramuscular each into the right and left deltoid muscle

Primary outcomes

• Summary of Diphtheria and Tetanus Post Primary Series Antibodies, Persistence and Booster Response Following Vaccination With Either DTaP-IPV Hep B-PRP T Vaccine or Infanrix Hexa Vaccine [Day 140 (Primary series) and Day 0 (Pre-booster)]: Anti-Diphtheria (D) antibodies were measured by a toxin neutralization test. Anti-Tetanus (T) antibodies were measured by enzyme-linked immunosorbent assay (ELISA). Antibody persistence for anti-Diphtheria and anti-Tetanus antibodies was defined as titers ≥0.01 IU/mL and ≥0.1 IU/mL before the booster dose at Day 0. Booster response to Diphtheria and Tetanus was defined as antibody titers ≥0.01 IU/mL and ≥0.1 IU/mL at Day 30 post-booster vaccination. Day 140 = Primary series; Day 0 = Pre-booster; and Day 30 = Post-booster titers
• Summary of Pertussis and Filamentous Haemagglutinin Post Primary Series Antibodies, Persistence and Booster Response Following Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine [Day 140 after primary vaccination, Day 0 (pre-vaccination), and Day 30 after final booster vaccination]: Anti-Pertussis toxin (PT) and anti-Filamentous haemagglutinin (FHA) antibodies were measured by ELISA. Antibody persistence for anti-PT and anti-FHA was defined as titers ≥ lower limit of quantitation (LLOQ) before the booster dose at Day 0. Booster responses for PT and FHA at Day 30 were defined as: pre-vaccination antibody concentrations < LLOQ and post-vaccination levels ≥ 4 x LLOQ, pre-vaccination antibody concentrations ≥ LLOQ but < 4 x LLOQ and post/pre vaccination ≥ 4, and pre-vaccination antibody concentrations ≥ 4 x LLOQ and post/pre-vaccination ≥ 2. Day 140 = Primary series; Day 0 = Pre-booster; and Day 30 = Post-booster titers.
• Summary of Polio Antibodies Post Primary Series, Persistence and Booster Response Following Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine [Day 140 after primary vaccination, Day 0 (pre-vaccination), and Day 30 after final booster vaccination]: Anti-Poliovirus types 1, 2, and 3 antibodies were measured by neutralization assay. Antibody persistence for anti-Poliovirus 1, 2, and 3 was defined as antibody titers ≥8 (1/dil) before the booster dose at Day 0. Booster response to Poliovirus 1, 2, and 3 was defined as antibody titers ≥8 (1/dil) at Day 30. Day 140 = Primary series; Day 0 = Pre-booster; and Day 30 = Post-booster titers.
• Summary of Hepatitis B and Haemophilus Influenzae Type B Post Primary Series Antibodies; Antibody Persistence, and Booster Response Following Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine [Day 140 after primary vaccination, Day 0 (pre-vaccination), and Day 30 after final booster vaccination]: Anti-Hepatitis B antibodies were measured by the commercially available VITROS ECi/ECiQ Immunodiagnostic System. Anti-Haemophilus influenza type b capsular polyribosyl ribitol phosphate (PRP) antibodies were measured using a Farr type radioimmunoassay that used radiolabeled PRP (3H PRP) in the presence of 36Cl (volume marker). Anti-Hepatitis antibody titers ≥ 10 mIU/mL and ≥ 100 mIU/mL at Day 0 confirmed antibody persistence and booster response at Day 30. Anti-PRP antibody titers ≥ 0.15 µg/ml and ≥ 1.0 µg/ml at Day 0 confirmed antibody persistence and booster response at Day 30. Day 140 = Primary series; Day 0 = Pre-booster; and Day 30 = Post-booster titers.

Secondary outcomes

• Summary of Geometric Mean Titers to Vaccine Antibodies Post Primary Vaccination Series; Before and After Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine. [Day 140 after primary vaccination, Day 0 (pre-vaccination), and Day 30 after final booster vaccination]: Anti-Diphtheria antibodies were measured by a toxin neutralization test. Anti-Tetanus, anti-PT, and anti-FHA antibodies were measured by ELISA. Anti-Poliovirus types 1, 2, and 3 were measured by neutralization assay. Anti-Hepatitis B antibodies were measured by the commercially available VITROS ECi/ECiQ Immunodiagnostic System. Anti-PRP antibodies were measured using a Farr type radioimmunoassay that used radiolabeled PRP (3H PRP) in the presence of 36Cl (volume marker). Day 140 = Primary series; Day 0 = Pre-booster; and Day 30 = Post-booster titers.
• Summary of Immune Response Against Serotypes in the Prevenar Vaccine After Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine [Day 30 after final booster vaccination]: Anti-Streptococcus pneumococcal type specific antibody (anti-Pn PS) was measured by ELISA. Booster response to pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F was defined as antibody titers ≥0.35 µg/mL at Day 30.
• Summary of Geometric Mean Titers to Prevenar Vaccine Antibodies After Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine [Day 30 after final booster vaccination]: Anti-Streptococcus pneumococcal type specific antibody (anti-Pn PS) was measured by ELISA.
• Summary of Booster Response to Vaccine Antigens Before and After Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine By Age Strata [Day 0 (pre-vaccination) and Day 30 after final booster vaccination]: Anti-PT and anti-FHA antibodies were measured by ELISA.
• Summary of Geometric Mean Titers to Vaccine Antigens After Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine by Age Strata [Day 30 after final booster vaccination]: Anti-Diphtheria antibodies were measured by a toxin neutralization test. Anti-FHA antibodies were measured by ELISA. Anti-Poliovirus types 1, 2, and 3 were measured by neutralization assay.
• Number of Participants Reporting a Solicited Injection Site or Systemic Reactions Following Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine [Day 0 up to Day 7 after final booster vaccination]: Solicited injection site: Pain, Erythema, Swelling, and Extensive swelling of vaccinated limb; Solicited systemic reactions: Pyrexia (Temperature), Vomiting, Crying, Somnolence, Anorexia, and Irritability. Grade 3 Injection site: Pain, Cries if limb is moved or reduced movement; Erythema and Swelling, ≥5 cm; Extensive swelling of limb, Severe. Grade 3 Systemic reactions: Pyrexia (Temperature) >39.5˚C; Vomiting, ≥ 6 times per 24 hours or needing parenteral nutrition; Crying, >3 hours; Somnolence, Sleeping often or difficulty waking; Anorexia, refuses ≥3 meals; and Irritability, Inconsolable.
• Number of Participants Reporting a Solicited Injection Site Following Booster Vaccination With Prevenar Vaccine [Day 0 up to Day 7 after final booster vaccination]: Solicited injection site: Pain, Erythema, Swelling, and Extensive swelling of vaccinated limb. Grade 3 Injection site: Pain, cries if limb is moved or reduced movement; Erythema and Swelling, ≥5 cm; and Extensive swelling of limb, Severe.

Sex: All, ages: 12 Months to 24 Months, accepts healthy volunteers

Inclusion Criteria:

* Aged 12 to 24 months on the day of inclusion.
* Informed consent form has been signed and dated by the parent(s) or other legally acceptable representative (and by an independent witness(es) if required by local regulations).
* Subject and parent/guardian are able to attend all scheduled visits and to comply with all trial procedures.
* Toddlers previously included in Study A3L24 who completed the three-dose primary series vaccination of either DTaP-IPV-Hep B-PRP\~T or Infanrix hexa™ at 2,4 and 6 months of age according to protocol (both concomitantly administered with Prevenar™ and Rotarix™).

Exclusion Criteria:

* Participation in another clinical trial investigating a vaccine, drug, medical device, or medical procedure in the 4 weeks preceding the booster vaccinations.
* Planned participation in another clinical trial during the present trial period.
* Receipt of any vaccine in the 4 weeks preceding the booster vaccinations, except in case of pandemic influenza vaccination, which may be received at least two weeks before the study vaccines.
* Planned receipt of any vaccine in the 4 weeks following the trial vaccinations.
* Previous booster vaccination against pertussis, tetanus, diphtheria, poliomyelitis, Haemophilus influenzae type b, hepatitis B and pneumococcal infection(s) with either the trial vaccine or another vaccine.
* Receipt of blood or blood-derived products in the past 3 months, which might interfere with assessment of the immune response.
* Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 3 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months).
* Laboratory-confirmed or clinical suspicion of personal or maternal seropositivity for Human Immunodeficiency Virus (HIV), hepatitis B, or hepatitis C, as reported by the parent/guardian.
* History of pertussis, tetanus, diphtheria, poliomyelitis, Haemophilus influenzae type b, hepatitis B and pneumococcal infection(s), confirmed either clinically, serologically, or microbiologically.
* At high risk for opportunistic infection during the trial.
* Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine(s) used in the trial or to a vaccine containing any of the same substances.
* History of contraindication to receipt of pertussis-containing vaccine.
* Laboratory-confirmed or clinical suspicion of thrombocytopenia contraindicating Intramuscular vaccination.
* Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination.
* History of seizures .
* Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion.
* Receipt of oral or injected antibiotic therapy within 72 hours prior to the first blood draw
* Febrile illness (temperature ≥ 38.0°C) or moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination.

Participant flow

Outcome results

• Summary of Diphtheria and Tetanus Post Primary Series Antibodies, Persistence and Booster Response Following Vaccination With Either DTaP-IPV Hep B-PRP T Vaccine or Infanrix Hexa Vaccine (Primary), Number, Participants: Group 1: DTaP IPV Hep B PRP T + Prevenar™ Primary and Booster 392; Group 2DTaP IPV Hep B PRP T Primary/Infanrix Hexa+PCV7 Booster 391 (0 to 0); Group 3Infanrix Hexa Primary/DTaP IPV Hep B PRP T+PCV7 Booster 259 (0 to 0)
• Summary of Pertussis and Filamentous Haemagglutinin Post Primary Series Antibodies, Persistence and Booster Response Following Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine (Primary), Number, Participants: Group 1: DTaP-IPV Hep B-PRP~T + Prevenar™ Primary and Booster 393; Group 2:DTaP-IPV-HepB-PRP~T Primary/Infanrix Hexa+PCV7 Booster 391 (0 to 0); Group 3:Infanrix Hexa Primary/DTaP-IPV-HepB-PRP~T+PCV7 Booster 259 (0 to 0)
• Summary of Polio Antibodies Post Primary Series, Persistence and Booster Response Following Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine (Primary), Number, Participants: Group 1: DTaP IPV Hep B PRP T + Prevenar™ Primary and Booster 338; Group 2DTaP IPV Hep B PRP T Primary/Infanrix Hexa+PCV7 Booster 329 (0 to 0); Group 3Infanrix Hexa Primary/DTaP IPV Hep B PRP T+PCV7 Booster 214 (0 to 0)
• Summary of Hepatitis B and Haemophilus Influenzae Type B Post Primary Series Antibodies; Antibody Persistence, and Booster Response Following Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine (Primary), Number, Participants: Group 1: DTaP-IPV-Hep B-PRP~T + Prevenar™ Primary and Booster 391; Group 2:DTaP-IPV-HepB-PRP~T Primary/Infanrix Hexa+PCV7 Booster 391 (0 to 0); Group 3:Infanrix Hexa Primary/DTaP-IPV-HepB-PRP~T+PCV7 Booster 260 (0 to 0)
• Summary of Geometric Mean Titers to Vaccine Antibodies Post Primary Vaccination Series; Before and After Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine. (Secondary), Geometric mean, Titers: Group 1: DTaP IPV Hep B PRP T + Prevenar™ Primary and Booster 0.265 (0.237 to 0.295); Group 2DTaP IPV Hep B PRP T Primary/Infanrix Hexa+PCV7 Booster 0.254 (0.227 to 0.285); Group 3Infanrix Hexa Primary/DTaP IPV Hep B PRP T+PCV7 Booster 0.251 (0.220 to 0.286)
• Summary of Immune Response Against Serotypes in the Prevenar Vaccine After Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine (Secondary), Number, Participants: Group 1: DTaP-IPV-Hep B-PRP~T + Prevenar™ Primary and Booster 160; Group 2:DTaP-IPV-HepB PRP~T Primary/Infanrix Hexa+PCV7 Booster 146 (0 to 0); Group 3:Infanrix Hexa Primary/DTaP-IPV-HepB-PRP~T+PCV7 Booster 94 (0 to 0)
• Summary of Geometric Mean Titers to Prevenar Vaccine Antibodies After Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine (Secondary), Geometric mean, Titers: Group 1: DTaP-IPV-Hep B-PRP~T + Prevenar™ Primary and Booster 2.79 (2.47 to 3.15); Group 2:DTaP-IPV-HepB-PRP~T Primary/Infanrix Hexa+PCV7 Booster 3.03 (2.64 to 3.47); Group 3:Infanrix Hexa Primary/DTaP-IPV-HepB-PRP~T+PCV7 Booster 3.58 (3.07 to 4.17)
• Summary of Booster Response to Vaccine Antigens Before and After Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine By Age Strata (Secondary), Number, Participants: Group 1: DTaP-IPV-Hep B-PRP~T + Prevenar™ Primary and Booster 100; Group 2:DTaP-IPV-HepB-PRP~T Primary/Infanrix Hexa+PCV7 Booster 104 (0 to 0); Group 3:Infanrix Hexa Primary/DTaP-IPV-HepB-PRP~T+PCV7 Booster 61 (0 to 0)
• Summary of Geometric Mean Titers to Vaccine Antigens After Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine by Age Strata (Secondary), Geometric mean, Titers: Group 1: DTaP-IPV-Hep B-PRP~T + Prevenar™ Primary and Booster 3.20 (2.72 to 3.76); Group 2:DTaP-IPV-HepB-PRP~T Primary/Infanrix Hexa+PCV7 Booster 2.73 (2.30 to 3.24); Group 3:Infanrix Hexa Primary/DTaP-IPV-HepB-PRP~T+PCV7 Booster 3.82 (3.01 to 4.84)
• Number of Participants Reporting a Solicited Injection Site or Systemic Reactions Following Booster Vaccination With Either DTaP-IPV-Hep B-PRP~T Vaccine or Infanrix Hexa Vaccine (Secondary), Number, Participants: Group 1: DTaP-IPV-Hep B-PRP~T + Prevenar™ Primary and Booster 232; Group 2:DTaP-IPV-HepB-PRP~T Primary/Infanrix Hexa+PCV7 Booster 205 (0 to 0); Group 3:Infanrix Hexa Primary/DTaP-IPV-HepB-PRP~T+PCV7 Booster 160 (0 to 0)
• Number of Participants Reporting a Solicited Injection Site Following Booster Vaccination With Prevenar Vaccine (Secondary), Number, Participants: Group 1: DTaP-IPV-Hep B-PRP~ T + Prevenar™ Primary and Booster 224; Group 2: DTaP-IPV-HepB-PRP~Tprimary/Infanrix Hexa+PCV7 Booster 184 (0 to 0); Group 3:Infanrix Hexa Primary/DTaP-IPV-HepB-PRP~T+PCV7 Booster 140 (0 to 0)

Adverse events

Time frame: Adverse event data were collected from Day 0 (post-vaccination) up to Day 30 after final booster vaccination.

Serious adverse events by term

Other adverse events by term

• Medical Director, Study director, Sanofi Pasteur SA