This Study Will Evaluate the Immunogenicity, Reactogenicity and Safety of the Routine Infant Vaccines Pediarix®, Hiberix® and Prevenar 13® When Co-administered With GlaxoSmithKline (GSK) Biologicals' Liquid Human Rotavirus Vaccine (HRV) as Compared to GSK's Licensed Lyophilized Vaccine

• Rotarix (Biological), also known as GSK Biologicals' PCV-free liquid formulation of oral live attenuated HRV vaccine., GSK Biologicals' lyophilized formulation of oral live attenuated HRV vaccine.: Two doses administered orally according to a 0, 2 month schedule as per the immunization schedule for HRV vaccine administration in the US.
• Pediarix (Biological), also known as GSK Biologicals' Diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (recombinant) and inactivated poliovirus vaccine.: Three doses administered intramuscularly according to a 0, 2, 4 month schedule.
• Hiberix (Biological), also known as GSK Biologicals' Haemophilus b conjugate vaccine (tetanus toxoid conjugate): Three doses administered intramuscularly according to a 0, 2, 4 month schedule.
• Prevenar 13 (Biological), also known as Pfizer's Pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 Protein): Three doses administered intramuscularly according to a 0, 2, 4 month schedule.

Primary outcomes

• Number of Seroprotected Subjects With Anti-diphtheria (Anti-D) and Anti-tetanus (Anti-T) Antibody Concentrations Above or Equal to Cut-off Value. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Immunogenicity was assessed using Enzyme Linked Immunosorbent Assay (ELISA) in terms of seroprotection rates against diphtheria toxoid. A seroprotected subject is a subject whose antibody concentration is greater than or equal to (≥) the level defining clinical protection. The following seroprotection thresholds were applicable:anti-D antibody concentrations ≥ 0.1 International Units/milliliter (IU/mL), anti-T antibody concentrations ≥ 0.1 IU/mL.
• Number of Seroprotected Subjects With Anti-hepatitis B (Anti-HBs) Antibody Concentrations Above or Equal to Cut-off Value. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Immunogenicity was assessed using ChemiLuminescence ImmunoAssay (CLIA) in terms of seroprotection rates against Hepatitis B. A seroprotected subject is a subject whose antibody concentration is ≥ the level defining clinical protection. The following seroprotection thresholds were applicable:anti-HB antibody concentrations ≥ 10 milli International Units/milliliter (mIU/mL).
• Number of Seroprotected Subjects With Anti-polio Virus Types 1, 2 and 3 Antibody Titers Above or Equal to Cut-off Value. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Immunogenicity was assessed using virus micro-neutralization test in terms of seroprotection rates against polio virus types 1, 2 and 3. A seroprotected subject is a subject whose antibody concentration is ≥ the level defining clinical protection. The following seroprotection thresholds were applicable:anti-polio virus types 1, 2 and 3 types antibody titers ≥ 8 Estimated Dose 50% (ED50).
• Immunogenicity in Terms of Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Hemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibody Concentrations. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Antibody concentrations against PT, FHA and PRN were determined and expressed as Geometric Mean Concentrations (GMCs).The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations.
• Immunogenicity in Terms of Anti-pneumococcal Serotypes (Anti-PnPS) Antibody Concentrations. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Antibody concentrations against pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) were determined and expressed as GMCs in micrograms per milliliter (µg/mL).The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations.
• Number of Seroprotected Subjects With Anti-polyribosyl Ribitol Phosphate (Anti-PRP) Antibody Concentrations Above or Equal to Cut-off Value of 0.15 µg/mL. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Immunogenicity was assessed in terms of seroprotection rates against PRP antibodies. A seroprotected subject is a subject whose antibody concentration is ≥ the level defining clinical protection. The following seroprotection thresholds were applicable:anti-PRP antibody concentrations ≥ 0.15 µg/mL.
• Number of Seroprotected Subjects With Anti-polyribosyl Ribitol Phosphate (Anti-PRP) Antibody Concentrations Above or Equal to Cut-off Value of 1.0 µg/mL. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Immunogenicity was assessed in terms of seroprotection rates against PRP antibodies. A seroprotected subject is a subject whose antibody concentration is ≥ the level defining clinical protection. The following seroprotection thresholds were applicable:anti-PRP antibody concentrations ≥ 1.0 µg/mL.
• Number of Subjects With Seroresponse to Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Hemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibodies. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Seroresponse is defined as the percentage of subjects showing an antibody concentration above a threshold that leads to 95% seroresponse in the HRV lyophilized Group. The cut-offs used were as follows: anti-PT (18.566 IU/mL), anti-FHA (35.711 IU/mL) and anti-PRN (11.034 IU/mL).

Secondary outcomes

• Number of Seropositive Subjects With Anti-Rota Virus Immunoglobulin A (Anti-RV IgA) Antibody Concentrations Above or Equal to Cut-off Value of 20 Units/Milliliter (U/mL). [At Month 5 (Three months after Dose 2 of HRV vaccine)]: Immunogenicity was assessed in terms of seropositivity against Rota virus IgA antibodies. The cut off used was ≥ 20 U/mL.
• Number of Seropositive Subjects With Anti-RV IgA Antibody Concentrations Above or Equal to Cut-off Value of 90 U/mL. [At Month 5 (Three months after Dose 2 of HRV vaccine)]: Immunogenicity was assessed in terms of seropositivity against Rota virus IgA antibodies. The cut off used was ≥ 90 U/mL.
• Number of Seropositive Subjects With Anti-PT, Anti-FHA and Anti-PRN Antibody Concentrations Above or Equal to Cut-off Value. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Immunogenicity was assessed using ELISA technique in terms of seropositivity against PT, FHA and PRN antibodies. The cut-offs for antibodies were the Lower Limit Of Quantification (LLOQ) of the assays which were ≥ 2.693 IU/mL (anti-PT), ≥ 2.046 IU/mL (anti-FHA) and ≥ 2.187 IU/mL (anti-PRN). The Limit of Quantification is the lowest analyte concentration that can be quantitatively detected with a stated accuracy and precision, and LLOQ is the lowest standard curve point obtained by extrapolation, that can still be used for quantification.
• Number of Seropositive Subjects With Anti-PnPS Antibody Concentrations Above or Equal to Cut-off Value. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Immunogenicity was assessed using ELISA technique in terms of seropositivity against Pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) antibodies. The cut-off used was ≥ 0.35 µg/mL.
• Immunogenicity in Terms of Anti-D and Anti-T Antibody Concentrations. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Antibody concentrations against diphtheria and tetanus were determined and expressed as GMCs. The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations.
• Immunogenicity in Terms of Anti-PRP Antibody Concentrations. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Antibody concentrations against PRP were determined and expressed as GMCs. The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations.
• Immunogenicity in Terms of Anti-HBs Antibody Concentrations. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Antibody concentrations against Hepatitis B were determined and expressed as GMCs. The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations.
• Immunogenicity in Terms of Anti-poliovirus Types 1, 2 and 3 Antibody Titers. [At Month 5 (One month after Dose 3 of co-administered vaccines)]: Antibody concentrations against Poliovirus types 1, 2 and 3 were determined and expressed as Geometric Mean Titers (GMTs).
• Number of Subjects With Any Solicited General Adverse Events (AEs). [During the 8-day (Days 1-8) follow-up period after each HRV vaccination.]: Assessed solicited general AEs were cough/runny nose; diarrhoea; fever measured by 3 routes which were oral, axillary and rectal, defined as temperature ≥ 38.0 degrees Celsius (°C); irritability; loss of appetite and vomiting. Any = any solicited general AE irrespective of its intensity grade and relationship to vaccination
• Number of Subjects With Any Unsolicited AEs. [During the 31-day (Days 1-31) follow-up period after each HRV vaccination.]: Unsolicited AEs assessed include any AE reported in addition to those solicited during the clinical study. Also any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms were reported as an unsolicited AE. Any= Any unsolicited AE irrespective of its intensity grade and relationship to vaccination.
• Number of Subjects With Any Serious Adverse Events (SAEs). [During the entire study period (Day 1 to Month 10)]: SAEs assessed include any untoward medical occurrence that resulted in death, were life-threatening, required hospitalization or prolongation of existing hospitalization or resulted in disability/incapacity.

Sex: All, ages: 6 Weeks to 12 Weeks, accepts healthy volunteers

Inclusion Criteria:

* Subjects' parent(s)/\[LAR(s)\] who, in the opinion of the investigator can and will comply with the requirements of the protocol.
* A male or female between, and including, 6 and 12 weeks (42-90 days) of age at the time of the first study vaccination.
* Written or witnessed/thumb printed informed consent obtained from the parent(s)/LAR(s) of the subject prior to performing any study specific procedure.
* Healthy subjects as established by medical history and clinical examination before entering into the study.

Exclusion Criteria:

* Child in care.
* Use of any investigational or non-registered product other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day-29 to Day 1), or planned use during the study period.
* Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs since birth. For corticosteroids, this will mean prednisone (≥0.5 mg/kg/day, or equivalent). Inhaled and topical steroids are allowed.
* Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period.
* Administration of long-acting immune-modifying drugs at any time during the study period.
* Planned administration/administration of a vaccine not foreseen by the study protocol within the period starting 30 days before the first dose of vaccine administration and ending at Visit 4, with the exception of the inactivated influenza vaccine, which is allowed at any time during the study, if administered at a site which is different from the sites used to administer the co-administered vaccines.
* Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product.
* Uncorrected congenital malformation of the gastrointestinal tract that would predispose for Intussusception (IS).
* History of IS.
* Very prematurely born infants (born ≤28 weeks of gestation).
* Family history of congenital or hereditary immunodeficiency.
* Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
* Major congenital defects or serious chronic illness.
* Previous vaccination against Haemophilus type b (Hib), diphtheria, tetanus, pertussis, pneumococcus, RV and/or poliovirus.
* Previous confirmed occurrence of RV GE, Hib, diphtheria, tetanus, pertussis, pneumococcus, hepatitis B and/or polio disease.
* Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
* GE within 7 days preceding the study vaccine administration.
* History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.
* Hypersensitivity to latex.
* History of any neurological disorders or seizures.
* History of Severe combined immunodeficiency (SCID).
* Acute disease and/or fever at the time of enrolment.

  * Fever is defined as temperature ≥38.0°C/100.4°F. The preferred location for measuring temperature in this study will be the oral cavity, the axilla and the rectum.
  * Subjects with a minor illness without fever may be enrolled at the discretion of the investigator.

Participant flow

Outcome results

• Number of Seroprotected Subjects With Anti-diphtheria (Anti-D) and Anti-tetanus (Anti-T) Antibody Concentrations Above or Equal to Cut-off Value. (Primary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 478; HRV Lyophilized Group 486
• Number of Seroprotected Subjects With Anti-hepatitis B (Anti-HBs) Antibody Concentrations Above or Equal to Cut-off Value. (Primary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 457; HRV Lyophilized Group 471
• Number of Seroprotected Subjects With Anti-polio Virus Types 1, 2 and 3 Antibody Titers Above or Equal to Cut-off Value. (Primary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 477; HRV Lyophilized Group 486
• Immunogenicity in Terms of Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Hemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibody Concentrations. (Primary), Geometric mean, IU/mL: HRV Porcine Circovirus (PCV)-Free Liquid Group 51 (47.8 to 54.5); HRV Lyophilized Group 54.2 (51.3 to 57.4)
• Immunogenicity in Terms of Anti-pneumococcal Serotypes (Anti-PnPS) Antibody Concentrations. (Primary), Geometric mean, µg/mL: HRV Porcine Circovirus (PCV)-Free Liquid Group 1.95 (1.81 to 2.10); HRV Lyophilized Group 1.89 (1.76 to 2.03)
• Number of Seroprotected Subjects With Anti-polyribosyl Ribitol Phosphate (Anti-PRP) Antibody Concentrations Above or Equal to Cut-off Value of 0.15 µg/mL. (Primary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 473; HRV Lyophilized Group 479
• Number of Seroprotected Subjects With Anti-polyribosyl Ribitol Phosphate (Anti-PRP) Antibody Concentrations Above or Equal to Cut-off Value of 1.0 µg/mL. (Primary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 394; HRV Lyophilized Group 404
• Number of Subjects With Seroresponse to Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Hemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibodies. (Primary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 440; HRV Lyophilized Group 470 (p <.0001)
• Number of Seropositive Subjects With Anti-Rota Virus Immunoglobulin A (Anti-RV IgA) Antibody Concentrations Above or Equal to Cut-off Value of 20 Units/Milliliter (U/mL). (Secondary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 318; HRV Lyophilized Group 336
• Number of Seropositive Subjects With Anti-RV IgA Antibody Concentrations Above or Equal to Cut-off Value of 90 U/mL. (Secondary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 219; HRV Lyophilized Group 238
• Number of Seropositive Subjects With Anti-PT, Anti-FHA and Anti-PRN Antibody Concentrations Above or Equal to Cut-off Value. (Secondary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 485; HRV Lyophilized Group 495
• Number of Seropositive Subjects With Anti-PnPS Antibody Concentrations Above or Equal to Cut-off Value. (Secondary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 442; HRV Lyophilized Group 463
• Immunogenicity in Terms of Anti-D and Anti-T Antibody Concentrations. (Secondary), Geometric mean, IU/mL: HRV Porcine Circovirus (PCV)-Free Liquid Group 1.85 (1.72 to 1.98); HRV Lyophilized Group 1.88 (1.75 to 2.02)
• Immunogenicity in Terms of Anti-PRP Antibody Concentrations. (Secondary), Geometric mean, µg/mL: HRV Porcine Circovirus (PCV)-Free Liquid Group 4.41 (3.82 to 5.09); HRV Lyophilized Group 4.28 (3.71 to 4.94)
• Immunogenicity in Terms of Anti-HBs Antibody Concentrations. (Secondary), Geometric mean, mIU/mL: HRV Porcine Circovirus (PCV)-Free Liquid Group 2031.3 (1834.6 to 2249.0); HRV Lyophilized Group 2168.9 (1977.5 to 2378.9)
• Immunogenicity in Terms of Anti-poliovirus Types 1, 2 and 3 Antibody Titers. (Secondary), Geometric mean, Titers: HRV Porcine Circovirus (PCV)-Free Liquid Group 747.2 (673.5 to 828.8); HRV Lyophilized Group 728.2 (656.3 to 808.0)
• Number of Subjects With Any Solicited General Adverse Events (AEs). (Secondary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 172; HRV Lyophilized Group 180
• Number of Subjects With Any Unsolicited AEs. (Secondary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 294; HRV Lyophilized Group 327
• Number of Subjects With Any Serious Adverse Events (SAEs). (Secondary), Count of participants, Participants: HRV Porcine Circovirus (PCV)-Free Liquid Group 20; HRV Lyophilized Group 19

Adverse events

Time frame: Solicited AEs: During the 8-day (Day 1 to Day 8) follow-up period after each HRV vaccination. Unsolicited AEs: During the 31-day (Day 1 to Day 31) follow-up period after each HRV vaccination. SAEs: Throughout the study period (Day 1 to Month 10).

Serious adverse events by term

Other adverse events by term

145 more terms not shown.

• Study Protocol (PDF, 2016-10-27)
• Statistical Analysis Plan (PDF, 2017-08-01)

• GSK Clinical Trials, Study director, GlaxoSmithKline

NIH grants: 2016