Safety and Immunogenicity of GSK Meningococcal Group B Vaccine and 13-valent Pneumococcal Vaccine Administered Concomitantly With Routine Infant Vaccines to Healthy Infants

Infections, Meningococcal Clinical Trial

Official title:

Safety and Immunogenicity of GSK Meningococcal Group B Vaccine and 13-valent Pneumococcal Vaccine Administered Concomitantly With Routine Infant Vaccines to Healthy Infants

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03621670
• Other study ID #: 205239
• Secondary ID: 2016-003268-37V7
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 27, 2018
• Est. completion date: October 8, 2024

Study information

• Verified date: February 2024
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety and immunogenicity of Bexsero (meningococcal group B vaccine-rMenB+OMV NZ) in North American infants 6 weeks through 12 weeks of age, when administered concomitantly with Pneumococcal conjugate vaccine (PCV 13) and other recommended routine infant vaccines(RIV).

Description:

This study will be divided into 3 timepoints:

• Epoch 1- Primary- From Day 1 to Day 301

• Epoch 2-Secondary-From Day 301 to Day 331

• Epoch 3-Safety follow up -From Day 331 to study end (Day 481 or Day 661). For subjects who have not yet reached the 6-month safety follow-up after the last dose at the time protocol amendment 7 takes effect, Visit 7 will take place on Day 481.

In addition to receiving the study vaccines, infants will also receive non-study vaccines such as Diphtheria, tetanus toxoids and acellular pertussis adsorbed vaccine (DTPa, Infanrix) and Haemophilus influenzae type b Conjugate Vaccine (Hib, Hiberix), to ease the disruption to the standard infant vaccine schedule caused by participating in this study.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1200
• Est. completion date: October 8, 2024
• Est. primary completion date: October 8, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 6 Weeks to 12 Weeks

Eligibility

Inclusion Criteria:

All subjects must satisfy all the following criteria at study entry:

• Subjects' parent(s)/Legally Acceptable Representative(s) [LAR(s)] who, in the opinion of the investigator, can and will comply, with the requirements of the protocol (e.g. completion of the eDiary, return for follow-up visits).

• Written informed consent obtained from the parent(s)/LAR(s) of the subject prior to performing any study specific procedure.

• A male or female between, and including, 42 and 84 days of age (i.e., 6 through 12 weeks) at the time of the 1st vaccination.

• Healthy subjects as established by medical history and clinical examination before entering into the study.

• Born full-term (i.e. after a gestation period of = 38 weeks).

Exclusion Criteria:

If any exclusion criterion applies, the subject must not be included in the study:

• Child in care

Each subject must not have:

• Progressive, unstable or uncontrolled clinical conditions.

• Hypersensitivity, including allergy to any component of vaccines, medicinal product or medical equipment whose use is foreseen in this study.

• Hypersensitivity to latex.

• Clinical conditions representing a contraindication to intramuscular vaccination and blood draws.

• Abnormal function of the immune system resulting from:

• Clinical conditions.

• Systemic administration of corticosteroids (PO/IV/IM) for more than 14 consecutive days from birth.

• Administration of antineoplastic and immunomodulating agents or radiotherapy for any duration from birth.

• Autoimmune disorders (including, but not limited to: blood, endocrine, hepatic, muscular, nervous system or skin autoimmune disorders; lupus erythematosus and associated conditions; rheumatoid arthritis and associated conditions; scleroderma and associated disorders) or immunodeficiency syndromes (including, but not limited to: acquired immunodeficiency syndromes and primary immunodeficiency syndromes).

• Received immunoglobulins or any blood products from birth.

• Received an investigational or non-registered medicinal product from birth.

• Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the subject due to participation in the study.

• Neuroinflammatory disorders (including but not limited to: demyelinating disorders, encephalitis or myelitis of any origin), congenital and peripartum neurological conditions, encephalopathies, seizures (including all subtypes such as: absence seizures, generalised tonic-clonic seizures, partial complex seizures, partial simple seizures or febrile convulsions).

• Congenital or peripartum disorders resulting in a chronic condition (including but not limited to: chromosomal abnormalities, cerebral palsy, metabolism or synthesis disorders, cardiac disorders).

• Study personnel as an immediate family or household member.

• Current or previous, confirmed or suspected disease caused by N. meningitidis

• Household contact with and/or intimate exposure from birth to an individual with laboratory confirmed N. meningitidis and/or Streptococcus pneumoniae infection or colonization.

• Previous administration of meningococcal B or pneumococcal vaccine at any time prior to informed consent.

• Received a dose of DTPa-HBV-IPV, HRV, MMR, VV and/or Hib at any time prior to informed consent. Receipt of one dose of HBV up to 4 weeks prior to informed con-sent is allowed.

• Serious chronic illness.

• Uncorrected congenital malformation (such as Meckel's diverticulum) of the gastrointestinal tract that would predispose for Intussusception (IS).

Related Conditions & MeSH terms

• Infections, Meningococcal
• Meningococcal Infections

Intervention

Biological:
• Bexsero (GSK Biologicals' Meningococcal group-B vaccine/ rMenB+OMV NZ)
Bexsero is to be administered intramuscularly on upper side of the right thigh as a 4-dose schedule on Visit 1 (Day 1), Visit 2 (Day 61), Visit 3 (Day 121) and Visit 5 (Day 301) to all subjects in the MenB+PCV group.
• Prevnar13
Prevnar13 (PCV13) is to be administered intramuscularly on upper side of the left thigh as a 4-dose schedule on Visit 1 (Day 1), Visit 2 (Day 61), Visit 3 (Day 121) and Visit 5 (Day 301) to all subjects in the MenB+PCV group and Placebo+PCV group.
• Pediarix
Pediarix (DTPa-HBV-IPV) is to be administered intramuscularly on lower side of the left thigh as a 3-dose schedule on Visit 1 (Day 1), Visit 2 (Day 61) and Visit 3 (Day 121) to all subjects in the MenB+PCV group and Placebo+PCV group.
• Hiberix
Hiberix (Hib) is to be administered intramuscularly on lower side of the right thigh as a 3-dose schedule on Visit 1 (Day 1), Visit 2 (Day 61) and Visit 3 (Day 121) to all subjects in the MenB+PCV group and Placebo+PCV group.
• Rotarix
Rotarix (HRV) is to be administered orally as a 2-dose schedule on Visit 1 (Day 1), Visit 2 (Day 61) to all subjects in the MenB+PCV group and Placebo+PCV group.
• M-M-R II
M-M-R II (MMR) is to be administered subcutaneously on upper side of the right arm as a single dose on Visit 5 (Day 301) to all subjects in the MenB+PCV group and Placebo+PCV group.
• Varivax
Varivax (VV) is to be administered subcutaneously on upper side of the left arm as a single dose on Visit 5 (Day 301) to all subjects in the MenB+PCV group and Placebo+PCV group.
• Placebo (saline water)
Placebo is to be administered intramuscularly on upper side of the right thigh as a 4-dose schedule on Visit 1 (Day 1), Visit 2 (Day 61), Visit 3 (Day 121) and Visit 5 (Day 301) to all subjects in the Placebo+PCV group.
• Prevnar 20
Prevnar 20 (PCV13) is to be administered intramuscularly as a booster dose on Visit 5 (Day 301) to all subjects in the MenB+PCV group and Placebo+PCV group who have received 3 PCV13 doses before 12 months of age but have not received their fourth booster dose.

Locations

Country	Name	City	State
Puerto Rico	GSK Investigational Site	San Juan
United States	GSK Investigational Site	Anaheim	California
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Bardstown	Kentucky
United States	GSK Investigational Site	Beaumont	Texas
United States	GSK Investigational Site	Bingham Farms	Michigan
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Boone	North Carolina
United States	GSK Investigational Site	Bryan	Texas
United States	GSK Investigational Site	Charleston	South Carolina
United States	GSK Investigational Site	Charleston	South Carolina
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Clarksville	Tennessee
United States	GSK Investigational Site	Daly City	California
United States	GSK Investigational Site	Dayton	Ohio
United States	GSK Investigational Site	Dayton	Ohio
United States	GSK Investigational Site	Fairfield	Ohio
United States	GSK Investigational Site	Fall River	Massachusetts
United States	GSK Investigational Site	Hermitage	Pennsylvania
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Jonesboro	Arkansas
United States	GSK Investigational Site	Kansas City	Missouri
United States	GSK Investigational Site	Kingsport	Tennessee
United States	GSK Investigational Site	La Vista	Nebraska
United States	GSK Investigational Site	Lake Mary	Florida
United States	GSK Investigational Site	Layton	Utah
United States	GSK Investigational Site	Lincoln	Nebraska
United States	GSK Investigational Site	Liverpool	New York
United States	GSK Investigational Site	Louisville	Kentucky
United States	GSK Investigational Site	Louisville	Kentucky
United States	GSK Investigational Site	Louisville	Kentucky
United States	GSK Investigational Site	Marshfield	Wisconsin
United States	GSK Investigational Site	McAllen	Texas
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Nampa	Idaho
United States	GSK Investigational Site	Nampa	Idaho
United States	GSK Investigational Site	Newton	Kansas
United States	GSK Investigational Site	Oakland	California
United States	GSK Investigational Site	Orem	Utah
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Provo	Utah
United States	GSK Investigational Site	Raleigh	North Carolina
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Roseville	California
United States	GSK Investigational Site	Roy	Utah
United States	GSK Investigational Site	Salt Lake City	Utah
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	Sioux Falls	South Dakota
United States	GSK Investigational Site	South Euclid	Ohio
United States	GSK Investigational Site	Spokane	Washington
United States	GSK Investigational Site	Syracuse	Utah
United States	GSK Investigational Site	Syracuse	New York
United States	GSK Investigational Site	Tampa	Florida
United States	GSK Investigational Site	Topeka	Kansas
United States	GSK Investigational Site	Walnut Creek	California
United States	GSK Investigational Site	West Covina	California

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentages of subjects with solicited local (administration site event) and systemic Adverse Events (AEs)	Assessed solicited local AEs are hardness and swelling of the skin and redness, tenderness or discomfort to touch at injection site.; Assessed solicited systemic AEs are decreased eating, increased sleepiness, vomiting/throwing up, loose stools/diarrhea, irritability, persistent/continuous crying and fever, defined as body temperature greater than or equal to (=)38.0°C/100.4°F.; Each solicited local and systemic AE are summarized as "any". Any=Occurrence of the solicited local/systemic AE regardless of the intensity grade.	During the 7-day follow-up period after the 1st vaccination
Primary	Percentages of subjects with solicited local (administration site event) and systemic AEs	Assessed solicited local AEs are hardness and swelling of the skin and redness, tenderness or discomfort to touch at injection site.; Assessed solicited systemic AEs are decreased eating, increased sleepiness, vomiting/throwing up, loose stools/diarrhea, irritability, persistent/continuous crying and fever, defined as body temperature =38.0°C/100.4°F.; Each solicited local and systemic AE are summarized as "any". Any=Occurrence of the solicited local/systemic AE regardless of the intensity grade.	During the 7-day follow-up period after the 2nd vaccination
Primary	Percentages of subjects with solicited local (administration site event) and systemic AEs	Assessed solicited local AEs are hardness and swelling of the skin and redness, tenderness or discomfort to touch at injection site.; Assessed solicited systemic AEs are decreased eating, increased sleepiness, vomiting/throwing up, loose stools/diarrhea, irritability, persistent/continuous crying and fever, defined as body temperature =38.0°C/100.4°F.; Each solicited local and systemic AE are summarized as "any". Any=Occurrence of the solicited local/systemic AE regardless of the intensity grade.	During the 7-day follow-up period after the 3rd vaccination
Primary	Percentages of subjects with solicited local (administration site event) and systemic AEs	Assessed solicited local AEs are hardness and swelling of the skin and redness, tenderness or discomfort to touch at injection site.; Assessed solicited systemic AEs are decreased eating, increased sleepiness, vomiting/throwing up, loose stools/diarrhea, irritability, persistent/continuous crying and fever, defined as body temperature =38.0°C/100.4°F.; Each solicited local and systemic AE are summarized as "any". Any=Occurrence of the solicited local/systemic AE regardless of the intensity grade.	During the 7-day follow-up period after the 4th vaccination
Primary	Percentages of subjects with solicited systemic AEs	For MMR and VV-specific solicited systemic AEs assessed are parotid/salivary gland swelling, fever and rash and are summarized. Each solicited systemic AE are further summarized as "any". "Any" = Occurrence of the solicited systemic AE regardless of intensity grade.	During the 30-day (Day 1 - Day 30) follow-up period after the 4th vaccination
Primary	Percentages of subjects with all unsolicited AEs	An unsolicited AEs is an AE that is not solicited using a subject diary and that is spontaneously communicated by the parent(s)/LAR(s) who has signed the informed consent or a solicited local or systemic AE that continues beyond the solicited period after vaccination.; Assessed unsolicited AEs include serious adverse events (SAEs), AEs leading to withdrawal, AEs of special interest (AESIs), and medically attended AEs.	During the 30-day follow-up period after the 1st vaccination
Primary	Percentages of subjects with all unsolicited AEs	An unsolicited AEs is an AE that is not solicited using a subject diary and that is spontaneously communicated by the parent(s)/LAR(s) who has signed the informed consent or a solicited local or systemic AE that continues beyond the solicited period after vaccination.; Assessed unsolicited AEs include serious adverse events (SAEs), AEs leading to withdrawal, AEs of special interest (AESIs), and medically attended AEs.	During the 30-day follow-up period after the 2nd vaccination
Primary	Percentages of subjects with all unsolicited AEs	An unsolicited AEs is an AE that is not solicited using a subject diary and that is spontaneously communicated by the parent(s)/LAR(s) who has signed the informed consent or a solicited local or systemic AE that continues beyond the solicited period after vaccination.; Assessed unsolicited AEs include serious adverse events (SAEs), AEs leading to withdrawal, AEs of special interest (AESIs), and medically attended AEs.	During the 30-day follow-up period after the 3rd vaccination
Primary	Percentages of subjects with all unsolicited AEs	An unsolicited AEs is an AE that is not solicited using a subject diary and that is spontaneously communicated by the parent(s)/LAR(s) who has signed the informed consent or a solicited local or systemic AE that continues beyond the solicited period after vaccination.; Assessed unsolicited AEs include serious adverse events (SAEs), AEs leading to withdrawal, AEs of special interest (AESIs), and medically attended AEs.	During the 30-day follow-up period after the 4th vaccination
Primary	Percentages of subjects with SAEs, AEs leading to withdrawal, AESIs and medically attended AEs	A SAE is any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization and that results in disability/incapacity.; An AE leading to withdrawal includes any AEs/SAEs collected and recorded from the time of the 1st receipt of study vaccines until study end which are identified as reasons for withdrawal of the subject from the study.; Adverse events of special interest (AESIs) are pre-defined (serious or non-serious) AEs of scientific and medical concern specific to the product or program which might warrant further investigation in order to characterize and understand it.; A medically attended AE includes any AEs that requires medical visit.	Throughout the study period [Day 1 up to study end (Day 481 or Day 661)]
Primary	Percentages of subjects with human serum bactericidal assay (hSBA) antibody titers = Lower Limit of Quantitation (LLOQ) for each of the M14459, 96217, NZ98/254 and M13520 test strains	The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520 respectively. Each of these strains measures bactericidal activity primarily directed against one of the major bactericidal antigens included in the vaccine.; The sufficiency of the immune response to rMenB+OMV NZ at 1 month after the 3rd vaccination is demonstrated if the adjusted lower confidence limit for the percentage of subjects achieving hSBA titers =LLOQ is =60% for the N. meningitidis serogroup B test strains M14459, 96217, NZ98/254, M13520 (individually).	At 1 month after the 3rd vaccination (Day 151)
Primary	Percentages of subjects with hSBA antibody titers =LLOQ for all strains combined (M14459, 96217, NZ98/254 and M13520)	The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520 respectively. Each of these strains measures bactericidal activity primarily directed against one of the major bactericidal antigens included in the vaccine.; The sufficiency of the immune response to rMenB+OMV NZ at 1 month after the 3rd vaccination is demonstrated if the adjusted lower confidence limit for the percentage of subjects achieving hSBA titers =LLOQ is = 50% for all strains combined (composite endpoint).	At 1 month after the 3rd vaccination (Day 151)
Primary	Percentages of subjects with hSBA titers = 8 (for strains M14459, NZ98/254, M13520) and =16 (for strain 96217) for each of the test strains	The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520 respectively. Each of these strains measures bactericidal activity primarily directed against one of the major bactericidal antigens included in the vaccine.; The sufficiency of the immune response to rMenB+OMV NZ is demonstrated if the adjusted lower confidence limit for the percentage of subjects with hSBA titers = 8 (for strains M14459, NZ98/254, M13520) and =16 (for strain 96217) is =75% for the individual N. meningitidis serogroup B test strains.	At 1 month after the 4th vaccination (Day 331)
Primary	Percentages of subjects with hSBA titers = 8 (for strains M14459, NZ98/254, M13520) and =16 (for strain 96217) for all strains combined (composite endpoint)	The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520 respectively. Each of these strains measures bactericidal activity primarily directed against one of the major bactericidal antigens included in the vaccine.; The sufficiency of the immune response to rMenB+OMV NZ is demonstrated if the adjusted lower confidence limit for the percentage of subjects with hSBA titers = 8 (for strains M14459, NZ98/254, M13520) and =16 (for strain 96217) is =65% for all strains combined (composite endpoint).	At 1 month after the 4th vaccination (Day 331)
Primary	Antibody Geometric Mean Concentrations (GMC) using electrochemiluminescence (ECL) assay for each of the 13 PCV13 antigens	Pneumococcal serotype-specific immunoglobin G (IgG) antibodies is measured by validated multiplex assays (ECL1 and ECL2 assays).	At 1 month after the 3rd vaccination (Day 151)
Secondary	Antibody GMCs using ECL for each of the 13 PCV13 serotypes	Pneumococcal serotype-specific IgG antibodies is measured by validated multiplex assays (ECL1 and ECL2 assays).	At 1 month after the 4th vaccination (Day 331)
Secondary	Percentages of subjects with serum pneumococcal anti-capsular polysaccharide IgG =0.35 µg/mL	Pneumococcal serotype-specific IgG antibodies is measured by validated multiplex assays (ECL1 and ECL2 assays).	At one month after the 3rd vaccination (Day 151) and one month after 4th vaccination (Day 331)
Secondary	GMCs against 3 pertussis antigens (pertussis toxin [PT], pertactin [PRN], filamentous hemagglutinin [FHA])	Antibodies (IgG's) against the pertussis components PT, PRN and FHA having 2.693, 2.187, 2.046 assay cut-off, respectively. The antibodies GMCs are measured by Enzyme linked immunosorbent assay (ELISA) expressed as International Units per millilitre (IU/mL) to evaluate the immunogenicity of acellular B. pertussis containing vaccines. The seropositivity for all 3 pertussis antibodies is based on new respective ELISA cut-off, where subjects with antibody concentration below the cut-off being considered seronegative.; For the analysis of the immune responses to the Routine Infant Vaccine (RIV) antigens, subjects in each of the 2 study groups are randomly assigned to different immunogenicity subsets. The assignment of the immunogenicity subsets are performed by a second randomization, whereas the first randomization is performed at the enrolment to assign subjects to Group MenB+PCV or Group Placebo+PCV.	At 1 month after the 3rd vaccination (Day 151)
Secondary	Percentages of subjects with antibodies concentrations against hepatitis B surface antigen (AntiHBsAg) =10 mIU/mL	Antibodies against the anti-HBs are measured using a ChemiLuminescence ImmunoAssay (CLIA) expressed as milli-international units per millilitre. The cut-off of the test has been set at 6.2 mIU/mL. An antibody concentration =10 mIU/mL defines seroprotection.; For the analysis of the immune responses to the Routine Infant Vaccine (RIV) antigens, subjects in each of the 2 study groups are randomly assigned to different immunogenicity subsets. The assignment of the immunogenicity subsets are performed by a second randomization, whereas the first randomization is performed at the enrolment to assign subjects to Group MenB+PCV or Group Placebo+PCV.	At 1 month after the 3rd vaccination (Day 151)
Secondary	Percentages of subjects with anti-diphtheria and anti-tetanus antibody concentrations =0.1 IU/mL	Specific antibodies against diphtheria toxoid (anti-diphtheria IgG's) and tetanus toxoid (anti-tetanus IgG's) are measured by ELISA. The clinical acceptable cut-off of ELISA was set at 0.1 IU/mL, which provided a conservative estimate of the percentage of subjects deemed to be protected.; For the analysis of the immune responses to the Routine Infant Vaccine (RIV) antigens, subjects in each of the 2 study groups are randomly assigned to different immunogenicity subsets. The assignment of the immunogenicity subsets is performed by a second randomization, whereas the first ran-domization is performed at the enrolment to assign subjects to Group MenB+PCV or Group Placebo+PCV.	At 1 month after the 3rd vaccination (Day 151)
Secondary	Percentages of subjects with anti-polyribosyl-ribitol phosphate (PRP) concentration =0.15 µg/mL and =1 µg/mL	Concentrations of IgG antibodies against the Hib polysaccharide PRP is measured by ELISA. An immunological correlate of protection has been established when anti-PRP concentrations =0.15 µg/mL.; For the analysis of the immune responses to the Routine Infant Vaccine (RIV) antigens, subjects in each of the 2 study groups are randomly assigned to different immunogenicity subsets. The assignment of the immunogenicity subsets are performed by a second randomization, whereas the first randomization is performed at the enrolment to assign subjects to Group MenB+PCV or Group Placebo+PCV.	At 1 month after the 3rd vaccination (Day 151)
Secondary	GMCs for anti-Varicella (VV) antibodies	A suitable ELISA assay for analysis of anti-VV antibody concentrations is yet to be selected and/or developed. For the analysis of the immune responses to the Routine Infant Vaccine (RIV) antigens, subjects in each of the 2 study groups are randomly assigned to different immunogenicity subsets. The assignment of the immunogenicity subsets are performed by a second randomization, whereas the first randomization is performed at the enrolment to assign subjects to Group MenB+PCV or Group Placebo+PCV.	At 1 month after the 4th vaccination (Day 331)
Secondary	GMCs for anti-measles antibodies	A suitable ELISA assay for analysis of anti-measles virus antibody concentrations is yet to be selected and/or developed. For the analysis of the immune responses to the Routine Infant Vaccine (RIV) antigens, subjects in each of the 2 study groups are randomly assigned to different immunogenicity subsets. The assignment of the immunogenicity subsets are performed by a second randomization, whereas the first randomization is performed at the enrolment to assign subjects to Group MenB+PCV or Group Placebo+PCV.	At 1 month after the 4th vaccination (Day 331)
Secondary	GMCs for anti-mumps antibodies	A suitable ELISA assay for analysis of anti-mumps virus anti-body concentrations is yet to be selected and/or developed.; For the analysis of the immune responses to the Routine Infant Vaccine (RIV) antigens, subjects in each of the 2 study groups are randomly assigned to different immunogenicity subsets. The assignment of the immunogenicity subsets are performed by a second randomization, whereas the first randomization is performed at the enrolment to assign subjects to Group MenB+PCV or Group Placebo+PCV.	At 1 month after the 4th vaccination (Day 331)
Secondary	GMCs for anti-rubella antibodies	A suitable ELISA assay for analysis of anti-rubella virus antibody concentrations is yet to be selected and/or developed.; For the analysis of the immune responses to the Routine Infant Vaccine (RIV) antigens, subjects in each of the 2 study groups are randomly assigned to different immunogenicity subsets. The assignment of the immunogenicity subsets are performed by a second randomization, whereas the first randomization is performed at the enrolment to assign subjects to Group MenB+PCV or Group Placebo+PCV.	At 1 month after the 4th vaccination (Day 331)
Secondary	Percentages of subjects with hSBA antibody titers =5 and =8 and =16 for each of the M14459, 96217, NZ98/254 and M13520 test strains	The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520. The number of subjects having antibody titers =5, and =8 and =16 for each of the strains are presented.; Each of these strains measures bactericidal activity primarily directed against one of the major bactericidal antigens included in the vaccine.	At 1 month after the 3rd vaccination (Day 151)
Secondary	Percentages of subjects with hSBA antibody titers =5 and =8 for each of the M14459, 96217, NZ98/254 and M13520 test strains	The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520. The number of subjects having antibody titers =5 and =8 for each of the strains are presented.; Each of these strains measures bactericidal activity primarily directed against one of the major bactericidal antigens included in the vaccine.	At 6 months after the 3rd vaccination (Day 301)
Secondary	Percentages of subjects with hSBA antibody titers =5 for each of the M14459, 96217, NZ98/254 and M13520 test strains	The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520. The number of subjects having antibody titers =5 for each of the strains are presented.; Each of these strains measures bactericidal activity primarily directed against one of the major bactericidal antigens included in the vaccine.	At 1 month after the 4th vaccination (Day 331)
Secondary	hSBA Geometric Mean Titers for the M14459, 96217, NZ98/254 and M13520 test strains	Serum antibody titers are presented as hSBA GMTs.The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520. The GMTs calculated is described for the four strains.	At 1 month after the 3rd vaccination (Day 151) and 6 months after 3rd vaccination (Day 301) and 1 month after 4th vaccination (Day 331)
Secondary	Percentages of subjects with hSBA antibody titers =LLOQ for each of the M14459, 96217, NZ98/254 and M13520 test strains	The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520 respectively.; Each of these strains measures bactericidal activity primarily directed against one of the major bactericidal antigens included in the vaccine.	At 6 months after the 3rd vaccination (Day 301) and 1 month after 4th vaccination (Day 331)
Secondary	hSBA Geometric Mean Ratios (GMR) of GMTs over pre 4th vaccination for the M14459, 96217, NZ98/254 and M13520 test strains	The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520. The GMR calculated at one month post 4th vaccination versus pre-4th vaccination is described for the four strains.	At 1 month after the 4th vaccination (Day 331) versus pre-4th vaccination (Day 301)
Secondary	Percentages of subjects with 4-fold rise in hSBA titers (from pre-4th vaccination) for each of the M14459, 96217, NZ98/254 and M13520 test strains	The 4 selected meningococcal B strains are M14459, 96217, NZ98/254 and M13520 respectively.; A 4-fold rise in hSBA titers is defined as: if pre-vaccination titer < LOD, then a post-vaccination titer = 4 times the LOD or = LLOQ, whichever is greater; if pre-vaccination titer is =LOD but if pre-vaccination titer is =LLOQ, then a post-vaccination titer =4 times the pre-vaccination titer, where pre-vaccination titer=pre-4th dose titers (Day 301).	At 1 month after the 4th vaccination (Day 331)
Secondary	Percentages of subjects with anti-HBs antibody concentrations =100 mIU/mL	Antibodies against the anti-HBs are measured using CLIA expressed as milli-international units per millilitre. The cut-off of the test has been set at 6.2 mIU/mL. An antibody concentration =10 mIU/mL defines seroprotection.	At 1 month after the 3rd vaccination (Day 151)
Secondary	GMCs for Anti-HBsAg antibodies	Antibodies against the anti-HBs is measured using CLIA. The cut-off of the test has been set at 6.2 mIU/mL. An antibody concentration =10 mIU/mL defines seroprotection.	At 1 month after the 3rd vaccination (Day 151)
Secondary	Percentages of subjects with anti-diphtheria and anti-tetanus antibody concentrations =1 IU/mL	Specific antibodies against diphtheria toxoid (anti-diphtheria IgG's) and tetanus toxoid (anti-tetanus IgG's) are measured by ELISA. The clinical acceptable cut-off of ELISA was set at 0.1 IU/mL, which provided a conservative estimate of the percentage of subjects deemed to be protected.	At 1 month after the 3rd vaccination (Day 151)
Secondary	GMCs for anti-diphtheria and anti-tetanus antibodies	Specific antibodies against diphtheria toxoid (anti-diphtheria IgG's) and tetanus toxoid (anti-tetanus IgG's) are measured by ELISA. The clinical acceptable cut-off of ELISA was set at 0.1 IU/mL, which provided a conservative estimate of the percentage of subjects deemed to be protected.	At 1 month after the 3rd vaccination (Day 151)
Secondary	Percentages of subjects with anti-polio type 1, 2 and 3 neutralization antibody titers =8	Antibodies against poliovirus types 1, 2 and 3 are determined by a virus micro neutralization test. Titers are expressed in terms of the reciprocal of the dilution resulting in 50% inhibition (ED50TR). The assay cut-off for anti-polio 1, 2 and 3 is 8 ED50.	At 1 month after the 3rd vaccination (Day 151)
Secondary	Percentages of subjects showing seroresponse for anti-Varicella (VV), anti-measles virus, anti-mumps virus and anti-rubella virus antibodies	Seroresponse is defined as post-vaccination anti-VV virus, anti-measles virus, anti-mumps virus and anti-rubella virus antibody concentration = a protective threshold among subjects who were seronegative (antibody concentration A suitable ELISA assay for analysis of anti-VZV, anti-measles virus, anti-mumps virus and anti-rubella virus antibody concentrations is yet to be selected and/or developed.	At 1 month after the 4th vaccination (Day 331)