Percentages of subjects with solicited local 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.
Percentages of subjects with solicited local 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.
Percentages of subjects with solicited local 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.
Percentages of subjects with solicited local 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.
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.
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.
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.
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.
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.
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.
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).
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).
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.
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).
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).
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).
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 <LLOQ, then a post-vaccination titer ≥4 times the LLOQ;
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).
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.
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.
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.
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.
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.
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 <assay cut-off) before vaccination.
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.