Infections, Meningococcal
Conditions
Keywords
Meningitis, Immune response, Sufficiency, Neisseria meningitides, Bexsero
Brief 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 vaccinesv(RIV).
Detailed description
This study is divided into three timepoints: Epoch 1 - Primary: Day 1 to Day 301 Epoch 2 - Secondary: Day 301 to Day 331 Epoch 3 - Safety follow-up: Day 331 to the end of the study (Day 481 or Day 661). For participants who have not yet reached the 6-month safety follow-up after their last dose at the time Protocol Amendment 7 takes effect, visit 7 takes place on Day 481. In addition to receiving the study vaccines, infants 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 minimize disruption to the standard infant vaccination schedule caused by participation in this study. Participants receive rMenB+OMV NZ (Bexsero) concomitantly with PCV13 (Prevnar13) and other routine infant vaccines (Pediarix, Hiberix, Rotarix, M-M-R II, Varivax) at 2, 4, 6, and 12 months of age. Participants who have received three PCV13 doses before 12 months of age but have not yet received their fourth booster dose receive either PCV13 or PCV20 at 12 months of age (Visit 5).
Interventions
BIOLOGICALBexsero (GSK Biologicals' Meningococcal group-B vaccine/ rMenB+OMV NZ)
Bexsero was administered intramuscularly on Day 1, Day 61, Day 121 and Day 301.
BIOLOGICALPrevnar13
Prevnar13 (PCV13) was administered intramuscularly on Day 1, Day 61, Day 121 and Day 301.
BIOLOGICALPediarix
Pediarix (DTPa-HBV-IPV) was administered intramuscularly on Day 1, Day 61, and Day 121.
BIOLOGICALHiberix
Hiberix (Hib) was administered intramuscularly on Day 1, Day 61, and Day 121.
BIOLOGICALRotarix
Rotarix (HRV) was administered intramuscularly on Day 1 and Day 61.
BIOLOGICALM-M-R II
M-M-R II (MMR) was administered intramuscularly on Day 301.
BIOLOGICALVarivax
Varivax (VV) was administered intramuscularly on Day 301.
BIOLOGICALPlacebo (saline water)
Placebo was administered intramuscularly on Day 1, Day 61, Day 121 and Day 301.
BIOLOGICALPrevnar 20
Prevnar 20 (PCV13) was administered intramuscularly as a booster dose on Day 301 group who have received 3 PCV13 doses before 12 months of age but have not received their fourth booster dose.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Observer-blind study Data are collected in an observer-blind manner. Observer-blind means that throughout the study, the participant/parent/caregiver, as well as site and sponsor personnel involved in the clinical evaluation of participants, are blinded, while other study personnel are aware of the treatment assignment. To maintain this blinding, authorized medical personnel prepare and administer the vaccines but do not participate in any clinical evaluation assays or procedures. Serological data that could lead to unblinding of the study groups are not available during the study to any investigator or personnel involved in the clinical conduct of the study. The laboratory responsible for the testing is blinded to the treatment, participant, and visit number, and uses coded identifiers to link the participant, visit, and study to each sample.
Eligibility
Sex/Gender
ALL
Age
6 Weeks to 12 Weeks
Healthy volunteers
Yes
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Any Solicited Administration Site Events After the First Vaccination Administered at Day 1 | Day 1 to Day 7 | Assessed solicited administration site events include injection site tenderness (administration site pain), erythema (redness), swelling and induration. Any solicited administration site events = occurrence of the event regardless of intensity grade. Rotarix was administered orally; therefore, no administration site events were analyzed. |
| Number of Participants Reporting Any Solicited Systemic Events After the First Vaccination Administered at Day 1 | Day 1 to Day 7 | Assessed systemic events include change in eating habits, sleepiness, vomiting, diarrhea, irritability, persistent crying, and fever, defined as body temperature greater than or equal to (≥)38.0°C/100.4°F. Any solicited systemic events = occurrence of the event regardless of intensity grade. |
| Number of Participants Reporting Any Solicited Administration Site Events After the Second Vaccination Administered at Day 61 | Day 61 to Day 67 | Rotarix was administered orally; therefore, no administration site events were analyzed. |
| Number of Participants Reporting Any Solicited Systemic Events After the Second Vaccination Administered at Day 61 | Day 61 to Day 67 | — |
| Number of Participants Reporting Any Solicited Administration Site Events After the Third Vaccination Administered at Day 121 | Day 121 to Day 127 | — |
| Number of Participants Reporting Any Solicited Systemic Events After the Third Vaccination Administered at Day 121 | Day 121 to Day 127 | — |
| Number of Participants Reporting Any Solicited Administration Site Events After the Fourth Vaccination Administered at Day 301 | Day 301 to Day 307 | — |
| Number of Participants Reporting Any Solicited Systemic Events After the Fourth Vaccination Administered at Day 301 | Day 301 to Day 307 | — |
| Number of Participants With Any Solicited Systemic AEs During the 30 Days After the Fourth Vaccination at Day 301 | Day 301 to Day 330 | Systemic events assessed included rash, parotid/salivary gland swelling, and fever. These systemic adverse events were recorded for 30 days following MMR and VV vaccine administration. Any solicited systemic events = occurrence of the event regardless of intensity grade. |
| Number of Participants Reporting Any Unsolicited Adverse Events (AEs) After the First Vaccination Administered at Day 1 | Day 1 to Day 30 | 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. Any = occurrence of the event regardless of the intensity grade. |
| Number of Participants Reporting Any Unsolicited AEs After the Second Vaccination Administered at Day 61 | Day 61 to Day 90 | — |
| Number of Participants Reporting Any Unsolicted AEs After the Third Vaccination Administered at Day 121 | Day 121 to Day 150 | — |
| Number of Participants Reporting Any Unsolicited AEs After the Fourth Vaccination Administered at Day 301 | Day 301 to Day 330 | — |
| Number of Participants Reporting Any SAEs, AEs Leading to Withdrawal, AESIs and MAAEs | Day 1 up to study end (Day 481 for participants who have not reached 6-month follow-up at the time of Protocol Amendment 7; Day 661 for all others) | An 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 participant from the study. 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. MAAEs includes any AEs that required hospitalization, or an otherwise unscheduled visit to or from medical personnel for any reason, including emergency room visits. |
| Percentage of Participants With Human Serum Bactericidal Assay (hSBA) Antibody Titers >= Lower Limit of Quantitation (LLOQ) for Each of the Serogroup B Test Strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4) and M13520 (NHBA) | At Day 151 (1 month after the third vaccination) | Serum bactericidal activity is assessed using human complement (hSBA) against Neisseria meningitidis serogroup B test strains: M14459 (fHbp); 96217 (NadA); NZ98/254 (PorA P1.4); M13520 (NHBA). The sufficiency of the immune response to rMenB+OMV NZ at one month after the third vaccination was to be demonstrated if the lower confidence limit for the percentage of participants achieving hSBA titers ≥ LLOQ is ≥ 60% for each of the M14459, 96217, NZ98/254, M13520 test strain. This outcome measure evaluated immune response to the rMenB+OMV NZ vaccine only, hence it was not applicable to the Placebo+PCV group. |
| Percentage of Participants With hSBA Titers >= LLOQ Against All Serogroup B Test Strains Combined (Composite Response) | At Day 151 (1 month after the third vaccination) | The immune response to the rMenB+OMV NZ vaccine is assessed by measuring serum bactericidal activity using hSBA against four Neisseria meningitidis serogroup B test strains: M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4), and M13520 (NHBA). The composite response is defined as the percentage of participants with hSBA titers ≥ Lower Limit of Quantitation (LLOQ) across all four strains combined. The sufficiency of the immune response to rMenB+OMV NZ at one month after the third vaccination was to be demonstrated if the lower confidence limit for the percentage of participants achieving hSBA titers ≥ LLOQ is ≥ 50% for all strains combined. This outcome measure evaluated immune response to the rMenB+OMV NZ vaccine only, hence it was not applicable to the Placebo+PCV group. |
| Percentage of Participants With hSBA Antibody Titers >= 8 for Strains M14459 (fHbp); 96217 (NadA); NZ98/254 (PorA P1.4); M13520 (NHBA) and >= 16 for Strain 96217 | At Day 331 (1 month after the fourth vaccination) | Serum bactericidal activity is assessed using human complement (hSBA) against Neisseria meningitidis serogroup B test strains: M14459 (fHbp); 96217 (NadA); NZ98/254 (PorA P1.4); M13520 (NHBA). The sufficiency of the immune response to rMenB+OMV NZ at one month after the 4th vaccination was to be demonstrated if the lower confidence limit for the percentage of participants achieving hSBA titers ≥ 8 (for strains M14459, NZ98/254, M13520) and ≥16 (for strain 96217) is ≥75% for each of the M14459, 96217, NZ98/254, M13520 test strains. This outcome measure evaluated immune response to the rMenB+OMV NZ vaccine only, hence it was not applicable to the Placebo+PCV group. |
| Percentage of Participants With hSBA Antibody Titers >= 8 for Strains M14459 (fHbp), NZ98/254 (PorA P1.4), and M13520 (NHBA) and >= 16 for Strain 96217 (NadA) (Composite Response Across All Strains) | At Day 331 (1 month after the fourth vaccination) | The immune response to the rMenB+OMV NZ vaccine is assessed by measuring serum bactericidal activity using hSBA against four Neisseria meningitidis serogroup B test strains: M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4), and M13520 (NHBA). The composite response is defined as the percentage of participants with hSBA titers ≥ Lower Limit of Quantitation (LLOQ) across all four strains combined. The sufficiency of the immune response to rMenB+OMV NZ at one month after the 4th vaccination was to be demonstrated if the lower confidence limit for the percentage of participants achieving hSBA titers ≥ 8 (for strains M14459, NZ98/254, M13520) and ≥16 (for strain 96217) is ≥65% for all strains combined. This outcome measure evaluated immune response to the rMenB+OMV NZ vaccine only, hence it was not applicable to the Placebo+PCV group. |
| Adjusted Geometric Mean Concentrations (GMCs) of Immunoglobubin (IgG) Antibodies Against 13 PCV13 Antigens at 1 Month After Third Vaccination | At Day 151 (1 month after the third vaccination) | The immune response to PCV13 is evaluated by measuring IgG levels using electrochemiluminescence (ECL) assay. Adjusted GMCs are assessed for each of the 13 PCV13 antigens at 1 month after the third vaccination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted GMCs of IgG Antibodies Against 13 PCV13 Antigens at 1 Month After the Fourth Vaccination Administered at Day 301 | At Day 331 (1 month after the fourth vaccination) | The immune response to PCV13 is evaluated by measuring IgG levels using ECL assay. Adjusted GMCs are assessed for each of the 13 PCV13 antigens at 1 month after the 4th vaccination. |
| Percentage of Participants With Serum Pneumococcal Anti-capsular Polysaccharide IgG >= 0.35 μg/mL | At Day 151 (1 month after the third vaccination) and Day 331 (1 month after the fourth vaccination) | The immune response to PCV13 is evaluated by measuring the percentage of participants with serum IgG concentrations ≥ 0.35 μg/mL for each of the 13 PCV13 antigens at 1 month after the third and fourth vaccinations. |
| Adjusted GMCs Against 3 Pertussis Antigens (Pertussis Toxin [PT], Pertactin [PRN], Filamentous Hemagglutinin [FHA]) | At Day 151 (1 month after the third vaccination) | The immune response to DTaP-HBV-IPV (Pediarix) vaccine is evaluated. IgG concentrations for pertussis antigens (PT, FHA, PRN) are measured at 1 month after the third vaccination and are expressed as international units per millilitre (IU/mL). |
| Percentage of Participants With Antibodies Concentrations Against Hepatitis B Surface Antigen (AntiHBsAg) >= 10 mIU/mL | At Day 151 (1 month after the third vaccination) | The immune response to DTaP-HBV-IPV vaccine administered with rMenB+OMV NZ and PCV13 is evaluated. IgG concentrations for Hepatitis B (HepB) antigens are measured at 1 month after the third vaccination. |
| Percentage of Participants With Anti-diphtheria and Anti-tetanus Antibody Concentrations >= 0.1 IU/mL | At Day 151 (1 month after the third vaccination) | The immune response to DTaP-HBV-IPV vaccine administered with rMenB+OMV NZ and PCV13 is evaluated. IgG concentrations for diphtheria (D) and tetanus (T) were measured at 1 month after the third vaccination. |
| Percentage of Participants With Anti-polyribosyl-ribitol Phosphate (PRP) Concentration >= 0.15 µg/mL and >= 1 µg/mL | At Day 151 (1 month after the third vaccination) | The immune response to Hib vaccine administered with rMenB+OMV NZ and PCV13 is evaluated. IgG concentrations for Haemophilus influenzae type b (Hib) are measured at 1 month after the third vaccination. |
| Adjusted GMCs for Anti-measles Antibodies | At Day 331 (1 month after the fourth vaccination) | The immune response to MMR vaccine administered with rMenB+OMV NZ and PCV13 is evaluated. IgG concentrations for measles antigens are measured using adjusted GMCs at 1 month after fourth vaccination and are expressed as milli-International Units per milliliter (mIU/mL). |
| Adjusted GMCs for Anti-mumps Antibodies | At Day 331 (1 month after the fourth vaccination) | The immune response to MMR vaccine administered with rMenB+OMV NZ and PCV13 is evaluated. IgG concentrations for mumps antigens are measured using adjusted GMCs at 1 month after fourth vaccination. |
| Adjusted GMCs for Anti-rubella Antibodies | At Day 331 (1 month after the fourth vaccination) | The immune response to MMR vaccine administered with rMenB+OMV NZ and PCV13 is evaluated. IgG concentrations for rubella antigens are measured using adjusted GMCs at 1 month after fourth vaccination. |
| Adjusted GMCs for Anti-Varicella (VV) Antibodies | At Day 331 (1 month after the fourth vaccination) | The immune response to varicella (VV) vaccine administered with rMenB+OMV NZ and PCV13 is evaluated. IgG concentrations for varicella antigens are measured using GMCs at 1 month after fourth vaccination. |
| Percentage of Participants With hSBA Antibody Titers >= 5, >= 8 and >=16 for Each of the Serogroup B Test Strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4), and M13520 (NHBA) | At Day 151 (1 month after the third vaccination) | This immune response to the rMenB+OMV NZ vaccine only is evaluated, hence it was not applicable to the Placebo+PCV group. |
| Percentage of Participants With hSBA Antibody Titers >= 5 and >= 8 for Each of the Serogroup B Test Strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4), and M13520 (NHBA) | At Day 301 (6 months after third vaccination) | This immune response to the rMenB+OMV NZ vaccine only is evaluated, hence it was not applicable to the Placebo+PCV group. |
| Percentage of Participants With hSBA Antibody Titers >= 5 for Each of the Serogroup B Test Strain M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4), and M13520 (NHBA) | At Day 331 (1 month after the fourth vaccination) | This immune response to the rMenB+OMV NZ vaccine only is evaluated, hence it was not applicable to the Placebo+PCV group. |
| hSBA Geometric Mean Titers (GMTs) Against Each of the Serogroup B Test Strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4), and M13520 (NHBA) | At Day 151 (1 month after the third vaccination), Day 301 (6 months after the third vaccination), and Day 331 (1 month after the fourth vaccination) | This immune response to the rMenB+OMV NZ vaccine only is evaluated, hence it was not applicable to the Placebo+PCV group. |
| hSBA Geometric Mean Ratios (GMRs) Over Pre Fourth Vaccination Against Each of the Serogroup B Test Strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4), and M13520 (NHBA) | At Day 331 (1 month after the fourth vaccination) compared to Day 301 (pre-fourth vaccination) | This immune response to the rMenB+OMV NZ vaccine only is evaluated, hence it was not applicable to the Placebo+PCV group. |
| Percentage of Participants With hSBA Antibody Titers >= LLOQ for Each of the Serogroup B Test Strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4), and M13520 (NHBA) | At Day 301 (6 months after the third vaccination) and Day 331 (1 month after the fourth vaccination) | This immune response to the rMenB+OMV NZ vaccine only is evaluated, hence it was not applicable to the Placebo+PCV group. |
| Percentage of Participants With 4-fold Rise in hSBA Titers for Each of the Serogroup B Test Strains M14459 (fHbp), 96217 (NadA), NZ98/254 (PorA P1.4), and M13520 (NHBA) | At Day 331 (1 month after the fourth vaccination) relative to Day 301 (pre-fourth vaccination) | A 4-fold rise in hSBA titers is defined as - if pre-vaccination titer \<Limit of Detection (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). This outcome measure evaluated immune response to the rMenB+OMV NZ vaccine only, hence it was not applicable to the Placebo+PCV group. |
| Percentage of Participants With Anti-HBs Antibody Concentrations >= 100 mIU/mL | At Day 151 (1 month after the third vaccination) | — |
| GMCs for Anti-HBsAg Antibodies | At Day 151 (1 month after the third vaccination) | — |
| Percentage of Participants With Anti-diphtheria and Anti-tetanus Antibody Concentrations >= 1 IU/mL | At Day 151 (1 month after the third vaccination) | — |
| GMCs for Anti-diphtheria and Anti-tetanus Antibodies | At Day 151 (1 month after the third vaccination) | — |
| Percentage of Participants With Anti-polio Type 1, 2 and 3 Neutralization Antibody Titers >= 8 | At Day 151 (1 month after the third vaccination) | — |
| Percentage of Participants With Seroresponse for Anti-Varicella (VV), Anti-measles Virus, Anti-mumps Virus and Anti-rubella Virus Antibodies | At Day 331 (1 month after the fourth vaccination) | Seroresponse is defined as post-vaccination anti-VZV virus, anti-measles virus, anti-mumps virus and anti-rubella virus antibody concentration \>= a protective threshold among participants who were seronegative (antibody concentration \< assay cut-off) before vaccination. |
Countries
Puerto Rico, United States
Contacts
STUDY_DIRECTORGSK Clinical Trials
GlaxoSmithKline
Participant flow
Pre-assignment details
Out of the 1196 participants enrolled, only 1184 participants were included in the Exposed Set and started the study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 8.6 Weeks STANDARD_DEVIATION 1 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants |
| Race/Ethnicity, Customized Asian | 60 Participants |
| Race/Ethnicity, Customized Black or African American | 117 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Other (Not specified) | 163 Participants |
| Race/Ethnicity, Customized White | 819 Participants |
| Sex: Female, Male Female | 576 Participants |
| Sex: Female, Male Male | 401 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 781 | 0 / 403 |
| other Total, other adverse events | 771 / 781 | 389 / 403 |
| serious Total, serious adverse events | 35 / 781 | 19 / 403 |
Outcome results
None listed