Prevention, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Study Overview
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Brief Summary
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This study was aimed to explore safety and immunogenicity of two formulations of a Meningococcal B Vaccine when administered to healthy infants.

Official Title
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A Phase 2, Open Label, Multi-Center, Controlled, Randomized Study of the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine±OMV, When Administered to Healthy Infants at 2, 4, 6 and/or 12 Months of Age

Conditions
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Healthy

Intervention / Treatment
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* Biological: rMenB
* Biological: rMenB+OMV
* Biological: DTaP-Hib-IPV
* Biological: PC7
* Biological: MenC-CRM
* Biological: MenC-Hib
* Biological: MMR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects eligible to be enrolled in the study: healthy 2-month old infants (55-89 days, inclusive), born after full term pregnancy with an estimated gestational age ≥37 weeks and a birth weight ≥2.5 kg; for whom a parent/legal guardian had provided written informed consent after the nature of the study had been explained; those available for all the visits scheduled in the study; those in good health as determined by: medical history physical examination clinical judgment of the investigator Exclusion Criteria: Individuals were not to be enrolled into the study: 1. whose parents/legal guardians were unwilling or unable to give written informed consent to participate in the study; 2. who had previously received any meningococcal B vaccine; 3. who had received prior vaccination with Diphtheria Tetanus Pertussis (DTP) (acellular or whole cell), Inactivated Polio Vaccine (IPV) or Oral Polio Vaccine (OPV), H influenzae type b (Hib) or Heptavalent Pneumococcal Conjugate (PC7) vaccine; 4. who had a previous ascertained or suspected disease caused by N meningitidis, S pneumoniae, C diphtheriae, tetani, Poliovirus, Hib, or B pertussis (history of laboratory confirmed, or clinical condition of spasmodic cough for a period ≥2weeks associated with apnea or whooping); 5. who had household contact with and/or intimate exposure to an individual with laboratory confirmed N meningitidis, B pertussis, Hib, C diphtheriae or Polio infection since birth; 6. who had a history of any anaphylactic shock, asthma, urticaria or other allergic reaction after previous vaccinations or known hypersensitivity to any vaccine component; 7. who had experienced significant acute or chronic infection within the previous 7 days or had experienced fever (≥38.0°C) within the previous 3 days; 8. who had any present or suspected serious acute or chronic disease (e.g., with signs of cardiac, renal failure, hepatic disease, or severe malnutrition or insulin dependent diabetes), or progressive neurological disease, or a genetic anomaly/known cytogenic disorders (e.g., Down's syndrome); 9. who had leukemia, lymphomas; 10. who had a known or suspected autoimmune disease or impairment/alteration of immune function resulting from (for example): receipt of any immunosuppressive therapy since birth receipt of immunostimulants since birth receipt of any systemic corticosteroid since birth 11. with a suspected or known HIV infection or HIV related disease; 12. who had ever received blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation from birth and for the full length of the study; 13. with a known bleeding diathesis, or any condition that might be associated with a prolonged bleeding time; 14. who had experienced any seizure, either associated with fever or as part of an underlying neurological disorder or syndrome 15. who had taken antibiotics within 7 days prior to enrollment (exception: antibiotics taken once daily within 14 days after the last dose); 16. who had either received, or for whom there was intent to immunize with any other vaccine(s), with respect to the study vaccines, within 30 days prior and throughout the study period; 17. who had ever received another investigational agent from birth prior to enrollment and unwilling to refuse participation in another investigational trial through the end of the study; 18. whose parents/legal guardians, were planning to leave the area of the study site before the end of the study period; 19. with any condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives.

Ages Eligible for Study
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Minimum Age: 55 Days
Maximum Age: 89 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rMenB<br>Infants received 4 doses of recombinant meningococcal serogroup B (rMenB) vaccine without outer membrane vesicle (OMV-NZ) at 2, 4, 6 and 12 months of age. Infants also received routine vaccines - 3 doses each of Diphtheria Tetanus Pertussis-Haemophilus influenzae type b-Inactivated Polio Vaccine (DTaP-Hib-IPV) (at 2, 3, and 4 months) and Heptavalent Pneumococcal Conjugate (PC7) (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and Measles Mumps Rubella (MMR) (at 13 months). | Biological: rMenB<br>* One dose (0.5 mL) of rMenB vaccine without OMV-NZ supplied as a full liquid formulation in a prefilled syringe was administered into the anterolateral area of the right thigh.<br>* Other names: Serogroup B meningococcal recombinant vaccine without OMV-NZ;Biological: DTaP-Hib-IPV<br>* Intramuscular (IM) injections of 3 doses of 0.5 mL each of DTaP-Hib-IPV supplied in prefilled vial were administered at 2, 3 and 4 months in the anterolateral area of the left thigh (when given concomitantly with rMenB±OMV-NZ) or the right thigh.<br>* Other names: and inactivated polio vaccine; Pediacel;Biological: PC7<br>* IM injections of 3 doses of 0.5 mL each of PC7 supplied in prefilled syringe were administered at 2, 4 and 13 months of age in the anterolateral area of the left thigh (when given concomitantly with rMenB±OMV-NZ) or the right thigh.<br>* Other names: Heptavalent Streptoccus pneumonia vaccine; Prevenar;Biological: MenC-CRM<br>* MenC-CRM was obtained by extemporaneous mixing just before injection of the lyophilized Men C component to be re-suspended with the saline solvent (aluminum hydroxide suspension) supplied. IM injection of 2 doses each of 0.5 mL were administered into the anterolateral area of the left thigh.<br>* Other names: CRM197 conjugated meningococcal C vaccine; Menjugate;Biological: MenC-Hib<br>* MenC-Hib was obtained by extemporaneous mixing of powder and solvent just before injection. One dose (0.5 mL) of MenC-Hib was administered at 12 months of age as an IM injection into the anterolateral area of the thigh.<br>* Other names: Combined meningococcal C and Haemophilus influenzae type B vaccine; Menitorix;Biological: MMR<br>* IM injection of one dose of 0.5 mL of MMR obtained by extemporaneous mixing just before injection of powder and the solvent for solution was administered at 13 months of age in the anterolateral area of the left thigh.<br>* Other names: Measles, mumps, and rubella vaccine; Priorix;|
| Experimental: rMenB+OMV<br>Infants received 4 doses of rMenB vaccine with OMV-NZ at 2, 4, 6 and 12 months of age. Infants also received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). | Biological: rMenB+OMV<br>* One dose (0.5 mL) of rMenB vaccine with OMV-NZ supplied as a full liquid formulation in a prefilled syringe was administered into the anterolateral area of the right thigh.<br>* Other names: Serogroup B meningococcal recombinant vaccine with OMV-NZ;Biological: DTaP-Hib-IPV<br>* Intramuscular (IM) injections of 3 doses of 0.5 mL each of DTaP-Hib-IPV supplied in prefilled vial were administered at 2, 3 and 4 months in the anterolateral area of the left thigh (when given concomitantly with rMenB±OMV-NZ) or the right thigh.<br>* Other names: and inactivated polio vaccine; Pediacel;Biological: PC7<br>* IM injections of 3 doses of 0.5 mL each of PC7 supplied in prefilled syringe were administered at 2, 4 and 13 months of age in the anterolateral area of the left thigh (when given concomitantly with rMenB±OMV-NZ) or the right thigh.<br>* Other names: Heptavalent Streptoccus pneumonia vaccine; Prevenar;Biological: MenC-CRM<br>* MenC-CRM was obtained by extemporaneous mixing just before injection of the lyophilized Men C component to be re-suspended with the saline solvent (aluminum hydroxide suspension) supplied. IM injection of 2 doses each of 0.5 mL were administered into the anterolateral area of the left thigh.<br>* Other names: CRM197 conjugated meningococcal C vaccine; Menjugate;Biological: MenC-Hib<br>* MenC-Hib was obtained by extemporaneous mixing of powder and solvent just before injection. One dose (0.5 mL) of MenC-Hib was administered at 12 months of age as an IM injection into the anterolateral area of the thigh.<br>* Other names: Combined meningococcal C and Haemophilus influenzae type B vaccine; Menitorix;Biological: MMR<br>* IM injection of one dose of 0.5 mL of MMR obtained by extemporaneous mixing just before injection of powder and the solvent for solution was administered at 13 months of age in the anterolateral area of the left thigh.<br>* Other names: Measles, mumps, and rubella vaccine; Priorix;|
| Experimental: Routine<br>Infants received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). Infants also received single dose of rMenB vaccine without OMV-NZ at 12 months of age. | Biological: rMenB<br>* One dose (0.5 mL) of rMenB vaccine without OMV-NZ supplied as a full liquid formulation in a prefilled syringe was administered into the anterolateral area of the right thigh.<br>* Other names: Serogroup B meningococcal recombinant vaccine without OMV-NZ;Biological: DTaP-Hib-IPV<br>* Intramuscular (IM) injections of 3 doses of 0.5 mL each of DTaP-Hib-IPV supplied in prefilled vial were administered at 2, 3 and 4 months in the anterolateral area of the left thigh (when given concomitantly with rMenB±OMV-NZ) or the right thigh.<br>* Other names: and inactivated polio vaccine; Pediacel;Biological: PC7<br>* IM injections of 3 doses of 0.5 mL each of PC7 supplied in prefilled syringe were administered at 2, 4 and 13 months of age in the anterolateral area of the left thigh (when given concomitantly with rMenB±OMV-NZ) or the right thigh.<br>* Other names: Heptavalent Streptoccus pneumonia vaccine; Prevenar;Biological: MenC-CRM<br>* MenC-CRM was obtained by extemporaneous mixing just before injection of the lyophilized Men C component to be re-suspended with the saline solvent (aluminum hydroxide suspension) supplied. IM injection of 2 doses each of 0.5 mL were administered into the anterolateral area of the left thigh.<br>* Other names: CRM197 conjugated meningococcal C vaccine; Menjugate;Biological: MenC-Hib<br>* MenC-Hib was obtained by extemporaneous mixing of powder and solvent just before injection. One dose (0.5 mL) of MenC-Hib was administered at 12 months of age as an IM injection into the anterolateral area of the thigh.<br>* Other names: Combined meningococcal C and Haemophilus influenzae type B vaccine; Menitorix;Biological: MMR<br>* IM injection of one dose of 0.5 mL of MMR obtained by extemporaneous mixing just before injection of powder and the solvent for solution was administered at 13 months of age in the anterolateral area of the left thigh.<br>* Other names: Measles, mumps, and rubella vaccine; Priorix;|
| Experimental: Routine+OMV<br>Infants received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). Infants also received single dose of rMenB vaccine with OMV-NZ at 12 months of age. | Biological: rMenB+OMV<br>* One dose (0.5 mL) of rMenB vaccine with OMV-NZ supplied as a full liquid formulation in a prefilled syringe was administered into the anterolateral area of the right thigh.<br>* Other names: Serogroup B meningococcal recombinant vaccine with OMV-NZ;Biological: DTaP-Hib-IPV<br>* Intramuscular (IM) injections of 3 doses of 0.5 mL each of DTaP-Hib-IPV supplied in prefilled vial were administered at 2, 3 and 4 months in the anterolateral area of the left thigh (when given concomitantly with rMenB±OMV-NZ) or the right thigh.<br>* Other names: and inactivated polio vaccine; Pediacel;Biological: PC7<br>* IM injections of 3 doses of 0.5 mL each of PC7 supplied in prefilled syringe were administered at 2, 4 and 13 months of age in the anterolateral area of the left thigh (when given concomitantly with rMenB±OMV-NZ) or the right thigh.<br>* Other names: Heptavalent Streptoccus pneumonia vaccine; Prevenar;Biological: MenC-CRM<br>* MenC-CRM was obtained by extemporaneous mixing just before injection of the lyophilized Men C component to be re-suspended with the saline solvent (aluminum hydroxide suspension) supplied. IM injection of 2 doses each of 0.5 mL were administered into the anterolateral area of the left thigh.<br>* Other names: CRM197 conjugated meningococcal C vaccine; Menjugate;Biological: MenC-Hib<br>* MenC-Hib was obtained by extemporaneous mixing of powder and solvent just before injection. One dose (0.5 mL) of MenC-Hib was administered at 12 months of age as an IM injection into the anterolateral area of the thigh.<br>* Other names: Combined meningococcal C and Haemophilus influenzae type B vaccine; Menitorix;Biological: MMR<br>* IM injection of one dose of 0.5 mL of MMR obtained by extemporaneous mixing just before injection of powder and the solvent for solution was administered at 13 months of age in the anterolateral area of the left thigh.<br>* Other names: Measles, mumps, and rubella vaccine; Priorix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Bactericidal Titers, BCA ≥1:4, 30 Days After the Third Immunization | Immunogenicity was measured as percentage of subjects who achieved bactericidal titers ≥1:4 against meningococcal strains 44/76-SL, 5/99 and NZ98/254, evaluated using serum bactericidal assay, before vaccination (baseline) and at one month after third-dose of Infants series vaccination of rMenB vaccine with and without OMV administered at 6 months of age. | Baseline and one month after third-dose of infants series | 
| Geometric Mean Bactericidal Titers Against Meningococcal Strains One Month After Third-Dose of Infants Series Vaccination of rMenB Vaccine With and Without OMV-NZ | The immune response was measured as the geometric mean bactericidal titers directed against meningococcal strains 44/76-SL, 5/99 and NZ98/254, before vaccination (baseline) and at one month after third-dose of infants series vaccination of rMenB vaccine with and without OMV administered at 6 months of age. | Baseline and one month after third-dose of infants series | 
| Number of Subjects Who Reported Solicited Local Reactions After Each Vaccination of rMenB Vaccine With and Without OMV | Safety was assessed as the number of subjects who reported solicited local reactions from day 1 through day 7 after each vaccination of rMenB vaccine with and without OMV administered at 2 months (vaccination 1), 4 months (vaccination 2), 6 months (vaccination 3) and 12 months (vaccination 4; vaccination 1 for Routine and Routine+OMV groups). | Day 1 through day 7 after each vaccination | 
| Number of Subjects Who Reported Solicited Local Reactions After Each Vaccination of PC7 | Safety was assessed as the number of subjects who reported solicited local reactions from day 1 through day 7 after each vaccination of PC7 administered at 2 months (vaccination 1) and 4 months (vaccination 3). | Day 1 through day 7 after each vaccination | 
| Number of Subjects Who Reported Solicited Local Reactions After Each Vaccination of DTaP-Hib-IPV Pentavalent Vaccine | Safety was assessed as the number of subjects who reported solicited local reactions from day 1 through day 7 after each vaccination of the pentavalent vaccine DTaP-Hib-IPV administered at 2 months (vaccination 1), 3 months (vaccination 2) and 4 months (vaccination 3). | Day 1 through day 7 after each vaccination | 
| Number of Subjects Who Reported Solicited Local Reactions After Each Vaccination of MenC-CRM or MenC-Hib | Safety was assessed as the number of subjects who reported solicited local reactions from day 1 through day 7 after each vaccination of MenC-CRM administered at 2 months (vaccination 1) and 5 months (vaccination 2). MenC-Hib was administered at 12 months of age (vaccination 3). | Day 1 through day 7 after each vaccination | 
| Number of Subjects Who Reported Solicited Systemic Reactions And Other Indicator of Reactogenicity After Each Vaccination Administered During Study | Safety was assessed as the number of subjects who reported solicited systemic reactions and other indicator of reactogenicity from day 1 through day 7 after each vaccination administered during study as follow: rMenB vaccine with and without OMV, PC7, DTaP-Hib-IPV at 2 months (vaccination 1), MenC-CRM, DTaP-Hib-IPV at 3 months (vaccination 2), rMenB vaccine with and without OMV, PC7, DTaP-Hib-IPV at 4 months (vaccination 3), MenC-CRM at 5 months (vaccination 4), rMenB vaccine with and without OMV at 6 months (vaccination 5; rMenB and rMenB+OMV groups only), rMenB vaccine with and without OMV at 12 months (vaccination 5; routine and routine+OMV groups only), and rMenB vaccine with and without OMV (vaccination 6; rMenB and rMenB+OMV groups only). | Day 1 through day 7 after each vaccination | 
| Percentage of Subjects With Fourfold Rises in Bactericidal Titers Against Meningococcal Strains One Month After Third-Dose of Infants Series Vaccination or rMenB Vaccine With and Without OMV-NZ. | Percentage of subjects fourfold increase in bactericidal titers against meningococcal strains 44/76-SL, 5/99 and NZ98/254 were measured at one month after third-dose and calculated respect to baseline titers. | 30 days after the third vaccination | 
| Geometric Mean Ratios to Baseline Against a Panel of Genetically Distinct Meningococcal Strains 30 Days After the Third Immunization. | Geometric Mean Ratios (GMRs) as measure of the bactericidal activity against the for the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) in subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) at 30 days after the third immunization. The analysis was done on the Per Protocol population at one month after third injection. | At baseline (pre-vaccination) and 30 days after the third vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of Subjects With Fourfold Rises in Bactericidal Titers 1 Month After First Vaccination | Percentages of subjects treated with Routine + Novartis rMenB Vaccine +/- OMV NZ (Groups III and IV) with fourfold rises in bactericidal titers for the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) 1 month after first vaccination. The analysis was done on the Per Protocol population 1 month after first vaccination. | 1 month after first vaccination | 
| Geometric Mean Titers Against a Panel of Genetically Distinct Meningococcal Strains Prior to the First Dose, 30 Days After the Second Immunization and at 12 Months Age | Geometric mean bactericidal titers as measure of the Bactericidal activity against meningococcal strains 44/76-SL, 5/99 and NZ98/254, before vaccination (baseline) and at 30 days after second immunization, at 12 months age,and 30 days after the fourth (booster) vaccination. | prior 1st dose, 30 days post-2nd vaccination, 12 months age to 1 month post 4th vaccination | 
| Geometric Mean Titers Against a Panel of Genetically Distinct Meningococcal Strains Prior to and 30 Days After a Single Dose Administered at 12 Months of ageVaccination of rMenB Vaccine With and Without OMV-NZ | Geometric Mean Titers (GMTs) as measure of the bactericidal activity against the for the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) in subjects treated with Routine +Novartis rMenB Vaccine +/- OMV NZ (Groups III and IV) at 12 months age, i.e. pre-first vaccination and 1 month after first vaccination. The analysis was done on the Per Protocol population. | pre-first vaccination and 1 month after first vaccination | 
| Geometric Mean Ratios (GMRs) to Baseline Against a Panel of Genetically Distinct Meningococcal Strains 30 Days After the Second Immunization and 1 Month After Fourth (Booster) Vaccination | Geometric Mean Ratios (GMRs) as measure of the bactericidal activity against meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) in subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) at 30 days after the second immunization and 1 month after fourth (booster) vaccination. The analysis was done on the Per Protocol population at 30 days after the second immunization and 1 month after fourth (booster) vaccination.of age. | 30 days after the second vaccination and 1 month after fourth (booster) vaccination | 
| Percentages of Subjects With Bactericidal Titers ≥1:4 at 12 Months Age | Percentages of subjects treated with Routine + Novartis rMenB Vaccine +/- OMV NZ (Groups III and IV) with a bactericidal activity (BCA) measured as BCA titer ≥1:4 for the for three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) at 12 months age, i.e. pre-first vaccination, and 1 month after first vaccination. The analysis was done on the Per Protocol population at 12 months age, i.e. pre-first vaccination, and 1 month after first vaccination. | pre-first vaccination and 1 month after first vaccination | 
| Geometric Mean Ratios to Baseline Against a Panel of Genetically Distinct Meningococcal Strains 30 Days After a Single Dose Administered at 12 Months of Age | Geometric Mean Ratios to baseline against a panel of genetically distinct meningococcal strains 30 days after a single dose administered at 12 months of age. | 1 month after first vaccination | 
| Percentages of Subjects With Fourfold Rises in Bactericidal Titers After the Second Immunization and at 12 Months Age | Percentages of subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) with fourfold rises in bactericidal titers for the three meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) at 30 days after the second vaccination and at 12 months age, i.e. 6 months after third (pre-booster) vaccination, and 1 month after fourth (booster) vaccination. The analysis was done on the Per Protocol population 30 days after the second vaccination and at 12 months age. | At pre-vaccination and 30 days post the 2nd vaccination and at 12 months age, and 1 month post 4th (booster) vaccination. | 
| Percentages of Subjects With Bactericidal Titers, BCA, ≥1:4 After the Second Immunization and at 12 Months Age | Percentages of subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) with a BCA titer ≥1:4 for the three meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) at 30 days after the second vaccination and at 12 months age, and 1 month after fourth (booster) vaccination. The analysis was done on the Per Protocol population. | At baseline (pre-vaccination) and 30 days after the second vaccination and at 12 months age. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Meningococcal disease, prevention, vaccination