A Phase 3B, Open Label, Multi-Center Study to Evaluate the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine When Administered Alone to Healthy Infants According to Different Immunization Schedules and to Healthy Children Aged 2 to 10 Years

Study Overview
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Brief Summary
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The proposed study is aimed at assessing the safety and immunogenicity of rMenB+OMV NZ when administered alone without routine infant vaccines to healthy infants in their first year of life according to different two and three dose immunization schedules, which are suitable to be adopted by various national programs. This study will also investigate antibody persistence post primary series and administration of a subsequent booster dose of rMenB+OMV NZ at 11 months of age. In addition, this study will assess the safety and immunogenicity of two catch-up doses of rMenB+OMV NZ when administered to healthy children 2 to 10 years of age. This study will also evaluate the safety and immunogenicity of the concomitant administration of rMenB+OMV NZ with meningococcal C conjugate vaccine (MenC-CRM) according to a 3, 5 and 12-month schedule.

Official Title
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A Phase 3B, Open Label, Multi-Center Study to Evaluate the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine When Administered Alone to Healthy Infants According to Different Immunization Schedules and to Healthy Children Aged 2 to 10 Years

Conditions
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Meningococcal Disease, Meningococcal Meningitis

Intervention / Treatment
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* Biological: rMenB + OMV NZ vaccine
* Biological: rMenB + OMV NZ vaccine
* Biological: rMenB + OMV NZ vaccine
* Biological: rMenB + OMV NZ vaccine
* Biological: Meningococcal C oligosaccharide conjugated vaccine
* Biological: Pneumococcal polysaccharide conjugate vaccine, 10 valent adsorbed.
* Biological: rMenB + OMV NZ vaccine
* Biological: rMenB + OMV NZ vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy infants and children according to the following age groups: Healthy infants 2½ months of age (71 -79 days, inclusive), (only applicable to group I) Healthy infants 3½ months of age (101 -109 days, inclusive), (only applicable to group II) Healthy infants 6 months of age (only applicable to group III) (The age window is defined as the first day the subject turns 6 months of age up to the day before the subject turns 7 months of age). Healthy children 2 to 5 years of age (only applicable to group IVa) (The age window is defined as the first day the subject turns 2 years of age up to the day before the subject turns 6 years of age). Healthy children 6 to 10 years of age (only applicable to group IVb) (The age window is defined as the first day the subject turns 6 years of age up to the day before the subject turns 11 years of age). Healthy infants 3 months of age (83-104 days, inclusive), (only applicable to Group V and VI). For whom parent(s)/legal guardian(s) have given written informed consent according to local regulations after the nature of the study has been explained; Available for all the visits scheduled in the study; Individuals in good health as determined by the outcome of medical history, physical examination and clinical judgment of the investigator. Exclusion Criteria: Individuals whose parent(s)/legal guardian(s) are unwilling or unable to give written informed consent to participate in the study; Children's parents or legal guardian who are not able to comprehend and to follow all required study procedures for the whole period of the study. History of any meningococcal B vaccine administration; Previous ascertained or suspected disease caused by N. meningitidis; Household contact with and/or intimate exposure to an individual with laboratory confirmed N. meningitidis; History of severe allergic reaction after previous vaccinations or hypersensitivity to any vaccine component Significant acute or chronic infection within the previous 7 days or temperature 38° C within the previous day of receiving the study vaccine; Antibiotics treatment within 6 days prior to enrollment; Individuals with history of allergy to vaccine components. Any serious chronic or progressive disease according to the judgment of the investigator (e.g., neoplasm, diabetes mellitus Type I, cardiac disease, hepatic disease, neurological disease or seizure, either associated with fever or as part of an underlying neurological disorder or syndrome, autoimmune disease, HIV infection or AIDS, or blood dyscrasias or diathesis, signs of cardiac or renal failure or severe malnutrition); Known or suspected impairment/alteration of the immune system, immunosuppressive therapy, use of high dose systemic corticosteroids or chronic use of inhaled high-potency corticosteroids within 14 days prior to enrollment (use of low or moderate doses of inhaled steroids is not an exclusion); Receipt of blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation within 90 days prior to enrollment. Receipt of, or intent to immunize with, any other vaccine(s) within 7 days prior to enrollment. Individuals participating in any clinical trial with another investigational product 30 days prior to first study visit or intent to participate in another clinical study at any time during the conduct of this study. Family members and household members of research staff Individuals with history or any illness that, in the opinion of the investigator, might interfere with the results of the study or pose additional risk to the subjects due to participation in the study. History of any meningococcal C vaccine administration (Only applicable to group V and VI). History of any Pneumococcal vaccine administration (Only applicable to group V and VI).

Ages Eligible for Study
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Minimum Age: 71 Days
Maximum Age: 10 Years

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: B_2h3h5_11<br>Subjects, approximately 2.5 months of age, received 3 dose primary vaccination of rMenB+OMV NZ at 2.5, 3.5, 5 months of age, followed by a booster dose at 11 months of age. | Biological: rMenB + OMV NZ vaccine<br>* 3 doses (2.5, 3.5, 5 months if age) plus booster (11 months of age)<br>* Other names: rMenB for Group I;|
| Experimental: B_3h5_11<br>Subjects, approximately 3.5 months of age, received 2 dose primary vaccination of rMenB+OMV NZ at 3.5 and 5 months of age, followed by a booster dose at 11 months of age. | Biological: rMenB + OMV NZ vaccine<br>* 2 doses (3.5, 5 months of age) plus booster (11 months of age)<br>* Other names: rMenB for Group II;|
| Experimental: B_68_11<br>Subjects, approximately 6 months of age, received 2 dose primary vaccination of rMenB+OMV NZ at 6 and 8 months of age, followed by a booster dose at 11 months of age. | Biological: rMenB + OMV NZ vaccine<br>* 2 doses (6, 8 months of age) plus booster (11 months of age)<br>* Other names: rMenB for Group III;|
| Experimental: B_02_2_5<br>Subjects, 2-5 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start. | Biological: rMenB + OMV NZ vaccine<br>* 2 doses 2 months apart<br>* Other names: rMenB for Group IV;|
| Experimental: B_02_6_10<br>Subjects, 6-10 years of age received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Blood draw at 0 and 3 months since study start. | Biological: rMenB + OMV NZ vaccine<br>* 2 doses 2 months apart<br>* Other names: rMenB for Group IV;|
| Experimental: BC_35_12<br>Subjects, 3 months of age received rMenB+OMV NZ + MenC-CRM and Synflorix concomitantly at 3, 5 and 12 months of age and an additional dose of Synflorix alone dose at 7 months of age. | Biological: Meningococcal C oligosaccharide conjugated vaccine<br>* Schedule 3, 5, 7, 12, Meningococcal C oligosaccharide conjugated vaccine<br>Biological: Pneumococcal polysaccharide conjugate vaccine, 10 valent adsorbed.<br>* Schedule 3, 5, 7, 12 Pneumococcal polysaccharide conjugate vaccine, 10 valent adsorbed.<br>Biological: rMenB + OMV NZ vaccine<br>* Schedule 3, 5, 12 rMenB + OMV vaccine<br>* Other names: rMenB for Group V;|
| Experimental: C_35_12<br>Subjects, 3 months of age received MenC-CRM and Synflorix concomitantly at 3, 5 and 12 months of age and an additional dose of Synflorix alone at 7 months of age and rMenB+OMV NZ alone at 13 and 15 months of age. | Biological: Meningococcal C oligosaccharide conjugated vaccine<br>* Schedule 3, 5, 7, 12, Meningococcal C oligosaccharide conjugated vaccine<br>Biological: Pneumococcal polysaccharide conjugate vaccine, 10 valent adsorbed.<br>* Schedule 3, 5, 7, 12 Pneumococcal polysaccharide conjugate vaccine, 10 valent adsorbed.<br>Biological: rMenB + OMV NZ vaccine<br>* Schedule 13,15 rMenB + OMV vaccine<br>* Other names: rMenB for Group VI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of Subjects With Serum Bactericidal Activity Using Human Serum (hSBA) Titers ≥ 4 or hSBA Titers ≥ 5 (Strain M10713) Following a 2-dose Primary Series of rMenB+OMV Vaccination. | Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254 and hSBA titers ≥ 5 against strain M10713 following 2-dose primary series of vaccination with rMenB+OMV NZ at 3.5 and 5 months of age or at 6 and 8 months of age. Analysis was done on Full analysis set (FAS)-Primary series. | 1 month after second vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of Subjects With hSBA Titers ≥ 4, hSBA Titers ≥ 5 (Strain M10713) and hSBA ≥ 8 Following a 3-dose Primary Series of rMenB+OMV Vaccination | Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254; hSBA titers ≥ 5 against strain M10713 and hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713, following 3-dose primary series of vaccination with rMenB+OMV NZ at 2.5, 3.5 and 5 months of age. Analysis was done on FAS-primary series. | 1 month after third vaccination | 
| Percentages of Subjects With hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (Strain M10713) and hSBA ≥ 8 Following a 2-dose Catch-up Series of rMenB+OMV Vaccination | Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254; hSBA titers ≥ 5 against strain M10713 and hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713; following 2-dose catch-up series of vaccination with rMenB+OMV NZ in healthy children aged 2-10 years (0, 2 month schedule). Analysis was done on FAS-primary series. | 1 month after second vaccination | 
| Percentages of Subjects Achieving Four-fold Rise Over Baseline hSBA Titers Following a 2-dose Catch-up Series of rMenB+OMV Vaccination | Immunogenicity was assessed in terms of percentages of subjects achieving 4-fold increase in hSBA titers as compared to baseline against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254, M10713; following 2-dose catch-up series of vaccination with rMenB+OMV NZ in healthy children aged 2-10 years (0, 2 month schedule). Analysis was done on FAS- primary series. | 1 month after second vaccination | 
| Geometric Mean hSBA Titers (GMTs) Following 2 or 3 Dose Primary Series of Vaccination With rMenB+OMV | Immunogenicity was assessed in terms of Geometric mean hSBA titers (GMTs) against N meningitidis serogroup B indicator strains following 2 or 3 dose primary series of vaccination rMenB+OMV NZ (1 month after 3rd infant vaccination in B_2h3h5_11 and 1 month after 2nd infant vaccination in B_3h5_11, B_68_11 and B_02). Analysis was done on FAS-primary series. | 1 month after primary series vaccination | 
| Geometric Mean hSBA Titers (GMTs) After First Infant Vaccination With rMenB+OMV. | Immunogenicity was assessed in terms of Geometric mean hSBA titers (GMTs) against N meningitidis serogroup B indicator strains after the first infant vaccination in groups B_2h3h5_11b, B_3h5_11b and B_68_11b (after 1 month for group B_2h3h5_11b, 1.5 months for group B_2h3h5_11b and 2 months for group B_68_11b). Analysis was done on FAS-post first dose. | 1, 1.5 or 2 months after first infant vaccination | 
| Percentages of Subjects With hSBA Titers ≥ 4 or hSBA Titers ≥ 5 and hSBA ≥ 8 After First Infant Vaccination With rMenB+OMV | Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254, hSBA titers ≥ 5 against strain M10713 and hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713 after the first infant vaccination in groups B_2h3h5_11b, B_3h5_11b and B_68_11b (at 3.5, 5, and 8 months of age respectively). Analysis was done on FAS-post first dose. | Post- first dose (1 month for B_2h3h5_11b, 1.5 month for B_3h5_11b and 2 months for B_68_11b after 1st vaccination) | 
| Percentages of Subjects With hSBA Titers ≥ 4 or hSBA Titers ≥ 5 and hSBA ≥ 8 Following a Booster Dose of rMenB+OMV Vaccination | Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254; hSBA titers ≥ 5 against strain M10713; hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713; following a booster dose of rMenB+OMV NZ given at 11 months of age (4th dose for B_2h3h5_11 and 3rd dose for B_3h5_11 and B_68_11). Analysis was done on FAS-booster. | 1 month post-booster dose | 
| Antibody Persistence in Terms of Percentages of Subjects With hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (M10713) and hSBA ≥ 8 Following 2 or 3-dose Primary Series of Vaccination With rMenB+OMV NZ | Persistence of bactericidal antibodies at 11 months of age was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254; hSBA titers ≥ 5 against strain M10713; hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713 in subjects who previously received a primary series of 2 or 3-doses of rMenB+OMV NZ vaccine. Analysis was done on FAS-persistence. | 11 months of age (persistence) | 
| Antibody Persistence in Terms of Geometric Mean Titers Following 2 or 3-dose Primary Series of Vaccination With rMenB+OMV NZ | Persistence of bactericidal antibodies at 11 months of age was assessed in terms of GMTs against N meningitidis serogroup B indicator strains in subjects who previously received a primary series of 2 or 3-doses of rMenB+OMV NZ. Analysis was done on FAS-persistence. | 11 months of age (persistence) | 
| Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following 2 or 3-dose Primary Series and Booster Dose of Vaccination With rMenB+OMV NZ | Immunogenicity was assessed in terms of Geometric mean ELISA concentrations (GMCs) against N meningitidis serogroup B vaccine antigen 287-953, following 2 or 3 dose primary series and booster dose of rMenB+OMV NZ. Analysis was done on FAS-persistence and FAS-booster. | 1 month after primary vaccination, pre-booster vaccination (persistence) and 1 month after booster vaccination | 
| Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 After a Two Dose Catch-up rMenB+OMV NZ Immunization Series in Children 2-10 Years of Age | Immunogenicity was assessed in terms of Geometric mean ELISA concentrations (GMCs) against N meningitidis serogroup B vaccine antigen 287-953, after a two dose catch-up immunization series with rMenB+OMV NZ in children 2-10 years of age. Analysis was done on FAS-primary series. | 1 month after second vaccination | 
| Percentages of Subjects With hSBA Titers ≥ 8 Against Serogroup C Following Concomitant Administration of rMenB+OMV NZ With MenC-CRM or MenC-CRM Alone | Non-inferiority of MenC-CRM was determined following co-administration of MenC-CRM and rMenB+OMV NZ or MenC-CRM alone at 3 and 5 months and booster dose at 12 months, as measured by the percentages of subjects achieving hSBA titers ≥ 8 against serogroup C. Analysis was done on PPS-primary series and PPS-booster. | Baseline, 1 month after second vaccination and 1 month after booster vaccination | 
| GMTs Following Concomitant Administration of rMenB+OMV NZ With MenC-CRM or MenC-CRM Alone | Immunogenicity was assessed in terms of GMTs against N meningitidis serogroup C strain following co-administration of MenC-CRM and rMenB+OMV NZ or MenC-CRM alone at 3 and 5 months and booster dose at 12 months. Analysis was done on FAS-primary series and FAS-booster. | 1 month after second vaccination, 1 month after booster vaccination | 
| GMTs Following Concomitant Administration of rMenB+OMV NZ With MenC-CRM or MenC-CRM Alone - Persistence | Immunogenicity was assessed in terms of GMTs against N meningitidis serogroup C strain following co-administration of MenC-CRM and rMenB+OMV NZ or MenC-CRM alone at 3 and 5 months and booster dose at 12 months. Analysis was done on FAS-persistence. | Pre-booster vaccination (persistence; 12 months of age) | 
| Percentages of Subjects With hSBA Titers ≥ 4 or hSBA Titers ≥ 5 (M10713) and hSBA ≥ 8 Following Concomitant Administration of rMenB+OMV NZ With MenC-CRM | Immunogenicity was assessed in terms of percentages of subjects with hSBA titers ≥ 4 against N meningitidis serogroup B strains H44/76, 5/99, NZ98/254; hSBA titers ≥ 5 against strain M10713; hSBA titers ≥ 8 against strains H44/76, 5/99, NZ98/254, M10713; following co-administration of MenC-CRM and rMenB+OMV NZ at 3 and 5 months and a booster at 12 months. Analysis was done on FAS-primary series and FAS-booster. | 1 month after second vaccination and 1 month after booster vaccination | 
| GMTs Against N. Meningitidis Serogroup B Strains Following Concomitant Administration of rMenB+OMV NZ With MenC-CRM | Immunogenicity was assessed in terms of GMTs against N meningitidis serogroup C strain following co-administration of MenC-CRM and rMenB+OMV NZ at 3 and 5 months and booster dose at 12 months. Analysis was done on FAS-persistence and FAS-booster. | 1 month after second vaccination, pre-booster vaccination and 1 month after booster vaccination | 
| Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following Concomitant Administration of rMenB+OMV NZ With MenC-CRM | Immunogenicity was assessed in terms of Geometric mean ELISA concentrations against N meningitidis serogroup B vaccine antigen 287-953, following co-administration of MenC-CRM and rMenB+OMV NZ at 3 and 5 months and booster dose at 12 months. Analysis was done on FAS-primary and FAS-booster. | 1 month after second vaccination, pre-booster vaccination and 1 month after booster vaccination | 
| Geometric Mean ELISA Concentrations Against Vaccine Antigen 287-953 Following Concomitant Administration of rMenB+OMV NZ With MenC-CRM - Persistence | Immunogenicity was assessed in terms of GMTs against Geometric mean ELISA concentrations against N meningitidis serogroup B vaccine antigen 287-953, following co-administration of MenC-CRM and rMenB+OMV NZ at 3 and 5 months and booster dose at 12 months. Analysis was done on FAS-persistence. | Pre-booster vaccination (persistence; 12 months of age) | 
| Number of Subjects Who Reported Immediate Reactions Within 30 Minutes After Any Vaccination With rMenB+OMV NZ | Safety was assessed in terms of number of subjects who reported immediate reactions within 30 minutes following a 4-dose regimen (2.5, 3.5, 5 and 11 months) or a 3-dose regimen (3.5, 5 and 11 months or 6, 8 and 11 months) of rMenB+OMV NZ. Analysis was done on solicited safety set. | Within 30 minutes after any vaccination | 
| Number of Subjects With Solicited Local and Systemic Adverse Events (AEs) Following a 3 or 4-dose Regimen of rMenB+OMV NZ | Safety was assessed in terms of number of subjects with solicited local and systemic AEs after any vaccination following a 4-dose regimen (2.5, 3.5, 5 and 11 months) or as a 3-dose regimen (3.5, 5 and 11 months or 6, 8 and 11 months) of rMenB+OMV NZ. Analysis was done on solicited safety set. | Day 1 to day 7 after any vaccination | 
| Number of Subjects Who Reported Immediate Reactions Within 30 Minutes After Any Vaccination - Groups B_02_2_5 and B_02_6_10 | Safety was assessed in terms of number of subjects with solicited local and systemic AEs after any vaccination in subjects aged 2 - 10 years who received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Analysis was done on solicited safety set. | Within 30 minutes after any vaccination | 
| Number of Subjects With Solicited Local and Systemic AEs in Groups B_02_2_5 and B_02_6_10 | Safety was assessed in terms of number of subjects with solicited local and systemic AEs after any vaccination in subjects aged 2- 10 years who received 2 catch-up doses of rMenB+OMV NZ, each at 0 and 2 months. Analysis was done on solicited safety set. | Day 1 to day 7 after any vaccination | 
| Number of Subjects Who Reported Immediate Reactions Within 30 Minutes After Any rMenB+OMV NZ or MenC-CRM Vaccination | Safety was assessed in terms of number of subjects with solicited local and systemic AEs after any vaccination with rMenB+OMV NZ or MenC-CRM. Analysis was done on solicited safety set. | Within 30 minutes after any vaccination | 
| Number of Subjects With Solicited Local and Systemic AEs in Groups BC_35_12 and C_35_12 After Any rMenB+OMV NZ or MenC-CRM Vaccination | Safety was assessed in terms of number of subjects with solicited local and systemic AEs after any vaccination with rMenB+OMV NZ or MenC-CRM. Analysis was done on solicited safety set. | Day 1 to day 7 after any vaccination | 
| Number of Subjects Reporting Unsolicited AEs Following Any Vaccination With rMenB+OMV NZ in Groups B_2h3h5_11, B_3h5_11 and B_68_11 | Safety was assessed in terms of number of subjects reporting any unsolicited AEs (day 1-7 after any vaccination), serious adverse events (SAEs), medically attended AEs, AEs leading to premature withdrawal from the study (collected throughout the study period) following any vaccination with rMenB+OMV. Analysis was done on unsolicited safety set. | Until 12 months of age; Day 1 to day 7 (All AEs) | 
| Number of Subjects Reporting Unsolicited AEs Following Any Vaccination With rMenB+OMV NZ in Groups B_02_2_5 and B_02_6_10 | Safety was assessed in terms of number of subjects reporting any unsolicited AEs (day 1-7 after any vaccination), serious adverse events (SAEs), medically attended AEs, AEs leading to premature withdrawal from the study (collected throughout the study period) following any vaccination with rMenB+OMV NZ. Analysis was done on unsolicited safety set. | Day 1 to day 7 (All AEs). Throughout the study period (SAEs, medically attended or leading to premature withdrawal AEs) | 
| Number of Subjects Reporting Unsolicited AEs Following Any Vaccination With rMenB+OMV NZ in Group BC_35_12 and C_35_12 | Safety was assessed in terms of number of subjects reporting any unsolicited AEs (day 1-7 after any vaccination), serious adverse events (SAEs), medically attended AEs, AEs leading to premature withdrawal from the study (collected throughout the study period) following any vaccination with rMenB+OMV NZ or MenC-CRM. Analysis was done on unsolicited safety set. | Day 1 to Day 301 for BC_35_12 and C_35_12, Day 302 to Day 391 for C_35_12; Day 1 to day 7 (All AEs) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Meningococcal disease, Vaccines, intercalated administration