Study of the Safety and Immune Response of a Meningococcal Vaccine Administered to Healthy Infants

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, immunogenicity and induction of immune memory after two or three doses of Novartis (Formerly Chiron) Meningococcal ACWY Conjugate Vaccine administered to healthy infants.

Official Title
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A Phase II, Randomized, Open Label, Controlled, Multicenter Study to Evaluate the Safety, Immunogenicity and Induction of Immunological Memory After Two or Three Doses of Novartis (Formerly Chiron) Meningococcal ACWY Conjugate Vaccine Administered to Healthy Infants at 2, 3, 4 or 2, 4, 6 Months of Age

Conditions
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Prevention of Meningococcal Disease

Intervention / Treatment
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* Biological: MenACWY Ad- (MenACWY-CRM, non adjuvanted formulation)
* Biological: MenACWY Ad+ (MenACWY-CRM, adjuvanted formulation)
* Biological: MenACWY PS (MenACWY-CRM, polysaccharide vaccine)
* Biological: HBV (Hepatitis B vaccine)
* Biological: Prevnar (pneumococcal polysaccharide serotypes 4, 9V, 14, 18C, 19F, 23F & 6B conjugated to the CRM197)
* Biological: MMR (Measles, Mumps and Rubella vaccine)
* Biological: DTaPHibIPV (Diphtheria, Tetanus, acellular Pertussis, H. Influenzae type b, Inactivated Poliovaccine)
* Biological: Menjugate (Men C conjugated vaccine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Individuals eligible for enrollment in this study were male, and female infants: Who were 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 has given written informed consent after the nature of the study has been explained; Who were available for all the visits scheduled in the study; Who were in good health as determined by: Medical history; Physical examination; Clinical judgment of the investigator. Exclusion Criteria Ineligible for the study were infants: Whose parents/legal guardians were unwilling, or unable to give written informed consent for the subject to participate in the study; Who previously received any meningococcal vaccine; Who received prior vaccination with D, T, P (acellular, or whole cell), IPV, or OPV, HBV, H influenzae type b (Hib), or Pneumococcus; Who had a previously ascertained or suspected disease caused by N meningitidis, C diphtheriae, C tetani, Poliovirus, Hepatitis B, Hib, Pneumococcus, or B pertussis (history of laboratory-confirmed or clinical condition of spasmodic cough for a period ≥ 2 weeks associated with apnea or whooping cough); Who had household contact with and/or intimate exposure to an individual with laboratory-confirmed N meningitis (serogroups A, C, W-135, or Y), B pertussis, Hib, C diphtheriae, Polio, or pneumococcal infection since birth; Who had a history of any anaphylactic shock, asthma, urticaria, or other allergic reaction after previous vaccinations, or known hypersensitivity to any vaccine component; Who had experienced significant acute or chronic infection within the previous 7 days, or fever (≥ 38.0°C) within the previous 3 days; Who had any present, or suspected serious, acute (e.g., leukemia, lymphomas), or chronic disease (e.g., with signs of cardiac, renal failure, or severe malnutrition, or insulin-dependent diabetes); or progressive neurological disease; or a genetic anomaly or known cytogenic disorders (e.g., Downs syndrome); 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 immunostimulant since birth; receipt of any systemic corticosteroid since birth. Who had a suspected or known HIV infection, or HIV-related disease; Who had ever received blood, blood products and/or plasma derivatives, or any parenteral immunoglobulin preparation; Who had a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time; Who had a history of seizure disorder: Febrile seizure; Any other seizure disorder. Who had taken systemic antibiotics (either oral or parenteral) within the previous 14 days (EXCEPTION: subjects who received an oral or parenteral β-lactam antibiotic [examples: penicillin, amoxicillin, ceftriaxone, cefuroxime, cephalexin, etc.] may be enrolled 7 days following the last dose); Who with their parents/legal guardians were planning to leave the area of the study site before the end of the study period; Who had any condition that, in the opinion of the investigator, might interfere with the evaluation of the study objectives; Who had taken any antipyretic medication in the previous 6 hours.

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 6 Months

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: UK234+ (MenACWY Ad+ at 2, 3, 4 m)<br>Three doses of MenACWY Ad+ vaccine were given at 1-month intervals concomitantly with DTaPHibIPV at 2, 3, and 4 months of age in the UK group. A fourth dose of MenACWY Ad+ was given at 12 months of age. | Biological: MenACWY Ad+ (MenACWY-CRM, adjuvanted formulation)<br>* MenACWY-CRM conjugate vaccine formulated with adjuvant was injected IM in the anterolateral area of the right thigh.<br>Biological: DTaPHibIPV (Diphtheria, Tetanus, acellular Pertussis, H. Influenzae type b, Inactivated Poliovaccine)<br>* DTaPHibIPV at 2, 3, 4 months of age, administered IM in the anterolateral area of the left thigh.<br>|
| Experimental: UK24+ (MenACWY Ad+ at 2, 4 m)<br>Two doses of MenACWY Ad+ vaccine were given at a 2-month interval concomitantly with DTaPHibIPV at 2 and 4 months of age. A third dose of MenACWY Ad+ vaccine was given at 12 months of age. | Biological: MenACWY Ad+ (MenACWY-CRM, adjuvanted formulation)<br>* MenACWY-CRM conjugate vaccine formulated with adjuvant was injected IM in the anterolateral area of the right thigh.<br>Biological: DTaPHibIPV (Diphtheria, Tetanus, acellular Pertussis, H. Influenzae type b, Inactivated Poliovaccine)<br>* DTaPHibIPV at 2, 3, 4 months of age, administered IM in the anterolateral area of the left thigh.<br>|
| Experimental: UKMenC (Menjugate at 2, 4 m)<br>Two doses of Menjugate were given at a 2-month interval concomitantly with DTaPHibIPV at 2 and 4 months of age. One dose of MenACWY Ad+ vaccine was given at 12 months of age. | Biological: MenACWY Ad+ (MenACWY-CRM, adjuvanted formulation)<br>* MenACWY-CRM conjugate vaccine formulated with adjuvant was injected IM in the anterolateral area of the right thigh.<br>Biological: DTaPHibIPV (Diphtheria, Tetanus, acellular Pertussis, H. Influenzae type b, Inactivated Poliovaccine)<br>* DTaPHibIPV at 2, 3, 4 months of age, administered IM in the anterolateral area of the left thigh.<br>Biological: Menjugate (Men C conjugated vaccine)<br>* Menjugate was injected IM in the anterolateral area of the right thigh.<br>|
| Experimental: CA246+ (MenACWY Ad+ at 2, 4, 6 m)<br>Three doses of MenACWY Ad+ vaccine were given at 2-month intervals concomitantly with DTaPHibIPV, HBV, and Prevnar at 2, 4, and 6 months of age of the Canadian group (Prevnar at 6 months was optional and was given if available).One subgroup of subjects was given a reduced dose (1/5) of MenACWY PS vaccine concomitantly with MMR (and Prevnar, if available) at 12 months of age. Another subgroup was administered one dose of MMR (and Prevnar, if available) at 12 months of age. | Biological: MenACWY Ad+ (MenACWY-CRM, adjuvanted formulation)<br>* MenACWY-CRM conjugate vaccine formulated with adjuvant was injected IM in the anterolateral area of the right thigh.<br>Biological: MenACWY PS (MenACWY-CRM, polysaccharide vaccine)<br>* MenACWY polysaccharide vaccine was injected in the anterolateral area of the right thigh.<br>Biological: HBV (Hepatitis B vaccine)<br>* Hepatitis B vaccine at 2, 4, 6 months of age administered IM in the anterolateral area of the left thigh.<br>Biological: Prevnar (pneumococcal polysaccharide serotypes 4, 9V, 14, 18C, 19F, 23F & 6B conjugated to the CRM197)<br>* Prevnar was administered IM in the anterolateral area of the left thigh.<br>Biological: MMR (Measles, Mumps and Rubella vaccine)<br>* MMR at 12 month of age, administered in the left arm.<br>Biological: DTaPHibIPV (Diphtheria, Tetanus, acellular Pertussis, H. Influenzae type b, Inactivated Poliovaccine)<br>* DTaPHibIPV at 2, 3, 4 months of age, administered IM in the anterolateral area of the left thigh.<br>|
| Experimental: CA24+ (MenACWY Ad+ at 2, 4 m)<br>Two doses of MenACWY Ad+ vaccine were given at a 2-month interval concomitantly with DTaPHibIPV, HBV, and Prevnar at 2 and 4 months of age.One dose of MenACWY Ad+ vaccine or one reduced dose (1/5) of MenACWY PS vaccine was given concomitantly with MMR (and Prevnar, if available) at 12 months of age. | Biological: MenACWY Ad+ (MenACWY-CRM, adjuvanted formulation)<br>* MenACWY-CRM conjugate vaccine formulated with adjuvant was injected IM in the anterolateral area of the right thigh.<br>Biological: MenACWY PS (MenACWY-CRM, polysaccharide vaccine)<br>* MenACWY polysaccharide vaccine was injected in the anterolateral area of the right thigh.<br>Biological: HBV (Hepatitis B vaccine)<br>* Hepatitis B vaccine at 2, 4, 6 months of age administered IM in the anterolateral area of the left thigh.<br>Biological: Prevnar (pneumococcal polysaccharide serotypes 4, 9V, 14, 18C, 19F, 23F & 6B conjugated to the CRM197)<br>* Prevnar was administered IM in the anterolateral area of the left thigh.<br>Biological: MMR (Measles, Mumps and Rubella vaccine)<br>* MMR at 12 month of age, administered in the left arm.<br>Biological: DTaPHibIPV (Diphtheria, Tetanus, acellular Pertussis, H. Influenzae type b, Inactivated Poliovaccine)<br>* DTaPHibIPV at 2, 3, 4 months of age, administered IM in the anterolateral area of the left thigh.<br>|
| Experimental: UK24- (MenACWY Ad- at 2, 4 m)<br>Two doses of MenACWY Ad- vaccine were given at a 2-month interval concomitantly with DTaPHibIPV at 2 and 4 months of age. A third dose of MenACWY Ad- vaccine was given at 12 months of age. | Biological: MenACWY Ad- (MenACWY-CRM, non adjuvanted formulation)<br>* MenACWY-CRM conjugate vaccine formulated without adjuvant was injected IM (intramuscularly) in the anterolateral area of the right thigh.<br>Biological: DTaPHibIPV (Diphtheria, Tetanus, acellular Pertussis, H. Influenzae type b, Inactivated Poliovaccine)<br>* DTaPHibIPV at 2, 3, 4 months of age, administered IM in the anterolateral area of the left thigh.<br>|
| Experimental: CA24- (MenACWY Ad- at 2, 4 m)<br>Two doses of MenACWY Ad- vaccine were given at a 2-month interval concomitantly with DTaPHibIPV, HBV, and Prevnar at 2 and 4 months of age.One dose of MenACWY Ad- vaccine or one reduced dose of MenACWY PS vaccine was given concomitantly with MMR (and Prevnar, if available) at 12 months of age. | Biological: MenACWY Ad- (MenACWY-CRM, non adjuvanted formulation)<br>* MenACWY-CRM conjugate vaccine formulated without adjuvant was injected IM (intramuscularly) in the anterolateral area of the right thigh.<br>Biological: MenACWY PS (MenACWY-CRM, polysaccharide vaccine)<br>* MenACWY polysaccharide vaccine was injected in the anterolateral area of the right thigh.<br>Biological: HBV (Hepatitis B vaccine)<br>* Hepatitis B vaccine at 2, 4, 6 months of age administered IM in the anterolateral area of the left thigh.<br>Biological: Prevnar (pneumococcal polysaccharide serotypes 4, 9V, 14, 18C, 19F, 23F & 6B conjugated to the CRM197)<br>* Prevnar was administered IM in the anterolateral area of the left thigh.<br>Biological: DTaPHibIPV (Diphtheria, Tetanus, acellular Pertussis, H. Influenzae type b, Inactivated Poliovaccine)<br>* DTaPHibIPV at 2, 3, 4 months of age, administered IM in the anterolateral area of the left thigh.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of Subjects With hSBA Titers ≥ 1:4 Against N. Meningitidis Serogroups A, C, W, and Y Following 3 Doses of MenACWY Ad+ Vaccine | Immunogenicity was measured as the percentage of subjects with human serum bactericidal assay (hSBA) titers ≥ 1:4 and associated 95% CI, directed against N. Meningitidis serogroups A, C, W and Y, at the baseline and 1 month after primary vaccination by groups. | Baseline and at 1 month after the 3 dose primary vaccination series | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of Subjects With hSBA Titers ≥ 1:8 Against N. Meningitidis Serogroups A, C, W, and Y Following 3 Doses of MenACWY Ad+ Conjugate Vaccine | Immunogenicity was measured by percentages of subjects With hSBA titers ≥ 1:8 and associated 95% CI, directed against N. Meningitidis serogroups A, C, W and Y, at baseline and 1 month after primary vaccination by groups. | Baseline and 1 month after the 3 dose primary vaccination series | 
| Geometric Mean hSBA Titers (GMTs) Following 3 Doses of MenACWY Ad+ Conjugate Vaccine | Immunogenicity was measured as hSBA GMTs and associated 95% CI, against N meningitis serogroups A, C, W, and Y, at the baseline and 1 month after primary vaccination by groups. | Baseline and 1 month after the 3 dose primary vaccination series | 
| Percentages of Subjects With hSBA Titers ≥ 1:4 or ≥ 1:8 Against N. Meningitidis Serogroups A, C, W, and Y Following 2 Doses of Novartis MenACWY Ad+ or Novartis MenACWY Ad- Conjugate Vaccines | Immunogenicity was measured as the percentages of subjects With hSBA titers ≥ 1:4 and ≥ 1:8 and associated 95% CI, directed against N. Meningitidis serogroups A, C, W, and Y, at Baseline and 1 month after second vaccination by groups. | Baseline and 1 month after second vaccination | 
| Geometric Mean hSBA Titer (GMTs) Following 2 Doses of MenACWY Ad+ and MenACWY Ad- Conjugate Vaccines | Immunogenicity was measured as hSBA GMTs and associated 95% CI against N. Meningitidis serogroups A, C, W, and Y at baseline and 1 month after second vaccination by groups. | Baseline and 1 month after second vaccination | 
| Percentages of Subjects With hSBA Titers ≥ 1:4 or ≥ 1:8 Against N. Meningitidis Serogroups A, C, W & Y After a Booster Dose of MenACWY Ad+ or Ad- Vaccine in a Subgroup of Subjects Following 2 or 3 Doses or MenACWY Ad+ or 2 Doses of MenACWY Ad- Vaccine | Immunogenicity was measured as the percentages of subjects with hSBA ≥ 1:4 or ≥ 1:8 and associated 95% CI, against N. Meningitidis serogroups A, C, W, and Y, at 12 months of age and 1 month after booster by groups. | at 12 months of age and 1 month after booster vaccination | 
| Geometric Mean hSBA Titers (GMT) After a Booster Dose of MenACWY Ad+ or Ad- Vaccine Conjugate in a Subgroup of Subjects Following Either 2 or 3 Doses of MenACWY Ad+ Vaccine or 2 Doses of MenACWY Ad- Conjugate Vaccines | Immunogenicity was measured as GMT and associated 95% CI against N. Meningitidis serogroups A, C, W, and Y, at 12 months of age and 1 month after booster by group. | at 12 months of age and 1 month after booster vaccination | 
| Percentages of Subjects With hSBA Titers ≥ 1:4 and ≥ 1:8 Against N. Meningitidis Serogroups A, C, W and Y Following 2 Doses of Novartis MenACWY Ad+ Vaccine, Novartis MenACWY Ad- Vaccine or Novartis Menjugate Vaccine | The persistence of immune response was measured as the percentages of subjects with hSBA ≥ 1:4 and ≥ 1:8 against N. Meningitidis serogroups A, C, W, and Y at 12 months of age by groups. | at 12 months of age | 
| Geometric Mean hSBA Titers (GMTs) After 2 Doses of Novartis MenACWY Ad+ Vaccines, Novartis MenACWY Ad- Vaccine, or Novartis Menjugate Vaccine. | The persistence of immune response as measured by hSBA GMT and associated 95% CI against N. Meningitidis serogroups A, C, W, and Y, at 12 months of age by groups. | at 12 months of age | 
| Percentages of Subjects With hSBA Titers ≥ 1:4 and ≥ 1:8 Against N. Meningitidis Serogroup A, C, W and Y Following 3 Doses of Novartis MenACWY Ad+ Conjugate Vaccine | The persistence of immune response as measured by percentages of subjects with hSBA≥ 1:4 and hSBA ≥ 1:8 and associated 95% CI, against N. Meningitidis serogroups A, C, W, and Y, at 12 months by groups. | at 12 months of age | 
| Geometric Mean hSBA Titers (GMTs) Following 3 Doses of Novartis MenACWY Ad+ Conjugate Vaccine | The persistence of immune response as measured by hSBA GMTs and associated 95% CI against N. Meningitidis serogroups A, C, W, and Y,at 12 months by groups. | at 12 months of age | 
| Percentages of Subjects With hSBA Titers ≥ 1:4 or ≥ 1:8 in Subjects Challenged With a Reduced Dose of Licensed Meningococcal ACWY PS Vaccine Following 3 Doses of Novartis MenACWY Ad+ Conjugate Vaccine | The induction of immunological memory was measured as percentages of subjects with hSBA ≥ 1:4 and hSBA ≥ 1:8 and associated 95% CI, against N. Meningitidis serogroups A, C, W, and Y , before challenge at 12 months of age and 1 month after PS challenge. | before challenge at 12 months of age and 1 month after PS challenge. | 
| Geometric Mean hSBA Titers (GMTs) in Subjects Challenged With a Reduced Dose of Licensed Meningococcal ACWY PS Vaccine Following 3 Doses of Novartis MenACWY Ad+ Conjugate Vaccine | The induction of immunological memory was measured as hSBA Geometric Mean Titers (GMTs) and associated 95% CI, directed against N. Meningitidis serogroups A, C, W, and Y , before challenge at 12 months of age and 1 month after PS challenge. | before challenge at 12 months of age and 1 month after PS challenge. | 
| Percentages of Subjects With hSBA Titers ≥ 1:4 or ≥ 1:8 in Subjects Challenged With a Reduced Dose of Licensed Meningococcal ACWY PS Vaccine Following Two Doses of Novartis MenACWY Ad+ or MenACWY Ad- Conjugate Vaccine | The Induction of immunological memory was measured as percentage of subjects with hSBA ≥ 1:4, hSBA ≥ 1:8 and associated 95% CI, directed against N. Meningitidis serogroups A, C, W, and Y, before challenge at 12 months and 1 month after PS challenge by groups. | Before challenge at 12 months of age and 1 month after PS challenge. | 
| Geometric Mean hSBA Titers (GMTs) in Subjects Challenged With a Reduced Dose of Licensed Meningococcal ACWY PS Vaccine Following Two Doses of Novartis MenACWY Ad+ or MenACWY Ad- Conjugate Vaccine | Induction of immunological memory was measured by hSBA Geometric Mean Titers (GMTs) and associated 95% CI, directed against N. Meningitidis serogroups A, C, W, and Y, before challenge at 12 months and 1 month after PS challenge by groups. | Before challenge at 12 months of age and 1 month after PS challenge. | 
| Percentages of Subjects With hSBA ≥ 1:4 and ≥ 1:8 of MenACWY Ad+ Conjugate Vaccine | The immunogenicity was measured as percentages of subject with hSBA≥ 1:4 and hSBA ≥ 1:8 and associated 95% CI, directed against N. Meningitidis serogroups A, C, W, and Y, baseline and 1 month after 2 or 3 dose primary series by groups. | Baseline and 1 month after the 2 or 3 dose primary vaccination series | 
| Percentages of Subjects With hSBA ≥ 1:4 and ≥ 1:8 in Subjects Challenged With a Reduced Dose of a Licensed Meningococcal ACWY PS Vaccine Following 2 or 3 Doses of MenACWY Ad+ Conjugate Vaccine | The memory response was measured as percentages of subjects with hSBA ≥ 1:4 and hSBA ≥ 1:8 and associated 95% CI, directed against N. Meningitidis serogroups A, C, W, and Y, at 12 months of age and 1 month after PS challenge by groups. | at 12 months of age and 1 month after PS challenge | 
| Percentages of Subjects With Antibody Response to Routine Vaccines (Hib, Diphtheria, Tetanus, Hepatitis B) When Routine Vaccines Are Given Concomitantly With Novartis MenACWY Ad+ or Novartis MenACWY Ad- Conjugate Vaccines | To assess the immunogenicity of routine vaccines when given concomitantly to Novartis MenACWY Ad+ or Novartis MenACWY Ad- conjugate vaccines. Hib, diphtheria, tetanus, pertussis will be evaluated as the first priority, followed by pneumococcus, polio, hepatitis B, and MMR (measles, mumps, and rubella) depending on the availability of sera. | Baseline and 1 month after the 2 or 3 dose primary vaccination series | 
| ELISA GMT Concentrations for Routine Vaccines (Hib, Diphtheria, Tetanus, Hepatitis B) When Given Concomitantly With Novartis MenACWY Ad+ or Novartis MenACWY Ad- Conjugate Vaccines for Hib, Diphtheria, Tetanus, Hepatitis B | To assess the Enzyme-linked immunosorbent assay (ELISA) GMT of Hib, Diphtheria, Tetanus, Hepatitis B, administered Concomitantly with Novartis MenACWY Ad+ or MenACWY Ad-conjugate vaccines, at the baseline and 1 month after primary vaccination by groups. | Baseline and 1 month after the 2 or 3 dose primary vaccination series | 
| Percentages of Subjects With hSBA ≥ 1:4 and ≥ 1:8 Against N. Meningitidis Serogroup C Following 2 Doses of MenACWY Ad+ or Ad- Conjugate Vaccine (Containing 5 μg of MenC Oligosaccharide) or 2 Doses of Menjugate (Containing 10 μg of MenC Oligosaccharide) | The immunogenicity was measured as percentages of subjects with hSBA ≥ 1:4 and ≥ 1:8 and associated 95% CI, directed against N. Meningitidis serogroup C, at baseline and 1 month after second vaccination by groups. | Baseline and 1 month after second vaccination | 
| Number of Subjects Reporting Solicited Local and Systemic Adverse Events After 2 or 3 Dose Primary Vaccination Series With MenACWY Ad+ or MenACWY Ad- | Safety and tolerability of Novartis MenACWY Ad+ and MenACWY Ad- conjugate vaccine when given in a 2 or 3 dose primary vaccination series concomitantly with licensed pediatric vaccines. | 7 days after each vaccination | 
| Number of Subjects Reporting Solicited Local and Systemic Adverse Events After MenACWY Ad+ and MenACWY Ad- Booster or Polysaccharide Challenge Administered at 12 Months of Age | The safety profile of Novartis MenACWY Ad+ and MenACWY Ad- conjugate vaccines when given at 12 months of age. | 7 days after vaccination at 12 months of age |