Safety, Tolerability and Immunogenicity of Meningococcal B Recombinant Vaccine Administered With or Without Routine Infant Vaccinations to Healthy Infants According to Different Immunization Schedules

A Phase 2b, Open Label, Randomized, Parallel-Group, Multi-Center Study to Evaluate the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine When Administered With or Without Routine Infant Vaccinations to Healthy Infants According to Different Immunization Schedules.

Primary :1.To demonstrate a sufficient immune response of rMenB+OMV NZ, when given concomitantly with routine infant vaccines to healthy infants at 2, 4 and 6 and 2, 3 and 4 months of age, as measured by percentage of subjects with serum bactericidal activity (SBA) titer ≥1:5, at 1 month after the third vaccination Secondary :To demonstrate that immunogenicity of routine infant vaccines, when given concomitantly with rMenB+OMV NZ to healthy infants at 2, 3 and 4 months of age, was non-inferior to that of routine infant vaccines given without rMenB+OMV NZ. 2. To demonstrate that the immunogenicity of rMenB+OMV NZ when given concomitantly with routine infant vaccines was non-inferior to that of rMenB+OMV NZ given without routine infant vaccines at 2, 4 and 6 months of age. 3. To assess prevalence of meningococcal B antibodies over the study period by evaluation of SBA, at baseline and at 1 month after third vaccination, in subjects- received routine infant vaccine without rMenB+OMV NZ.

Study Overview

• Status: Completed
• Conditions: Meningococcal Infections
• Intervention / Treatment: Biological: rMenB+OMV NZ; Biological: combined diphtheria,tetanus,pertussis+polio+Hepatitis B+Haemophilus influenzae B vaccine; Biological: Pneumococcal vaccine

• Study Type: Interventional
• Enrollment (Actual): 1885
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium, 2018
    • Novartis Investigational Site Nr. 55
  • Namur, Belgium, 5000
    • Novartis Investigational Site Nr. 58
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Novartis Investigational Site Nr. 59
  • Brussels-Capital Region
    • Brussels, Brussels-Capital Region, Belgium, 1090
      • Study Investigational Site Nr. 60
    • Brussels, Brussels-Capital Region, Belgium, 1200
      • Novartis Investigational Site Nr. 57
  • Limburg
    • Hasselt, Limburg, Belgium, 3500
      • Novartis Investigational Site Nr. 56
• Czech Republic
  • Hradec Králové, Czech Republic, 500 00
    • Novartis Investigational Site Nr. 93
  • Pardubice, Czech Republic, 530 01
    • Novartis Investigational Site Nr. 94
  • Hradec Králové
    • Červený Kostelec, Hradec Králové, Czech Republic, 549 41
      • Novartis Investigational Site Nr. 95
  • South Bohemian
    • Jindřichův Hradec, South Bohemian, Czech Republic, 377 01
      • Novartis Investigational Site Nr. 96
• Germany
  • Berlin, Germany, 13125
    • Novartis Investigational Site Nr. 70
  • Hamburg, Germany, 22415
    • Novartis Investigational Site Nr. 72
  • Baden-Württemberg
    • Bad Saulgau, Baden-Württemberg, Germany, 88348
      • Novartis Investigational Site Nr. 68
    • Bretten, Baden-Württemberg, Germany, 75015
      • Novartis Investigational Site Nr. 65
    • Kehl, Baden-Württemberg, Germany, 77694
      • Novartis Investigational Site Nr. 62
    • Oberstenfeld, Baden-Württemberg, Germany, 71720
      • Novartis Investigational Site Nr. 64
    • Welzheim, Baden-Württemberg, Germany, 73642
      • Novartis Investigational Site Nr. 66
  • Bavaria
    • Aschaffenburg, Bavaria, Germany, 63739
      • Novartis Investigational Site Nr. 69
  • Bremen
    • Bremerhaven, Bremen, Germany, 27568
      • Novartis Investigational Site Nr. 71
  • Hesse
    • Baunatal, Hesse, Germany, 34225
      • Novartis Investigational Site Nr. 73
  • Lower Saxony
    • Bramsche, Lower Saxony, Germany, 49565
      • Novartis Investigational Site Nr. 75
  • North Rhine-Westphalia
    • Bochum, North Rhine-Westphalia, Germany, 44866
      • Novartis Investigational Site Nr. 81
    • Heiligenhaus, North Rhine-Westphalia, Germany, 42579
      • Novartis Investigational Site Nr. 79
    • Kleve Materborn, North Rhine-Westphalia, Germany, 47533
      • Novartis Investigational Site Nr. 80
    • Monchengladbach, North Rhine-Westphalia, Germany, 41236
      • Novartis Investigational Site Nr. 78
    • Munster, North Rhine-Westphalia, Germany, 48163
      • Novartis Investigational Site Nr. 82
    • Warburg, North Rhine-Westphalia, Germany, 34414
      • Novartis Investigational Site Nr. 83
  • North-Rhine Westphalia
    • Bielefeld, North-Rhine Westphalia, Germany, 33617
      • Novartis Investigational Site Nr. 85
  • Rhineland-Palatinate
    • Mainz, Rhineland-Palatinate, Germany, 55131
      • Novartis Investigational Site Nr. 61
    • Schweigen, Rhineland-Palatinate, Germany, 76889
      • Novartis Investigational Site Nr. 67
  • Saxony-Anhalt
    • Wanzleben, Saxony-Anhalt, Germany, 39164
      • Novartis Investigational Site Nr. 86
  • Schleswig-Holstein
    • Itzenhoe, Schleswig-Holstein, Germany, 25524
      • Novartis Investigational Site Nr. 88
    • Itzenhoe, Schleswig-Holstein, Germany, 25524
      • Novartis Investigational Site Nr. 89
    • Stockelsdorf, Schleswig-Holstein, Germany, 23617
      • Novartis Investigational Site Nr. 87
  • Thuringia
    • Erfurt, Thuringia, Germany, 99086
      • Novartis Investigational Site Nr. 90
• Italy
  • Lombardy
    • Milano, Lombardy, Italy, 20122
      • Novartis Investigational Site Nr. 5
    • Milano, Lombardy, Italy, 20157
      • Novartis Investigational Site Nr. 52
  • Piedmont
    • Novara, Piedmont, Italy, 28100
      • Novartis Investigational Site Nr. 6
  • Tuscany
    • Firenze, Tuscany, Italy, 50139
      • Novartis Investigational Site Nr. 7
  • Veneto
    • Padova, Veneto, Italy, 35100
      • Novartis Investigational Site Nr. 9
• Spain
  • Valencia, Spain, 46011
    • Novartis Investigational Site Nr. 17
  • Valencia, Spain, 46017
    • Novartis Investigational Site Nr. 24
  • Valencia, Spain, 46021
    • Novartis Investigational Site Nr. 15
  • Valencia, Spain, 46022
    • Novartis Investigational Site Nr. 18
  • Valencia, Spain, 46022
    • Novartis Investigational Site Nr. 19
  • Valencia, Spain, 46024
    • Novartis Investigational Site Nr. 16
  • Valencia, Spain, 46200
    • Novartis Investigational Site Nr. 23
  • A Coruña
    • Santiago de Compostela, A Coruña, Spain, 15706
      • Novartis Investigational Site Nr. 46
  • Asturias
    • Oviedo, Asturias, Spain, 33006
      • Novartis Investigational Site Nr. 49
  • Castelló
    • Vall D'Uixo, Castelló, Spain, 12600
      • Novartis Investigational Site Nr. 12
  • Castellón
    • Almassora, Castellón, Spain, 12550
      • Novartis Investigational Site Nr. 11
    • Castellon de la Plana, Castellón, Spain, 12006
      • Novartis Investigational Site Nr. 10
  • Pontevedra
    • Vigo Pontevedra, Pontevedra, Spain, 36204
      • Novartis Investigational Site Nr. 48
  • Valencia
    • Catarroja, Valencia, Spain, 46470
      • Novartis Investigational Site Nr. 25
    • La Eliana, Valencia, Spain, 46183
      • Novartis Investigational Site Nr. 21
    • Sagunto, Valencia, Spain, 46500
      • Novartis Investigational Site 14
• United Kingdom
  • London, United Kingdom, SW17 0RE
    • Novartis Investigational Site Nr. 2
  • South East England
    • Oxford, South East England, United Kingdom, OX3 7LE
      • Novartis Investigational Site Nr. 1
  • South West England
    • Bristol, South West England, United Kingdom, BS8 1TH
      • Novartis Investigational Site 3
    • Exeter, South West England, United Kingdom, EX2 5DW
      • Novartis Investigational Site Nr. 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 2 months (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy 2-month old infants (55-89 days, inclusive), who were 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.

Exclusion Criteria:

• History of any meningococcal B or C vaccine administration;
• prior vaccination with routine infant vaccines (Diphtheria, Tetanus, Pertussis, Polio, Haemophilus influenzae type b (Hib), and Pneumococcal antigens);
• Previous ascertained or suspected disease caused by 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 axillary temperature major or equal to38 degrees within the previous day;
• Antibiotics within 6 days prior to enrollment;
• Any serious chronic or progressive disease;
• Known or suspected impairment or alteration of the immune system;
• Receipt of blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: B+R246; Subjects in this group received rMenB+OMV NZ vaccine at 2, 4, and 6 months of age, administered concomitantly with routine infant vaccinations.	Biological: rMenB+OMV NZ; Biological: combined diphtheria,tetanus,pertussis+polio+Hepatitis B+Haemophilus influenzae B vaccine; Other Names: Infanrix Hexa; Biological: Pneumococcal vaccine; Other Names: Prevenar
Experimental: B246_R357; Subjects in this group received rMenB+OMV NZ vaccine at at 2, 4, and 6 months of age; routine infant vaccinations were administered at 3, 5 and 7 months of age.	Biological: rMenB+OMV NZ; Biological: combined diphtheria,tetanus,pertussis+polio+Hepatitis B+Haemophilus influenzae B vaccine; Other Names: Infanrix Hexa; Biological: Pneumococcal vaccine; Other Names: Prevenar
Experimental: B+R234; Subjects in this group received rMenB+OMV NZ vaccine at 2, 3, 4 months of age, administered concomitantly with routine infant vaccinations.	Biological: rMenB+OMV NZ; Biological: combined diphtheria,tetanus,pertussis+polio+Hepatitis B+Haemophilus influenzae B vaccine; Other Names: Infanrix Hexa; Biological: Pneumococcal vaccine; Other Names: Prevenar
Active Comparator: R234; Subjects in this group received routine infant vaccines administered at 2, 3 and 4 months of age.	Biological: combined diphtheria,tetanus,pertussis+polio+Hepatitis B+Haemophilus influenzae B vaccine; Other Names: Infanrix Hexa; Biological: Pneumococcal vaccine; Other Names: Prevenar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects With Serum Bactericidal Activity ≥1:5 After Receiving Three Doses of rMenB+OMV NZ Vaccine	The percentage of subjects with serum bactericidal activity(hSBA)titer ≥1:5 after receiving three doses of rMenB+OMV NZ vaccine were evaluated to demonstrate sufficient immune response following rMenB+OMV NZ vaccination, when given concomitantly with routine infant vaccines to healthy infants. The serum bactericidal antibodies directed against serogroup B meningococci, are measured by human complement Serum Bactericidal Assay (hSBA). The immune response was considered sufficient for groups B+R246 and B+R234 if the lower limit of the 2-sided 95% confidence interval was ≥ 70% for all three strains.	One month after third Men B vaccination
Safety and Tolerability of 3 Doses of rMenB - Concomitantly With Routine Infant Vaccines at 2, 4 and 6 Months of Age - Concomitantly With Routine Vaccines at 2, 3 and 4 Months of Age - Alone at 2, 4 and 6 Months of Age	Safety and Tolerability of 3 Doses of rMenB was assessed in terms of the number of subjects who reported solicited local and systemic adverse events when administered concomitantly with routine infant vaccines at 2,4,6 months of age (B+R246) to when rMenB+OMV NZ and routine vaccines were administered separately (group B246_R357).	10 months (groups 1 and 2); 8 months (groups 3 and 4)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-inferiority of Immune Response to rMenB+OMV NZ Vaccination When Administered Concomitantly With Routine Infant Vaccines at 2,4,6 Months of Age	The non-inferiority of immune response to rMenB+OMV NZ vaccination when administered concomitantly with routine infant vaccines at 2,4,6 months of age(B+R246) to when rMenB+OMV NZ and routine vaccines were administered separately (group B246_R357)was assessed in terms of percentage of subjects With hSBA≥ 1:5.	One month after 3rd Men B vaccination
Non-inferiority of Immune Response to Diphtheria and Tetanus Antigens When Routine Vaccines Are Administered Concomitantly With rMen+OMV NZ Vaccine	Non-inferiority of immune response to routine vaccine antigens when routine vaccines were administered concomitantly with rMenB+OMV NZ vaccine [group B+R234] to when only routine vaccines were given [Group R234] were assessed in terms of percentage of subjects with antibody concentrations ≥0.1 IU/mL against Diphtheria and Tetanus antigens as measured by enzyme-linked immunosorbent assay.	One month after 3rd vaccination
Geometric Mean Titers Against Neisseria Meningitidis Serogroup B, When rMenB+OMV NZ Vaccine is Administered Concomitantly With Routine Infant Vaccines.	The hSBA antibody titers when rMenB+OMV NZ vaccine is administered concomitantly with routine infant vaccines to when rMenB+OMV NZ vaccine and routine vaccines were given separately are reported in terms of vaccine-group-specific geometric mean titers.	One month after third Men B vaccination
Geometric Mean Ratio of hSBA Titers, When rMenB+OMV NZ Vaccine is Administered Concomitantly With Routine Infant Vaccines.	The geometric mean ratio(GMR) of GMTs at 1 month after 3rd rMenB+OMV NZ vaccination to prevaccination GMTs, when rMenB+OMV NZ was administered concomitantly with routine infant vaccines to when rMenB+OMV NZ vaccine and routine vaccines were given separately.	one month after third Men B vaccination
Percentage of Subjects With hSBA ≥1:8 After Receiving Three Doses of rMenB+OMV NZ Vaccine.	The percentage of subjects with hSBA titers ≥1:8, following rMenB+OMV NZ vaccination when given concomitantly with routine infant vaccines to when rMenB+OMV NZ and routine vaccines were given separately.	One month after third Men B vaccination
Percentage of Subjects With 4-fold Rise in hSBA Titers, When rMenB+OMV NZ Vaccine is Administered Concomitantly With Routine Infant Vaccines.	The percentage of subjects with 4-fold rise in hSBA titers at 1 month after 3rd rMenB+OMV NZ vaccination from baseline, when rMenB+OMV NZ was administered concomitantly with routine infant vaccines to when rMenB+OMV NZ vaccine and routine vaccines were given separately.	One month after third Men B vaccination
Non-inferiority of Immune Response to Acellular Pertussis Antigens When Routine Vaccines Are Administered Concomitantly With rMen+OMV NZ Vaccine.	Non-inferiority of immune response to routine vaccine antigens when routine vaccines were administered concomitantly with rMenB+OMV NZ vaccine [group B+R234] to when only routine vaccines were given [Group R234] were assessed in terms of percentage of subjects achieving seroconversion for pertussis antigens - Filamentous Hemagglutinin (FHA), Pertactin and Pertussis Toxoid (PT) at 1 month after 3rd vaccination versus baseline. Seroconversion was defined as a 4-fold increase for each pertussis antigen or in those initially seropositive, persistence of the pre-vaccination antibody concentration at least at the same antibody concentration as before vaccination, taking into account the decay of maternal antibodies.	1 month after 3rd vaccination

Collaborators and Investigators

• Sponsor: Novartis Vaccines

Publications and helpful links

General Publications

• Zafack JG, Bureau A, Skowronski DM, De Serres G. Adverse events following immunisation with four-component meningococcal serogroup B vaccine (4CMenB): interaction with co-administration of routine infant vaccines and risk of recurrence in European randomised controlled trials. BMJ Open. 2019 May 19;9(5):e026953. doi: 10.1136/bmjopen-2018-026953.
• Gossger N, Snape MD, Yu LM, Finn A, Bona G, Esposito S, Principi N, Diez-Domingo J, Sokal E, Becker B, Kieninger D, Prymula R, Dull P, Ypma E, Toneatto D, Kimura A, Pollard AJ; European MenB Vaccine Study Group. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA. 2012 Feb 8;307(6):573-82. doi: 10.1001/jama.2012.85.

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: July 22, 2008
• First Submitted That Met QC Criteria: July 23, 2008
• First Posted (Estimate): July 24, 2008

Study Record Updates

• Last Update Posted (Estimate): March 23, 2015
• Last Update Submitted That Met QC Criteria: March 17, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Infants; Prevention,; Meningococcal disease,; Neisseria meningitidis serogroup B,; Vaccination,
• Additional Relevant MeSH Terms: Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Neisseriaceae Infections; Meningococcal Infections; Physiological Effects of Drugs; Immunologic Factors; Vaccines; Heptavalent Pneumococcal Conjugate Vaccine
• Other Study ID Numbers: V72P12