Bexsero™and Routine Infant Vaccines: Effect of Coadministration on the Safety of Immunization

Study Overview
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Brief Summary
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Bexsero™ is a four component serogroup B meningococcal vaccine (4CMenB) licensed in Europe, Canada, and Australia in 2014. Prelicensure studies and post marketing surveillance data showed that 4CMenB has a high reactogenicity especially when coadministered with other infant routine vaccines [1-2]. While this suggests that coadministration causes an interaction resulting in a greater risk of adverse events following Immunization (AEFI) only the AEFI after the 4CMenB dose and not those occurring after routine vaccine immunizations were reported, underestimating the total risk associated with immunization at separate visits. For financial and practical reasons, coadministration of infant vaccines is preferred to separate visits. Separate visits may however be preferred if the sum of the AEFI risk at each visit is significantly smaller than the risk with coadministration and/or if the AEFI has a lesser severity. The purpose of this study is to recalculate the risk of occurrence and severity of AEFI with the coadministration of Bexsero™ and routine vaccines compared to separate injections to assess the interaction occurring with co-administration. Investigators will also estimate the risk of recurrence of AEFI at subsequent immunizations with the 4CMenB and assess if this risk varies with separate or coadministration with routine vaccines. To achieve these purposes, investigators will perform a secondary analysis of the data of three randomized controlled trials (clinicaltrials.gov identifiers: NCT00657709, NCT00847145 and NCT00721396) that evaluated 5025 children aged 2 to 14 months of whom 4535 were randomized to receive 3 to 4 doses of 4CMenB concomitantly or alternatively with routine vaccinations (DTaP-Inactivated polio virus -HepatitisB/Haemophilus influenzae type b [Infanrix Hexa™], Pneumococcal conjugate vaccine, 7 valent [Prevenar™] or Measles-Mumps-Rubella-Varicella vaccine [Priorix-Tetra™]) [1,2].

Official Title
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Interaction Between Meningococcal Serogroup B Vaccine (Bexsero™) and Routine Infant Vaccines on the Risk of Occurrence and Recurrence of Adverse Events Following Immunization.

Conditions
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Meningococcal Infections

Intervention / Treatment
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* Biological: 4CMenb
* Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB
* Biological: conjugated pneumococcal vaccine
* Biological: MMRV


Participation Criteria
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Eligibility Criteria
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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 Parent/legal guardian has given written informed consent after the nature of the study has been explained. Main 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.

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 14 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Coadministration B_RV246<br>Subjects in this group received 4CMenB vaccine at 2, 4, and 6 months of age, administered concomitantly with routine infant vaccinations (Infanrix Hexa+Prevenar). | Biological: 4CMenb<br> <br> * Other names: Bexsero;Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB<br> <br> * Other names: Infanrix Hexa;Biological: conjugated pneumococcal vaccine<br> <br> * Other names: Prevenar;|
| Coadministration B_RV234<br>Subjects in this group received 4CMenB vaccine at 2, 3 and 4 months of age, administered concomitantly with routine infant vaccinations (Infanrix Hexa+Prevenar).. | Biological: 4CMenb<br> <br> * Other names: Bexsero;Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB<br> <br> * Other names: Infanrix Hexa;Biological: conjugated pneumococcal vaccine<br> <br> * Other names: Prevenar;|
| Coadministration B_MMRV12<br>Subjects in this group previously received three doses of 4CMenB and routine vaccine at 2, 4 and 6 months of age,respectively. They also received a booster (fourth) dose at 12 months of age concomitantly with one dose of MMRV vaccine. | Biological: 4CMenb<br> <br> * Other names: Bexsero;Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB<br> <br> * Other names: Infanrix Hexa;Biological: conjugated pneumococcal vaccine<br> <br> * Other names: Prevenar;Biological: MMRV<br> <br> * Other names: Priorix Tetra;|
| Separate administration B246_RV357<br>Subjects in this group received 4CMenB vaccine at 2, 4, and 6 months of age; routine infant vaccinations (Infanrix Hexa+Prevenar) were administered at 3, 5 and 7 months of age. | Biological: 4CMenb<br> <br> * Other names: Bexsero;Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB<br> <br> * Other names: Infanrix Hexa;Biological: conjugated pneumococcal vaccine<br> <br> * Other names: Prevenar;|
| Separate administration B12_MMRV13<br>Subjects in this group previously received three doses of 4CMenB and routine vaccines (Infanrix Hexa+Prevenar) at 2, 4 and 6 months of age. They also received a booster (fourth) dose of 4CMenB at 12 months of age and one dose of MMRV vaccine at 13 months of age. | Biological: 4CMenb<br> <br> * Other names: Bexsero;Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB<br> <br> * Other names: Infanrix Hexa;Biological: conjugated pneumococcal vaccine<br> <br> * Other names: Prevenar;Biological: MMRV<br> <br> * Other names: Priorix Tetra;|
| Routine vaccines only at 2, 3 and 4 months of age (RV234)<br>Subjects in this group received routine infant vaccines (Infanrix Hexa+Prevenar) at 2, 3 and 4 months of age. | Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB<br> <br> * Other names: Infanrix Hexa;Biological: conjugated pneumococcal vaccine<br> <br> * Other names: Prevenar;|
| Routine vaccines only at 2, 4 and 6 months of age.(RV246)<br>Subjects in this group received routine infant vaccines (Infanrix Hexa+Prevenar) at 2, 4 and 6 months of age. | Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB<br> <br> * Other names: Infanrix Hexa;Biological: conjugated pneumococcal vaccine<br> <br> * Other names: Prevenar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fever | Temperature ≥ 38°C | AT RISK INTERVAL 4CMenB and inactivated routine vaccines (InRV) : Onset 24 hours following immunization (post-Imm). MMRV: Onset day 5 to day 13 post-Imm.CONTROL INTERVAL 4CMenB and InRV : Onset day 4 to 7post-Imm . MMRV: Onset day 0 to 4 post-Imm | 
| Systemic reactions other than fever | systemic signs/symptoms (e.g. change in eating habits, sleepiness, unusual crying, vomiting, diarrhea, irritability…) without signs of localized infection (respiratory, urinary, etc...). | AT RISK INTERVAL 4CMenB and InRV : Onset 24 hours post-Imm. MMRV: Onset day 5 to day 13 post-Imm.CONTROL INTERVAL 4CMenB and InRV : Onset day 4 to 7post-Imm . MMRV: Onset day 0 to 4 post-Imm | 
| Fever or systemic reactions other than fever | all systemic signs/symptoms including fever (Temperature ≥ 38°C) | AT RISK INTERVAL 4CMenB and InRV : Onset 24 hours post-Imm. MMRV: Onset day 5 to day 13 post-Imm.CONTROL INTERVAL 4CMenB and InRV : Onset day 4 to 7post-Imm . MMRV: Onset day 0 to 4 post-Imm | 
| Injection site reactions |  | AT RISK INTERVAL all injection site reactions regardless of their delay of onset. Baseline (CONTROL) risk null. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vaccine safety, interaction