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

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

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].

Study Overview

• Status: Completed
• Conditions: Meningococcal Infections
• Intervention / Treatment: Biological: MMRV; Biological: 4CMenb; Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB; Biological: conjugated pneumococcal vaccine

• Study Type: Observational
• Enrollment (Actual): 4535

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Healthy children aged 2 to 14 months selected to participate in clinical trials assessing the safety and immunogenicity of 4 component meningococcal serogroup B vaccine (4CMenB) in Austria, Belgium, Czech Republic, Finland, Germany, Italy, Spain, United Kingdom.

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
• 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.

Study Plan

How is the study designed?

Number of groups / cohorts

7

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Coadministration B_RV246; 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; Other Names: Bexsero; Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB; Other Names: Infanrix Hexa; Biological: conjugated pneumococcal vaccine; Other Names: Prevenar
Coadministration B_RV234; 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; Other Names: Bexsero; Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB; Other Names: Infanrix Hexa; Biological: conjugated pneumococcal vaccine; Other Names: Prevenar
Coadministration B_MMRV12; 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: MMRV; Other Names: Priorix Tetra; Biological: 4CMenb; Other Names: Bexsero; Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB; Other Names: Infanrix Hexa; Biological: conjugated pneumococcal vaccine; Other Names: Prevenar
Separate administration B246_RV357; 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; Other Names: Bexsero; Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB; Other Names: Infanrix Hexa; Biological: conjugated pneumococcal vaccine; Other Names: Prevenar
Separate administration B12_MMRV13; 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: MMRV; Other Names: Priorix Tetra; Biological: 4CMenb; Other Names: Bexsero; Biological: diphtheria,tetanus,pertussis+polio+Hepatitis B+HiB; Other Names: Infanrix Hexa; Biological: conjugated pneumococcal vaccine; Other Names: Prevenar
Routine vaccines only at 2, 3 and 4 months of age (RV234); 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; Other Names: Infanrix Hexa; Biological: conjugated pneumococcal vaccine; Other Names: Prevenar
Routine vaccines only at 2, 4 and 6 months of age.(RV246); 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; Other Names: Infanrix Hexa; Biological: conjugated pneumococcal vaccine; Other Names: Prevenar

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: CHU de Quebec-Universite Laval
• Collaborators: GlaxoSmithKline; Canadian Immunization Research Network
• Investigators: Principal Investigator: Gaston De Serres, MD, PhD, Chu De Quebec

Publications and helpful links

General Publications

• 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.
• Vesikari T, Esposito S, Prymula R, Ypma E, Kohl I, Toneatto D, Dull P, Kimura A; EU Meningococcal B Infant Vaccine Study group. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. Lancet. 2013 Mar 9;381(9869):825-35. doi: 10.1016/S0140-6736(12)61961-8. Erratum In: Lancet. 2013 Mar 9;381(9869):804.
• Baker MA, Lieu TA, Li L, Hua W, Qiang Y, Kawai AT, Fireman BH, Martin DB, Nguyen MD. A vaccine study design selection framework for the postlicensure rapid immunization safety monitoring program. Am J Epidemiol. 2015 Apr 15;181(8):608-18. doi: 10.1093/aje/kwu322. Epub 2015 Mar 13.
• 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.

Helpful Links

• Rapport intérimaire de surveillance de la sécurité de la première dose du vaccin contre le méningocoque de sérogroupe B au Saguenay-Lac-Saint-Jean

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (ACTUAL): August 1, 2010
• Study Completion (ACTUAL): April 1, 2019

Study Registration Dates

• First Submitted: March 14, 2016
• First Submitted That Met QC Criteria: March 17, 2016
• First Posted (ESTIMATE): March 18, 2016

Study Record Updates

• Last Update Posted (ACTUAL): August 7, 2019
• Last Update Submitted That Met QC Criteria: August 5, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: interaction; vaccine safety
• 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; Heptavalent Pneumococcal Conjugate Vaccine
• Other Study ID Numbers: 1224 (Lineberger Cancer Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO