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

Joseline Guetsop Zafack, Alexandre Bureau, Danuta M Skowronski, Gaston De Serres, Joseline Guetsop Zafack, Alexandre Bureau, Danuta M Skowronski, Gaston De Serres

Abstract

Objectives: (1) To assess if co-administration of four-component meningococcal serogroup B vaccine (4CMenB) and other routine vaccines caused an interaction increasing the risk and/or severity of adverse events following immunisation (AEFI) compared with administration at separate visits and (2) to estimate the risk of AEFI recurrence.

Design: Risk-interval design SETTING: Three randomised controlled trials conducted in Europe.

Participants: A total of 5026 healthy 2-month-old to 15-month-old infants.

Interventions: 4CMenB and routine vaccines (hexavalent combined diphtheria-tetanus-acellular pertussis-inactivated polio-Haemophilus influenzae type b-hepatitis B vaccine+seven-valent pneumococcal conjugate vaccine or measles-mumps-rubella-varicella vaccine) administered concomitantly or separately 1 month apart, in regular (2, 4, 6 and 12 months), accelerated (2, 3, 4 and 12 months) or delayed (two doses of 4CMenB at ≥12 months of age) schedules.

Outcome measures: Primary: Fever (≥38°C) during the first 48 hours post immunisation. Secondary: crying, change in eating habits, diarrhoea, irritability and tenderness at the 4CMenB injection site.

Results: Compared with separate administration, concomitant administration decreased the overall incidence of fever (≥38°C), 86% versus 75%, and other systemic AEFIs but increased the incidence of 4CMenB injection site tenderness, 55% versus 66%, moderate/severe fevers (≥39°C), 13% versus 18%, and long-lasting (>1 day) fevers, 23% versus 33%. Co-administration reduced AEFI risk by 4%-49% with the greatest impact among infants with prior AEFI(s). Fever recurrence risk was proportional to the number of prior fever events: 79% at dose 2 with one prior episode; 44% and 74% at dose 3 with one and two prior episodes, respectively; and 29%, 45% and 60% at dose 4 with one, two and three prior episodes, respectively. Severity was not increased at recurrence and a similar pattern of recurrence risk proportional to the number of prior events was observed for other AEFIs.

Conclusions: The cumulative risk of AEFI is reduced with concomitant versus separate administration of 4CMenB and routine infant vaccines. Infants with a prior AEFI are at higher risk of the same AEFI at subsequent immunisations, but severity with recurrence is usually not increased.

Trials registration number: NCT00657709, NCT00847145, NCT00721396 and NCT02712177; Pre-results.

Keywords: 4CMenB; adverse event; interaction; recurrence; vaccine.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Cumulative incidence of adverse events following immunisation (dose 1–3 administered before 12 months of age). 4CMenB, four-component meningococcal serogroup B vaccine; AEFIs, adverse events following immunisations.
Figure 2
Figure 2
Interaction contrast for dose 1–3 administered before 12 months of age evaluating the impact of co-administration in children who previously had the same AEFI or not. AEFI, adverse events following immunisation.

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