Short-term safety of 4CMenB vaccine during a mass meningococcal B vaccination campaign in Quebec, Canada
Introduction
Between 2007 and 2011, the incidence in Canada of invasive meningococcal disease due to serogroup B (IMD-B) was 0.33 per 100 000 person-years, nearly three times the rate reported in the United States [1], [2]. The province of Quebec had the highest incidence at 0.76 per 100 000 person-years and this was associated with the emergence of strains belonging to the ST-269 clonal complex [3]. The Saguenay– Lac-St-Jean was the most affected region of the province with an overall incidence of 3.4/100,000 between 2006 and 2013, nearly 5 times the provincial average, and an incidence of 11.5/100,000 person-years in individuals <20 years-old [3]. As the ST-269 cc expressed two (fHbp and NHBA) of the four antigens (PorA, NadA, fHbp and NHBA) included in the four-component serogroup B meningococcal vaccine (4CMenB) (Bexsero®, previously Novartis Vaccines now GSK), a vaccination campaign targeting ≈60,000 individuals 2 months-20 years-old was launched in May 2014 in this region shortly after Canadian licensure of this product [3].
At the time of the Quebec vaccination campaign, available vaccine safety data on 4CMenB were based on 7 published clinical trials conducted in ≈9,000 individuals including 7,200 infants ≤12 months, 113 children 40–44 months, and 1,755 adolescents and adults 11–50 years-old [4], [5], [6], [7], [8], [9], [10]. These previous data showed the 4CMenB to be quite reactogenic and associated with a higher incidence of fever occurring shortly after each dose and local reactions than other pediatric vaccines. Antipyretic prophylaxis reduces the risk of fever following administration of 4CMenB in infants [11]. Other safety signals of possible concern emerging from these studies included Kawasaki Disease (KD) [5], [6], febrile convulsions [5], [6], fever ≥40 °C [6], severe arthralgia and juvenile arthritis [4], [9], as well as relatively high rates of post-vaccination absenteeism [4]. Because of the limited clinical experience with this vaccine, the Quebec Ministry of Health mandated active surveillance for adverse events following immunization (AEFIs) with the 4CMenB vaccine in order to closely monitor its safety profile as the campaign progressed.
This article describes the findings of this active surveillance for the seven-day period following each dose with a focus on the reduction of fever associated with antipyretic prophylaxis and on absenteeism during this period related to injection site reactions or systemic AEFIs.
Section snippets
Methods
The vaccination campaign targeted all individuals born between May 6, 1993 and December 31, 2014 and residing or attending an educational institution in the region. Vaccination was voluntary and administered free of charge in schools for individuals 5–20 years-old and in public health clinics for others, starting on May 5, 2014. As recommended by the manufacturer, the schedule consisted of 4 doses for children 2 to 5 months of age (three infant doses with a two-month interval and a fourth dose
Vaccine coverage and participation in active surveillance
By July 17, 2015, 83% and 77% of the 59,098 individuals targeted by the campaign had received a first and a second dose of 4CMenB and 88% and 40% of eligible infants had received their third and fourth doses, respectively (Table 1). Overall, 70% of vaccinees provided an email address. Participation rates in the active surveillance component ranged by age from 31% to 39% among vaccinees with an email address (18% to 27% among all vaccinees). There were few differences between the
Discussion
This enhanced surveillance evaluation of a large-scale population use of the 4CMenB vaccine identified no unexpected AEFIs during the seven days post-immunization and showed a short-term safety profile consistent with previous findings under more limited clinical trial conditions. The vaccine was associated, as anticipated, with painful injection site reactions which, along with malaise and fever, resulted in absenteeism in 3%-5% of vaccinees for each dose. Co-administration with other
Contributors’ statements
Gaston De Serres, Marie-Noëlle Billard conceptualized and designed the study, supervised the data collection, carried out the initial analysis and drafted the initial manuscript.
Marie-Claude Gariépy, Isabelle Rouleau conceptualized and designed the study, made substantial contribution to the data collection and analysis, and revised critically the article for important intellectual content.
Eveline Toth, Monique Landry, Nicole Boulianne, Hélène Gagné, Vladimir Gilca, Geneviève Deceuninck, Manale
Acknowledgements
We would like to thank Chantale Bilodeau, France Bouchard, Sophie Auger, Rémi Gagné, Maryline Vivion, Joseline Zafack and the nurses who contacted individuals who reported serious adverse events.
Funding source
This study was funded by the Quebec Ministry of Health and Social Services (Ministère de la Santé et des Services sociaux du Québec) which had no role in the study design, the data collection, analysis and interpretation of data, in the writing of the report and in the decision to submit the article for publication.
Conflict of Interest
Gaston De Serres has received grants for investigator-initiated studies from GSK and Pfizer and provided paid expert testimony for the Ontario Nurses Association, the Quebec Ministry of Justice and GSK. Other authors have no conflicts of interest to declare.
References (26)
- et al.
Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study
Lancet
(2012) - et al.
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) - et al.
Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials
Lancet
(2009) - et al.
Rapid surveillance for health events following a mass meningococcal B vaccine program in a university setting
A Can Immun Res Network study. Vacc
(2016) - et al.
Safety of multicomponent meningococcal group B vaccine (4CMenB) in routine infant immunisation in the UK: a prospective surveillance study
Lancet Child Adolesc Health
(2018) - National Advisory Comittee on Immunization. Advice for the use of the Multicomponent Meningococcal Serogroup B (4CMenB)...
- et al.
Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP)
MMWR Recomm Rep
(2013) - et al.
Impact of an immunization campaign to control an increased incidence of serogroup B meningococcal disease in one region of Quebec, Canada
Clin Infect Dis Off Publ Infect Dis Soc Am.
(2017) - et al.
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) - et al.
Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates
Clin Vaccine Immunol mars
(2011)
Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy
Clin Infect Dis
Persistence of bactericidal antibodies following early infant vaccination with a serogroup B meningococcal vaccine and immunogenicity of a preschool booster dose
CMAJ
The first use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in humans
Hum Vaccin
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2020, VaccineCitation Excerpt :The delivery of healthy infants in our study participants provides some reassurance of no adverse impact in pregnancy, although data are limited and safe use in pregnancy cannot be inferred. To control the spread of MenB disease in the Saguenay-Lac-Saint-Jean region in Quebec, Canada, a targeted program was implemented for people up to 20 years of age attending educational institutions in this region [7,8]. AEFI following the first dose were monitored in real-time for early identification of any safety signals.
Surveillance of invasive meningococcal disease in the Tel Aviv District, Israel, 2007–2017
2019, VaccineCitation Excerpt :First, due to logistic challenges. 4CMenB would need to be given separately due to the high incidence of fever after vaccine administration [17,18] and its need for fever prophylaxis, which is not recommended for the other vaccines routinely administered [19,20]. This would require additional appointments and work force.
Nephrotic syndrome following four-component meningococcal B vaccination: Epidemiologic investigation of a surveillance signal
2019, VaccineCitation Excerpt :Dose 3 had been administered to 3443 infants and dose 4 to 1050. Ten SAEs, all related to hospitalizations, were reported for the 7 day period following immunization: three for bronchospasm, three for bronchiolitis, two for febrile seizures, one for anaphylaxis and one for mesenteric lymphadenitis [9]. During the period between dose1 and dose2 (∼four months for children ≥ 1 year old) and the six-month period following the last dose, 272 (115 after dose1 and 157 after dose2) participants respectively reported an SAE (Table 1).