Safety of multicomponent meningococcal group B vaccine (4CMenB) in routine infant immunisation in the UK: a prospective surveillance study

doi:10.1016/S2352-4642(18)30103-2

The Lancet Child & Adolescent Health

Volume 2, Issue 6, June 2018, Pages 395-403

https://doi.org/10.1016/S2352-4642(18)30103-2 Get rights and content

Summary

Background

Safety data for the multicomponent meningococcal group B vaccine (4CMenB) has so far been limited to experience from clinical trials and isolated local outbreaks. Since the UK is the first country to implement a nationwide routine immunisation programme with 4CMenB (at age 8 weeks, 16 weeks, and then 1 year), we aimed to assess the safety of 4CMenB in this setting.

Methods

In this prospective surveillance study, we assessed suspected adverse reactions of 4CMenB in children up to age 18 months reported in the UK Yellow Card Scheme and primary care records extracted from the Clinical Practice Research Datalink (CPRD). We proactively assessed reports of fever, local reactions, Kawasaki disease, seizures, and sudden death, and compared the number of spontaneous reports with the expected number of events based on background incidence and the number of children vaccinated. We also identified any unexpected adverse reactions and estimated compliance with subsequent doses of routine vaccinations.

Findings

From Sept 1, 2015, to May 31, 2017, approximately 1·29 million children aged 2–18 months received about a combined 3 million doses of 4CMenB. 902 reports of suspected adverse reactions were received through the UK Yellow Card Scheme, of which 366 (41%) were related to local reactions and 364 (40%) related to fever. The only unexpected finding was that 160 reports of local reactions described a persistent nodule at the site of injection, usually without other local symptoms. There were 55 (6%) reports of seizures, with an age-adjusted observed-to-expected ratio of 0·13 (95% CI 0·10–0·17). Ecological analyses found similar rates of seizures within 7 days of routine immunisation in the periods before and after 4CMenB introduction, with incidence rate ratios of 1·30 (95% CI 0·56–3·00) at age 2 months, 1·53 (0·49–4·74) at age 4 months, and 1·26 (0·69–2·32) at age 12 months. Of the 902 reports, three (<1%) were of Kawasaki disease (observed-to-expected ratio 1·40, 95% CI 0·29–4·08) and three (<1%) of sudden infant death syndrome within 3 days of vaccination in children aged 2–4 months (0·44, 0·12–1·14). Analysis of routine immunisations recorded in CPRD found that 11 602 (95·1%) of 12 199 children had received the second dose of 4CMenB by 26 weeks of age, 1793 (84·7%) of 2117 had received the third dose by 62 weeks of age, and 4CMenB introduction had not reduced compliance with doses of other routine vaccinations.

Interpretation

We found no significant safety concerns after widespread use of 4CMenB in UK infants, and the vaccine appears to have been well accepted by parents. However, it is important to continue monitoring the safety and long-term effect of the immunisation programme in the UK to further characterise the reported suspected adverse reactions.

Funding

None.

Introduction

In September, 2015, the UK became the first country to implement a nationwide routine infant immunisation programme with a multi-component, broad-spectrum meningococcal group B vaccine (4CMenB; Bexsero, GlaxoSmithKline Biologicals, Belgium).¹ Before this programme, the use of 4CMenB was limited mainly to clinical trials and in localised disease outbreaks. As advised by the UK Joint Committee on Vaccination and Immunisation,² the vaccine is recommended for all infants alongside their routine immunisations at age 8 weeks (diphtheria, tetanus, and acellular pertussis, inactivated polio, and Haemophilus influenzae type b vaccine [DTaP/IPV/Hib]; 13-valent pneumococcal conjugate vaccine [PCV13]; and the oral rotavirus vaccine) and age 16 weeks (DTaP/IPV/Hib and PCV13), followed by a booster on their first birthday, given concomitantly with an H influenzae type b and meningococcal C combination vaccine; the measles, mumps, and rubella (MMR) vaccine; and PCV13. Children attending for their routine vaccinations at 12 weeks of age were also eligible for 4CMenB vaccination as a limited catch-up at the beginning of the immunisation programme. There was no catch-up campaign for older cohorts. Because of high reported numbers of fever and other vaccine-associated reactions when 4CMenB is coadministered with the other routine immunisations in those aged 1 year,3, 4 three doses of prophylactic paracetamol are recommended to be given with the 8-week and 16-week immunisations; the first dose of paracetamol should be administered around the time of vaccination with two additional doses at 4–6 h intervals.5, 6

Research in context

Evidence before this study

We considered published reports of pre-licensure pivotal clinical trials and post-licensure use in Canada of the multicomponent meningococcal group B vaccine (4CMenB). In these reports, 4CMenB was associated with high rates of local reactions and fever when given at the same time as other routine infant vaccines. However, very rare adverse reactions and the potential effect of the increased reactogenicity can only be identified and characterised during use in large population cohorts.

Added value of this study

Following widespread use of 4CMenB in UK infants, the safety profile appears consistent with that seen in clinical trials, with local reactions and fever being the most commonly reported adverse reactions. Additionally, our study showed no significant new safety concerns arising and high compliance with the second and third 4CMenB doses, and the addition of 4CMenB to the routine infant immunisation schedule did not seem to have had an adverse effect on compliance with other vaccinations.

Implications of all the available evidence

Alongside the emerging data for vaccine effectiveness, the experience so far from the UK routine immunisation programme shows that 4CMenB has a favourable benefit–risk profile. It is important that safety remains under continual review to further characterise the reported suspected adverse reactions.

Early data suggested that laboratory-confirmed cases of invasive meningococcal group B infection halved in vaccine-eligible infants during the first 10 months of the immunisation programme, with an estimated effectiveness of 94% against vaccine-preventable strains.⁷ The Medicines and Healthcare Products Regulatory Agency (MHRA) has statutory responsibility for the safety of vaccines and medicines in the UK, and the UK National Institute for Biological Standards and Control (NIBSC) is a batch release authority for 4CMenB. In this study, we aimed to present the outcome of an MHRA and NIBSC proactive pharmacovigilance strategy for 4CMenB since its introduction in the UK's routine infant immunisation programme.

Section snippets

Data sources

We assessed suspected adverse reactions of 4CMenB using data from the UK Yellow Card Scheme. Introduced in 1964, the Yellow Card Scheme is a passive safety surveillance system through which health-care professionals and members of the public can report a spontaneous suspected adverse reaction to any vaccine or medicinal product directly to the MHRA. Yellow Cards can be submitted by post, online, or via a smartphone application. Pharmaceutical companies are also legally obliged to report serious

Results

From Sept 1, 2015, to May 31, 2017, an estimated 1·29 million first doses, 1·17 million second doses, and 585 000 third doses were administered to approximately 1·29 million infants in the UK as part of the national immunisation schedule. During this 20-month surveillance period, the MHRA received 902 Yellow Card reports, of which 467 (52%) were coded as serious, for 4CMenB in children younger than 18 months across the UK (including all reports with unspecified age), equivalent to a passive

Discussion

After more than 3 million doses given to about 1·29 million infants over 20 months across the UK, our analysis is the most comprehensive assessment of 4CMenB safety to date. The safety profile of 4CMenB has been broadly as expected, with no serious safety concerns identified so far, and the anticipated reactogenicity has not adversely affected compliance with subsequent vaccine doses. Alongside the data for vaccine effectiveness, the experience so far from the UK routine immunisation programme

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Co-administration with Men-B vaccine increases Rotavirus vaccination coverage: A 5-year regionwide retrospective cohort study (STORM study)
2024, Vaccine
In Italy Rotavirus vaccination (RVV) is provided free of charge from 2018, however, the coverage is scattered and suboptimal. The narrow time frame to complete the schedule is a barrier to uptake, and co-administration with other vaccines may potentially increase the coverage. Although the co-administration of RV vaccine and Meningococcal Group B vaccine (MenB) is not included in the product labels, we aimed at studying its impact on RVV coverage.
This Surveillance study on Timing and cOverage of Rotavirus and MenB vaccine co-administration (STORM study) used the Regional Vaccination Registry to collect data about children born in Campania Region between January 2016 and December 2020, and receiving vaccines scheduled in the first year of life.
Among the 224,110 children enrolled, 60,614 (27.0%) completed the RVV schedule, with a vaccination rate that increased over time from 1.15% in 2016 to 56.92% in 2020.
The first and last dose of RVV schedule were administered beyond the recommended time in 6% of the study population, respectively.
Co-administration of RV vaccine with MenB vaccine increased from 0.7 % in 2016 to 46.85 % in 2020. Children receiving RV/MenB vaccines concomitantly had a significantly higher chance of completing the RV schedule compared to those receiving RVV alone during a specific appointment (94.78 % vs 72.26 %, Prevalence Ratio -PR- 1.275, 95 %CI 1.245–1.295p < 0.00001). The positive driving effect of RV/MenB co-administration was more evident for children receiving pentavalent (PR 1.288) than monovalent RVV (PR 1.115) which was confirmed when adjusted for confounding variables (i.e., year of vaccination, local district, gender).
Although still far from the target, RVV coverage has increased in recent years in Campania Region. Co-administration with MenB vaccine may aid in increasing RVV coverage, especially for pentavalent RVV. Further safety data are needed to support co-administration as a key tool to increase coverage.
Public health perspective of a pentavalent meningococcal vaccine combining antigens of MenACWY-CRM and 4CMenB
2022, Journal of Infection
Invasive meningococcal disease (IMD) is a life-threatening disease that can rapidly progress to death or leave survivors with severe, life-long sequelae. Five meningococcal serogroups (A, B, C, W and Y) account for nearly all IMD. Meningococcal serogroup distribution fluctuates over time across the world and age groups. Here, we consider the potential public health impact of a pentavalent MenABCWY vaccine developed to help further control meningococcal disease and improve immunisation rates.
The GSK MenABCWY vaccine combines the antigenic components of MenACWY-CRM (Menveo®) and 4CMenB (Bexsero®), building on a wide body of clinical experience and real-world evidence. Both approved vaccines have acceptable safety profiles, demonstrate immunogenicity, and are broadly used, including in national immunisation programmes in several countries. Since the advent of quadrivalent vaccines, public health in relation to IMD has improved, with a decline in the overall incidence of IMD and an increase in vaccine coverage.
A pentavalent MenABCWY has the potential to provide further public health benefits through practical, broad IMD protection programmes encompassing serogroups A, B, C, W and Y, and is currently in late-stage development.
Immunogenicity of a single 4CMenB vaccine booster in adolescents 11 years after childhood immunisation
2022, Vaccine
The clinical development of the meningococcal vaccine, 4CMenB, included 2 doses in vaccine-naïve adolescents, which was considered unlikely to be cost-effective for implementation. Theoretically, priming with 4CMenB in early childhood might drive strong immune responses after only a single booster dose in adolescents and reduce programmatic costs. To address this question, children over 11 years old who took part in previous trials involving the administration of 3–5 doses of 4CMenB at infant/preschool age from 2006 were recruited into a post licensure single-centre trial, and were divided into two groups: those who received their last dose at 12 months old (infant group) and those who received their last dose at 3 years old (infant + preschool group). Naïve age-matched controls were randomised to receive one (adolescent 1 group) or two doses at days 0 and 28 (adolescent 2 group) of 4CMenB. Serum bactericidal antibody (SBA) assays using human complement were performed against three reference strains prior to vaccination, and at 1, 6 and 12 months. Previous vaccination was associated with a higher response to a single booster dose at 11 years of age, one-month post-vaccination, when compared with a single dose in naïve age-matched controls. At day 180, the highest responses were observed in participants in the infant + preschool group against strain 5/99 (GMT 316.1 [CI 158.4 to 630.8]), as compared with naïve adolescents who received two doses (GMTs 84.5 [CI 57.7 to 123.6]). When the last dose was received at 12-months of age, responses to a single adolescent dose were not as robust (GMT 61.1 [CI 14.8 to 252.4] to strain 5/99). This descriptive study indicates that the highest SBA responses after a single dose in adolescence were observed in participants who received a preschool dose, suggesting that B cell memory responses are not sufficiently primed at less than 12 months of age.
Trial registration EudraCT 2017-004732-11, ISRCTN16774163.
Timing of meningococcal vaccination with 4CMenB (Bexsero®) in children with invasive meningococcal group B (MenB) disease in England
2022, Vaccine
Timely vaccination is critical for providing early protection against meningococcal B (MenB) disease because of the high incidence in early childhood. We assessed the timeliness of vaccination in children with confirmed MenB disease after 4CMenB (a recombinant protein-based vaccine) implementation into the national infant immunisation programme in England.
Public Health England (PHE) conducts surveillance of invasive meningococcal disease (IMD) in England. Children born since 01 July 2015 who developed MenB disease between 01 September 2015 and 31 August 2019 (four surveillance years) were included in the analysis.
There were 276 children with laboratory-confirmed MenB disease, including 36 infants who were too young for vaccination, 59 who were eligible for one 4CMenB dose, 104 for two doses and 77 for 3 doses before they developed MenB disease. Prior to developing MenB disease, there were 59 opportunities for vaccination with two 4CMenB doses in 48/104 (46.5%) eligible infants and 41 opportunities in 28/77 (36.6%) children aged ≥ 1 year who were under-immunised. A schedule with a shorter interval at 8 and 12 weeks of age, compared to the current schedule at 8 and 16 weeks, had the potential to offer an additional 4CMenB dose to 35/58 infants (58.6%) who developed MenB disease between 10 and 18 weeks of age.
A high proportion of infants and toddlers with laboratory-confirmed MenB disease had not received their scheduled 4CMenB vaccine prior to developing MenB disease. An infant priming schedule with a shorter interval of 4 weeks has the potential to provide earlier protection against MenB disease.
Recent advances in the prevention of meningococcal B disease: real evidence from 4CMenB vaccination
2021, Vacunas
4CMenB es una vacuna que confiere protección frente a la enfermedad meningocócica invasiva por el serogrupo B (EMI por MenB). Autorizada en todo el mundo a partir de los datos de inmunogenicidad y seguridad, disponemos ahora de datos de su efectividad e impacto. Hemos revisado de manera exhaustiva toda la evidencia recopilada en el mundo real desde su autorización.
Los datos de 7 países aportan evidencia de efectividad e impacto en diferentes entornos y grupos de edad, incluidos programas de inmunización nacionales/regionales, estudios observacionales y control de brotes. La administración de al menos 2 dosis de 4CMenB redujo la enfermedad meningocócica invasiva (EMI) por MenB en un 50-100% en personas de 2 meses a 20 años. Las estimaciones de la efectividad vacunal en las cohortes completamente vacunadas oscilaron entre el 59 y el 100%. El perfil de seguridad de 4CMenB en el mundo real se correspondió con los datos de los ensayos clínicos previos a su autorización.
La EMI por MenB es una enfermedad poco frecuente pero potencialmente mortal, con una epidemiología imprevisible. Los datos sobre efectividad e impacto de 4CMenB respaldan su uso para la prevención de la EMI. Los resultados subrayan la importancia de la protección directa de los grupos con mayor riesgo: lactantes/niños pequeños y adolescentes. La protección directa a través de la inmunización sistemática en los lactantes (con rescate de los niños pequeños) y la vacunación sistemática en la adolescencia podrían constituir la modalidad preferida para el control de la enfermedad por MenB.
En Figshare encontrará un resumen en vídeo relacionado con este artículo: https://doi.org/10.6084/m9.ﬁgshare.
The 4CMenB vaccine confers protection against serogroup B invasive meningococcal disease (MenB IMD). Licensed worldwide based on immunogenicity and safety data, we now have data on its effectiveness and impact. We have exhaustively reviewed all the evidence gathered in the real world since the vaccine was licensed.
Data from 7 countries provide evidence of effectiveness and impact in different settings and age groups, including national/regional immunisation programmes, observational studies, and outbreak control.
The administration of at least 2 doses of 4CMenB reduced IMD by 50-100% in individuals from 2 months to 20 years of age. Estimation of the effectiveness of the vaccine in fully vaccinated cohorts ranged from 59 to 100%. The real-world safety profile of 4CMenB corresponded with the data from the clinical trials undertaken prior to its licensing.
MenB IMD is a rare but potentially fatal disease, with unpredictable epidemiology. The data on the effectiveness and impact data of 4CMenB support its use in the prevention of IMD. The results underline the importance of directly protecting the groups most at risk: infants/young children and adolescents. Direct protection through systematic immunisation in infancy (with salvage in young children) and systematic immunisation in adolescents could constitute the preferred model for the control of MenB disease.
Recent advances in meningococcal B disease prevention: real-world evidence from 4CMenB vaccination
2021, Journal of Infection
Citation Excerpt :
They include the administration of more than 3 million 4CMenB doses in infants in the UK;64,65 administration to approximately 30,500 adolescents in South Australia;66 passive surveillance in Australia after market introduction;67 surveillance during implementation in university outbreaks the US;68 and post-marketing surveillance in Italy60 and Germany.69 Post-marketing surveillance in the UK found no evidence of an increased risk of seizures, febrile seizures or Kawasaki disease after 4CMenB vaccination.64,65 No immune-mediated or neurological safety signals were identified in post-marketing surveillance in Germany.69
4CMenB is a broadly protective vaccine against invasive meningococcal capsular group B disease (MenB IMD). Licensed worldwide based on immunogenicity and safety data, effectiveness and impact data are now available. We comprehensively reviewed all available real-world evidence gathered from use of 4CMenB since licensure.
Data from 7 countries provide evidence of effectiveness and impact across different healthcare settings and age-groups, including national/regional immunization programs, observational studies and outbreak control. At least 2 4CMenB doses reduced MenB IMD by 50%-100% in 2-month to 20-year-olds depending on length of follow-up. Estimates of vaccine effectiveness in fully vaccinated cohorts ranged from 59%-100%. The safety profile of 4CMenB administered in real-world settings was consistent with pre-licensure clinical trial data.
MenB IMD is an uncommon but life-threatening disease with unpredictable epidemiology. The substantial body of data demonstrating 4CMenB effectiveness and impact supports its use in IMD prevention. The results reinforce the importance of direct protection of the highest risk groups; infants/young children and adolescents. Direct protection via routine infant immunization with catch-up in young children and routine adolescent vaccination could be the preferred option for MenB disease control.
A Video Abstract linked to this article is available on Figshare: https://doi.org/10.6084/m9.figshare.14546790.

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ArticlesSafety of multicomponent meningococcal group B vaccine (4CMenB) in routine infant immunisation in the UK: a prospective surveillance study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Data sources

Results

Discussion

J Infect

Lancet

Lancet

Lancet

Lancet

Vaccine

Vaccine

Vaccine

JCVI position statement on use of Bexsero meningococcal B vaccine in the UK

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

Question 1: does prophylactic paracetamol prevent fever after vaccination in infants?

Arch Dis Child

A phase 2 randomized controlled trial of a multicomponent meningococcal serogroup B vaccine (I)

Hum Vaccin Immunother

Data resource profile: Clinical Practice Research Datalink (CPRD)

Int J Epidemiol

Safety of pertussis vaccine in pregnant women in UK: observational study

BMJ

Statistical bulletin: unexplained deaths in infancy, England and Wales

Rising incidence of Kawasaki disease in England: analysis of hospital admission data

BMJ

Statistical bulletin: unexplained deaths in infancy, England and Wales

Articles
Safety of multicomponent meningococcal group B vaccine (4CMenB) in routine infant immunisation in the UK: a prospective surveillance study