Clinical experience with the meningococcal B vaccine, Bexsero®: Prospects for reducing the burden of meningococcal serogroup B disease

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Review

Clinical experience with the meningococcal B vaccine, Bexsero® : Prospects for reducing the burden of meningococcal serogroup B disease Philip S. Watson a,∗,1 , David P.J. Turner b a b

GlaxoSmithKline Services Unlimited, Weybridge, Surrey, UK University of Nottingham and Department of Clinical Microbiology, Nottingham University Hospitals NHS Trust, Nottingham, Nottinghamshire, UK

a r t i c l e

i n f o

Article history: Received 24 June 2015 Received in revised form 4 November 2015 Accepted 16 November 2015 Available online xxx Keywords: Meningococcal disease MenB Bexsero Vaccine Meningitis

a b s t r a c t Although rare, invasive meningococcal disease remains an important cause of mortality and morbidity in children and young adults. Vaccines have been successfully introduced to help protect against meningococcal disease caused by serogroups A, C, W and Y, but until recently, a vaccine for serogroup B (MenB) was not available. In many industrialised countries, MenB causes the majority of meningococcal disease. Moreover, MenB outbreaks occur unpredictably, particularly in high-risk populations, such as university students. In 2013, Bexsero® became the first broad-coverage vaccine to be licensed for active immunisation against MenB disease. Bexsero is now licensed in more than 35 countries worldwide for varying age groups, including the EU, Australia, Brazil, Canada, Chile, Uruguay and the USA. Clinical recommendations for the use of Bexsero have been published in several countries. Recommendations include use in high-risk groups, outbreak control and routine infant immunisation. Since initial licensure, considerable clinical experience has been gained. In Canada, 43,740 individuals received Bexsero during a vaccination programme in the Saguenay–Lac-Saint-Jean region of Quebec, where local disease incidence was high. In the USA, Bexsero was administered to >15,000 individuals during two college outbreaks prior to licensure, under an Investigational New Drug protocol. In the UK, the Joint Committee on Vaccination and Immunisation has recommended the inclusion of Bexsero in the routine immunisation schedule for infants. Publically funded vaccination programmes have been initiated in Italy, and there has been widespread use of the vaccine outside of publically reimbursed programmes. Overall, >1,000,000 doses of Bexsero have been distributed in 19 countries worldwide since 2013. The emerging clinical experience with Bexsero is consistent with findings from pre-licensure clinical studies, and no new safety concerns have been identified. Additional data on length of protection, potential impact on meningococcal carriage and transmission and strain coverage have also been published and will be reviewed. © 2015 Elsevier Ltd. All rights reserved.

1. Introduction Globally, Neisseria meningitidis is responsible for an estimated 1.2 million cases of invasive meningococcal disease (IMD) and 135,000 deaths each year [1]. IMD can be rapidly fatal and, among survivors, sequelae are common: About a tenth have major disabling deficits and more than a third have one or more deficits

∗ Corresponding author. E-mail addresses: [email protected] (P.S. Watson), [email protected] (D.P.J. Turner). 1 PSW was previously an employee of Novartis Vaccines, which is now part of GlaxoSmithKline.

in physical, cognitive and psychological functioning [2–5]. N. meningitidis can be divided into 12 serogroups, defined by the immunochemistry of their capsular polysaccharides [6]. Of these, serogroups A, B, C, W, X and Y are the cause of almost all invasive disease cases [7–9]. Meningococcal serogroup B (MenB) disease occurs throughout the world and is endemic in Europe and Latin America [10]. In Europe, MenB is the leading cause of infant bacterial meningitis and sepsis [6]. This serogroup is also responsible for prolonged outbreaks of disease in Latin America, the Pacific Northwest of the USA, Canada and Australasia [11,12]. Comprehensive vaccination programmes have been successful in aiding the reduction of IMD. In the UK, introduction of a meningococcal C (MenC) vaccine in England and Wales in 1999 successfully helped to reduce the incidence of disease by 81% within

http://dx.doi.org/10.1016/j.vaccine.2015.11.057 0264-410X/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Watson PS, Turner DPJ. Clinical experience with the meningococcal B vaccine, Bexsero® : Prospects for reducing the burden of meningococcal serogroup B disease. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2015.11.057

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2 years [1,13]. In the Netherlands, between 2002 (when the MenC vaccine was introduced) and 2012, there was 99% decrease in the disease in individuals eligible for the vaccine, and a 93% decrease in ineligible individuals [14]. Similarly, between 2002 and 2012, the introduction of the MenC vaccine in Canada saw an 83% decrease in cases of the disease in 15–24-year-olds [15]. The challenge of developing a broadly protective MenB vaccine has been significant due to the poor immunogenicity of the serogroup B capsular polysaccharide and the antigenic variability of subcapsular surface proteins [16]. Achieving the first regulatory approvals in various countries for Bexsero in 2013 was the end result of a circa 15-year development programme using the novel approach of reverse vaccinology [17]. Bexsero combines conserved, highly immunogenic, surface-expressed protein antigens (fHbp, NadA and NHBA) with an outer membrane vesicle (OMV) preparation, previously used successfully to help control a clonal MenB outbreak in New Zealand [18]. The clinical development programme included infants, children and adults (up to 50 years) [19–23]. Overall, 8776 individuals received at least one dose of Bexsero as part of 14 studies, which included nine randomised, controlled trials. Clinical studies showed that Bexsero was suitable for use from 2 months of age and could be co-administered with other routine childhood vaccines. Bexsero is highly immunogenic in infants aged >2 months when administered as a three-dose primary series (followed by a booster in the second year of life) and in older children and adults when administered according to a two-dose schedule (Table 1). Bexsero is approved for use in more restricted age groups in Canada (2 months to 17 years) and the USA (10–25 years) [24,25]. Regulatory approval has been followed by national and regional clinical recommendations from public health authorities in many countries. The impact of Bexsero on the MenB disease burden in individual countries will depend upon the successful implementation of effective vaccination strategies. Appropriate vaccination strategies may vary according to local epidemiology, although modelling studies suggest that a comprehensive vaccination programme including infants and adolescents/young adults may deliver the greatest reduction in MenB disease [26,27].

2. Understanding the potential of a MenB vaccination While data from clinical studies demonstrate that Bexsero provides an effective level of immunogenicity and has an acceptable tolerability profile, the number of subjects enrolled in these studies is comparatively small. The implementation of large-scale vaccination programmes provides further data in a varied patient population. Data on the following factors are important in refining and informing vaccination strategy: strain coverage; safety and tolerability; immunogenicity and length of protection; and impact on nasopharyngeal carriage.

3. Strain coverage The epidemiology of IMD is unpredictable; disease incidence, serogroup prevalence and strain diversity within serogroups all vary considerably over time and by geographical region. Whilst some countries have recently reported downward trends in MenB case numbers, MenB disease incidence has historically been cyclical [28]. The strain coverage of Bexsero has been widely assessed using the Meningococcal Antigen Typing System (MATS), a technique that combines conventional PorA genotyping with an enzyme-linked immunosorbent assay. Applied to individual MenB strains, MATS measures the level of expression of fHbp, NadA and NHBA antigens, and the immunologic cross-reactivity of each with the corresponding vaccine antigen. MATS results predict killing of strains in the serum bactericidal antibody assay (hSBA), the established correlate of disease protection [29,30]. MATS was developed to provide a practical method of predicting MenB strain coverage by Bexsero; the hSBA assay being impractical due to the number of diverse circulating MenB strains and the volumes of serum that would be required [29]. MATS predicts that a high proportion of circulating MenB strains will be covered by Bexsero: Evaluation of 1052 different disease-causing strains of MenB from five European countries between 2007 and 2008 found that Bexsero coverage varied from 73% to 87% (country dependent), with an overall coverage of 78% [19,31]. In Canada, a study of 157 isolates using the MATS assay indicated an overall coverage of 66%, with high levels of coverage of the two most prevalent clones, ST-269 (95%) and ST-154 (100%) [32]. As vaccination programmes using Bexsero are implemented, ongoing surveillance of IMD and assessment of strain coverage will remain important. A study that aimed to validate the accuracy of the MATS assay by comparing it to an hSBA assay, utilising pathogenic MenB strains isolated in England and Wales between 2007 and 2008, found a significant association (p = 0.022). The MATS assay was found to have an accuracy of 78% and a positive predictive value of 96% compared to the hSBA assay [33]. In addition, 66% of the strains that MATS predicted would not be covered were killed in the hSBA assay, suggesting MATS may underestimate strain coverage of the vaccine [33]. This was further corroborated by a Spanish study, which tested 10 MATS-negative strains against adolescent and infant pooled sera from Bexsero-vaccinated subjects. Of these strains, all were killed by the adolescent pooled sera, with 5 of the 10 killed at low hSBA titre levels by the infant pooled sera [34]. While Bexsero is only licensed to protect against disease due to MenB strains, the main vaccine antigens fHbp, NHBA and NadA are also present in other meningococcal serogroups, which suggests that Bexsero may offer some protection against non-MenB strains [35]. In a study by Tomei et al., a panel of 147 strains belonging to serogroups C, W and Y were tested by hSBA, utilising pooled sera from adolescents and infants vaccinated with Bexsero,

Table 1 Posology of Bexsero (according to EU SmPC) [19].a Age group

Primary immunisation

Intervals between primary doses

Booster

Infants 2 months to 5 months

Not less than 1 month

Yes, one dose between 12 and 15 months

Unvaccinated infants, 6 months to 11 months

Three doses each of 0.5 ml, with first dose given at 2 months of age Two doses each of 0.5 ml

Not less than 2 months

Unvaccinated children, 12 months to 23 months

Two doses each of 0.5 ml

Not less than 2 months

Children 2 years to 10 years Adolescents (from 11 years of age) and adultsa

Two doses each of 0.5 ml Two doses each of 0.5 ml

Not less than 2 months Not less than 1 month

Yes, one dose in the second year of life with an interval of at least 2 months between the primary series and booster dose Yes, one dose with an interval of 12 months to 23 months between the primary series and booster dose Need not established Need not established

a

Posology according to EU Bexsero SmPC. Dosing recommendations vary in other regions, as described in the text.

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respectively. Bactericidal activity was observed against most of the strains examined. Overall, 45–90% of MenC, Y and W strains were killed at hSBA titres ≥8 [35]. Since 2009, the UK has seen an increase in IMD caused by MenW, associated with the virulent clonal complex, cc11. In 2013–2014, MenW was responsible for 15% of all cases of IMD in the UK [36]. The Joint Committee on Vaccination and Immunisation (JCVI) has suggested that the inclusion of Bexsero in the UK national immunisation programme may offer some protection against disease caused by the cc11 MenW strain [37].

4. Safety and tolerability The safety and tolerability profile of Bexsero exhibited during the clinical development programme was considered acceptable by regulatory authorities. Recent clinical experience from vaccination campaigns in populations with both active and passive safety reporting has provided valuable additional data. In 2013, prior to the licensure of Bexsero in the USA, the Food and Drug Administration authorised vaccination campaigns under a Centers for Disease Control and Prevention-sponsored Investigational New Drug protocol in response to two unrelated MenB outbreaks on college campuses [38]. Overall, 15,236 individuals were vaccinated, with 28,229 doses of the vaccine administered. The reported rate of serious adverse events (SAEs) was 3.3 per 1000 individuals vaccinated. SAEs included 48 incidences of hospitalisation, one life-threatening event and one death. Causal association with Bexsero was suspected for two SAEs: rhabdomyolysis (possibly related) and anaphylaxis (related) (0.13/1000 vaccinees); both individuals recovered fully. All other SAEs were not related to the vaccine [38]. No cases of MenB disease were reported among vaccinated individuals [38]. In May 2014, the Comité sur l’Immunisation du Québec (CIQ) initiated a targeted vaccination programme in the Saguenay–LacSaint-Jean region of Quebec for individuals ≤20 years who were attending an educational institution or residing in this region, due to the higher local incidence of MenB compared with the rest of the province since 2004 [39]. Overall, 43,740 individuals, between 2 months and 20 years of age, received an initial dose of Bexsero between May and June 2014. Active and passive surveillances for adverse events were conducted. Of the vaccinated individuals, 13,230 and 9559 completed a questionnaire after the first dose and second dose, respectively, to determine the rates of adverse events associated with the vaccine [39,40]. Six percent of vaccinees after the first dose and 9% after the second dose sought a medical consultation due to an adverse event or reported absenteeism (of the vaccine recipient or parent) during the seven days following immunisation. After the first and second dose, 2.9% and 5.7% of vaccinees, respectively, reported absence because of an adverse event. The most frequently reported adverse events that resulted in absenteeism (n = 764) were general malaise (56%), local reactions (49%), gastrointestinal problems (34%) or respiratory problems (24%). During this programme, no unexpected vaccinerelated health problems were reported; however, a relatively high incidence of painful local reactions (97%, n = 2073) among those who reported local reactions as well as relatively high rates of fever (44%, n = 342) and general malaise (35%, n = 270) among individuals who reported systemic events were confirmed. Two children were hospitalised within seven days of vaccination because of SAEs possibly related to the vaccine. The first hospitalisation was due to an allergic reaction (the child having had a similar reaction to another vaccine); the other due to febrile seizures. Both children recovered quickly and completely. Overall, 99% of respondents to the surveillance questionnaire stated their intention to receive the second dose of the vaccine. The school-based vaccination programme has now ended, but infant vaccination is

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continuing [39]. These data have shown no new safety concerns arising from the use of Bexsero in a large vaccination campaign encompassing infants, adolescents and young adults. 4.1. Incidence of fever and its management Clinical experience and study data have shown that fever is a common adverse event, especially in infants and children. Typically, fever occurs soon after vaccination and resolves quickly. In clinical trials, where adverse events were actively monitored, 26–41% of infants experienced fever after receiving Bexsero with no other routine vaccinations [20]. In a summary of two clinical studies in infants, Vesikari et al. found that 77% of infants had a fever of ≥38.5 ◦ C following vaccination with Bexsero, compared with 45% of infants who only received other routine vaccinations [22]. Additionally, the co-administration of the MenB vaccine with other routine childhood vaccinations also appeared to increase the likelihood of fever [20,21,23]. However, the reported incidence of fever in real-world studies has been lower. In the Canadian surveillance programme, fever was reported within seven days by 11% (1346) of vaccinated individuals. The incidence of fever was higher in children <2 years of age (14–15%) compared with children 2–4 years of age (12%) and children ≥5 years (6–8%) [39]. Prophylactic use of paracetamol (acetaminophen) has been reported to reduce the incidence of fever in infants [41]. Oral paracetamol given at the time of vaccination, followed by two further doses at 4–6-h intervals, reduced the incidence of fever by 51–65% in the seven days following vaccination. The use of paracetamol did not have an impact on the immunogenicity of the vaccine or the response to other routine vaccines, demonstrating that fever can be effectively managed with paracetamol [41]. Clinical recommendations on the use of prophylactic paracetamol have been issued by some health authorities. The Australian Technical Advisory Group on Immunisation (ATAGI) recommends the use of prophylactic paracetamol with every dose of Bexsero in children <2 years of age [42]. An initial dose of 15 mg/kg is recommend by ATAGI to be given 30 min prior to immunisation, with a further two doses given 6 h apart, irrespective of the presence of fever [42]. In the UK, it is recommended that paracetamol should be offered prophylactically when Bexsero is given with other routine vaccines in infants under 1 year. Liquid paracetamol should be given orally at a dose of 10–15 mg/kg before or at the time of vaccination. Doses can be repeated every 4–6 h after vaccination if needed [43]. 5. Immunogenicity and duration of protection The immunogenicity of Bexsero was demonstrated during the clinical development programme in all age groups from infants (>2 months) to adults (<50 years) by measurement of hSBA titres to each of the four vaccine antigens [19]. The hSBA is the immunological correlate of protection against IMD and is accepted for vaccine licensure [44]. At the time of licensure, limited information regarding the length of protection against disease was available. However, data on antibody persistence after Bexsero vaccination continue to accumulate (Table 2). Most recently, antibody persistence data from children aged 5 years following an additional pre-school booster have been reported [47,50]. Children were immunised with Bexsero at 6, 8, 12 and 40 months, or at 40 and 42 months. Overall, 67%, 100%, 17% and 45% of those vaccinated with Bexsero in infancy had hSBA titres of ≥1:4 for strains 44/76, 5/99, NZ98/254 and M10713, respectively at 5 years of age [47,50]. In children who were vaccinated with Bexsero at 40 and 42 months of age, 38%, 100%, 0% and 83% had hSBA titres ≥1:4 for the same respective strains at 5 years of age [47,50]. These variable rates

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Table 2 Persistence of protective titres after administration of Bexsero. Initial vaccination age

Age at which vaccine administered (months)

Interval between final dose and hSBA measurement (months)

Infants [45] Infants [46] Infants [47] Toddlers [19,48] Children [47,50] Adolescents [49]

2,4,6,12 6,8,12 6,8,12,40 13,15 40, 42 Two doses

28 28 20 12 18 18–23

% subjects with protective titres, by straina 44/76-SL

5/99

NZ98/254

M10713

65 36 67 74 38 82

76 100 100 97 100 94

41 14 17 18 0 77

67 79 45 38 83 NA

hSBA titres ≥1:4 were considered protective in all studies, except those described in reference 19 and 48 where titres ≥1:5 were considered protective. a Strains were chosen to assess the immunogenicity of each of the four antigenic components of Bexsero. Strains 44/76-SL, 5/99, NZ98/254 and M10713 were used to assess response to fHbp, NadA, PorA (the dominant antigen in OMV) and NHBA, respectively.

of antibody waning make it difficult to estimate the effective duration of protection, but suggest that infant vaccination programmes, even if supplemented with an additional pre-school booster, will not lead to protection extending into adolescence. Similar patterns of antibody waning were seen following MenC vaccination in the UK. However, in the latter case, catch-up campaigns including older children, teenagers and young adults generated significant herd immunity which contributed to the effectiveness of the immunisation programme at a populationbased level [51]. On the basis of unpublished immunogenicity data and previous experience with other vaccines, the JCVI suggested that a twodose schedule of Bexsero in infants, followed by a booster at 12 months, should provide sufficient protection against MenB disease in infants and toddlers [52]. However, the resulting recommendation to implement a routine 2 + 1 infant schedule in the UK is not consistent with the licensed indication of the vaccine [19]. 6. Impact on carriage While the incidence of IMD is highest in infants, asymptomatic carriage of meningococci is highest among adolescents in many countries [53]. The success of the MenC vaccination campaign in the UK was due to the comprehensive coverage that was achieved from 2 months to 19 years of age (later extended to 24 years) [13,54,55]. This approach provided direct protection for the vaccinated individuals and protection of non-vaccinated individuals by interrupting meningococcal transmission [13,54]. As Bexsero has only recently been licensed, there are no data currently available to assess the impact of the vaccine on the transmission of MenB at a population level. A study of almost 3000 18–24-year-olds in the UK showed that Bexsero helped to significantly reduce meningococcal carriage in the 12 months after vaccination [56]. However, further data are required to determine

whether this will translate to a significant population-level effect following a large-scale vaccination programme which includes adolescents and young adults. If so, the addition of a ‘catch-up’ programme in this age group would be an effective strategy to provide a sustained reduction in disease, including in infants <2 months of age. Modelling suggests that the addition of a 5-year or 17-year catch-up campaign to an infant vaccination programme could lead to a 43% or 66% reduction, respectively, in MenB cases within 5 years [26]. An infant, adolescent and 5-year catch-up vaccination strategy with a vaccine efficacy of ≥55% could prevent ≥90% of vaccine-preventable cases of MenB disease [26]. 7. Implementation of a vaccination strategy Bexsero is now approved in 37 countries worldwide and clinical recommendations regarding the use of the vaccine have been made by national expert bodies in 14 countries (Table 3). These recommendations are not typically linked with any commitment to reimbursement or national public funding. Overall, these recommendations not only target high-risk groups, such as infants, but also take into account the use of the vaccine to help curtail outbreaks. The cost-effectiveness of any new vaccine must inevitably be assessed. Yet, as the introduction of the MenC vaccine demonstrated, it is difficult to accurately estimate this at the time of approval [57]. Gaps in the data remain that can only be addressed following a large-scale implementation programme, such as impact on carriage and strain coverage [57]. Data on the frequency and impact of meningococcal disease sequelae are also limited, and it remains problematic to evaluate the quality of life effects in survivors of childhood infection. While economic considerations play an important role in decisions regarding public spending on healthcare, caution must also be applied in the use of cost-effectiveness analyses as a ‘gating

Table 3 Populations in which clinical recommendations have been made for Bexsero use.a Clinically recommended

Countries

Infants ≥2 months (up to 2 years) Children Adolescents and adults Catch-up Special populations High risk groupsc (all ages unless specified)

Australia, Austria, Czech Republic, Germany, Greece, Hungary, Ireland, Italy, Poland, Portugal, Spain, United Kingdomb Poland, Portugal (2–10 years of age), USA (10–25 years) Australia (15–19 years of age), Czech Republic (13–15 years of age), Poland, Portugal, USA (10–25 years) Austria (all children and adolescents)

Outbreaks or hyperendemic areas

Australia, Austria, Canada, Czech Republic, France, Germany (travellers only), Hungary (children ≤2 years of age, and those with underlying medical conditions [all ages]), Ireland (≥1 year of age, close contacts of index cases), Poland, Spain, United Kingdom Canada, France, Ireland, Spain (includes hospital use), United Kingdom, USA

a

Recommendations from national clinical expert bodies, not typically linked to reimbursement or public funding. The UK Secretary of State for Health has a duty to implement JCVI recommendations in England for national vaccination programmes that demonstrate cost-effectiveness. From September 2015, Bexsero will be provided as a routine vaccination at the ages of 2, 4 and 12 months. c High risk conditions – splenectomy, complement deficiencies – these may vary by country References available in supplementary material. b

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criteria’ to decide which vaccines should be developed or routinely used. Furthermore, it has been suggested that such analyses must assume a secondary role in our vaccine decision-making processes if the primary goal is to prevent disease morbidity and mortality, rather than achieve healthcare cost savings [59]. Consideration might also be given to the public’s preferences on spending, as determined through discrete choice experiments which provide an attribute-based measure of benefit [60]. Following the implementation of a vaccination programme, ongoing monitoring for rare adverse events and enhanced disease surveillance will be essential. Further research will also be necessary. For example, in the UK, the JCVI advised that a carriage study in adolescents be carried out to determine the impact of Bexsero on meningococcal carriage acquisition, as this would provide additional information on the cost-effectiveness of the vaccine [52]. Additional information on the duration of protection in infants and the incidence of adverse events was also considered of importance [52]. As the clinical experience and understanding of the potential impact of the vaccine grows, the schedule of vaccination may be further refined, as was the case with the MenC vaccine. Depending on meningococcal epidemiology and improved understanding of Bexsero antibody persistence (or waning) in older children, the requirement for additional MenB booster doses, particularly in adolescents, may be considered in the future [50].

8. The future of Bexsero Clinical studies with Bexsero are still ongoing and clinical experience with Bexsero continues to increase. There is the potential that Bexsero might provide some additional protection against non-B serogroups, which requires further evaluation. This could include MenC/W or Y strains, or even the emerging MenX strain for which there is no currently licensed glycoconjugate vaccine [61]. As noted previously, the virulent MenW cc11 strain is on the rise in the UK, drawing comparisons with the rise of MenC in the 1990s. MenY disease (particularly due to cc23 strains) has also become more common in recent years [36]. Indeed, the changeable epidemiological landscape of N. meningitidis indicates that a combination of Bexsero with MenACWY vaccines may become important to ensure optimum protection against meningococcal disease. Studies on vaccine combinations that target serogroups A, B, C, W and Y are in progress. However, the immediate focus should be the implementation of Bexsero, the first available, broadly protective MenB vaccine and the determination of its impact on disease and herd protection.

Conflicts of interest PSW is an employee of GSK but was employed by Novartis group companies at the time the review was conducted. DPJT has received support from Novartis Vaccines (now a part of GSK), Sanofi Pasteur and GSK, including honoraria, grants and travel assistance for conferences. He was an external advisor on the guidelines development group for the UK NICE guidelines on ‘Meningococcal disease and meningitis in children and young people’ (http://www.ncbi. nlm.nih.gov/books/NBK83080/).

Acknowledgements Writing assistance was provided by Stephanie Gibson of Zoetic Science, an Ashfield company, part of UDG Healthcare plc, Macclesfield, UK; this support was funded by GSK.

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Please cite this article in press as: Watson PS, Turner DPJ. Clinical experience with the meningococcal B vaccine, Bexsero® : Prospects for reducing the burden of meningococcal serogroup B disease. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2015.11.057