Articles
Immunogenicity and safety of the multicomponent meningococcal B vaccine (4CMenB) in children and adolescents: a systematic review and meta-analysis

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Summary

Background

The multicomponent meningococcal serogroup B vaccine (4CMenB) has been licensed in more than 35 countries. However, uncertainties remain about the lowest number of doses required to induce satisfactory, persistent immune responses. We did a systematic review and meta-analysis to provide quantitative estimates for the immunogenicity, persistence of immunogenicity, and safety of 4CMenB vaccine in children and adolescents.

Methods

For this systematic review and meta-analyses (proportion, head to head, and network), we searched MEDLINE, Scopus, Embase, and ClinicalTrials.gov from database inception to June 30, 2017, for randomised trials that compared the immunogenicity or safety of the 4CMenB vaccine with its originator meningococcal B recombinant vaccine or routine vaccines in children or adolescents. For proportion meta-analyses, we also included single arm trials and follow-up studies of randomised controlled trials. Trials that assessed immunogenicity against at least one of four Neisseria meningitidis serogroup B reference strains (44-76/SL, 5/99, NZ98/254, and M10713) and included participants younger than 18 years who had received two or more doses of the 4CMenB vaccine were eligible for inclusion. We requested individual patient-level data from study authors and extracted data from published reports and online trial registries. We did meta-analyses to assess 4CMenB safety and immunogenicity against the four reference strains 30 days after a primary immunisation course (three doses for children, two doses for adolescents), 30 days after the primary course plus one booster dose (children only), 6 months or more after primary course, and 6 months or more after the booster dose.

Findings

736 non-duplicate records were screened, and ten randomised trials and eight follow-on extension trials on 4CMenB met the inclusion criteria. In intention-to-treat analyses, the overall proportion of children and adolescents who achieved seroconversion 30 days after the primary course of 4CMenB was 92% (95% CI 89–95 [I2=95%, p<0·0001]) for the 44/76-SL strain, 91% (87–95 [I2=95%, p<0·0001]) for the 5/99 strain, 84% (77–90 [I2=97%, p<0·0001]) for the NZ98-254 strain, and 87% (68–99 [I2=97%, p<0·0001]) for the M10713 strain. 6 months after the primary course, the immunogenicity remained adequate to high against all three tested strains (5/99, 44/76-SL, and NZ98/254) in adolescents (≥77%), and against two of four strains (5/99 and 44/76-SL) in children (≥67%): the proportion of patients who achieved seroconversion substantially declined for M10713 (<50%) and NZ98/254 (<35%). A booster dose re-enhanced the proportion of patients who achieved seroconversion (≥93% for all strains). However, immunogenicity remained high 6 months after the booster dose for strains 5/99 (95%) and M10713 (75%) only, whereas the proportion of patients who achieved seroconversion against strains 44/76-SL and NZ98/254 returned to similar proportions recorded 6 months after the primary course (62% for 44/76-SL, 35% for NZ98/254). The incidence of potentially vaccine-related, acute serious adverse events in individuals receiving 4CMenB was low (5·4 per 1000 individuals), but was significantly higher than routine vaccines (1·2 per 1000 individuals).

Interpretation

4CMenB has an acceptable short-term safety profile. The primary course is sufficient to achieve a satisfactory immune response within 30 days of vaccination. A booster dose is required for children to prolong the protection against strain M10713, and the long-term immunogenicity against strain NZ98/254 remains suboptimal.

Funding

None.

Introduction

Neisseria meningitidis (meningococcus) is responsible for an estimated 1·2 million cases of invasive meningococcal disease and 135 000 deaths annually, worldwide.1 At present, of the 13 isolated meningococcal serogroups, N meningitidis serogroup B (MenB) is the leading cause of infant bacterial meningitis and sepsis in Europe,2 and has been responsible for long-lasting global outbreaks.3 Mortality can be as high as 10%, and more than 30% of survivors have sequelae.4

Attempts to develop an effective vaccine against MenB were initiated in the early 1980s;5 however, the development of a broadly protective vaccine has been challenging because of the diversity of serogroup B strains and the poor immunogencity of the MenB capsular polysaccharide.6, 7 Concerns about autoimmunity have also prevented the applicability of the MenB polysaccharide capsule because it has a similar structure to polysialic acid on human neuronal cells.8

Research in context

Evidence before this study

We searched MEDLINE, Scopus, and Cochrane online databases from inception to Feb 28, 2017, for previously published systematic reviews and meta-analyses on the immunogenicity or safety of meningococcal serogroup B vaccine (4CMenB) in children or adolescents using the following search terms, without language restrictions: “(4CMenB OR rMenB+OMV OR meningococcal B*)” AND “vaccin*” AND “(immunogenicity OR efficacy OR effectiveness OR safety OR adverse event*)” AND “(systematic review OR meta-analysis). Our literature search showed that no systematic reviews or meta-analyses had been done on the immunogenicity and safety of the 4CMenB vaccine before this study. Results of single studies are difficult to interpret, and thus uncertainties remain about the lowest number of doses required to induce a satisfactory short-term and long-term immune response.

Added value of this study

This is the first meta-analysis of randomised controlled trials on both the immunogenicity and safety of 4CMenB vaccine in children and adolescents. We found that 30 days after the primary immunisation course, 4CMenB vaccination of children and adolescents induced seroconversion against all four tested strains in more than 91% of individuals. The addition of a booster dose, which is recommended for children in several countries, re-enhanced the proportion of individuals who achieved seroconversion (≥93% for all strains). However, the immunogenicity remained high 6 months after the booster dose for the 5/99 and M10713 strains only, whereas the proportion of patients who achieved seroconversion against the 44/76-SL and NZ98/254 strains returned to values similar to those observed 6 months after the primary course. In the overall comparative meta-analyses, 4CMenB had increased immunogenicity (short-term and persistence) compared with rMenB against strain NZ98/254 (for which rMenB had inadequate response).

Implications of all the available evidence

With an acceptable short-term safety profile, high immunogenicity in children and adolescents within the first months after vaccination, and adequate-to-high persistence of immunogenicity (against all tested strains in adolescents and against three of four strains in children), 4CMenB might be a crucial tool to control meningococcal B disease. The primary course is sufficient to achieve a satisfactory immune response within 30 days of vaccination. A booster dose is required for children to prolong the protection against strain M10713, and the long-term immunogenicity against strain NZ98/254 remains suboptimal. The clinical significance of the poor persistence against the NZ98/254 strain, and coverage against outbreak strains, require further study.

Two protein-based vaccines against multiple MenB strains are now available: the bivalent factor H binding protein (FHbp; Trumenba, Pfizer, New York, NY, USA) and the multicomponent meningococcal serogroup B vaccine (4CMenB; Bexsero, Novartis, Basel, Switzerland). The FHbp vaccine was approved for use in the USA and Europe in May, 2017,9 and the 4CMenB vaccine has been licensed in more than 35 countries.3, 10

The 4CMenB vaccine is modified version of the investigational, non-licensed, recombinant meningococcal serogroup B vaccine (rMenB),7 which was composed of three recombinant proteins: FHbp, NadA, and neisseria heparin binding antigen.11, 12 The 4CMenB vaccine was developed by the addition of an outer membrane vesicle porin protein (OMV-PorA) extracted from the New Zealand outbreak strain NZ98/254.11

Evidence about the effectiveness and safety of 4CMenB relies largely on immunogenicity and safety data from phase 1–3 randomised controlled trials,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 in which 4CMenB was compared against rMenB or against different routine vaccines, using various schedules. However, the available evidence is highly heterogeneous, the results are too complex to interpret by examining single trials, and several uncertainties remain about the lowest number of doses needed to induce a satisfactory immune response.10, 36 We did a systematic review and meta-analysis to address these questions and systematically appraise the evidence on the immunogenicity and safety of the 4CMenB vaccine in children and adolescents.

Section snippets

Search strategy and selection criteria

We searched MEDLINE, Scopus, and Embase databases and the ClinicalTrials.gov website for randomised controlled trials published before June 30, 2017, that assessed the immunogenicity or safety of 4CMenB vaccine compared with other control vaccines in children or adolescents, using the following search terms, without language restrictions: “(4CMenB OR rMenB+OMV OR meningococcal B*)” AND “vaccin*” AND “(immunogenicity OR efficacy OR effectiveness OR safety OR adverse event*)”. For proportion

Results

Our systematic search of the literature identified 804 records, of which 68 duplicates were identified (figure 1). Of the 50 full-text articles and ClinicalTrials.gov database records assessed for eligibility, 19 publications14, 15, 16, 18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 32, 33, 34, 46, 47 reporting on ten randomised trials and eight follow-on extension trials, which assessed the immunogenicity or the safety of 4CMenB among infants or children (age range at enrolment, 2 months to 10

Discussion

Our results suggest that 4CMenB vaccine has an acceptable short-term safety profile, generates high immunogenicity in the short term in both children and adolescents, and shows adequate-to-high persistence of immunogenicity in adolescents, but less consistently so against one of the four tested strains (NZ98/254) in children. The 4CMenB vaccine was approved by the US Food and Drug Administration in individuals aged 10 years or older on the basis of its immunogenicity after two doses in 62–88%

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