Pharmacological Research xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Review
Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis Paolo Pellegrino a,1 , Valentina Perrone a,1 , Sonia Radice a,∗ , Annalisa Capuano d , Emilio Clementi b,c a
Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital “Luigi Sacco”, Università di Milano, 20157 Milan, Italy Scientific Institute, IRCCS E. Medea, 23842 Bosisio Parini, Lecco, Italy c Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, Consiglio Nazionale delle Ricerche Institute of Neuroscience, University Hospital “Luigi Sacco”, Università di Milano, 20157 Milan, Italy d Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Faculty of Medicine and Surgery, Second University of Naples, Campania, Via De Crecchio, 7, 80138 Naples, Italy b
a r t i c l e
i n f o
Article history: Received 17 October 2014 Accepted 20 October 2014 Keywords: Meningococcal meningitis MenACWY-TT Meningococcal vaccine
a b s t r a c t Meningococcal meningitis represents one of the leading cause of bacterial meningitis in developed countries. Among the thirteen described serogroups, only five are usually responsible of invasive infections making immunisation against multiple serogroups the best strategy to protect individuals from this disease. Herein we carried out a systematic review and meta-analysis, in accordance with the PRISMA statement, of the recently EU-licensed meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT). We included 15 randomised clinical trials, comparing MenACWY-TT and Men-PS (ten studies), MenACWY-TT and MenC-CRM197 (four studies) and MenACWY-TT and MenACWY-DT (one study). All studies included in the meta-analysis showed high immunogenicity for MenACWY-TT vaccines in all tested serogroups. Our results suggest that the MenACWY-TT vaccine is as immunogenic as the other commercial avaiable meningococcal vaccines. © 2014 Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Literature search and study identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis and synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Study identification and selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Description of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison between MenACWY-TT and Men-PS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison between MenACWY-TT and MenC-CRM197 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison between MenACWY-TT and MenACWY-DT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Science, University Hospital “Luigi Sacco”, University of Milan, Via G. B. Grassi, 74, 20157 Milano, Italy. Tel.: +39 0250319643; fax: +39 0250319682. E-mail address: [email protected] (S. Radice). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.phrs.2014.10.006 1043-6618/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pellegrino P, et al. Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.006
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P. Pellegrino et al. / Pharmacological Research xxx (2014) xxx–xxx
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Neisseria meningitides, a bacterium, is responsible a for a group of severe pathological conditions, termed invasive meningococcal disease (IMD), that occurs suddenly in healthy person and with a high incidence in infants and young children [1]. An estimated 500,000 cases of IMD occur annually worldwide and are cause significant mortality and morbidity, with a case fatality rate that can reach up to 10% [2]. Nearly 20% of survivors are bound to develop permanent sequelae, including neurodevelopmental disabilities, psychological disturbances, hearing and visual impairment, skin scarring and amputation [2]. IMD may present with several severe clinical manifestations [3], among these meningitis, which represents one of the most common causes of bacterial meningitis worldwide [1]. Meningococcal meningitis represents the leading cause of bacterial meningitis in countries where conjugate vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) have been added to the national immunisation schedules [1,4]. Human is the only host for N. meningitides and colonisation, which could be transient or permanent, do not lead always to IMD. Infected and colonised persons may transmit the disease through respiratory aerosol droplets or contact with oral secretions [5,6]. Thirteen different serotypes, differring by specific features of their polysaccharide capsule, have been described so far [2]. Of these, only five usually cause invasive infections; these serotypes have also specific epidemiological features and geographic distribution [2]: serogroups B, C and Y are commoner in the United States of America (USA), while serogroups A and X prevail in Africa and Russia [2]. Vaccines are the best control strategy to prevent IMD, especially during epidemics, when post-exposure chemoprophylaxis is not cost effective and increases the chances of antibiotic resistance [7,8]. The first developed meningococcal polysaccharide vaccine (MPSV) was aimed against serogroups A and C, as a response to meningitis epidemics among military recruits in the USA in the 1970. It was later used for outbreak control and travellers to endemic areas, as well as in hyperendemic regions and in dormitory for students [8]. Meningococcal polysaccharide vaccines are currently licensed as bivalent (serogroups A and C), trivalent (serogroups A, C, and W-135), or tetravalent (serogroups A, C, Y, and W-135) vaccines [8]. These vaccines are safe and elicit bactericidal antibodies in children and adult, but are poorly immunogenic in infants and do not build immunological memory because polysaccharides are T-cellindependent antigens that do not stimulate memory B cells [8]. Since the late 1990s meningococcal conjugate vaccines use has become widespread in the developed world. This new class of vaccines was proven to be superior to polysaccharide vaccines in eliciting B- and T-cell responses [8]. Moreover, at variance with polysaccharides vaccines, conjugate vaccines are immunogenic also in children aged less than 2 years [8]. To date there are three meningococcal quadrivalent conjugate vaccine: the 2005-approved MenACWY-DT, which uses diphtheria toxin as a carrier protein; the MenACWY-CRM197 using a nontoxic mutant variant of Corynebacterium diphtheriae toxin, termed cross-reactive material197 , approved in February 2010; and the meningococcal tetanus toxoid conjugate vaccine (MenACWY-TT), approved in April 2012 by the European Medicines Agency [8].
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Herein, we review and systematise available published studies comparing the immunogenicity of the new MenACWY-TT with other licensed meningococcal vaccines. We also carried out a metaanalysis matching results of randomised clinical trial comparing this vaccine to licensed MPSV and MenC-CRM197 . Methods We conducted a systematic review and meta-analysis of the literature according to the Recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [9]. Literature search and study identification A systematic bibliographic search of medical literature was conducted using the electronic databases of MedLine, the Clinical Trial Register (www.clinicaltrial.gov) and Google Scholar up to June 2014. We included only studies written in English. Literature search was performed combining the following medical subject headings (MeSH), terms and free terms: “meningococcal conjugate vaccines”, “MenACWY-TT”, “meningococcal tetanus toxoid conjugate vaccine”, “efficacy”, “immunogenicity”, “safety”, “child”, “infant”, “toddler”, “adult”, “elderly”, “randomised clinical trial”, and “clinical trial”. To identify other undetected published articles, we performed a manual search of the bibliographies of relevant studies and specialised medical journals. Study selection Two investigators (P.P. and V.P.) screened the titles and abstracts of the localised references. The definitive inclusion of potentially eligible studies was based on reading of the full text. Inclusion criteria were randomised clinical trial with subjects vaccinated with MenACWY-TT compared to MPSV, MenC-CRM197 or quadrivalent meningococcal conjugate vaccines. The first outcome of interest was immunogenicity measured as serum bactericidal activity (SBA). We also analysed differences in geometric mean titres (GMTs) (g/mL). We did not contact authors to request additional information and excluded non-original articles, non-randomised studies, observational studies, case-series studies, editorials, comments, letters, experimental vaccines and laboratory studies. Analysis and synthesis Vaccine response to meningococcal vaccines is usually measured with the SBA assay, which has been proven to be the best proxy to define protection for all serogroups [10]. For this reason, the selected endpoints were: vaccine response rate, percent of patients achieving a SBA (rabbit complement source (rSBA) titre of ≥1:8, percent of patients achieving a rSBA titre of ≥1:128 and rSBA GMT. Vaccine response rate was defined as: (i) rSBA titres of ≥1:32 in initially seronegative subjects; (ii) ≥4-fold increase in subjects with pre-vaccination rSBA titres between 1:8 and 1:128; (iii) ≥2-fold increase in subjects with pre-vaccination rSBA titres ≥1:128. We carried out the analyses using a fixed effects model when no heterogeneity existed among studies. Otherwise, the DerSimonian and Laird random-effects model was used. Statistical heterogeneity
Please cite this article in press as: Pellegrino P, et al. Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.006
P. Pellegrino et al. / Pharmacological Research xxx (2014) xxx–xxx
3
Fig. 1 shows the flowchart of studies from their identification through final inclusion in the meta-analysis. Description of included studies We included ten studies comparing MenACWY-TT and MenPS [13,16,17,19,22,23,25,26,28,29] (Table 1), four comparing MenACWY-TT and MenC-CRM197 [14,18,20,27] (Table 2) and one comparing MenACWY-TT and MenACWY-DT [30]. All of these studies were published between 2009 and 2013; they included 6543 (comparison with Men-PS), 1801 (comparison with MenC-CRM197 ) and 1016 (MenACWY-TT and MenACWY-DT) subjects. Four studies included subjects aged 12–24 months, four children between 2 and 10 years, one enrolled subjects aged over 56 years old and the other ones included subjects aged between 11 and 55 years. In all included studies vaccine schedule required a single administration. All relevant data about considered studies are summarised in Tables 1 and 2. Comparison between MenACWY-TT and Men-PS.
Fig. 1. Flowchart of the published clinical trial evaluated for inclusion in the metaanalysis.
was measured using the Q statistic (p < 0.10 was considered indicative of statistically significant heterogeneity) and expressed with I2 statistic. I2 values were quantified with the lying between 0% and 100%, where values less than 40% suggest that homogeneity is good for the reliability of a meta-analysis. Visual inspection of asymmetry in funnel plots was conducted to estimate the potential publication bias when more than 10 studies were included in a single analysis. For immunological response, we estimated the difference in proportion (with 95% confidence interval, CI), between the proportion of subjects achieving vaccine response and cut-off rSBA titres; for GMT outcomes, we calculated the standardised mean difference (SMD) (95% CI). If subgrouping for age and for response was reported, we included this latter datum. All p values are 2-sided. Results were considered statistically significant with a p value of ≤0.05. All analyses were carried out with the Cochrane Collaboration review manager (RevMan version 5) and R softwares.
Data on vaccine response rate was reported in 10 studies [13,16,17,19,22,23,25,26,28,29], including patients of various age groups (Table 1). Fig. 2 shows the difference in percentage (risk difference) of the vaccine response rate obtained in the meta-analysis using the random-effects model for serotypes A and C and serotypes W135 and Y, respectively. As three of the included studies provide subgrouping information based on subjects’ age, our analysis was carried out considering 13 smaller groups. MenACWY-TT vaccine was not inferior to Men-PS for all serotypes in all age subgroups. We observed significant discrepancies in vaccine response rate between various serotypes and age subgroups, with MenACWY-TT vaccine being more effective that Men-PS in subjects aged 18–55, with the exception of the C serotype, and in subjects aged 2–10 years for serotypes C and Y. The MenACWY-TT vaccine was superior for A and Y serotypes in subject aged 11–18 years, but not in patients aged over 55 years old. Seven studies reported data (mean plus 95% CI) of GMT and were included in the study. Geometric mean antibody titres with 95% CI were compared for each serogroup, according to age subgrouping (Table 3). We found that GMT levels were higher after 1 month in subjects receiving MenACWY-TT, with the exception of subjects aged over 65 years. Additionally, we found significant difference in subjects aged 18–55 years for serogroup C. We retrieved eight studies reporting the proportion of patients achieving rSBA titre ≥1:8 and seven studies reporting the proportion of rSBA titres ≥1:128. As shown in Table 4, no significant difference was noted between MenACWY-TT and Men-PS.
Results Comparison between MenACWY-TT and MenC-CRM197 Study identification and selection The systematic search, aimed at finding original articles, provided 275 references. We excluded 22 duplicates and 199 papers through title and abstract screening. Of the 54 records screened, only 21 were considered potentially relevant studies for inclusion criteria and data extraction [3,11–30]. Six studies were excluded because did not meet inclusion criteria (lack of data, lack of data on vaccine response after 1 month, no comparison with other vaccines). Finally, 15 randomised clinical trials fulfilled all inclusion criteria and were selected for the systematic review and meta-analysis.
As highlighted in Table 2, four studies comparing MenACWY-TT and MenC-CRM197 met the inclusion criteria for this meta-analysis. Comparison of GMT levels between MenACWY-TT and MenCCRM197 recipients is reported in Table 3 and included three studies. As expected, we found significantly higher titres for serotypes A, W-135 and Y in MenACWY-TT recipients. For serotype C, GMT was higher in subjects aged 12–23 months [18,27], but lower in 2–10 years ones [14]. When all these three studies were included, the standard mean difference for C serotypes was 0.31 (CI 95%; −0.53, 1.15; NS) and heterogeneity rose to 97% (Table 3). After exclusion of data regarding subjects aged 2–10 years, the standard mean
Please cite this article in press as: Pellegrino P, et al. Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.006
4
Authors
Year
N (tot)
Lupisan et al.
2013
1170
n
Age (Years)
2013
369
2013
500
2012
2012
1247
2012
520
2010
268
2009
175
2011
1501
2011
MenACWY-TT MenPS
None None
Single Single
MenACWY-TT MenPS
None None
Single Single
MenACWY-TT lot A MenACWY-TT lot B MenACWY-TT lot C MenPS
None None None None
Single Single Single Single
MenACWY-TT lot A MenACWY-TT lot A MenPS
None FluarixTM None
Single Single Single
MenACWY-TT F1 MenACWY-TT F2 MenACWY-TT F3 MenACWY-TT F4 MenPS
None None None None None
Single Single Single Single Single
MenACWY-TT 2.5 MenACWY-TT 5/2.5 MenACWY-TT 5A MenACWY-TT 5B MenACWY-TT 5 C MenPS
None None None None None None
Single Single Single Single Single Single
MenACWY-TT MenPS
None None
Single Single
MenACWY-TT MenPS
None None
Single Single
2–10 1125 376
Bermal et al.
Single Single
18–25 (n = 50) and 15–19 (n = 125) 25 25 25 25 25 + 25 25
Memish et al.
None None
3–5 54 53 54 54 53
Østergaard et al.
MenACWY-TT MenPS
18–55 311 105 104
Knuf et al.
Single Single Single
18–55 311 311 313 312
Aplasca-De Los Reyes et al.
None None None
2–10
309 231 78
Dbaibo et al.
MenACWY-TT lot A MenACWY-TT lot B Men-PS
11–17 and 18–55 374 126
Vesikari et al.
Schedule
Over 56 274 95
Borja-Tabora et al.
Concomitant vaccines
18–25 390 390 390
Dbaibo et al.
Intervention vs. comparison
1025
11–17 768 257
Outcome
Registry number at www.Clinicaltrial.gov
Immunogenicity; GMT
NCT01154088
Immunogenicity; GMT
NCT01235975
Immunogenicity; GMT
NCT00356369
Immunogenicity; GMT
NCT00427908
Immunogenicity
NCT00453986
Immunogenicity
NCT00453986
Immunogenicity
NCT00126984
Immunogenicity; GMT
NCT00196950 and NCT00126945
Immunogenicity; GMT
NCT00514904
Immunogenicity; GMT
NCT00464815
P. Pellegrino et al. / Pharmacological Research xxx (2014) xxx–xxx
Please cite this article in press as: Pellegrino P, et al. Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.006
Table 1 Phase II and III studies comparing MenACWY-TT and Men-PS.
P. Pellegrino et al. / Pharmacological Research xxx (2014) xxx–xxx
5
Fig. 2. Meta-analysis of the difference in proportion of subjects achieving vaccine response after MenACWY-TT and MenPS according to age and meningococcal serogroup.
Please cite this article in press as: Pellegrino P, et al. Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.006
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P. Pellegrino et al. / Pharmacological Research xxx (2014) xxx–xxx
Table 2 Phase II and Phase II studies comparing MenACWY-TT and MenC-CRM197 . Authors
Year
N (tot)
Knuf et al.
2013
414
n
Age (Year)
103 2012
304
2010
240
2011
1000a
Registry number at www.Clinicaltrial.gov
MenACWY-TT
None
Single
Immunogenicity; GMT
NCT00674583
MenC-CRM197
None
Single Immunogenicity; GMT
NCT00427908
Immunogenicity
NCT00126984
Immunogenicity; GMT
NCT00474266
MenACWY-TT MenC-CRM197
None None
Single Single
MenACWY-TT F1 MenACWY-TT F2 MenACWY-TT F3 MenACWY-TT F4 MenC-CRM197
None None None None None
Single Single Single Single Single
1–2 375 374 126
a
Outcome
1–2 48 48 48 48 48
Vesikari et al.
Schedule
1 (12–13 months) 229 75
Knuf et al.
Concomitant vaccines
2–10 311
Vesikari et al.
Intervention vs. comparison
MenACWY-TT MenACWY-TT MenC-CRM197
MMRV None None
Single Single Single
125 subjects received only MMRV vaccine.
Table 3 Summary of meta-analysis results of GMT. Serotype
Age group (Years)
N. study
MenACWY-TT
2–10 11–17 18–55 Over 56
2 2 2 1
973 812 394 186
2–10 11–17 18 – 55 Over 56
2 2 2 1
2–10 11–17 18 – 55 Over 56 2–10 11–17 18 – 55 Over 56
MenPS
Std. Mean difference [CI 95%]
p
Heterogeneity (I2)
327 280 327 65
0.99 [0.86, 1.13] 0.69 [0.55, 0.83] 0.53 [0.38, 0.68] −0.62 [−0.91, −0.33]
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Review
Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis Paolo Pellegrino a,1 , Valentina Perrone a,1 , Sonia Radice a,∗ , Annalisa Capuano d , Emilio Clementi b,c a
Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital “Luigi Sacco”, Università di Milano, 20157 Milan, Italy Scientific Institute, IRCCS E. Medea, 23842 Bosisio Parini, Lecco, Italy c Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, Consiglio Nazionale delle Ricerche Institute of Neuroscience, University Hospital “Luigi Sacco”, Università di Milano, 20157 Milan, Italy d Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Faculty of Medicine and Surgery, Second University of Naples, Campania, Via De Crecchio, 7, 80138 Naples, Italy b
a r t i c l e
i n f o
Article history: Received 17 October 2014 Accepted 20 October 2014 Keywords: Meningococcal meningitis MenACWY-TT Meningococcal vaccine
a b s t r a c t Meningococcal meningitis represents one of the leading cause of bacterial meningitis in developed countries. Among the thirteen described serogroups, only five are usually responsible of invasive infections making immunisation against multiple serogroups the best strategy to protect individuals from this disease. Herein we carried out a systematic review and meta-analysis, in accordance with the PRISMA statement, of the recently EU-licensed meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT). We included 15 randomised clinical trials, comparing MenACWY-TT and Men-PS (ten studies), MenACWY-TT and MenC-CRM197 (four studies) and MenACWY-TT and MenACWY-DT (one study). All studies included in the meta-analysis showed high immunogenicity for MenACWY-TT vaccines in all tested serogroups. Our results suggest that the MenACWY-TT vaccine is as immunogenic as the other commercial avaiable meningococcal vaccines. © 2014 Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Literature search and study identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis and synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Study identification and selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Description of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison between MenACWY-TT and Men-PS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison between MenACWY-TT and MenC-CRM197 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison between MenACWY-TT and MenACWY-DT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Science, University Hospital “Luigi Sacco”, University of Milan, Via G. B. Grassi, 74, 20157 Milano, Italy. Tel.: +39 0250319643; fax: +39 0250319682. E-mail address: [email protected] (S. Radice). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.phrs.2014.10.006 1043-6618/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pellegrino P, et al. Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.006
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P. Pellegrino et al. / Pharmacological Research xxx (2014) xxx–xxx
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Neisseria meningitides, a bacterium, is responsible a for a group of severe pathological conditions, termed invasive meningococcal disease (IMD), that occurs suddenly in healthy person and with a high incidence in infants and young children [1]. An estimated 500,000 cases of IMD occur annually worldwide and are cause significant mortality and morbidity, with a case fatality rate that can reach up to 10% [2]. Nearly 20% of survivors are bound to develop permanent sequelae, including neurodevelopmental disabilities, psychological disturbances, hearing and visual impairment, skin scarring and amputation [2]. IMD may present with several severe clinical manifestations [3], among these meningitis, which represents one of the most common causes of bacterial meningitis worldwide [1]. Meningococcal meningitis represents the leading cause of bacterial meningitis in countries where conjugate vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) have been added to the national immunisation schedules [1,4]. Human is the only host for N. meningitides and colonisation, which could be transient or permanent, do not lead always to IMD. Infected and colonised persons may transmit the disease through respiratory aerosol droplets or contact with oral secretions [5,6]. Thirteen different serotypes, differring by specific features of their polysaccharide capsule, have been described so far [2]. Of these, only five usually cause invasive infections; these serotypes have also specific epidemiological features and geographic distribution [2]: serogroups B, C and Y are commoner in the United States of America (USA), while serogroups A and X prevail in Africa and Russia [2]. Vaccines are the best control strategy to prevent IMD, especially during epidemics, when post-exposure chemoprophylaxis is not cost effective and increases the chances of antibiotic resistance [7,8]. The first developed meningococcal polysaccharide vaccine (MPSV) was aimed against serogroups A and C, as a response to meningitis epidemics among military recruits in the USA in the 1970. It was later used for outbreak control and travellers to endemic areas, as well as in hyperendemic regions and in dormitory for students [8]. Meningococcal polysaccharide vaccines are currently licensed as bivalent (serogroups A and C), trivalent (serogroups A, C, and W-135), or tetravalent (serogroups A, C, Y, and W-135) vaccines [8]. These vaccines are safe and elicit bactericidal antibodies in children and adult, but are poorly immunogenic in infants and do not build immunological memory because polysaccharides are T-cellindependent antigens that do not stimulate memory B cells [8]. Since the late 1990s meningococcal conjugate vaccines use has become widespread in the developed world. This new class of vaccines was proven to be superior to polysaccharide vaccines in eliciting B- and T-cell responses [8]. Moreover, at variance with polysaccharides vaccines, conjugate vaccines are immunogenic also in children aged less than 2 years [8]. To date there are three meningococcal quadrivalent conjugate vaccine: the 2005-approved MenACWY-DT, which uses diphtheria toxin as a carrier protein; the MenACWY-CRM197 using a nontoxic mutant variant of Corynebacterium diphtheriae toxin, termed cross-reactive material197 , approved in February 2010; and the meningococcal tetanus toxoid conjugate vaccine (MenACWY-TT), approved in April 2012 by the European Medicines Agency [8].
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Herein, we review and systematise available published studies comparing the immunogenicity of the new MenACWY-TT with other licensed meningococcal vaccines. We also carried out a metaanalysis matching results of randomised clinical trial comparing this vaccine to licensed MPSV and MenC-CRM197 . Methods We conducted a systematic review and meta-analysis of the literature according to the Recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [9]. Literature search and study identification A systematic bibliographic search of medical literature was conducted using the electronic databases of MedLine, the Clinical Trial Register (www.clinicaltrial.gov) and Google Scholar up to June 2014. We included only studies written in English. Literature search was performed combining the following medical subject headings (MeSH), terms and free terms: “meningococcal conjugate vaccines”, “MenACWY-TT”, “meningococcal tetanus toxoid conjugate vaccine”, “efficacy”, “immunogenicity”, “safety”, “child”, “infant”, “toddler”, “adult”, “elderly”, “randomised clinical trial”, and “clinical trial”. To identify other undetected published articles, we performed a manual search of the bibliographies of relevant studies and specialised medical journals. Study selection Two investigators (P.P. and V.P.) screened the titles and abstracts of the localised references. The definitive inclusion of potentially eligible studies was based on reading of the full text. Inclusion criteria were randomised clinical trial with subjects vaccinated with MenACWY-TT compared to MPSV, MenC-CRM197 or quadrivalent meningococcal conjugate vaccines. The first outcome of interest was immunogenicity measured as serum bactericidal activity (SBA). We also analysed differences in geometric mean titres (GMTs) (g/mL). We did not contact authors to request additional information and excluded non-original articles, non-randomised studies, observational studies, case-series studies, editorials, comments, letters, experimental vaccines and laboratory studies. Analysis and synthesis Vaccine response to meningococcal vaccines is usually measured with the SBA assay, which has been proven to be the best proxy to define protection for all serogroups [10]. For this reason, the selected endpoints were: vaccine response rate, percent of patients achieving a SBA (rabbit complement source (rSBA) titre of ≥1:8, percent of patients achieving a rSBA titre of ≥1:128 and rSBA GMT. Vaccine response rate was defined as: (i) rSBA titres of ≥1:32 in initially seronegative subjects; (ii) ≥4-fold increase in subjects with pre-vaccination rSBA titres between 1:8 and 1:128; (iii) ≥2-fold increase in subjects with pre-vaccination rSBA titres ≥1:128. We carried out the analyses using a fixed effects model when no heterogeneity existed among studies. Otherwise, the DerSimonian and Laird random-effects model was used. Statistical heterogeneity
Please cite this article in press as: Pellegrino P, et al. Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.006
P. Pellegrino et al. / Pharmacological Research xxx (2014) xxx–xxx
3
Fig. 1 shows the flowchart of studies from their identification through final inclusion in the meta-analysis. Description of included studies We included ten studies comparing MenACWY-TT and MenPS [13,16,17,19,22,23,25,26,28,29] (Table 1), four comparing MenACWY-TT and MenC-CRM197 [14,18,20,27] (Table 2) and one comparing MenACWY-TT and MenACWY-DT [30]. All of these studies were published between 2009 and 2013; they included 6543 (comparison with Men-PS), 1801 (comparison with MenC-CRM197 ) and 1016 (MenACWY-TT and MenACWY-DT) subjects. Four studies included subjects aged 12–24 months, four children between 2 and 10 years, one enrolled subjects aged over 56 years old and the other ones included subjects aged between 11 and 55 years. In all included studies vaccine schedule required a single administration. All relevant data about considered studies are summarised in Tables 1 and 2. Comparison between MenACWY-TT and Men-PS.
Fig. 1. Flowchart of the published clinical trial evaluated for inclusion in the metaanalysis.
was measured using the Q statistic (p < 0.10 was considered indicative of statistically significant heterogeneity) and expressed with I2 statistic. I2 values were quantified with the lying between 0% and 100%, where values less than 40% suggest that homogeneity is good for the reliability of a meta-analysis. Visual inspection of asymmetry in funnel plots was conducted to estimate the potential publication bias when more than 10 studies were included in a single analysis. For immunological response, we estimated the difference in proportion (with 95% confidence interval, CI), between the proportion of subjects achieving vaccine response and cut-off rSBA titres; for GMT outcomes, we calculated the standardised mean difference (SMD) (95% CI). If subgrouping for age and for response was reported, we included this latter datum. All p values are 2-sided. Results were considered statistically significant with a p value of ≤0.05. All analyses were carried out with the Cochrane Collaboration review manager (RevMan version 5) and R softwares.
Data on vaccine response rate was reported in 10 studies [13,16,17,19,22,23,25,26,28,29], including patients of various age groups (Table 1). Fig. 2 shows the difference in percentage (risk difference) of the vaccine response rate obtained in the meta-analysis using the random-effects model for serotypes A and C and serotypes W135 and Y, respectively. As three of the included studies provide subgrouping information based on subjects’ age, our analysis was carried out considering 13 smaller groups. MenACWY-TT vaccine was not inferior to Men-PS for all serotypes in all age subgroups. We observed significant discrepancies in vaccine response rate between various serotypes and age subgroups, with MenACWY-TT vaccine being more effective that Men-PS in subjects aged 18–55, with the exception of the C serotype, and in subjects aged 2–10 years for serotypes C and Y. The MenACWY-TT vaccine was superior for A and Y serotypes in subject aged 11–18 years, but not in patients aged over 55 years old. Seven studies reported data (mean plus 95% CI) of GMT and were included in the study. Geometric mean antibody titres with 95% CI were compared for each serogroup, according to age subgrouping (Table 3). We found that GMT levels were higher after 1 month in subjects receiving MenACWY-TT, with the exception of subjects aged over 65 years. Additionally, we found significant difference in subjects aged 18–55 years for serogroup C. We retrieved eight studies reporting the proportion of patients achieving rSBA titre ≥1:8 and seven studies reporting the proportion of rSBA titres ≥1:128. As shown in Table 4, no significant difference was noted between MenACWY-TT and Men-PS.
Results Comparison between MenACWY-TT and MenC-CRM197 Study identification and selection The systematic search, aimed at finding original articles, provided 275 references. We excluded 22 duplicates and 199 papers through title and abstract screening. Of the 54 records screened, only 21 were considered potentially relevant studies for inclusion criteria and data extraction [3,11–30]. Six studies were excluded because did not meet inclusion criteria (lack of data, lack of data on vaccine response after 1 month, no comparison with other vaccines). Finally, 15 randomised clinical trials fulfilled all inclusion criteria and were selected for the systematic review and meta-analysis.
As highlighted in Table 2, four studies comparing MenACWY-TT and MenC-CRM197 met the inclusion criteria for this meta-analysis. Comparison of GMT levels between MenACWY-TT and MenCCRM197 recipients is reported in Table 3 and included three studies. As expected, we found significantly higher titres for serotypes A, W-135 and Y in MenACWY-TT recipients. For serotype C, GMT was higher in subjects aged 12–23 months [18,27], but lower in 2–10 years ones [14]. When all these three studies were included, the standard mean difference for C serotypes was 0.31 (CI 95%; −0.53, 1.15; NS) and heterogeneity rose to 97% (Table 3). After exclusion of data regarding subjects aged 2–10 years, the standard mean
Please cite this article in press as: Pellegrino P, et al. Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.006
4
Authors
Year
N (tot)
Lupisan et al.
2013
1170
n
Age (Years)
2013
369
2013
500
2012
2012
1247
2012
520
2010
268
2009
175
2011
1501
2011
MenACWY-TT MenPS
None None
Single Single
MenACWY-TT MenPS
None None
Single Single
MenACWY-TT lot A MenACWY-TT lot B MenACWY-TT lot C MenPS
None None None None
Single Single Single Single
MenACWY-TT lot A MenACWY-TT lot A MenPS
None FluarixTM None
Single Single Single
MenACWY-TT F1 MenACWY-TT F2 MenACWY-TT F3 MenACWY-TT F4 MenPS
None None None None None
Single Single Single Single Single
MenACWY-TT 2.5 MenACWY-TT 5/2.5 MenACWY-TT 5A MenACWY-TT 5B MenACWY-TT 5 C MenPS
None None None None None None
Single Single Single Single Single Single
MenACWY-TT MenPS
None None
Single Single
MenACWY-TT MenPS
None None
Single Single
2–10 1125 376
Bermal et al.
Single Single
18–25 (n = 50) and 15–19 (n = 125) 25 25 25 25 25 + 25 25
Memish et al.
None None
3–5 54 53 54 54 53
Østergaard et al.
MenACWY-TT MenPS
18–55 311 105 104
Knuf et al.
Single Single Single
18–55 311 311 313 312
Aplasca-De Los Reyes et al.
None None None
2–10
309 231 78
Dbaibo et al.
MenACWY-TT lot A MenACWY-TT lot B Men-PS
11–17 and 18–55 374 126
Vesikari et al.
Schedule
Over 56 274 95
Borja-Tabora et al.
Concomitant vaccines
18–25 390 390 390
Dbaibo et al.
Intervention vs. comparison
1025
11–17 768 257
Outcome
Registry number at www.Clinicaltrial.gov
Immunogenicity; GMT
NCT01154088
Immunogenicity; GMT
NCT01235975
Immunogenicity; GMT
NCT00356369
Immunogenicity; GMT
NCT00427908
Immunogenicity
NCT00453986
Immunogenicity
NCT00453986
Immunogenicity
NCT00126984
Immunogenicity; GMT
NCT00196950 and NCT00126945
Immunogenicity; GMT
NCT00514904
Immunogenicity; GMT
NCT00464815
P. Pellegrino et al. / Pharmacological Research xxx (2014) xxx–xxx
Please cite this article in press as: Pellegrino P, et al. Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.006
Table 1 Phase II and III studies comparing MenACWY-TT and Men-PS.
P. Pellegrino et al. / Pharmacological Research xxx (2014) xxx–xxx
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Fig. 2. Meta-analysis of the difference in proportion of subjects achieving vaccine response after MenACWY-TT and MenPS according to age and meningococcal serogroup.
Please cite this article in press as: Pellegrino P, et al. Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y) tetanus toxoid conjugate vaccine: Systematic review and meta-analysis. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.006
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P. Pellegrino et al. / Pharmacological Research xxx (2014) xxx–xxx
Table 2 Phase II and Phase II studies comparing MenACWY-TT and MenC-CRM197 . Authors
Year
N (tot)
Knuf et al.
2013
414
n
Age (Year)
103 2012
304
2010
240
2011
1000a
Registry number at www.Clinicaltrial.gov
MenACWY-TT
None
Single
Immunogenicity; GMT
NCT00674583
MenC-CRM197
None
Single Immunogenicity; GMT
NCT00427908
Immunogenicity
NCT00126984
Immunogenicity; GMT
NCT00474266
MenACWY-TT MenC-CRM197
None None
Single Single
MenACWY-TT F1 MenACWY-TT F2 MenACWY-TT F3 MenACWY-TT F4 MenC-CRM197
None None None None None
Single Single Single Single Single
1–2 375 374 126
a
Outcome
1–2 48 48 48 48 48
Vesikari et al.
Schedule
1 (12–13 months) 229 75
Knuf et al.
Concomitant vaccines
2–10 311
Vesikari et al.
Intervention vs. comparison
MenACWY-TT MenACWY-TT MenC-CRM197
MMRV None None
Single Single Single
125 subjects received only MMRV vaccine.
Table 3 Summary of meta-analysis results of GMT. Serotype
Age group (Years)
N. study
MenACWY-TT
2–10 11–17 18–55 Over 56
2 2 2 1
973 812 394 186
2–10 11–17 18 – 55 Over 56
2 2 2 1
2–10 11–17 18 – 55 Over 56 2–10 11–17 18 – 55 Over 56
MenPS
Std. Mean difference [CI 95%]
p
Heterogeneity (I2)
327 280 327 65
0.99 [0.86, 1.13] 0.69 [0.55, 0.83] 0.53 [0.38, 0.68] −0.62 [−0.91, −0.33]
