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Persistence of Bactericidal Antibodies After Infant Serogroup B Meningococcal Immunization and Booster Dose Response at 12, 18 or 24 Months of Age

Snape, Matthew D. MBBS, FRCPCH, MD; Voysey, Merryn MBiostat; Finn, Adam FRCP, PhD; Bona, Gianni MD; Esposito, Susanna MD; Principi, Nicola MD; Diez-Domingo, Javier MD, PhD; Sokal, Etienne MD, PhD; Kieninger, Dorothee MD; Prymula, Roman MD, PhD; Dull, Peter M. MD; Kohl, Igor PhD; Barone, Michelangelo MD; Wang, Huajun MSc; Toneatto, Daniela MD; Pollard, Andrew J. FRCPCH, PhDfor the European MenB Vaccine Study Group

The Pediatric Infectious Disease Journal: April 2016 - Volume 35 - Issue 4 - p e113–e123
doi: 10.1097/INF.0000000000001056
Vaccine Reports
Free

Background: A serogroup B meningococcal vaccine (4CMenB) is licensed for infant use in countries including Canada, Australia and those of the European Union. Data on serum bactericidal antibody (hSBA) waning and the ideal timing of a “toddler” booster dose are essential to optimize vaccine utilization.

Methods: An open-labeled, multicenter phase-2b follow-on European study conducted from 2009 to 2012. Participants previously receiving 4CMenB with routine vaccines at 2, 4 and 6 or 2, 3 and 4 months (246Con and 234Con) or at 2, 4 and 6 months intercalated with routine vaccines (246Int) received a booster dose at 12, 18 or 24 months. 4CMenB-naïve “Control” participants aged 12, 18 or 24 months received 2 doses of 4CMenB 2 months apart.

Results: One thousand five hundred eighty-eight participants were recruited. At 12 months, before any booster doses, the proportions with hSBA titers ≥1:5 for strain 44/76-SL (testing vaccine component fHBP) were 73% (120/165) for the “246Con” group, 85% (125/147) for “246Int,” 57% (51/90) for “234Con” and 13% (26/199) for Controls. For strain 5/99 (NadA) proportions were ≥96% (all 4CMenB-recipients) and 1% (Controls). For strain NZ98/254 (PorA), these were 18–35% (4CMenB-recipients) and 1% (Controls). By 24 months, 4CMenB-recipient proportions were 13–22% (44/76-SL), 82–94% (5/99) and 7–13% (NZ98/254) and in controls ≤4%. After a 12-month booster-dose, ≥95% of previously immunized participants had titers ≥1:5 (all strains).

Conclusions: A 4CMenB booster-dose can overcome waning hSBA titers after early-infant immunization. Administration at 12 months could help to maintain immunity during an age of high risk, and the persistence of this response requires further study.

From the *Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom; NIHR Oxford Biomedical Centre, Oxford University Hospital NHS Trust, Oxford, United Kingdom; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom; §Bristol Children’s Vaccine Centre, University of Bristol and University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom; Azienda Ospedaliero-Universitaria, Azienda Ospedaliero-Universitaria Maggiore della Carità—Clinica Pediatrica, Novara, Italy; Pediatric Highly Intensive Care Unit, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; **Vaccine Research Department, FISABIO-Public Health, Valencia, Spain; ††Department of Pediatrics, Cliniques Saint Luc, Université Catholique de Louvain, Bruxelles, Belgium; ‡‡Clinical Trial Centre, Department of Pediatrics, Johannes Gutenberg University Medical School, Mainz, Germany; §§Department of Social Medicine, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic; ¶¶Novartis Vaccines and Diagnostics Inc., Cambridge, MA; ‖‖Novartis Vaccines and Diagnostics S.r.l., Siena, Italy; and ***Novartis Pharma BV, Amsterdam, The Netherlands.

Accepted for publication November 14, 2015.

The members of the European MenB Vaccine Study Group are listed in Appendix.

The trial registration number was ClinicalTrials.gov NCT00721396.

Presented at the European Society of Paediatric Infectious Diseases Meeting in Milan, Italy, May 2013.

See Acknowledgments for disclosures and funding statements.

Address for correspondence: Matthew D. Snape, MBBS, FRCPCH, MD, Oxford Vaccine Group, Department of Paediatrics, University of Oxford, CCVTM, Churchill Hospital, Old Road Headington, Oxford OX3 7LE, United Kingdom. E-mail: matthew.snape@paediatrics.ox.ac.uk.

The recent licensing of a novel vaccine against serogroup B meningococcal disease (4CMenB) by the US Food and Drug Administration for individuals aged between 10 and 25 years,1 by the European Medicines Agency from 2 months of age in the European Union,2 are important steps towards the prevention of this potentially fatal infection. This vaccine has now been administered to more than 45,000 individuals aged 2 months to 20 years in the Saguenay-Lac Saint-Jean region of Quebec3 and has recently been introduced into the United Kingdom routine infant immunization schedule.4,5 An important consideration in cost-effectiveness calculations is whether the selected schedule can maintain protection during the early years of life. This, in turn, is likely to be dependent on the persistence of antibodies after immunization, as an association between waning antibodies and reduced vaccine effectiveness has been seen both for conjugate vaccines against serogroup C6 and for outer membrane vesicle-based vaccines against serogroup B.7–9

In a prelicensure study, participants received 4CMenB at 2, 4 and 6 months of age (alone or with routine concomitant vaccines) or at 2, 3 and 4 months of age (with concomitant vaccines).10 This study design provided the opportunity to assess the rate of bactericidal antibody waning after a range of infant 4CMenB immunization schedules, and accordingly, a follow-on study was performed to assess maintenance of vaccine-induced bactericidal antibodies to 12 months of age and beyond, as well as the immunogenicity of a booster dose of 4CMenB when administered at 12, 18 or 24 months of age.

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METHODS

Study Participants and Trial Design

This follow-on study of a phase IIb, open-label, randomized, parallel-group controlled trial was conducted between July 2009 and January 2012 in Belgium (6 centers), United Kingdom (4 centers), Czech Republic (4 centers), Germany (24 centers), Italy (5 centers) and Spain (16 centers). Appropriate regulatory authorities in each participating country granted approval for the trial. As previously described, participants in the parent study were randomized 2:2:1:1 to receive 4CMenB concomitantly with routine immunization at 2, 4 and 6 months of age (246Con); 4CMenB at 2, 4 and 6 months of age; intercalated to routine vaccines at 3, 5 and 7 months of age (246Int) and 4CMenB with routine vaccine at 2, 3 and 4 months (234Con) or routine vaccines alone (Control).10 At the last visit in this study, participants’ parents were invited to enroll their child into the follow-on study. Following parental informed consent, enrolled “follow-on” participants who previously received 4CMenB were randomized 1:1:1 to receive a booster dose of 4CMenB at 12, 18 or 24 months of age (Fig. 1) according to a centrally held randomization list (Novartis) using fixed block size of 3. Randomization in the follow-on study occurred before enrollment based on the participants completing the parent study, but follow-on randomization group was to have been concealed from parents up until the time of enrollment. Those who previously received routine vaccines alone received 4CMenB at 12 and 14 months of age (Controls 12 and 14). Additionally, 2 groups of 50 “control” participants who were 4CMenB naive were to be recruited to receive 4CMenB at 18 and 20 (Controls 18 and 20) or 24 and 26 months of age (Controls 24 and 26). Blood tests were taken immediately before the first dose of 4CMenB and 1 month after each dose.

FIGURE 1

FIGURE 1

Exclusion criteria were any history of meningococcal infection or close contact with someone experiencing meningococcal disease, prior receipt of meningococcal B (control participants only) vaccines, acute or chronic illness, known reactions to vaccine components, known or suspected immune disease or impairment including the administration of steroids, receipt of antibiotics within 6 days before enrollment, receipt of blood products or planned receipt of nonstudy vaccines (Table 1).

TABLE 1

TABLE 1

In the United Kingdom, control participants were recruited by information letters sent via National Health Service child health computer databases, whereas those in other study centers were recruited through pediatric hospitals or private practices.

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Intervention

4CMenB consists of 50 μg each of Neisserial adhesin A (NadA) and fusion proteins containing Neisseria heparin binding antigen (NHBA) and factor H binding protein (fHbp), 25 μg detoxified outer membrane vesicle-based vaccine from Neisseria meningitidis strain NZ98/254, 1.5 mg aluminum hydroxide and 10 mM histidine in 0.5 mL water for injection. All vaccines were administered by intramuscular injection in the anterolateral thigh. To maintain participant’s immunizations in line with their country’s immunizations program, routine immunizations were offered as per Table 2 but did not form part of the study evaluation. These vaccines were not administered within 30 days of the study vaccines.

TABLE 2

TABLE 2

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Functional Antibody

Serum bactericidal activity using human complement (hSBA) was assessed at the Novartis Vaccines Serology Laboratory, Marburg, Germany, against 3 reference strains chosen to determine the immunogenicity of individual vaccine components—strain 44/76-SL for fHbp, strain 5/99 for NadA and strain NZ98/254 for OMV. A strain not included in the original study (M10713) was used to assess the immunogenicity of NHBA as previously described.11 hSBA was expressed as interpolated titers according to reciprocal serum dilutions yielding 50% or greater killing of the target strain after 60 minutes of incubation compared with growth at time 0. An interpolated titer ≥1:5 represented 95% confidence that participants achieving this titer had a protective hSBA (≥1:4).12

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Safety

Parents recorded local injection site (pain, erythema, swelling and induration) and systemic reactions [ie, fever (axillary temperature ≥ 38°C), change in eating habits, sleepiness, unusual crying, vomiting, diarrhea, irritability and rash] for 7 days after each vaccination. Injection site pain was classified by the parents as mild (minor reaction to touch), moderate (cried or protested when touched) or severe (pain on limb movement). Erythema, induration and swelling were summarized by maximal severity (1–25, 25–50 and >50 mm). Adverse event recording was enhanced by telephone contact in the week after study vaccination. Safety follow-ups were completed 6 months after the last dose of 4CMenB. All serious adverse events reported during the study were recorded. Determination of the relationship between adverse events and the study vaccine was made by the study site’s investigator judgment based on temporal relationship and biological plausibility criteria.

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Statistics

The prespecified population for the immunogenicity analysis was the per-protocol population, analyzed as per-immunization course received and including all those receiving all the relevant vaccine doses correctly, provided evaluable serum samples at the relevant timepoints and having no protocol deviations with a significant impact on immunogenicity analysis.

The proportions of participants with hSBA ≥1:5 for the reference strains were calculated, as were the 2-sided 98.3% Clopper Pearson confidence intervals (CI). In addition, hSBA titers were log transformed and their geometric mean titers (GMTs) and 2-sided 95% CI calculated, as were the between-group ratios of GMTs and 2-sided 95% CIs (using 2-way analysis of variance with a factor for vaccine group and country).

The primary outcome was the proportion of participants in the 246Con group with hSBA titers ≥1:5 for strains 44/76-SL, NZ98/254 and 5/99 after a booster dose of 4CMenB at 12, 18 or 24 months of age. A sufficient immune response was prespecified as the lower limit of the 98.3% CI for this proportion being above 75% for at least 1 of the booster dose timings. Based on previous immunogenicity studies, indicating a likely “true” rate of 90% for participants having hSBA ≥ 1:5,13 performing 5000 simulations suggested a sample size of 180 participants would provide 99% power to demonstrate this.

The main secondary outcomes were the proportions with hSBA titers ≥1:5 and hSBA GMTs before the booster dose in the above participants and before and after the booster dose for 246Int and 234Con participants. The induction of immunological memory was assessed by comparison of the response to a single dose of 4CMenB at 12, 18 or 24 months in participants previously immunized in infancy and those who were MenB vaccine naive. The immunogenicity of 2 doses of 4CMenB given at 12 and 14, 18 and 20 and 24 and 26 months was also assessed. The above measures of hSBA activity against strain M10713 were determined as a post-hoc analysis.

Individuals who received at least 1 dose of vaccine and provided postbaseline safety data were included in the safety analyses, for which results were reported descriptively with no formal statistical analyses. Safety objectives were the tolerability of a booster dose of 4CMenB at 12, 18 or 24 months of age and of a 2-dose schedule commencing at these ages in MenB vaccine naive children.

Statistical analysis was performed using SAS version 9.1 (SAS Institute, Cary, NC).

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RESULTS

One thousand seven hundred ninety-nine participants completed the parent study; of whom 1481 were enrolled into this study and randomized to a booster dose at 12, 18 or 24 months of age. In addition, 51 new participants were recruited at 18 months and 56 at 24 months (Fig. 1). Of these 1588 participants, 826 (52%) were male and 94% were Caucasian.

One thousand four hundred ninety-five (94%) participants completed the study, the withdrawals primarily being due to withdrawal of consent (41), loss to follow-up (26), protocol deviations (14) and inappropriate enrollment (7). There was 1 death in a child after a car accident, before receipt of study vaccine. The per-protocol population for immunogenicity included 1221 (76%) of enrolled participants, and the safety analysis population included 1519 (96%).

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Immunogenicity

Primary Outcome

The proportion of 246Con participants with hSBA ≥1:5 after a booster dose of 4CMenB at 12 months of age was 97% (93–99) for strain 44/76-SL, 100% (97–100) for strain 5/99 and 95% (89–98) for strain NZ98/254 (Tables 3 and 4). As the lower 98.3% confidence limit for these proportions was above 75% for all three strains, the primary objective for the study was met. hSBA titers for this group after a booster dose at 18 and 24 months are shown in Table 3.

TABLE 3

TABLE 3

TABLE 4

TABLE 4

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Secondary Objectives

The proportions with hSBA ≥ 1:5 after the booster dose of 4CMenB administered at 12, 18 and 24 months to participants in groups 246Int and 234Con were similar to those in the 246Con group outlined above, being 98% or greater for strains 44/76-SL and 5/99, and 80–97% for strain NZ98/254 (Table 3).

Before administration of the booster doses at 12, 18 and 24 months of age progressive waning of these proportions was observed for all groups for strains 44/76-SL and NZ98/254, with waning particularly rapid for the latter strain (no greater than 13% by 18 months of age). In 4CMenB vaccine naive control participants, before immunization the proportion of participants with hSBA ≥ 1:5 were no higher than 13% for strains 44/76-SL, NZ98/254 and 5/99.

As a post-hoc analysis, strain M10713 hSBA titers for a subset of participants in the 234Con group and the Control groups were determined. Prior to the booster dose the proportions of these participants with hSBA ≥1:5 were similar regardless of whether they had been primed with 4CMenB or not (Table 3).

hSBA GMTs are demonstrated in Figure 2 and Table 4. For all strains, a greater rise in hSBA GMTs was seen after a single dose of 4CMenB in participants previously primed with this vaccine than in control recipients.

FIGURE 2

FIGURE 2

For the control participants, a 2-dose immunization schedule resulted in at least 91% of recipients having hSBA ≥1:5 for strains 44/76-SL, 5/99 and NZ98/254. For M10713 was 86% (Control 18, 20) and 81% (Control 24, 26).

Rates of fever after a single dose of 4CMenB ranged from 20% to 45% and were similar in children receiving 4CMenB for the first or fourth time (Fig. 3). A trend to increasing reported rates of severe tenderness at the injection site with increasing age was also apparent (Fig. 3); again, this was not influenced by the number of previous doses of 4CMenB received.

FIGURE 3

FIGURE 3

During the study, 70 serious adverse events affecting 58 participants were reported (including the death mentioned above). Three of these were classified by investigators as possibly being related to the study vaccine. One child enrolled into the control 12, 14 month group was diagnosed with autism at the age of 3 years, having initially presented with speech delay and learning difficulties at age 18 months. This child was immunized with his routine vaccines (as per United Kingdom schedule) at 12 and 14 months of age, and with 4CMenB at 15 and 17 months of age. The investigator considered it was not possible to exclude a relationship with the study vaccine given the temporal association. This child’s previous medical history was unremarkable, and speech and hearing assessments were normal. At 3.5 years of age the child had persistent difficulties with language development and social interaction. A second child, in the 246Con-24 group, developed idiopathic epilepsy, with the first convulsion at age 2 years and 3 months, 106 days after the booster dose of vaccine at 24 months of age. Electroencephalogram and magnetic resonance imaging tests were normal. By the age of 3.5 years the child had experienced 6 seizures (both febrile and afebrile), but none within the last 3 months. There was no developmental delay and the child was not receiving anticonvulsant therapy. A third child (Control 12, 14) developed 2 febrile convulsions on the day of the 12-month immunization and was also diagnosed with atypical pneumonia at the time of presentation.

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DISCUSSION

This study of more than 1500 participants provides novel data on the persistence through the second year of life of bactericidal antibody induced by various infant 4CMenB immunization regimens and on the immunogenicity and reactogenicity profile of 4CMenB given as 2 doses in the second year of life. These data, combined with local age-specific epidemiology, are vital for the design of the optimal strategies for implementation of 4CMenB immunization programs.

The United Kingdom recently introduced 4CMenB into its routine infant immunization program in a 2-, 4- and 12-month immunization schedule.4,5 Specific studies of the immunogenicity of this “2 + 1” schedule are currently underway.14 However, the European Medicines Agency marketing authorization for the vaccine is for a 3-dose priming schedule with a booster in the second year of life (3 + 1), a schedule that was informed by the data presented in this study2 and that may be selected by some national authorities.

Importantly, in this study the proportions of participants with SBA titers ≥1:5 before boosting in the second year of life was not influenced by whether the last priming vaccine was given at 4 or 6 months of age. For both schedules, the response to a single booster dose of 4CMenB was also similar and this, combined with the relatively lower hSBA GMTs after the first dose of 4CMenB in control participants, suggests both schedules effectively induced immunological memory.

These data provide reassurance that 4CMenB could be incorporated into either a 2-, 4- and 6-month schedule (as used in North America, Latin America and many European countries) or into an accelerated 2, 3 and 4 dose schedule without impacting on the persistence of immune protection through the first year of life or after the booster dose.

The study also informs the optimal timing of the booster dose. The ongoing waning of antibodies observed from 1 to 2 years of age in the second year of life is of some concern given the incidence of serogroup B meningococcal disease at this age is second only to infancy in Europe15 and suggests that where this is the case booster dose should not be delayed beyond 12 month. Whether or not this disadvantage could be offset by greater persistence of antibodies through preschool years following a delayed dose is not currently known and is being evaluated in a further persistence study.16

The licensed schedule for 4CMenB includes 2 doses given 2 months apart for children aged 12 months to 10 years, with a booster dose given 1–2 years later for children initially immunized at 12–23 months.17 These data demonstrate that although 88% or more of children developed SBA titers ≥ 1:5 for strains 44/76 and 5/99 after a single dose, a 2-dose priming schedule is required to be immunogenic for all 4 strains, supporting the licensed schedule for his age group. There was little apparent difference in immunogenicity across this age band.

There was also little difference in the reactogenicity profile between controls immunized at 12, 18 or 24 months, with the exception of a trend to higher rates of reported severe tenderness in older children. This trend was also noted with increasing age of the booster dose. It is possible that this reflects a trend to greater local reactogenicity with greater age; however, an alternative possibility is that severe tenderness (ie, tenderness on limb movement) might be more readily reported as the developing child becomes increasingly verbal. The rates of fever after 4CMenB given in the second year of life were similar to those reported when this vaccine was given without concomitant vaccines in infancy10; however, they are higher than those reported after glycoconjugate vaccines such as MenC given to 1–2 year olds.18–20 This tendency for the vaccine to be relatively reactogenic compared with other routinely used childhood immunizations has been described in previous clinical trials, and in the United Kingdom, parents are advised to routinely administer paracetamol prophylactically when their child receives their 2- and 4-month 4CMenB immunizations.21 No such recommendation is given for the 12-month booster immunization, although this was accompanied by fever rates of 30–45% in our study.

The bactericidal titers against the M10713 strain included as a post-hoc assessment of the immunogenicity of the NHBA component, warrant specific consideration. Only 36% of participants developed bactericidal antibodies against this strain after a 2-, 3- and 4-month schedule, and hSBA titers were similar to those of controls after priming and before boosting. Direct comparisons of immunogenicity against M10713 for 234 and 246 schedules were not possible within this study; however, for a previously reported study, more than 80% of participants receiving a 2-, 4- and 6-schedule had hSBA ≥ 1:5 for this strain, which was maintained at 60% before boosting at 12 months.22 Within the limits of cross-study comparisons, this does suggest that, for this antigen at least, a 2-, 4- and 6-month schedule may be preferable. It is worth noting that, as for the other strains, a greater rise in M10713 specific bactericidal antibodies was seen among primed infants than in those receiving this for the first time, again suggestive of immunological memory.

The data obtained in this study on antibody persistence after primary immunization in the absence of a booster dose complement those obtained in other studies after a 4CMenB toddler booster dose,11,23 a further booster dose at 3.5 years of age,24 primary immunization at 3.5 years of age24 and primary immunization in adolescence.25 As with meningococcal conjugate vaccines,26 antibody persistence seems to be enhanced with increasing age at primary immunization.

Another feature is the variable rate of waning between different strains, with bactericidal titers against strain 5/99 (NadA) being maintained in the majority of vaccine recipients, whereas those against NZ98/254 (PorA) waned more rapidly, and an intermediate rate of waning observed for strains 44/76 (fHBP) and M10713 (NHBA). This pattern of SBA waning has been highly consistent across multiple studies.11,23,24,27 In the absence of any data on whether relatively persistent SBA titers are reflected in more prolonged immunity against strains bearing the relevant antigens, is unclear whether this is likely to be clinically relevant or merely reflects different susceptibilities of the strains to killing in the serum bactericidal antibody assay.

This differential rate of waning has made predicting persistence of the immune protection provided by immunization with 4CMenB particularly difficult. The interim statement by the United Kingdom Joint Committee on Vaccines and Immunization published in July 2013 suggested that infant immunization with this vaccine would directly prevent approximately 25% of the lifetime risk of invasive MenB disease in the United Kingdom.28 Following the introduction of the vaccine into the routine infant immunization schedule in that country, extensive postimplementations surveillance is underway to monitor the accuracy of such predictions29 and whether strains bearing antigens targeted by “waning” antibodies will be over-represented as a cause of secondary vaccine failures.

A limitation of this study was the lower numbers of participants at the 18- and 24-month time points. This in part reflected an increasing number of withdrawals with advancing age of booster immunization, not only reflecting greater interval between enrollment and immunization, but also appears to reflect a discrepancy in numbers recruited to different randomized groups at the conclusion of the parent study. This may in turn reflect a problem with concealment of randomization group from the parents before enrollment. Of note is that although the routine vaccines administered during the study did differ between countries, these vaccines were not administered within 30 days of the study vaccine. In the parent study, we demonstrated that routine glycoconjugate and diphtheria, tetanus, pertussis and polio vaccines had minimal impact on 4CMenB immunogenicity, even when administered concomitantly.10 It is, therefore, highly unlikely these variable routine immunization schedules would have influenced the 4CMenB immunogenicity profile in this study.

Nevertheless, this study makes an important contribution to the expanding body of knowledge regarding 4CMenB. The recent 4CMenB mass immunization campaigns at Princeton University,30 University of California, Santa Barbara31 and Saguenay-Lac Saint Jean, Quebe,3 highlight the importance of a vaccine being available against this rapidly fatal infection. Information on duration of immunity is essential to plan schedules and provide understanding of how to best use this vaccine. Our data support the use of a booster dose early in the second year of life after infant immunization and the need for further studies to look at ongoing antibody persistence beyond the time points measured in this study. Nonetheless, as with other vaccines licensed based on immunologic surrogate measures, a firm understanding of the duration of protection will only be established after broad vaccine implementation with robust disease surveillance and vaccine coverage assessments.

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ACKNOWLEDGMENTS

M.D.S., A.F., S.E., N.P., D.K., J.D.-D., E.S. and R.P. act as investigators for clinical studies from both noncommercial funding bodies and commercial sponsors (ie, some or all of Novartis Vaccines, GlaxoSmithKline, Sanofi-Aventis, Sanofi-Pasteur MSD, MedImmune and Pfizer Vaccines) conducted on behalf of their institutions as listed in the affiliations. M.D.S. and A.F. participate in advisory boards and speaking engagements for vaccine manufacturers; all payments received are paid to their respective institutions. R.P., J.D.-D., S.E. and N.P. also undertake consultancy and advisory work and receive speaking honoraria, travel and accommodation reimbursements for several commercial sponsors. The NIHR Oxford Biomedical Research Centre provides salary support for M.D.S., who is a Jenner Investigator. A.J.P. is a Jenner Investigator and James Martin Senior Fellow. A.J.P. and A.F. do not receive any personal renumeration from vaccine manufacturers. A.J.P. is chair of the U.K. Department of Health’s (DH) Joint Committee on Vaccination and Immunization (JCVI); the views presented in this manuscript do not necessarily represent the views of DH or JCVI. P.M.D. was formerly an employee of Novartis Vaccines and Diagnostics. D.T, H.W., I.K. and M.B. are employees of Novartis Vaccines and Diagnostics. Novartis Vaccines and Diagnostics Srl, Siena, Italy, provided the funding for this study. With the lead investigators, Novartis Vaccines was involved in the design of the study as well as analysis of the data, review and comment on the manuscript. Data collection was undertaken by the study investigators. Editorial control of the manuscript was assigned to the University of Oxford. Statistical evaluation of the results was performed by Novartis Vaccines and confirmed by an independent statistician at Oxford University working with the Nuffield Department of Primary Care Health Sciences.

The authors thank all of the participants and their families for contributing to this study. The authors also thank Keith Veitch (keithveitch communications) for graphical support.

Authors’ Contributions: A.J.P., M.D.S., P.M.D., D.T., S.E., N.P. and R.P. contributed in study concept and design. E.S., J.D.-D., M.D.S., S.E., A.J.P., A.F., G.B., N.P., R.P., D.K., I.K. and M.B. involved in acquisition of data. M.D.S., A.J.P., D.T., P.M.D., S.E., G.B., M.V., N.P. and H.W. involved in analysis and interpretation of data. M.V. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. M.D.S. drafted the manuscript. A.J.P., D.T., J.D.-D., E.S., M.D.S., S.E., G.B., M.V., N.P., D.K., R.P., A.F., P.M.D., I.K., M.B. and H.W. did critical revision of the manuscript for important intellectual content. H.W. and M.V. involved in statistical analysis. E.S. provided administrative, technical or material support. A.J.P., P.M.D., D.T., M.D.S., S.E., G.B., N.P. and R.P. involved in study supervision.

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APPENDIX

The European Men B Vaccine Study Group: Paul T. Heath, MD and Clarissa Oeser, MD (Division of Child Health, St George’s University of London, United Kingdom); Andrew Collinson, MD and Jasmine Heslop, RN (MCRN South West Royal Cornwall Hospitals, NHS Trust); Tessa John, RN and Sarah Kelly, RN (Oxford Vaccine Group, Department of Paediatrics, University of Oxford, United Kingdom); Maurizio De Martino, MD and Luisa Galli, MD (Department of Sciences for Woman and Child’s Health, Anna Meyer Children’s University Hospital, University of Florence, Italy); Chiara Azzari, MD and Leila Bianchi, MD; Carlo Giaquinto, MD and Susanna Masiero, MD (Department of Pediatrics, University of Padua); Gianvincenzo Zuccotti, MD (Pediatria dell’Ospedale Sacco di Milano, Milano); Benedetta Ghezzi, Igor Kohl, Frank Baehner, Carina Nasemann, Simone Inzillo, Riccardo Belli, Lucie Hlavata (Novartis Vaccines, MA and Siena); Gianni Bona, MD and Nicolino Grasso, MD (Azienda Ospedaliero-Universitaria, Azienda Ospedaliero-Universitaria Maggiore della Carità—Clinica Pediatrica, Novara, Italy); Miguel A. Cabañero, MD (Centro de Salud San Lorenzo, Castellón, Spain); Eva Suárez, MD (Centro de Salud Almassora); Susana Peñarroja, MD (Centro de Salud Vall D’Uixo); Vicente Antón, MD, PhD (Centro de Salud Raval Sagunto, Valencia); Manolo Martínez, MD (Centro de Salud República Argentina); María D. Garcés, MD (Centro de Salud Nazaret); Angels Jubert, MD (Centro de Salud Malvarrosa); Maite Asensi, MD (Centro de Salud Serreria I); Ignacio Sorribes, MD (Centro de Salud Serreria II); Isabel Úbeda, MD, PhD (Centro de Salud de La Eliana); Victoria Planelles, MD (Centro de Salud Paiporta); Jose Villarroya, MD (Centro de Salud Plaza de Segovia); Miguel Tortajada-Gribes MD, PhD (Centro de Salud Catarroja); Federico Martinón-Torres, MD, PhD and Lorenzo Redondo Collazo, MD (Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela); Julián Rodriguez S., MD, PhD (Department of Paediatrics, Hospital Universitario Central de Asturias, Oviedo); André Vertruyen, MD, GZA (Campus Sint-Vincentius, Antwerp, Belgium); Jose Ramet, MD (University Hospital Antwerp); Marc Verghote, MD (Centre hospitalier regional de Namur, Namur); Marc Raes, MD (Virga Jesse Ziekenhuis, Hasselet); Anne Malfroot, MD (Department of Pediatrics, Clinic of Pediatric Respiratory Diseases, Infectious Diseases and Travel, UZB—Universitair Ziekenhuis Brussel, Brussels); Ulrich Behre, MD, Martin Kimmig, MD, Roland Knecht, MD, Dieter Schlegel, MD, Siegfried Simmet, MD, Michael Steiner, MD, Bernhard Sandner, MD, Martina Weh, MD, Eckhard Ziegler-Kirbach, MD, Friedrich Kaiser, MD, Gerhard Bleckmann, MD,Thomas Adelt, MD, Ralph Köllges, MD, Heidemarie Pankow-Culot, MD, Peter Soemantri, MD, Philip Fellner von Feldegg, MD, Dietmar Hauptmann, MD, Christian Weißhaar, MD, Roland Achtzehn, MD, Christian Horn, MD, Christoph Schäfer, MD, Brigitte Wilmsmeyer, MD and Eivy Franke-Beckmann, MD (NETSTAP e.V., Bochum, Germany); Roman Chlíbek, MD, PhD (Vaccination Center, Faculty of Military Health Sciences, University of Defense, Hradec Kralove, Czech Republic); Vladimír Němec, MD (Children´s Department Pardubice, Pardubice) and Luděk Týce, MD (Detske stredisko, Cerveny Kostelec); Daniel Dražan, MD (Samostatna ordinace praktickeho lekare pro deti a dorost, Jindrichuv Hradec).

Keywords:

Serogroup B meningococcal vaccine; persistence of immunity; serum bactericidal activity; paediatric

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