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.
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.
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.
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.
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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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:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Serogroup B meningococcal vaccine; persistence of immunity; serum bactericidal activity; paediatric
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