Background: In a previous study, 60 infants receiving an investigational serogroup B meningococcal vaccine containing recombinant meningococcal proteins alone (rMenB) or combined with an outer membrane vesicle from Neisseria meningitidis (4CMenB) at 6, 8 and 12 months of age produced serum bactericidal antibodies (SBAs) against meningococcal strains expressing vaccine antigens. We studied persistence of this response and the response to a booster dose of vaccine.
Methods: In this extension study, SBA titers were evaluated before and after a booster dose of rMenB or 4CMenB at 40 months of age. MenB vaccine naïve age-matched children served as a control group.
Results: Before the booster doses, the proportions of 4CMenB recipients with SBA titers ≥1:4 were 36% (n = 14, 95% confidence interval: 13–65%) for strain 44/76-SL, 100% (77–100%) for 5/99, 14% (2–43%) for NZ98/254 and 79% (49–95%) for M10713. These percentages were 14% to 29% for rMenB recipients (n = 14), except for 5/99 (93%, 66–100%). For controls (n = 40), these proportions were ≤3% for all strains except M10713 (53%, 36–68%). One month after the boosters, ≥93% of 4CMenB recipients had SBA titers ≥1:4 for all 4 strains. For controls receiving their first dose of 4CMenB, 23% (11–39%) had SBA titers ≥1:4 for NZ98/254, compared with 62% to 87% for the remaining strains.
Conclusions: Bactericidal antibodies wane after infant immunization with rMenB or 4CMenB, but there is an anamnestic response to a booster dose. Booster doses of 4CMenB may be required to maintain immune protection through childhood and adolescence.
From the *Department of Paediatrics, University of Oxford and NIHR Oxford Biomedical Research Centre; †Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom; ‡Novartis Vaccines and Diagnostics Srl, Siena, Italy; and §Novartis Vaccines and Diagnostics Inc., Cambridge, MA.
Accepted for publication May 6, 2013.
The trial registration number was ClinicalTrials.gov NCT01026974.
Novartis Vaccines and Diagnostics was the sponsor of the study. With the lead investigators, Novartis was involved in the design of the study as well as analysis of the data, and as authors, Novartis employees reviewed and commented on the article. Data collection was undertaken by the study investigators. Editorial control of the article was assigned to the University of Oxford. Novartis conducted the primary analysis of the data before review by L.-M.Y. L.-M.Y. had access to the full raw data set, protocol and analysis plan and ran her own analysis. All results reported in the article were reanalyzed by her. L.-M.Y. is independent of the sponsor, is employed by the UK National Health Service and was not compensated by Novartis.
Novartis Vaccines and Diagnostics provided the funding for this study. The NIHR Oxford Biomedical Research Centre provides salary support for M.D.S. and T.M.J. A.J.P. is a Jenner Investigator and James Martin Senior Fellow.
A.J.P. and M.D.S. act as chief and principal 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 the University of Oxford. M.D.S. also undertakes consultancy and advisory work for several commercial sponsors; any speaking honoraria, travel and accommodation reimbursements are paid to the University of Oxford Department of Paediatrics. M.D.S. and A.J.P. do not receive any financial support from vaccine manufacturers; all income from these sources is paid to the University of Oxford. L.-M.Y. was employed by the Centre for Statistics in Medicine at the time of manuscript preparation; this organization provides general and project-specific statistical support to Oxford Vaccine Group. P.M.D. is an employee of Novartis Vaccines and Diagnostics Inc., and D.T. and C.K. are employees of Novartis Vaccines and Diagnostics Srl. The authors have no other funding or conflicts of interest to disclose.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).
Address for correspondence: Matthew D. Snape, MD, c/o Oxford Vaccine Group, CCVTM, Churchill Hospital, Old Rd, Headington, Oxford OX37LE, United Kingdom. E-mail: firstname.lastname@example.org.
An investigational vaccine against serogroup B meningococcus has recently been licensed by the Committee for Medicinal Products for Human Use at the European Medicines Agency and offers the potential to reduce the burden of disease due to this potentially fatal infection. This vaccine, 4CMenB, consists of 3 recombinant proteins: factor H binding protein (fHbp), Neisserial adhesin A (NadA) and Neisseria heparin binding antigen (NHBA) combined with detergent-extracted outer membrane vesicles (OMVs) from the strain responsible for an epidemic of serogroup B meningococcal (MenB) disease in New Zealand (NZ98/254). 4CMenB also contains 2 additional antigens bound to fHbp and NHBA to create 2 fusion proteins (fHbp-GNA2091 and NHBA-GNA1030).
The vaccine has been administered to over 7800 infants, adolescents and adults and has been shown to be immunogenic against reference strains expressing the vaccine antigens.1–4 These studies include a phase II study in which vaccines consisting of the recombinant proteins with or without the OMV component were administered to 60 children at 6, 8 and 12 months of age,1 a schedule that could be used as part of a “catch-up” campaign to accompany introduction of the vaccine into an early routine infant schedule.
Persistence of antibodies induced by any infant immunization schedule through later childhood is important given that the incidence of invasive MenB disease in children aged 1 to 4 years in countries such as England and Wales is second only to the incidence in infancy.5 In this study, we took blood samples from 40- to 44-month-old children previously enrolled in a phase II late-infancy study and compared these to bactericidal titers in MenB vaccine-naïve age-matched participants (controls). The immunogenicity and reactogenicity of a booster dose given to the “follow-on” participants at this time were also assessed, as were those after a first dose of 4CMenB participants given to the control participants. Control participants then received a 2nd dose of 4CMenB to allow assessment of a 2 dose schedule at this age.
Participants in the original phase II study (NCT00433914) were recruited and randomized 1:1 to receive either the recombinant proteins with the OMV (4CMenB) or a formulation consisting of the recombinant proteins alone (rMenB) at 6, 8 and 12 months of age. All 57 participants completing the original study were invited to take part in this follow-on study, and recruitment of 50 vaccine naïve, age-matched participants as controls was planned. Inclusion criteria were healthy children aged 40 to 44 months who had completed the original study or, for controls, those had not previously received a MenB vaccine. Exclusion criteria were previous meningococcal disease (or household/intimate contact with anyone with meningococcal disease), allergy to vaccine components, severe acute or chronic disease, immune dysfunction, receipt of blood products, planned receipt of nonstudy vaccines within 30 days of the study vaccines, enrolment in another clinical trial, recent antibiotic use, being a family member of research staff and antipyretic use within 6 hours before enrolment. Written informed consent was obtained from participant’s parents or legal guardians. Ethical approval was obtained from Oxfordshire Research Ethics Committee (Ref: 09/H0605/89).
Participants previously enrolled in the original study had blood samples taken before and 30 days after a booster dose of their respective vaccines (Fig., Supplemental Digital Content 1, http://links.lww.com/INF/B591). Control participants received 2 doses of 4CMenB approximately 60 days apart. These participants had blood samples taken at enrolment and 30 days after each immunization.
Both vaccines contained 50 µg each of NadA allele 3, NHBA-GNA1030 fusion protein (containing NHBA peptide 2) and GNA2091-fHbp fusion protein (containing fHbp variant 1.1) as well as 1.5 mg aluminium hydroxide and 10 mM histidine. 4CMenB also contained 25 µg of detoxified outer membrane vesicles (OMVs) from Neisseria meningitidis strain NZ 98/254 (expressing the immunodominant antigen PorA serosubtype P1.4). The vaccines were 0.5 mL in volume and were administered by intramuscular injection into the deltoid area of the nondominant arm. Participants also received a combination diphtheria-toxoid, tetanus-toxoid, acellular pertussis and inactivated polio vaccine (Repevax, Sanofi Pasteur MSD, Maidenhead, UK) and a combination measles, mumps and rubella vaccine (MMRVaxPro, Sanofi Pasteur MSD, Maidenhead, UK) at the final study visit (41 months for 4CMenB and rMenB participants, 43 months for “control” participants). These vaccines did not form part of the study evaluation and were administered to keep participants immunized according to the UK routine schedule.
Sera were analyzed at the laboratories of Novartis Vaccines and Diagnostics (GmbH, Marburg, Germany) for bactericidal activity using a human complement source serum bactericidal antibody (hSBA). Laboratory staff were blinded to participant group. The correlate of protection used for descriptive statistics and analysis was an hSBA titer ≥1:4. As previously described,1 reference meningococcal strains were used to assess the immunogenicity of specific vaccine components. The fHbp response was assessed by strain 44/76-SL, NadA by strain 5/99 and PorA (the immunodominant antigen in OMV) by NZ98/254 (Table, Supplemental Digital Content 2, http://links.lww.com/INF/B592). A novel strain (M10713) was used to assess the immunogenicity of NHBA as this expresses NHBA cross-reactive to that contained in the vaccine (peptide 10) but is mismatched for the vaccine components fHbp (variant 2.24) and PorA (VR2 16-3) and does not contain the gene for NadA. Therefore, in accordance with the principle underlying the use of the existing reference strains, any increase in hSBA titers against M10713 after immunization could be attributed primarily to the NHBA component of the vaccine. Immunogenicity against additional strains was assessed to evaluate the impact of antigenic variation and expression on susceptibility to vaccine-induced antibodies (Table, Supplemental Digital Content 2, http://links.lww.com/INF/B592). Strain GB355 was specifically selected as a strain likely to be relatively resistant to vaccine-induced bactericidal antibodies as it was mismatched for all vaccine antigens. With the exception of M10713, all strains were the same as those analyzed as in the original study.1
Each day for 7 days after immunization, parents recorded their child’s axillary temperature, local reactions at the site of immunization (tenderness, erythema and induration), solicited systemic reactions (irritability, persistent crying, vomiting, diarrhea, sleepiness and anorexia) and the use of analgesic and antipyretic medication. Severe local tenderness was defined as inability to perform daily activity, whereas local erythema and induration were considered severe if >50 mm diameter and severe fever at temperature ≥40°C. Adverse events requiring a physician’s visit were recorded throughout the study. The relationship of adverse events to the study vaccine was determined by the study investigators taking temporal relationship and biological plausibility into account.
The primary immunogenicity objective of this study was to assess the persistence of bactericidal antibodies at 40 months of age in children who previously received 3 doses of 4CMenB or rMenB at 6, 8 and 12 months of age. The primary safety objective was to assess the safety and tolerability of a booster dose of these vaccines administered at 40 months of age.
Secondary objectives were to assess the increases in hSBA titers after a booster dose of these vaccines at 40 months of age and to assess the bactericidal antibody response and adverse reactions after a 2 dose “catch-up” immunization schedule of 4CMenB administered at 40 and 42 months of age in MenB vaccine naïve children.
The percentages of children in each study group with hSBA titers ≥1:4 were calculated for each strain at each blood sampling time-point, along with 2-sided 95% Clopper-Pearson confidence intervals (CIs). Similarly, hSBA geometric mean titers were calculated for each study group at each sampling time-point for each strain and 95% CI determined by exponentiating (base 10) the corresponding means and 95% CI of the log10 hSBA titer. Geometric mean ratios of postimmunization hSBA geometric mean titers to baseline (40 months) and 95% CI were also calculated, for which hSBA titers below the lower limit of detection of 4 were allocated a value of 2.
The primary population for immunogenicity analysis was the intention-to-treat analysis, consisting of all participants who were randomized and received at least 1 dose of either MenB vaccine and provided at least 1 evaluable serum sample. Safety analysis was conducted on a population consisting of all participants who received a dose of either MenB vaccine formulation and provided postbaseline safety data.
The sample size for the follow-on participants was determined by the number of participants completing the original study at the Oxford site. All comparisons were descriptive; however, it was calculated that if the percentage of participants with hSBA titers ≥1:4 was 40% in a follow-on group and 5% in the naïve group, a sample size of 20 participants in the follow-on group and 50 participants in the control group would provide 88% power to show superiority.
Of the 57 participants completing the original study, 30 were enrolled into this follow-on study, in addition to 41MenB vaccine naïve participants (Table, Supplemental Digital Content 3, http://links.lww.com/INF/B593). Median ages were 43.1 months (4CMenB group), 42.8 months (rMenB) and 41.7 months (control group). Sex distribution was similar in each group except 4CMenB (3 males and 11 females).
Immunogenicity: Primary Objective
At visit 1, 93% of participants in the rMenB group and all participants in the 4CMenB group had hSBA titers ≥1:4 against strain 5/99 (testing for NadA), compared with 0% of participants in the control group. Fewer 4CMenB recipients maintained hSBA titers ≥1:4 against the other strains: 36% and 14% of participants in the 4CMenB group had SBA titers ≥1:4 for strain 44/76-SL (testing for fHbp) and strain NZ98/254 (testing for PorA P1.4 in the OMV), respectively. As anticipated, minimal bactericidal activity against strain NZ98/254 was observed for the rMenB group. Against strain M10713 (testing for NHBA), a titer of ≥1:4 was seen in 79% of participants in the 4CMenB group compared with 53% of the control group and 29% of rMenB recipients. Results for the additional strains are shown in Table, Supplemental Digital Content 4, http://links.lww.com/INF/B594, whereas reverse cumulative distribution curves for hSBA titers and hSBA geometric mean titers for all strains are shown in Figure 1 and Table 1, respectively.
Immunogenicity: Secondary Objectives
A month after the booster dose of 4CMenB administered at 40 months of age, all children who had been primed by previous immunization with this vaccine had SBA titers ≥1:4 for 4 of the hSBA strains; of the remaining strains only strain GB355 had fewer than 85% of the 4CMenB group having titers ≥1:4 (Table, Supplemental Digital Content 4, http://links.lww.com/INF/B594).
Comparison of the rise in hSBA titers after the dose of 4CMenB at 40 months of age (as assessed by nonoverlapping CIs for the geometric mean ratio of hSBA titers from post/preimmunization) suggests a greater rise in the 4CMenB group than controls for strains 44/76-SL, NZ98/254 and UKP1.7-2,4, with this trend also observed for the remaining strains. Geometric mean titers from both this study and the original study are displayed in Figure, Supplemental Digital Content 5, http://links.lww.com/INF/B595.
The overall profile of solicited reactions between the groups receiving the booster 4CMenB vaccination at 40 months was similar. Most local and systemic reactions were mild to moderate in nature (Fig., Supplemental Digital Content 6, http://links.lww.com/INF/B596 and Fig. 2) and occurred within the first 3 days of vaccination (data not shown). Across all groups, the most common local reactions were erythema and pain. Severe pain was not reported in the rMenB group but occurred in 29% of subjects in the 4CMenB group and by 7% (first vaccination) and 24% (second vaccination) in the control group.
Fever with vaccination was seen in 25% in the rMenB group and 7% in the 4CMenB group and was transient, with the majority resolving within 2 days (data not shown). In the control group, 6 (15%) subjects after the first vaccination and 4 subjects (11%) after the second vaccination reported fever. Only 1 child developed fever ≥40°C: a MenB vaccine-naive participant after the first injection with 4CMenB vaccine.
A total of 3 children experienced serious adverse events. A control group participant developed a febrile convulsion 8 hours after the second dose of 4CMenB (considered as possibly related to the study vaccine). Another participant from the control group withdrew from the study after an acute febrile illness (onset 79 days after the first dose of 4CMenB) following which fever and some clumsiness persisted for several months before resolution. Investigation of cerebrospinal fluid at presentation revealed an elevated white cell count of 80/mm3 with a red cell count of 1408/mm3. Bacterial and viral studies of cerebrospinal fluid were normal, as were computed tomography and magnetic resonance imaging scan of brain. This was diagnosed as meningoencephalitis and was considered not related to the study vaccine. A case of cervical lymphadenitis 36 hours after a fourth dose of the rMenB was not considered related to the vaccine.
This is the first study to present data on persistence of anti-MenB antibodies following a 6-, 8- and 12-month infant immunization course of 4CMenB, a vaccine that has recently been licensed in the European Union. We found that, two years after the last dose of vaccine, bactericidal antibodies remain above the putative threshold of protection (hSBA titer ≥1:4) in more than 50% of participants for 5 out of 8 strains tested. In contrast, for participants previously immunized with rMenB, this was only the case for 2 of the 8 strains. A booster dose of 4CMenB at 40 months of age resulted in a greater increase in hSBA titers for 4CMenB primed participants than MenB vaccine-naïve controls, suggesting an anamnestic response. Although the majority of participants experienced irritability and a noteworthy rate of injection site tenderness or erythema after this booster dose, the rates of fever were lower than those recently reported in infants studies with the same vaccine.3
The immunization schedule of 6, 8 and 12 months assessed in the original study is unlikely to be used for routine immunization (in part because of the relatively high incidence of meningococcal disease before 6 months of age),6 but could be employed as part of a “catch-up” campaign to accompany the introduction of routine infant immunization. The data from this study suggest that there is waning of bactericidal antibody levels after immunization with 3 doses of 4CMenB in late infancy, although the significance of this in relation to efficacy or effectiveness is currently unknown. The effectiveness of OMV vaccines against MenB disease declined with increasing time after immunization in Norway7 and, according to provisional data, in New Zealand,8,9 and this decrease in effectiveness corresponded with waning of bactericidal antibodies. A similar phenomenon has been observed for serogroup C meningococcal conjugate vaccines.10 If a “preschool” booster dose of 4CMenB were to be required then this would have implications for the costeffectiveness of a 4CMenB immunization campaign. Of note, the bactericidal antibodies directed against some strains waned more rapidly than others. This may be an in vitro phenomenon that is of no clinical significance or it may indicate that induction of persistence is dependent on unknown antigen-specific characteristics. The bactericidal assay is a biological assay in which variability in the characteristics of different strains, and the requirement for different sources of complement for these strains, makes it inherently difficult to draw conclusions about differences in responses between strains. Data on how these levels of bactericidal activity for individual strains relate to effectiveness should clarify this issue in the future. Of importance, this could imply that effectiveness will be different over time and with different MenB strains.
This study identified some strikingly different responses to the components of the vaccine when compared with the responses in infancy. For example, the majority of participants receiving rMenB at 40 months of age developed bactericidal activity against UKP1.7-2.4, whereas only 1 of 21 toddlers showed such a response after receiving 3 doses of this vaccine. This strain lacks the gene for NadA but contains genes for fHbp subvariant 1.4 and NHBA variant 1.2 and antibodies against these antigens should induce bactericidal activity. The lack of bactericidal activity observed against this strain following infant immunization with rMenB suggests that either these proteins are expressed at a level below that required for bactericidal activity or that the antibodies generated by infant immunization with rMenB were insufficiently cross-reactive to provide a response to these proteins. The greater immunogenicity of rMenB for strain UKP1.7-2.4 when given at 40 months of age rather than in infancy suggests that a broadening of antibody responses for the fHbp and NHBA antigens may be seen with increasing age, or that the previous immunization with rMenB “primed” the immune response to these antigens without generating bactericidal antibodies.
Although the bactericidal activity observed against the strains in this study allows assessment of the immunogenicity of the individual vaccine components, the information it provides about the likely breadth of protection against MenB afforded by an immunization campaign with 4CMenB disease is limited. Because the use of hSBA for a very large panel of strains is not practical for technical reasons, attempts to predict coverage using surrogate assays more suitable for high throughput and standardization have been used. One example of this is the meningococcal antigen typing system developed by Novartis Vaccines,11 which relates the strength of binding of vaccine antigen-specific IgG in a representative panel of meningococcal strains to strain-specific bactericidal activity (performed using pooled sera obtained from 13-month-old 4CMenB recipients). This can then be used to predict the percentage of local invasive strains likely to be susceptible to antibodies against one or more of the vaccine components. Using this technique, meningococcal antigen typing system predicts vaccine “coverage” of 78% of invasive MenB strains in Europe,12 76% in Australia13 and 66% in Canada.14 Caution should be used in interpreting a surrogate (meningococcal antigen typing system) of a correlate (hSBA), but there is currently no alternative approach to estimate coverage. Given the demonstrated waning of antibodies from the peak at 13 months of age in this study, consideration must be given to the possibility that the breadth of protection afforded will also fall with time since immunization.
“Preschool” booster doses are currently required for many vaccines given in infancy, for example, the combination tetanus-toxoid, diphtheria-toxoid, acellular pertussis and inactivated polio vaccine used in the United Kingdom.15 Should a preschool booster dose also be required for 4CMenB, these data provide some reassurance that rates of fever are likely to be lower than experienced in infancy,3 although data on coadministration with other routine “preschool” immunizations are lacking. Reactogenicity at the injection site may be of more concern, as postimmunization pain and erythema were seen in almost all recipients of 4CMenB. Previous studies of tetanus-toxoid, diphtheria-toxoid, acellular pertussis and inactivated polio vaccine given at 3.5 to 5 years suggest these local reactions could be expected in fewer than half of children receiving the current UK schedule,16 Although comparisons with historical studies are problematic, these data do suggest introduction of 4CMenB into the routine preschool booster schedule could result in an increase in local reactions at this immunization visit compared with current rates. Importantly, the data show that a booster dose at this age results in an increase in hSBA titers, although the persistence of this increase after a “preschool booster” is unknown and is currently being evaluated in a study of 5-year-old children.17
This study had a number of limitations, including the relative small sample sizes as dictated by the number of participants in the original early phase II study. Data are, however, broadly in line with those of another study conducted at the same site evaluating persistence after immunization at 2, 4, 6 and 12 months of age.18 Approximately 50% of eligible participants took part in this follow-on study, creating the potential for bias as those participants experiencing significant reactions in the original study may be underrepresented in the current study. Follow-on studies are currently being conducted from the larger phase IIb and III studies19,20 and will provide additional data on antibody persistence and tolerability.
In conclusion, waning of hSBA titers is observed after immunization with 4CMenB in late infancy, consistent with other vaccines against meningococcal disease. The key to understanding the importance of this in the context of routine immunization with 4CMenB will require a robust surveillance program postimplementation, allowing early recognition of any decline in vaccine effectiveness. The data from this study provide welcome evidence that a booster dose of 4CMenB vaccine given at the “preschool” immunization visit would increase serum bactericidal activity against reference meningococcal strains, potentially extending protection against this lethal disease.
The authors thank all of the participants and their families for contributing to this study. We also thank all the nurses and doctors of the Oxford Vaccine Group who contributed to this study, Emma Plested for her administrative support and the child health computer departments of Oxfordshire, Buckinghamshire, Milton Keynes, East and West Berkshire and Northamptonshire.
1. Snape MD, Dawson T, Oster P, et al. Immunogenicity of two investigational serogroup B meningococcal vaccines in the first year of life: a randomized comparative trial. Pediatr Infect Dis J. 2010;29:e71–e79
2. Findlow J, Borrow R, Snape MD, et al. Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy. Clin Infect Dis. 2010;51:1127–1137
3. Gossger N, Snape MD, Yu LM, et al.European MenB Vaccine Study Group. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA. 2012;307:573–582
4. Santolaya ME, O'Ryan ML, Valenzuela MT, et al. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet. 2012;379:617–24
5. Ladhani SN, Flood JS, Ramsay ME, et al. Invasive meningococcal disease in England and Wales: implications for the introduction of new vaccines. Vaccine. 2102;30:3710–3716
6. Ladhani SN, Flood JS, Ramsay ME, et al. Invasive meningococcal disease in England and Wales: implications for the introduction of new vaccines. Vaccine. 2012;30:3710–3716
7. Holst J, Feiring B, Fuglesang JE, et al. Serum bactericidal activity correlates with the vaccine efficacy of outer membrane vesicle vaccines against Neisseria meningitidis
serogroup B disease. Vaccine. 2003;21:734–737
8. Galloway Y, Stehr-Green P, McNicholas A, et al. Use of an observational cohort study to estimate the effectiveness of the New Zealand group B meningococcal vaccine in children aged under 5 years. Int J Epidemiol. 2009;38:413–418
9. Jackson C, Lennon D, Wong S, et al. Antibody persistence following MeNZB vaccination of adults and children and response to a fourth dose in toddlers. Arch Dis Child. 2011;96:744–751
10. Trotter CL, Andrews NJ, Kaczmarski EB, et al. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet. 2004;364:365–367
11. Donnelly J, Medini D, Boccadifuoco G, et al. Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines. Proc Natl Acad Sci U S A. 2010;107:19490–19495
12. Vogel U, Taha MK, Vazquez JA, et al. Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment. Lancet Infect Dis. 2013;13:416–425
13. Smith HNM, Sloots T, Tozer S, et al. Estimating the potential strain coverage in Australia of a multicomponent vaccine targeting serogroup B meningococci.Presented at: 7th World Congress of the World Society for Pediatric Infectious Diseases (WSPID)November 16-19, 2011Melbourne, Australia
14. Bettinger JA, Scheifele DW, Halperin SA, et al. Diversity of Canadian meningococcal serogroup B isolates and estimated coverage by an investigational meningococcal serogroup B vaccine (4CMenB). Vaccine. [published online ahead of print April 12, 2013]. doi: 10.1016/j.vaccine.2013.03.063
16. Kitchin N, Southern J, Morris R, et al. Antibody persistence in UK pre-school children following primary series with an acellular pertussis-containing pentavalent vaccine given concomitantly with meningococcal group C conjugate vaccine, and response to a booster dose of an acellular pertussis-containing quadrivalent vaccine. Vaccine. 2009;27:5096–5102
17. Novartis Vaccines. . Extension Study Evaluating Antibody Persistence and Safety, Tolerability and Immunogenicity of a Booster Dose of Novartis rMenB±OMV NZ Vaccine in Healthy UK Children Who Previously Received Three Doses of the Same Vaccine. NCT01026974. 2012- [cited 2013 15 July]. Bethesda (MD) National Library of Medicine (US) Available from: http://clinicaltrials.gov/ct2/show/NCT01026974?term=V72P9E1&rank=1
NLM Identifier: NCT01026974. In: ClinicalTrials.gov
18. Saroey P, Snape MD, John TM, et al. Persistence of bactericidal antibodies following early infant immunisation with serogroup B meningococcal vaccines and immunogenicity of pre-school booster doses.Presented at: 30th Annual Meeting of the European Society for Paediatric Infectious DiseaseThessaloniki, GreeceMay 8-12, 2012
19. Novartis Vaccines. . Extension Study Evaluating Antibody Persistence and Safety, Tolerability and Immunogenicity of Booster Doses of Novartis rMenB±OMV NZ Vaccine in Healthy UK Children Who Previously Received One or Four Doses of the Same Vaccine. 2009 - [cited 2013 15 July]. Bethesda (MD) National Library of Medicine (US) Available at: http://clinicaltrials.gov/ct2/show/NCT01027351?term=p6E1&rank=2
NLM Identifier: NCT01027351. ClinicalTrials.gov
20. Novartis Vaccines. . Extension Study of V72P13 to Evaluate the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine When Administered as a Booster or as a Two-dose Catch-up to Healthy Toddlers. 2009 - [cited 2013 15 July]. Bethesda (MD) National Library of Medicine (US) Available at: http://clinicaltrials.gov/ct2/show/NCT00847145?term=V72P13&rank=1
NLM Identifier: NCT00847145. ClinicalTrials.gov
serogroup B meningococcal vaccine; persistence