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Immunogenicity and Safety of a Quadrivalent Meningococcal ACWY-tetanus Toxoid Conjugate Vaccine 6 Years After MenC Priming as Toddlers

Nolan, Terry MBBS, PhD*; Booy, Robert MBBS, MSc, MD; Marshall, Helen S. MBBS, MPH, MD‡,§; Richmond, Peter MBBS¶,‖; Nissen, Michael MBBS**,††; Ziegler, John B. MD‡‡; Baine, Yaela PhD§§; Traskine, Magali MSc¶¶; Jastorff, Archana PhD‖‖; Van der Wielen, Marie MD¶¶

Author Information
The Pediatric Infectious Disease Journal: June 2019 - Volume 38 - Issue 6 - p 643-650
doi: 10.1097/INF.0000000000002334


Invasive meningococcal disease (IMD) is life threatening but vaccine preventable. It leads to death in up to 10% of cases,1,2 and lifelong disability in 12.5%–20% of survivors, even in industrialized countries.3–5 The highest incidence of IMD is reported in infants <1 year of age, followed by children until 5 years of age, with a second peak in adolescence.1

The prevalence of the 6 most common Neisseria meningitidis serogroups causing IMD, A, B, C, W, X and Y varies both geographically and temporally.6,7 In Sub-Saharan Africa, serogroup A was responsible for most IMD cases before widespread vaccination against this serogroup.8 In the United States and Canada, serogroups B, C and Y are the major causes of IMD,7 while in Europe serogroups B and C predominate, with an increasing incidence of serogroups Y9 and W10 reported in some countries. In Australia, the incidence of IMD caused by serogroup C has declined after the introduction of meningococcal C (MenC) conjugate vaccine,11 and serogroup B has predominated until recently, when an increased incidence of serogroup W has occurred.12

Meningococcal conjugate vaccines contain one or more serogroup-specific oligosaccharide(s), conjugated to a carrier protein (CRM197, tetanus toxoid—TT or diphtheria toxoid). Primary meningococcal vaccination included in routine immunization programs targets one of the following age categories: (1) infants, using multiple doses of monovalent conjugate vaccines against serogroup C (MCC) or combination vaccines against MenC with or without Y and Haemophilus influenzae type b (Hib);13–16 (2) toddlers ≥1 year of age, using a single dose of MCC vaccines17–21 or quadrivalent conjugate vaccines against serogroups A, C, W and Y (MenACWY)22 or (3) adolescents, using one dose of quadrivalent conjugate vaccines.23 To extend the protection conferred by the primary vaccination, several countries have added a booster dose at the age of 12 months for toddlers primed in infancy,13,14,24,25 in adolescence, for primed toddlers15,21,26 or primed children and adolescents.27

However, serological studies show that the administration of MCC vaccines under the age of 5 years elicits immune responses that wane more rapidly, compared with vaccination of older children and adolescents.28–31 Therefore, children vaccinated as infants and/or toddlers may lose protection,32,33 with few children retaining protective antibody titers by 10 years after vaccination,34 before the adolescent IMD peak. A booster dose administered in older childhood, after the age of 5 years, could extend the duration of individual protection into adolescence. Use of a quadrivalent conjugate vaccine would boost the immune response against MenC and offer protection against other serogroups, in the context of the increasing incidence of MenW and MenY disease.

This study evaluated the immunogenicity, reactogenicity and safety of a single dose of MenACWY-TT (Nimenrix, Pfizer, New York, NY) administered 6 years after primary vaccination of toddlers 12–18 months of age against MenC and Hib, with either HibMenC-TT (Menitorix, GSK, Wavre, Belgium), or Hib-TT (Hiberix, GSK, Wavre, Belgium) and MCC-CRM197 (Meningitec, Nuron Biotech, Exton, PA).35 Antibody persistence 2 years after MenACWY-TT vaccination was also assessed.


Study Design and Participants

This phase IIIb, open, multicenter study was conducted between May 2013 and April 2016 in 7 centers in Australia.

In the primary study (NCT00326118), participants were randomized 3:1 to receive either HibMenC-TT conjugate vaccine and measles, mumps, rubella vaccine (Priorix, GSK; HibMenC group) or Hib-TT, MCC-CRM197 and measles, mumps, rubella vaccines (Hib+MCC group). At the time of vaccination in the primary study, participants were 12–18 months of age.35

In this extension study, participants were healthy children 84–95 months of age (7–8 years), who completed the primary study. In the vaccination phase of the extension study, all participants received a MenACWY-TT dose at 72 months post-primary vaccination and were followed up in the persistence phase for 24 months after receiving MenACWY-TT.

Children were not enrolled if they had a history of meningococcal disease and received/planned to receive any vaccine not foreseen by the protocol 30 days pre and post-study vaccination or had received a meningococcal vaccine other than the one received in the primary study at toddler age. A complete list with inclusion and exclusion criteria can be found in Supplemental Digital Content 1,

There was no randomization in the extension study. An internet-based randomization system was used at the investigators’ site to provide the treatment number associated with the MenACWY-TT vaccine, while respecting the randomization applied in the primary vaccination study.

The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Written informed consent was obtained from each participant’s parent/guardian before enrolment, and written informed assent was obtained in accordance with local laws and regulations. The study protocol and informed consent were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each center. The study is registered at (NCT01777308), and a protocol summary is available at (study ID 116727).

Study Objectives

The primary objective of this extension study was to evaluate the immunogenicity of MenACWY-TT in terms of percentage of participants with vaccine response to serogroups A, C, W and Y, evaluated by a serum bactericidal assay using baby rabbit complement (rSBA) at 1 month postvaccination.

Vaccine response to meningococcal antigens (A, C, W and Y) was defined as rSBA antibody titer ≥1:32, 1 month postvaccination for initially seronegative participants (prevaccination rSBA titer <1:8) and ≥4-fold increase in rSBA titers from prevaccination to 1 month postvaccination for initially seropositive participants (pre-vaccination rSBA titer ≥1:8). Secondary objectives are listed in Supplemental Digital Content 2,

Study Vaccines

One 0.5 mL dose of MenACWY-TT contains 5 μg of each meningococcal serogroup polysaccharide conjugated to TT (~44 μg in total) in a lyophilized pellet reconstituted with saline solution. MenACWY-TT vaccine was administered intramuscularly in the nondominant deltoid muscle.

Immunogenicity Assessment

Three blood samples were collected from all participants: prevaccination (M72), 1 month postvaccination (M73) and 2 years postvaccination (M96).

Antibody titers for each meningococcal serogroup were determined by rSBA (performed at the Public Health England laboratory, Manchester).36 An rSBA titer of ≥1:8 was used as a serological correlate of protection as previously established for MenC37–39 and extended to the other serogroups.40,41 The more stringent cutoff of 1:128 rSBA was also used in our study.

Anti-TT was assessed by a validated and approved in-house enzyme-linked immunosorbent assay (performed by GSK Biologicals Clinical Laboratory Science) and seropositivity was defined as an antibody concentration of ≥0.1 international unit (IU)/mL.

Safety and Reactogenicity Assessment

Postvaccination, solicited symptoms (local and general, days 0–3), and unsolicited adverse events (AEs), all serious AEs (SAEs) and new onset clinical illnesses (days 0–30) were recorded. Occurrence of SAEs related to MenACWY-TT booster vaccination, SAEs related to study participation, to a concurrent GSK medication/vaccine, all AEs/SAEs leading to withdrawal from the study or fatal SAEs were recorded throughout the entire study period. Full description of safety and reactogenicity assessment can be found in Supplemental Digital Content 3,

Statistical Analyses

The expected sample size of this study was driven by the sample size of the primary study, assumptions about the enrolment rate for the present extension study and assumptions about the annual dropout rate.

Four hundred twenty-eight participants, 320 in the HibMenC group and 108 in the Hib+MCC group were vaccinated and completed the primary study. Assuming approximately 7% of participants dropping out at every visit, 223 participants were expected to participate in the vaccination phase and 208 in the persistence phase of this extension study.

The primary analysis of immunogenicity was based on the according-to-protocol (ATP) cohort for immunogenicity at M73, which included all participants who had received one dose of MenACWY-TT, and for whom assay results were available for antibodies against at least one meningococcal antigen, had a blood sample taken between 21–48 days postvaccination and were not administered a vaccine not foreseen by the study protocol before the postvaccination blood sample. The primary analysis of antibody persistence was based on the ATP cohort for persistence at M96, which included all participants who had received one dose of MenACWY-TT, and for whom assay results were available for antibodies against at least one meningococcal antigen at M96, had a blood sample taken 2 years ± 9 weeks days postvaccination and who were not administered a vaccine not foreseen by the study protocol, did not have a history of meningococcal disease or an immunocompromising medical condition and did not receive immune modifying drugs before the blood sample at M96. For each group, the percentages of subjects retaining antibody titers above the predefined thresholds and antibody geometric mean titers (GMTs) were calculated with associated 95% confidence intervals (CIs). Results below the cutoff were arbitrarily set at half the value of the cutoff. Analyses were performed using Statistical Analysis Systems (SAS) under SAS Drug Development platform.



A total of 156 children (119 in HibMenC group, 37 in Hib+MCC group) were vaccinated with MenACWY-TT at M72 and 139 completed the study at M96. Reasons for withdrawal from the study and for exclusion from the ATP cohorts for immunogenicity are presented in Figure 1.

Study design and participant flow diagram. The present study is enclosed in the rectangle. HibMenC group received HibMenC-TT and MMR vaccines in the primary study and MenACWY-TT in the extension study; Hib+MCC group received Hib-TT, MCC-CRM197 and MMR vaccines in the primary study and MenACWY-TT in the extension study. Month 1, month of vaccination in primary study; month 72, prevaccination in the extension study; month 73, 1 month postvaccination in the extension study; month 96, 2 years postvaccination in the extension study. MMR indicates measles, mumps and rubella; N, number of participants.

Demographic characteristics were balanced between groups. The mean age of the children at vaccination was 7.0 years across all groups, and 45.5% of children were girls. The majority of the participants were of White Caucasian/European heritage (Table 1).

Demographic and baseline characteristics (total vaccinated cohort at month 73)


Immune Response to MenACWY-TT

One month post-MenACWY-TT vaccination, observed vaccine response rates were ≥97.1% in both groups for all meningococcal serogroups (Supplemental Digital Content 4,

At prevaccination (6 years post-primary vaccination), 18.3% and 14.7% of children had seroprotective levels of rSBA-MenC ≥1:8, which increased to 98.1% and 100% for the HibMenC group and Hib+MCC group, respectively, post-MenACWY-TT vaccination (Table 2). Observed MenC GMTs increased from 7.1 and 6.5 to 11819.2 and 7419.7 for the HibMenC group and Hib+MCC group, respectively (Fig. 2).

rSBA GMTs prevaccination and at 1 month and 2 years postvaccination (adapted ATP cohort). HibMenC group received HibMenC-TT and MMR vaccines in the primary study and MenACWY-TT in the extension study; Hib+MCC group received Hib-TT, MCC-CRM197 and MMR vaccines in the primary study and MenACWY-TT in the extension study. M72, prevaccination; M73, 1 month postvaccination; M96, 2 years postvaccination. Adapted ATP cohort: results for M72 and M73 are based on the ATP cohort for immunogenicity at month 73 and results for M96 are based on the ATP cohort for persistence at M96. M indicates study month; MMR, measles, mumps and rubella.

For all the other serogroups, the percentages of children having prevaccination rSBA ≥1:8 were 11.5% and 8.8% (MenA), 11.5% and 23.5% (MenW) and 20.2% and 14.7% (MenY) for the HibMenC group and Hib+MCC group, respectively. Postvaccination, percentage of children having rSBA ≥1:8 increased for MenA, MenW and MenY to ≥97.1% across study groups (Table 2). Observed GMTs for A, W and Y serogroups were 6.0 to 13.9 before vaccination with MenACWY-TT in both HibMenC and Hib+MCC groups and ranged from 3421.4 (MenA) to 17166.5 (MenW) in the HibMenC group and from 2925.1 (MenA) to 15747.7 (MenW) in Hib+MCC group 1 month postvaccination (Fig. 2).

Immune responses to N. meningitidis serogroups in terms of percentage of participants with rSBA titers ≥1:8 and ≥1:128 (adapted ATP cohort for immunogenicity)*

In both groups, all participants had anti-TT antibody concentrations ≥0.1 IU/mL at 1 month postvaccination (Supplemental Digital Content 5,

Antibody Persistence 2 Years After MenACWY-TT Vaccination

Two years post-MenACWY-TT vaccination, the percentage of children with rSBA antibody titers ≥1:8 decreased for some serogroups with values of 72.0% (MenA) to 100% (MenC) in the HibMenC group and 63.6% (MenA) to 93.9% (MenC) in the Hib+MCC group (Table 2).

Observed rSBA GMT values ranged from 174.9 (MenA) to 1002.9 (MenW) in the HibMenC group and from 79.0 (MenA) to 941.5 (MenW) in the Hib+MCC group (Fig. 2). GMT values declined over time for all serogroups but remained 13.2 to 29.2-fold higher than the prevaccination values for MenA, 27.0 to 46.9-fold higher for MenC, and 61.7 to 128.6-fold higher for MenW and MenY in both groups. The decline of GMT values was lowest for MenY (Fig. 2).

Safety and Reactogenicity

The most frequently reported solicited local symptom was pain, reported by 58.5% and 40.5% of participants, followed by redness, reported by 47.5% and 51.4% of participants in HibMenC and Hib+MCC groups, respectively (Fig. 3). Grade 3 pain was reported by 1 participant (0.8%) in group HibMenC, and grade 3 redness and swelling were reported by ≤5.4% of participants in both groups.

Incidence of solicited local and general symptoms during the 4-day period following the administration of MenACWY-TT vaccine (total vaccinated cohort at month 73). Grade 3 events were defined as “diameter >50 mm” for redness and swelling, “oral/axillary or tympanic temperature >39.0°C” for fever and “preventing normal every day activity” for all other events. HibMenC group received HibMenC-TT and MMR vaccines in the primary study and MenACWY-TT in the extension study; Hib+MCC group received Hib-TT, MCC-CRM197 and MMR vaccines in the primary study and MenACWY-TT in the extension study. GI indicates gastrointestinal; MMR, measles, mumps and rubella.

For both groups, the most frequently reported solicited general symptom was fatigue, reported by ≤27% of participants, followed by headache and gastrointestinal symptoms, reported by ≤24.6% of participants (Fig. 3).

At least one unsolicited AE was reported by 30.3% and 18.9% of participants in the HibMenC and Hib+MCC groups, respectively (Supplemental Digital Content 6, The most frequently reported unsolicited AE was upper respiratory tract infection reported by 5.9% in HibMenC group and 5.4% in Hib+MCC group. Unsolicited AEs of any intensity assessed by the investigator as causally related to vaccination were reported only in the HibMenC group by 6.7% of participants. Grade 3 unsolicited AEs were reported by 6.7% and 5.4% of participants in the HibMenC and Hib+MCC groups, respectively. Grade 3 unsolicited AE causally related to vaccination was reported by 1 participant in the HibMenC group (0.8%, injection site pruritus).

No SAEs (including Guillain-Barré syndrome and new onset of chronic illnesses) were reported within 31 days postvaccination. No SAEs considered related to vaccination, study procedures or GSK concomitant medication, no AEs/SAEs leading to withdrawal or fatal SAEs were recorded up to study end. There was no apparent difference in the rate of AEs in the 2 groups (Supplemental Digital Content 6,


Waning immune response represents a major issue in maintaining routine immunization programs targeting infants and toddlers. Persistence of functional antibodies is considered necessary for protection against IMD (memory being insufficient), due to the short incubation period and rapid evolution of the disease.33 Our results showed that 18.3% and 14.7% of children who received either HibMenC-TT or MCC-CRM197 + Hib-TT at 12–18 months retained rSBA-MenC titers ≥1:8, 6 years postvaccination. Low levels of persisting protective functional antibodies elicited by MenC vaccination in toddlers is a common finding in seroprevalence studies. Of 94 children, who had received MCC vaccine in early childhood, as part of the UK catch-up campaign, only 37% retained rSBA titers ≥1:8 approximately 2 years postvaccination.32 At 4 years postvaccination with one dose of MCC vaccine at the age of 12–23 months, 35.6% of children had rSBA ≥1:8,42 while at 5 years postvaccination, ≤25.0% of toddlers who received MCC vaccine in their second year of life had rSBA titers ≥1:8.31

The benefits of a MenACWY-TT booster dose were shown in a study where all 5-year-old children previously vaccinated with MenACWY-TT in the first year of life, achieved rSBA titers ≥1:8 for all ACWY serogroups 1 month post-MenACWY-TT booster vaccination. One year post-booster vaccination, ≥97.4% of children retained rSBA titers ≥1:8 for each serogroup.42 Another study reported similar results after MenACWY-TT booster vaccination in 6-year olds vaccinated 5 years before with 1 or 2 doses of MenACWY-TT. All children achieved human complement SBA titers ≥1:8 for all serogroups at 1 month post-booster vaccination, but no assessment on booster persistence was further done in this study.43

Here, we show that administering a quadrivalent conjugate vaccine to children 7–8 years of age, primed against MenC in the second year of life, boosts the immune response against MenC, irrespective of the MenC vaccine type used for primary vaccination. One month postvaccination with MenACWY-TT, vaccine response rates to MenC were 97.1% in both groups, with 98.1% and 100% of participants having rSBA titers ≥1:8 in HibMenC group and Hib+MCC group, respectively. Similar results were obtained in a study that assessed booster response in 250 children who had been vaccinated with MCC vaccine in the UK 1999–2000 catch-up campaign and boosted 6 years later using HibMenC.44

With respect to the other serogroups, here we show that while the SBA levels were low before vaccination with only 11.5%–23.5% of individuals having rSBA-MenW titers ≥1:8, before the emergence of the W strain in Australia,12 MenACWY-TT elicited strong immune responses to serogroups A, W and Y, 1 month postvaccination. Further, 2 years postvaccination, percentages of children retaining rSBA ≥1:8 remained high for serogroups C, W and Y in both groups, but for serogroup A, a moderate decline in the percentage of children retaining rSBA-MenA titers ≥1:8 was observed. Observed GMTs declined 2 years postvaccination for all serogroups; however, the values remained ≥13-fold above the pre-vaccination levels.

Long-term persistence study in children vaccinated with a single dose of quadrivalent conjugate vaccine showed that >47% of MenACWY-TT recipients who were vaccinated at the age of 6–10 years had rSBA titers ≥1:8 after 5 years (MenA: 91.8%, MenC: 47.1%, MenW: 58.8% and MenY: 76.5%).45 In children vaccinated at a younger age, immune responses elicited by MenACWY-TT declined faster.45,46 Another cross-sectional study assessing an English population after the introduction of MCC vaccines, describing the age-specific prevalence of SBAs, confirmed a higher protection and persistence when children were immunized at an older age.47

A recent study demonstrated that even though immune responses waned in young children vaccinated with one dose of MCC vaccine, a low number of children showed rises of rSBA titers in the absence of additional doses of vaccine. This natural boosting raises the concern of some ongoing MenC circulation and reduced herd immunity in the long term.48

The incidence of solicited local and general AEs and unsolicited AEs reported in this study was in line with those observed in European children vaccinated with MenACWY-TT at 2–10 years of age,49 but higher compared with the results of a study conducted in the Philippines, India, Lebanon and Saudi Arabia, in children of the same age.50 Unsolicited AEs considered to be related to vaccination were reported by 6.7% of participants in the HibMenC group, and 1 participant (0.8%) reported a grade 3 unsolicited AE that was considered causally related to vaccination. No SAEs were reported, and no new safety concerns were identified during the study.

Enrolment in the study was limited to the eligible participants from the primary study, who received vaccination in one of the 2 groups, 6 years before this study. Since only willing participants were enrolled, fewer than the expected number of children participated in this study. A longer follow-up period (eg, 4 instead of 2 years) for the persistence of immune responses to the booster dose would be useful in assessing the protection at the onset of adolescence; this constitutes a limitation of our study. However, our results still contribute to establishing the optimal interval for boosting in childhood. Another limitation is that all children included in the study had been previously primed against MenC. Therefore, the booster response to MenC following vaccination with a quadrivalent conjugate vaccine cannot be directly compared with the primary response that would have been elicited by MenACWY-TT in unprimed children in this age group. Also, a comparator group that would have received only a MenC dose at 7–8 years of age could have provided the opportunity to compare the primary responses to MenC at this age to booster responses. As some countries are now moving to toddler priming with MenACWY vaccine (eg, Australia),22 these are important issues that deserve further research.


One dose of MenACWY-TT administered to 7–8 year-old children who had been primed against MenC 6 years before, elicited strong immune responses 1 month postvaccination in both study groups, regardless of the primary vaccination regimen. Two years postvaccination, the percentage of children with protective antibody titers had dropped especially for serogroup A (≥63.6%) but was still ≥87.9% for serogroups C, W and Y, suggesting that although immune responses wane slowly over time, the decline for this age group is not as rapid as for younger children or toddlers.

The results of the present study suggest that MenACWY-TT has a clinically acceptable safety profile and the potential to offer protection against IMD to Australian children primed against MenC in toddlerhood, as it elicits a booster response to MenC and primary responses to the additional serogroups A, W and Y.

Trademark Statement

Nimenrix is a trademark owned by the GSK group of companies, licensed to Pfizer.

Menitorix, Hiberix and Priorix are trademarks owned by the GSK group of companies.

Meningitec is a trademark of Nuron Biotech.


The authors thank Marita Kefford, Janet Briggs, Clare Brophy, Lana Horng, Annmarie McEvoy, Adam Parslow, Mairead Phelan, Jane Ryrie, Judith Spotswood and Marie West from the MCRI Vaccine and Immunisation Research Group (VIRGo), and the Melbourne Health Pathology Service’s clinical trials team; Susan Evans, Suja Mathew, Su-San Lee, Mary Walker, Chris Heath, Michelle Clarke from the Vaccinology and Immunology Research Trials Unit, Women’s and Children’s Health Network, South Australia; Tanya Stoney and Jennifer Kent from the Vaccine Trials Group, Telethon Kids Institute, Perth. The authors also thank Brigitte Cheuvart (GSK) for the statistical analysis, Timea Kiss and Maria Cornelia Maior (XPE Pharma & Science) for medical writing services, and Régis Azizieh (XPE Pharma & Science C/O GSK) for publication management. Prof. Helen Marshall acknowledges support from the National Health and Medical Research Council of Australia: Career Development Fellowship (1084951).


1. Pelton SI. The global evolution of meningococcal epidemiology following the introduction of meningococcal vaccines. J Adolesc Health. 2016;59(2 suppl):S3S11.
2. Wang B, Santoreneos R, Giles L, et al. Case fatality rates of invasive meningococcal disease by serogroup and age: a systematic review and meta-analysis. Vaccine. 2019. doi: 10.1016/j.vaccine.2019.04.020.
3. Erickson LJ, De Wals P, McMahon J, et al. Complications of meningococcal disease in college students. Clin Infect Dis. 2001;33:737739.
4. Fellick JM, Sills JA, Marzouk O, et al. Neurodevelopmental outcome in meningococcal disease: a case-control study. Arch Dis Child. 2001;85:611.
5. Kaplan SL, Schutze GE, Leake JA, et al. Multicenter surveillance of invasive meningococcal infections in children. Pediatrics. 2006;118:e979e984.
6. Halperin SA, Bettinger JA, Greenwood B, et al. The changing and dynamic epidemiology of meningococcal disease. Vaccine. 2012;30(suppl 2):B26B36.
7. Bosis S, Mayer A, Esposito S. Meningococcal disease in childhood: epidemiology, clinical features and prevention. J Prev Med Hyg. 2015;56:E121E124.
8. Trotter CL, Lingani C, Fernandez K, et al. Impact of MenAfriVac in nine countries of the African meningitis belt, 2010-15: an analysis of surveillance data. Lancet Infect Dis. 2017;17:867872.
9. Bröker M, Emonet S, Fazio C, et al. Meningococcal serogroup Y disease in Europe: continuation of high importance in some European regions in 2013. Hum Vaccin Immunother. 2015;11:22812286.
10. Ladhani SN, Beebeejaun K, Lucidarme J, et al. Increase in endemic Neisseria meningitidis capsular group W sequence type 11 complex associated with severe invasive disease in England and Wales. Clin Infect Dis. 2015;60:578585.
11. Lawrence GL, Wang H, Lahra M, et al. Meningococcal disease epidemiology in Australia 10 years after implementation of a national conjugate meningococcal C immunization programme. Epidemiol Infect. 2016;144:23822391.
12. Martin NV, Ong KS, Howden BP, et al.; Communicable Diseases Network Australia MenW Working Group. Rise in invasive serogroup W meningococcal disease in Australia 2013-2015. Commun Dis Intell Q Rep. 2016;40:E454E459.
13. Campbell H, Borrow R, Salisbury D, et al. Meningococcal C conjugate vaccine: the experience in England and Wales. Vaccine. 2009;27(suppl 2):B20B29.
14. Garrido-Estepa M, León-Gómez I, Herruzo R, et al. Changes in meningococcal C epidemiology and vaccine effectiveness after vaccine introduction and schedule modification. Vaccine. 2014;32:26042609.
15. De Wals P, Deceuninck G, Lefebvre B, et al. Effectiveness of serogroup C meningococcal conjugate vaccine: a 7-year follow-up in Quebec, Canada. Pediatr Infect Dis J. 2011;30:566569.
16. Simões MJ, Cunha M, Almeida F, et al. Molecular surveillance of Neisseria meningitidis capsular switching in Portugal, 2002-2006. Epidemiol Infect. 2009;137:161165.
17. de Voer RM, Mollema L, Schepp RM, et al. Immunity against Neisseria meningitidis serogroup C in the Dutch population before and after introduction of the meningococcal c conjugate vaccine. PLoS One. 2010;5:e12144.
18. Kinlin LM, Jamieson F, Brown EM, et al. Rapid identification of herd effects with the introduction of serogroup C meningococcal conjugate vaccine in Ontario, Canada, 2000-2006. Vaccine. 2009;27:17351740.
19. Mattheus W, Hanquet G, Collard JM, et al. Changes in meningococcal strains in the era of a serogroup C vaccination campaign: trends and evolution in Belgium during the period 1997-2012. PLoS One. 2015;10:e0139615.
20. Hellenbrand W, Elias J, Wichmann O, et al. Epidemiology of invasive meningococcal disease in Germany, 2002-2010, and impact of vaccination with meningococcal C conjugate vaccine. J Infect. 2013;66:4856.
21. Kaaijk P, van der Ende A, Berbers G, et al. Is a single dose of meningococcal serogroup C conjugate vaccine sufficient for protection? experience from the Netherlands. BMC Infect Dis. 2012;12:35.
22. Department of Health, Australian Government. Quad-strain meningococcal vaccine to be added to National Immunisation Program. February 2, 2018. Available at: Accessed April 5, 2018.
23. Macneil JR, Cohn AC, Zell ER, et al.; Active Bacterial Core surveillance (ABCs) Team and MeningNet Surveillance Partners. Early estimate of the effectiveness of quadrivalent meningococcal conjugate vaccine. Pediatr Infect Dis J. 2011;30:451455.
24. Khatami A, Peters A, Robinson H, et al. Maintenance of immune response throughout childhood following serogroup C meningococcal conjugate vaccination in early childhood. Clin Vaccine Immunol. 2011;18:20382042.
25. Trotter CL, Ramsay ME. Vaccination against meningococcal disease in Europe: review and recommendations for the use of conjugate vaccines. FEMS Microbiol Rev. 2007;31:101107.
26. Donovan H, Bedford H. Immunisation: changes in the UK for children and young people. Nurs Child Young People. 2013;25:1620.
27. Centers for Disease Control and Prevention. Prevention and control of meningococcal disease recommendations of the Advisory Committee on Immunization Practices (ACIP) Morb Mortal Wkly Rep. 2013;62(No. RR-2):128.
28. Snape MD, Kelly DF, Lewis S, et al. Seroprotection against serogroup C meningococcal disease in adolescents in the United Kingdom: observational study. BMJ. 2008;336:14871491.
29. de Voer RM, van der Klis FR, Schepp RM, et al. Age-related immunity to meningococcal serogroup C vaccination: an increase in the persistence of IgG2 correlates with a decrease in the avidity of IgG. PLoS One. 2011;6:e23497.
30. de Whalley PC, Snape MD, Plested E, et al. Long-term seroprotection after an adolescent booster meningococcal serogroup C vaccination. Arch Dis Child. 2013;98:686691.
31. Booy R, Nolan T, Reynolds G, et al. Five-year antibody persistence and safety after a single dose of combined Haemophilus influenzae type b Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine in Haemophilus influenzae type b-primed toddlers. Pediatr Infect Dis J. 2015;34:13791384.
32. Snape MD, Kelly DF, Green B, et al. Lack of serum bactericidal activity in preschool children two years after a single dose of serogroup C meningococcal polysaccharide-protein conjugate vaccine. Pediatr Infect Dis J. 2005;24:128131.
33. Borrow R, Andrews N, Findlow H, et al. Kinetics of antibody persistence following administration of a combination meningococcal serogroup C and Haemophilus influenzae type b conjugate vaccine in healthy infants in the United Kingdom primed with a monovalent meningococcal serogroup C vaccine. Clin Vaccine Immunol. 2010;17:154159.
34. Ishola DA Jr, Borrow R, Findlow H, et al. Prevalence of serum bactericidal antibody to serogroup C Neisseria meningitidis in England a decade after vaccine introduction. Clin Vaccine Immunol. 2012;19:11261130.
35. Booy R, Richmond P, Nolan T, et al. Immediate and longer term immunogenicity of a single dose of the combined Haemophilus influenzae type b-Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine in primed toddlers 12 to 18 months of age. Pediatr Infect Dis J. 2011;30:340342.
36. Maslanka SE, Gheesling LL, Libutti DE, et al. Standardization and a multilaboratory comparison of Neisseria meningitidis serogroup A and C serum bactericidal assays. The Multilaboratory Study Group. Clin Diagn Lab Immunol. 1997;4:156167.
37. Andrews N, Borrow R, Miller E. Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England. Clin Diagn Lab Immunol. 2003;10:780786.
38. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med. 1969;129:13071326.
39. Borrow R, Andrews N, Goldblatt D, et al. Serological basis for use of meningococcal serogroup C conjugate vaccines in the United Kingdom: reevaluation of correlates of protection. Infect Immun. 2001;69:15681573.
40. Borrow R, Balmer P, Miller E. Meningococcal surrogates of protection–serum bactericidal antibody activity. Vaccine. 2005;23:22222227.
41. Centers for Disease Control and Prevention. Inadvertent misadministration of meningococcal conjugate vaccine-United States, June-August 2005. Morb Mortal Wkly Rep. 2006;55:10161017.
42. Vesikari T, Forsten A, Bianco V, et al. Immunogenicity, safety and antibody persistence of a booster dose of quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine compared with monovalent meningococcal serogroup C vaccine administered four years after primary vaccination using the same vaccines. Pediatr Infect Dis J. 2015;34:e298e307.
43. Klein NP, Baine Y, Kolhe D, et al. Five-year antibody persistence and booster response after 1 or 2 doses of meningococcal A, C, W and Y tetanus toxoid conjugate vaccine in healthy children. Pediatr Infect Dis J. 2016;35:662672.
44. Perrett KP, Winter AP, Kibwana E, et al. Antibody persistence after serogroup C meningococcal conjugate immunization of United Kingdom primary-school children in 1999-2000 and response to a booster: a phase 4 clinical trial. Clin Infect Dis. 2010;50:16011610.
45. Knuf M, Helm K, Kolhe D, et al. Antibody persistence and booster response 68 months after vaccination at 2-10 years of age with one dose of MenACWY-TT conjugate vaccine. Vaccine. 2018;36:32863295.
46. Vesikari T, Forsten A, Bianco V, et al. Antibody persistence up to 5 years after vaccination of toddlers and children between 12 months and 10 years of age with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine. Hum Vaccin Immunother. 2016;12:132139.
47. Trotter CL, Borrow R, Findlow J, et al. Seroprevalence of antibodies against serogroup C meningococci in England in the postvaccination era. Clin Vaccine Immunol. 2008;15:16941698.
48. Badahdah AM, Khatami A, Tashani M, et al. Evidence for rise in meningococcal serogroup C bactericidal antibody titers in the absence of booster vaccination in previously vaccinated children. Pediatr Infect Dis J. 2018;37:e66e71.
49. Knuf M, Romain O, Kindler K, et al. Immunogenicity and safety of the quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) in 2-10-year-old children: results of an open, randomised, controlled study. Eur J Pediatr. 2013;172:601612.
50. Memish ZA, Dbaibo G, Montellano M, et al. Immunogenicity of a single dose of tetravalent meningococcal serogroups A, C, W-135, and Y conjugate vaccine administered to 2- to 10-year-olds is noninferior to a licensed-ACWY polysaccharide vaccine with an acceptable safety profile. Pediatr Infect Dis J. 2011;30:e56e62.

quadrivalent meningococcal vaccine; children; bactericidal activity; persistence; safety

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