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.
MATERIALS AND METHODS
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, http://links.lww.com/INF/D450.
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 http://www.clinicaltrials.gov (NCT01777308), and a protocol summary is available at https://www.gsk-studyregister.com/ (study ID 116727).
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, http://links.lww.com/INF/D451.
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.
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, http://links.lww.com/INF/D452.
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.
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).
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, http://links.lww.com/INF/D453).
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).
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).
In both groups, all participants had anti-TT antibody concentrations ≥0.1 IU/mL at 1 month postvaccination (Supplemental Digital Content 5, http://links.lww.com/INF/D454).
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.
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, http://links.lww.com/INF/D455). 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, http://links.lww.com/INF/D455).
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.
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).
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