Neisseria meningitidis is a leading cause of meningitis and septicemia globally, with 6 serogroups responsible for most human disease: A, B, C, W, X and Y.1 Over the past century, Australia has experienced both large meningococcal outbreaks and endemic disease. Significant serogroup A meningococcal (MenA) outbreaks occurred in the context of the first and second World Wars, whereas endemic serogroup B (MenB) and C (MenC) disease, peaking in the winter months, has prevailed since the 1950s.2 In the late 1990s, almost in parallel to the United Kingdom, Australia observed an increase in the proportion of cases due to MenC among infants, teenagers and young adults. Accordingly, in 2003, monovalent MenC conjugate vaccine was included into the national immunization program3 as a single dose at 12 months of age, and a catch-up campaign for all children up to 19 years of age. Program success was unequivocally demonstrated with a decline in MenC disease across all ages (including the unimmunized, indicating herd protection) with no corresponding increase in cases due to other serogroups.4
As the UK was the first country to introduce routine MenC vaccination, much has been learned from their experience. Early direct effectiveness estimates of the initial 3-dose infant schedule were promising (over 90%).5 However, cases of clinical vaccine failure indicated that individual protection with an infant only schedule was short-lived.6 Even after the schedule was amended in 2006 to a 2-dose infant priming and second year of life booster (prime-boost schedule) no evidence of improved antibody persistence or superior protection was demonstrated.7,8 These observations raised concerns that protection offered by infant and/or early childhood immunization may not be sufficient to prevent invasive meningococcal disease through the vulnerable period of adolescence and early adulthood9
Surveillance of the phenotype and genotype of cases of meningococcal disease occurs routinely in most developed countries. In both the UK and Australia, there has recently been a modest increase in incidence of serogroup Y meningococcal (MenY) cases. Measurement of natural immunity to other vaccine preventable serogroups (A, W and Y) is vital both to inform appraisal of likely vulnerability to imported strains and to inform national meningococcal vaccine policy.
We measured serum bactericidal antibody (SBA) titers against MenC in 240 adolescents aged 11 to 16 years of age who had received a single catch-up dose of MenC conjugate vaccine in 2003/2004 (when aged between 2 and 8 years) to determine the impact on long-term immunity to MenC disease of this program. We also assessed the geometric mean concentration (GMC) of IgG against meningococcal A, C, W and Y to provide information on exposure and susceptibility to these serogroups in Australian children.
Study Design and Participants
Between June and December 2011, we collected serum from 240 children in Melbourne and Perth who had received a single catch-up dose of MenC vaccine in 2003/2004 (aged between 2 and 8 years). Children were identified through the Australian Childhood Immunization Register as having received 1 of 3 licensed MenC conjugate vaccines: MenC-CRM [A] (Menjugate®, CSL/Novartis Vaccines and Diagnostics); MenC-CRM [B] (Meningitec®, Pfizer Australia) or MenC-TT (NeisVac-C®, Baxter Healthcare). Each MenC vaccine contains 10 mcg of Neisseria meningitidis group C polysaccharide (strain C11) conjugated to either CRM-197 (a non-toxic mutant of diphtheria toxin) [MenC-CRM (A) and MenC-CRM (B)], or tetanus toxoid (MenC-TT). Letters to parents were sent by Medicare Australia.
Potential participants were excluded if they had: received any additional meningococcal vaccines (other than the single catch-up dose of MenC in 2003/2004); a known immunodeficiency or chronic illness; received any blood products including immunoglobulin; a previous meningococcal infection; ever received meningococcal chemoprophylaxis or had antibiotics within the previous 7 days.
Participants’ individual MenC vaccination history (date and brand) was verified from the parent-held child health record book, Australian Childhood Immunization Register, immunization certificate or General Practitioner records. Written informed consent was obtained from a parent and verbal consent from children aged 12 years and above. Following collection of a 5 mL blood sample, participants were offered a single dose of quadrivalent serogroup A, C, W and Y meningococcal (MenACWY) conjugate vaccine (Menveo®, Novartis Vaccines). Menveo is currently licensed in Australia for persons aged 11 years and older. Approval was obtained from ethics committees at the Royal Children’s Hospital (30207A) and Princess Margaret Hospital for Children (1877/EP).
Assays were performed at Public Health England Vaccine Evaluation Unit, Manchester, United Kingdom, using standard protocols.10 Serum was tested for SBA against the O-acetylated MenC strain C11 (C:16:P1.7-1,1) using baby rabbit complement (rSBA). In a subset of 60% (determined by sampling specimens across the range of titer distributions to assess correlation across a full spectrum of values), assays were repeated using human complement (hSBA). SBA titers were expressed as the final serum dilution in which 50% bacterial killing was observed after 60 minutes.11 The lower limit of detection was a titer of 4. Values below 4 were assigned a value of 2. Serogroup-specific serum IgG antibody concentrations to serogroup A, C, W and Y meningococci were measured by enzyme linked immunosorbent assays with lower limits of detection of 0.08, 0.06, 0.065 and 0.075 μg/mL, respectively.
The primary objective was to determine the proportion who had a MenC rSBA titer of ≥8 (the putative protective threshold)12 more than 7 years after vaccination. It was hypothesized that rSBA titers against MenC would have waned, leaving 50% or more of adolescents without demonstrable protection. A sample size of 240 participants would demonstrate this proportion with 95% confidence intervals (CI) 43.5%, 56.5%. Secondary objectives were to calculate the: proportion with a MenC hSBA titer of ≥413 and ≥8 (in 60% subset); MenC SBA geometric mean titers (GMT) and IgG GMCs against meningococcal serogroups A, C, W and Y. Analysis was conducted on all available data.
We used univariate and multivariate logistic regression to assess the impact of age at MenC immunization, sex of participant and brand of MenC vaccine on achievement of assay titers above the putative protective thresholds rSBA ≥ 812 and hSBA ≥ 4.13 Furthermore, we performed univariate and multivariate linear regression analysis for log rSBA and hSBA titers and MenC IgG concentrations, to examine the influence of the same variables across the full range of assay results. All analyses were carried out using Microsoft Excel® (version 14.3.9) and STATA (StataCorp®, version 11).
Of the almost 7000 families approached, 466 responded, 293 were assessed for eligibility and 53 were excluded. Reasons for exclusion included: no documentation of MenC vaccine, receipt of more than 1 previous MenC vaccine, long-term antibiotics, outside of age group or too busy. All 240 enrolled participants (160 from Melbourne and 80 from Perth) had blood available for analysis. The mean age at enrolment was 13.2 years (range, 11.1–16.8), mean interval as MenC immunization was 8.2 years (standard deviation, ±0.54) and mean age at receipt of MenC vaccine was 5.1 years (range, 2.4–8.8) (Table 1).
Overall in 2003/2004, 189 participants were immunized with MenC-TT, 21 with MenC-CRM [A], 21 with MenC-CRM [B] and for 9 participants no brand of MenC vaccine was recorded (Table 2). The breakdown by type of MenC vaccine used in each location was 117/20/19/4 for Melbourne and 72/1/2/5 for Perth for MenC-TT, MenC-CRM [A], MenC-CRM [B] and Unknown, respectively. MenC-TT recipients were significantly older than those who received MenC-CRM [A] (mean age 5.1 years compared with 4.5 years, linear regression coefficient -0.65 (95% CI: 1.29, 0.00), P = 0.049). At the completion of the study, 231 (96%) of 240 participants received MenACWY conjugate vaccine.
Overall, more than 7 years following MenC vaccination, 105 [44% (CI: 37–50%)] of 240 adolescents had an rSBA titer ≥ 8 (range, 22–75% in participants who received MenC at mean age 2.8 and 7.5 years, respectively (Table 3; Fig. 1). An rSBA titer ≥ 8 was found in 44 of 134 adolescents (33%), who received MenC vaccine aged 2 to 4 years compared with 61 of 106 adolescents (58%), who received MenC vaccine aged 5 to 8 years.
Overall the MenC rSBA GMT was 11.3 (CI: 8.7–14.8) and ranged from 3.7 to 33.4 in participants who had MenC vaccine at mean age 2.8 and 7.5 years, respectively (Table 3 and Fig., Supplemental Digital Content 1, http://links.lww.com/INF/C17). The MenC rSBA GMT was significantly lower [6.89 (CI: 4.96–9.56)] in adolescents who received MenC vaccine at 2 to 4 years of age compared with those who received MenC vaccine at 5 to 8 years of age [21.20 (CI: 14.0–32.1)] (P < 0.0001).
A MenC hSBA titer ≥ 4 was found in 48 of 140 adolescents [34% (CI: 26–42%)] and a titer ≥ 8 in 39 of 140 adolescents [28% (CI: 20–35%)] (data not shown).
Overall, the MenC IgG GMC was 0.29 μg/mL (CI: 0.25–0.33). Adolescents who received MenC vaccine at 2 to 4 years of age had a significantly lower MenC IgG GMC [0.24 μg/mL (CI: 0.20–0.29)] than adolescents who received MenC vaccine between 5 and 8 years of age [0.37 μg/mL (CI: 0.30–0.45)] (P = 0.0009).
Age at MenC immunization was the only parameter consistently shown to significantly affect the MenC rSBA titer, IgG concentration and proportion with rSBA ≥ 8, both by univariate and multivariate analysis (adjusting for sex of participant and brand of MenC vaccine) (Tables 4 and 5). There were no significant differences in these immune measures by participant sex.
There was a trend (not statistically significant) for those who received a tetanus-toxoid conjugate MenC vaccine (MenC-TT), rather than a CRM-197 conjugate MenC vaccine [MenC-CRM (A) or MenC-CRM (B)] to exhibit higher rSBA titers (rSBA titer and proportion with an rSBA titer ≥ 8) (Table 2). This reached statistical significance for MenC hSBA titers using human complement (hSBA titer and proportion with an hSBA titer ≥ 4) (Table 5).
Men A, W and Y IgG GMCs in the 11- to 16-year-old participants were 1.26, 0.38 and 0.47 μg/mL, respectively, and did not differ by age (data not shown).
This study shows that sustained vaccine-induced immunity to MenC disease during childhood is dependent on age at vaccination. Furthermore, more than half of the current cohort of Australian adolescents may be susceptible to MenC disease. Specifically, only 44% of the 11- to 16-year old in this study had persistent rSBA titers above the serological correlate of protection (rSBA titer of ≥ 8)12 more than 7 years after immunization. Long-term persistence of MenC antibody (rSBA, hSBA and IgG) following early childhood immunization improved with increasing age at primary vaccination (between 2 and 8 years of age). This is also the first study to show that natural immunity to other vaccine-preventable serogroups of meningococci (A, W and Y) is low in 11- to 16-year-old Australian adolescents.
The age-dependent MenC antibody findings of this study concur with previous evidence of poor antibody persistence following MenC vaccination in young children14,15 and improved antibody persistence in older children.16 In our study, only one-third of the adolescents immunized between 2 and 4 years of age had an rSBA titer ≥ 8, compared with almost 60% of adolescents immunized between 5 and 8 years of age. MenC rSBA titers and IgG concentrations followed a similar pattern providing further evidence that immune responses to meningococcal vaccines improve around the age of 5 years14–17 regardless of whether administered as a priming or booster dose.7
Human complement source SBA assays were performed in the original studies of SBA against MenC. A serum dilution ≥ 4 by hSBA is an historical population-level correlate of naturally induced immune protection,13 whereas a serum dilution of ≥ 8 by rSBA allows bridging comparison with population-derived correlates of direct protective efficacy following conjugate vaccine administration.18 Only 34% of adolescents in our study had a MenC hSBA titer ≥ 4 compared with 44% with a rSBA titer ≥ 8. This finding is consistent with previous evaluations of meningococcal correlates of protection that rSBA may give higher titers than hSBA and further, although a rSBA ≤ 8 predicts susceptibility (with high specificity) and a hSBA ≥ 4 indicates protection, a hSBA ≤ 4 does not always indicate susceptibility.11,13
Explanation for Findings
Immunological maturation has emerged as the most compelling explanation for age-dependent MenC antibody responses in childhood. Primary antibody responses to MenC conjugate vaccination are higher in adolescents than in younger children.19 Furthermore, natural decline in circulating MenC SBA titers with time has been shown in infants and likely occurs faster in younger children than adolescents.20 Younger children also appear to be less well primed for a secondary immune response.14 Immature intrinsic germinal center B-cell reactions and suboptimal microenvironmental factors in lymphoid tissue and bone marrow are thought to be some of the mechanisms behind these observations,21 culminating in generation of fewer long-lived plasma cells.22
Strengths and Weaknesses
In contrast to data from meningococcal serosurveys conducted using banked residual sera agnostic to vaccine status in the United Kingdom and the Netherlands;8,17,23,24 this study selectively recruited individuals with a confirmed date and brand of MenC vaccination. This study therefore allowed accurate determination of antibody persistence following MenC immunization in childhood by age and product. The uptake of MenC vaccine in the catch-up group (those aged 2 to 18 years) in Australia between 2003 and 2006 is estimated at 70%.25 Therefore, it is possible that our findings may underestimate the true susceptibility to MenC disease in the current Australian adolescent population.
This study was not powered to look at persistence of the immune response following childhood MenC immunization by brand of vaccine received, so interpretation of this analysis is limited due to the small sample size of adolescents primed with either of the MenC-CRM vaccines. Our data suggested a trend for better persistence following receipt of the MenC-TT tetanus toxoid conjugate MenC vaccine than either of the CRM conjugates for rSBA and statistically significantly by hSBA. Other studies have found superior immune responses following primary vaccination with the MenC-TT vaccine than either of the MenC-CRM vaccines.7,19 Larger cohort studies following recipients of alternative MenC vaccines would be required to make definitive conclusions regarding the influence of conjugate protein type on long-term persistence of MenC antibody in childhood.
Despite the strongly significant age-dependent antibody findings of this study, the MenC rSBA GMT and proportion with rSBA titer ≥ 8 were lower (nonstatistically significant) in the children immunized with MenC at 8 years compared with 7 years of age. This is likely due to the small sample size in the older age group (resulting in very wide CI), and limits the accuracy of the data for that age. Accordingly, for both age groups with small sample sizes (2 and 8 years of age) data was combined with the adjacent age group in Figure 1.
This study also indicates that the current cohort of Australian adolescents may be susceptible to other meningococcal serogroups. Although no definitive surrogate of protection has been defined for serogroups A, W or Y, IgG concentrations can be informative. MenW and Y IgG antibody concentrations were low and showed little variation by age in the 11- to 16-year-old adolescents. A recent seroprevalence study of MenW and Y rSBA in England also found natural immunity to be low particularly in young children, with no rise in adolescence. Instead, peak titers to these strains were observed in 20- to 24-year olds (W-135) and 30- to 44-year olds (Y).24 Historically, serogroup Y disease has been rare in the United Kingdom and Australia, but recently such cases have more than doubled both in the United Kingdom (from 29 in 2007/2008 to 81 in 2011/2012, an increase from 2% to 11% of all meningococcal cases)26,27 and in Australia (from 7 in 2008 to 15 in 2011, a rise from 2.8% to 7.0% of all cases).28,29 Therefore, the low levels of natural immunity to serogroup Y are of some concern. Furthermore, a recent study in university students in Nottingham, United Kingdom, found carriage rates of MenY have increased dramatically from 5% in 1999–200130 to up to 25% in 200931,32 suggesting MenY circulation in the United Kingdom may be increasing. No such Australian adolescent carriage studies have been performed. In our study, serogroup A IgG levels were higher than for MenW or Y despite no evidence of circulation in Australia.28 Similar seroprevalence findings were reported in the United Kingdom.23 These higher MenA concentrations may be attributable to the presence of cross-reacting antigens.33–35
In accordance with predictions, aging cohorts of children immunized with MenC vaccine in infancy and early childhood has been associated with an overall increase in the pool of apparently susceptible older children and adolescents.14,36 Serial UK seroprevalence studies show that the high levels of MenC immunity observed in 10- to 19-year olds in 2000–2004, representing those eligible for catch-up vaccination during primary and secondary school,23 persisted as they aged into the 15- to 24-year old group by 2009, 10 years following the catch-up campaign.8 In that same year, however, less than 30% of UK children aged from 1 to 14 years had persistent MenC SBA titers ≥ 8. These lower levels of seroprotection in the early teenage cohort in 2009 raise concerns that herd immunity, the predominant mechanism of disease control at present, will decline as catch-up cohorts continue to age.37 Accordingly, over the next 10 years, the likelihood of re-establishment of endemic transmission of imported strains will inevitably increase.
Although we did not measure persistence of immunity in children who had been immunized at the routine Australian MenC vaccination time-point of 12 months, our antibody results were strongly age-dependent. More than 7 years following MenC vaccination, only 22% of our youngest study participants (mean age at receipt of MenC, 2.8 years) had an rSBA titer ≥ 8, suggesting that the proportion of children with titers considered protective after receipt of MenC vaccine at 12 months would be even lower. Recently, a study of antibody persistence 5 years following either a single dose of combined Haemophilus influenzae type b-MenC or monovalent MenC conjugate vaccines at 12 to18 months of age reported only 19% and 25% of children, respectively, had an rSBA titer ≥ 8, similar levels to our study.38 We predict that by 2015, less than 1 in 5 Australian children entering adolescence (12 years of age) will have MenC rSBA titers sufficient for protection against MenC disease.
Circulation of MenC in Australia is currently low (only 11 laboratory-confirmed cases in 2012)39 and comparable to cases of W and Y (7 and 15 cases in 2012 respectively).39 By this measure alone, introduction of an adolescent meningococcal booster (MenC or MenACWY) may not be justified at this time. However in 2012, 3 cases of MenC disease occurred in the immunized cohort (15 to 24 years of age)39 and at least 5 cases of vaccine failure have occurred in children since the introduction of MenC vaccine in Australia (personal communication). What is not yet known, but critical for a formal cost–effectiveness evaluation of routine adolescent meningococcal vaccination in Australia, is the rate of carriage of circulating strains in adolescents and young adults (the major transmitters of disease in the pre-vaccine era). If the rate of endemic transmission is increasing in this cohort, as predicted with low levels of seroprotection, herd immunity (a significant component of the effectiveness of MenC vaccines) will decrease. In addition, even with appropriate antibiotics, meningococcal disease progresses rapidly resulting in an often devastating and potentially fatal course. Accordingly, due to the risk of a return to pre-vaccine disease patterns in adolescents, a preemptive adolescent booster meningococcal strategy in Australia should be considered. The dual benefit of this strategy is direct protection to the immunized adolescent going into the secondary peak risk period in the late teen years and early twenties and also indirect protection of these emergent parents to infants. In the United Kingdom, with the considerable MenC disease outbreak of the early 2000s still in recent memory, a preemptive adolescent MenC vaccine strategy has commenced.40 A catch-up campaign was implemented for all new starters at universities up to the age of 25 years.40 In the US, the incidence of meningococcal disease has declined among all age groups and in all vaccine-related serogroups since a single-dose of MenACWY conjugate vaccine was recommended at 11–12 years of age in 2005.41 Recently, the Advisory Committee on Immunization Practices (ACIP) revised the recommendation to a 2-dose strategy to optimize meningococcal protection through late adolescence into early adulthood.42
Our study has revealed both the current and potential future susceptibility of Australian adolescents to serogroups A, C, W and Y, and provides new evidence to inform considerations of meningococcal vaccine schedule requirements.
The authors are grateful to the participants of this study and their family members. The authors thank the contributions of the staff members of the Vaccine and Immunisation Research Group (Melbourne), Marita Kefford, Sharon Trevorrow, Mairead Phelan, Annmarie McEvoy, Jane Ryrie, Clare Brophy, Janet Briggs, Marie West, Jacinta Sonego, Jacinta O’Keefe, Judith Spotswood, Paula Nathan and Bernie McCudden; Caroline Talbot and Jennifer Kent of the Vaccine Trials Group (Perth); and Drs Helen Findlow and Xilian Bai of the Public Health England Vaccine Evaluation Unit (Manchester, United Kingdom).
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Neisseria meningitidis; monovalent serogroup C meningococcal vaccine; persistence of immunity; immunization; adolescence
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