The greatest risk for invasive meningococcal disease, caused by the Gram-negative bacterium Neisseria meningitidis, occurs in infancy and late adolescence.1 Despite antibiotic treatment, the fatality rate of invasive meningococcal disease is 5%–10%, even in high-income countries,2 and a substantial proportion of survivors are left with long-term sequelae.3 , 4 Thus, reducing the burden of invasive meningococcal disease relies primarily on prevention by vaccination.5 , 6
Meningococcal serogroup C (MenC) conjugate (MCC) vaccines were first introduced in the United Kingdom in 1999 as a 3-dose infant immunization schedule with catch-up campaigns targeting older children, adolescents and eventually young adults up to 25 years of age. Subsequently, MCC vaccines were introduced in several other European countries and Canada. In 2003, MCC vaccines were introduced in Australia as a single dose at 12 months of age, similarly with a staged catch-up campaign targeting individuals 1–19 years of age.7 Postlicensure effectiveness data from the United Kingdom allowed validation of correlates of protection against MenC disease that had been determined by serum bactericidal assay (SBA) using baby rabbit complement (rSBA), with titers ≥1:8 established as a correlate of short-term protection.8–10 Persistence of bactericidal antibody and herd immunity are crucial for long-term protection; however, no reliable correlate of long-term protection has been determined.
The introduction of MCC vaccines led to a dramatic decline in the incidence of invasive MenC disease7 , 11–17; however, evidence of rapid waning of effectiveness after infant immunizations led to recommendations to change the routine immunization schedule in several countries.5 For example, in the United Kingdom, the schedule was changed in 2006 to include two infant doses of vaccine at 3 and 4 months of age followed by a booster dose at 12 months of age. Further studies demonstrated waning of MenC SBA titers over time after both infant and toddler immunizations.18–24 Despite this, the incidence of MenC disease has remained low in the United Kingdom and also in Australia.7 , 8 , 25 , 26 It has been postulated that this is in large part caused by the development of herd immunity through reduction of nasopharyngeal carriage in adolescents and young adults who were immunized as older children and adolescents during the catch-up immunization campaigns of 1999 to 2002 in the United Kingdom and 2003 to 2007 in Australia.7 , 8 , 27–32
To maintain protective levels of bactericidal antibody in adolescents and young adults to ensure individual protection and ongoing maintenance of herd immunity, the UK Joint Committee on Vaccination and Immunisation recommended further changes to the routine immunization schedule in the United Kingdom in 2013, including the addition of an adolescent booster dose and the removal of one infant dose (ie, vaccinations at 3 months, 12 months and 14 years). Since 2015, a tetravalent MenACYW conjugate vaccine replaced the monovalent MCC vaccine for adolescents, and in 2016, all infant doses were removed from the schedule, leaving only the 12-month and adolescent doses of vaccine. On the other hand, there have been no adolescent or young adult immunization boosters in Australia since the introduction of MCC vaccines. Despite this, the incidence of invasive MenC disease has remained low for more than 10 years after the introduction of MCC vaccines.7 , 8 , 25 , 26 In addition to the effect of ongoing herd immunity from previous immunization of older children and adolescents, this may in part be caused by ongoing boosting of immunity in at least some children through exposure to meningococci (through carriage) or other bacterial species (cross-reactive antibodies), resulting in a rise in MenC bactericidal antibody titers over time in the absence of booster doses of vaccine. This study aimed to test this hypothesis by examining rSBA titers over a period of postvaccination follow up in the UK and Australian children who received an MCC vaccine in early childhood.
MATERIALS AND METHODS
The analysis for this study examined data that were collected as part of studies conducted in Australia and the United Kingdom between 2001 and 2010 involving children 12 to 48 months of age at the time of MCC vaccination.
The design of the Australian study has been described previously.33 Briefly, an open-label, randomized-controlled, multicenter trial was conducted in which children 12 to 18 months of age, previously primed with Haemophilus influenzae type b vaccine but no MenC vaccine as part of routine infant immunizations, were randomized (3:1) to receive either one dose of a combined Haemophilus influenzae type b and MenC-TT conjugate vaccine (Menitorix, GlaxoSmithKline Biologicals [GSK], Brentford, United Kingdom) or separate Haemophilus influenzae type b-TT vaccine (Hiberix, GSK Biologicals) and MenC vaccine conjugated to Cross-Reactive-Material-197 (CRM197) (Meningitec, Wyeth/Pfizer Vaccines, Pearl River, NY). Children were followed up for 5 years, and 7 blood samples were collected including pre-MCC and 1 month post-MCC vaccination and then on a yearly basis for 5 years. The study was conducted between 2006 and 2012. rSBA titers were measured at either GSK Biologicals central laboratory in Rixensart, Belgium, or at the Health Protection Agency (HPA) reference laboratory in Manchester, United Kingdom.
Data from the United Kingdom were drawn from an observational study conducted by the Oxford Vaccine Group in which children who had received a single dose of a licensed MCC vaccine as toddlers (between 13 and 45 months, median 21 months of age) had blood samples taken over 10 years between 2001 and 2010.23 The majority of vaccinations occurred as part of the national catch-up immunization campaign in 1999 to 2000, while 4/287 children were vaccinated between February 2001 and March 2002. Most children (259/287) had received a dose of MenC-CRM197 vaccine (Meningitec, Wyeth/Pfizer Vaccines), whereas the specific vaccine received could not be determined for 36 children.23 rSBA analysis was undertaken on these blood samples at the HPA reference laboratory, Manchester, United Kingdom.
Original data from both studies were obtained from the lead authors. A visit-to-visit comparison was done in which rSBA results at each visit were compared with all preceding visits (when performed at the same laboratory in the Australian cohort) to identify the occurrence of a ≥4-fold rise in titers (prevaccination sera were not included in the analysis). Children with missing results were excluded from the analysis at that particular visit-to-visit comparison only. A second episode of ≥4-fold rise in rSBA titers for an individual participant was only included if the episodes were separated by a period of waning in antibody titers. The proportion of children with a ≥4-fold rise in rSBA titers in paired sera at any visit-to-visit comparison was calculated using the total number of paired sera, with results available for analysis as the denominator for each comparison. Secondary analysis aimed to identify the proportion of children with ≥4-fold rise at each particular visit. For this analysis, only children with results available for a particular visit, and at least one earlier visit (from the same laboratory in the Australian cohort), were included and used as the denominator for each visit. Children with evidence of boosting in rSBA titers were grouped according to time (visit/age) at which this occurred. Mean age and range of ages at each visit were calculated for all children included in the analysis at that time point. In case of unavailability of raw data, the mean age and range of ages of the total cohort of children enrolled at that time point were used. Where data were available (for the Australian cohort only), the relationship between initial (1 month postvaccination) responses and evidence of subsequent boosting was also explored. No comparisons were made between results of assays performed at different laboratories.
rSBA titer results from the second- and third-year visits were only available from the GSK laboratory, while the results of the fourth- and fifth-year visits were only available from the HPA laboratory. Results from blood drawn 1 month and 1 year postvaccination were available from both laboratories.
Out of 433 children in the total cohort, 392 children had at least one set of comparable paired sera (ie, from the same laboratory) available for analysis. Of those, 72 children (18.4%) had a ≥4-fold rise in rSBA titers at least once at any time point after vaccination, including 6 children (1.5%) who had a ≥4-fold rise in rSBA titers occurring twice within the 5-year follow-up, that is, rSBA titers were high after vaccination, waned and subsequently boosted before waning and boosting again. Boosting seemed to occur most frequently between 2 and 3 years after vaccination (Table 1), as evidenced by the highest proportion of boosters identified (27 out of 291 [9.3%] children with paired samples) when blood drawn at 3 years postvaccination (mean age 48.5 months) was compared with the 2-year postvaccination visit (mean age 36.6 months). A slightly lower number (7.9%) also showed evidence of boosting later on between 4 and 5 years postvaccination.
In the Australian cohort, results available from both laboratories showed that nonboosters have higher initial (1 month postvaccination) antibody responses compared with those who later boosted, with geometric mean titers (GMTs) of 279 (215–362) versus 190 (115–313) and 515 (452–586) versus 404 (301–543) from HPA and GSK laboratories, respectively. Furthermore, irrespective of age or time since vaccination, there were 29 and 49 episodes where a ≥4-fold rise in rSBA titers was identified based on results from HPA and GSK laboratories, respectively. rSBA GMTs of blood drawn in the visit immediately before the boost were 5.59 and 9.82, with rSBA titers of <1:8 (lowest limit of detection) in 25/29 and 30/49, respectively. Conversely, rSBA GMTs of blood drawn at the visit when boosting was identified were 100.8 and 158.6, with minimum rSBA titers of 1:16 in all samples.
Of 300 children in the total cohort, 234 had at least one set of paired sera available for analysis. Thirty-nine children (16.7%) had a ≥4-fold rise in rSBA titers at least once at any time point after vaccination including 2 children (0.9%) who had a ≥4-fold rise in rSBA titers occurring twice during the 10-year follow-up period. The results for children from the United Kingdom are outlined in Table 2. In this cohort, boosting seemed to occur most frequently between 3 and 4–5 years postvaccination as evidenced by the highest proportion of boosters identified (15 out of 125 [12%] children with paired samples) when comparing blood drawn at 4–5 years postvaccination (mean age 84.4 months) compared with the 3-year postvaccination visit (mean age 60.4 months).
Irrespective of age or time since vaccination, there were 35 episodes where a ≥4-fold rise in rSBA titers was identified. rSBA GMT of blood drawn in the visit immediately before the boost was 3.70, with rSBA titers of <1:4 (lowest limit of detection) in 22/35. Conversely, rSBA GMT of blood drawn at the visit when boosting was identified was 48.5, with minimum rSBA titers of 1:8 in all samples.
Figure 1 and Table 3 outline the total number and proportion of children with ≥4-fold rise at each particular visit after vaccination for both cohorts.
The main findings from both original studies previously published elsewhere23 , 33 demonstrated that the majority of children had waning of rSBA titers over time after vaccination. Investigators reported a substantial (nearly 10-fold) decrease in rSBA GMTs in the Australian cohort from 1 month (621.0 [95% confidence interval: 480.3–802.9]) to 12 months (63.8 [43.3–94.1]) postvaccination.33 Similarly, results from United Kingdom demonstrated that by 10 years after immunization, only 15% of children had MenC rSBA titers above the threshold for protection (≥1:8).23 This is in line with results from many studies of MCC vaccine immunogenicity that show initially robust immune responses but waning immunity over several years.23 , 24 , 34
MCC vaccines are highly immunogenic in young children, with at least 91% and up to 100% of children developing MenC rSBA titers ≥1:8 one month after immunization at age of 12–18 months.33–35 The introduction of MCC vaccines has proved to be very effective in both the United Kingdom and Australia in controlling invasive disease, with disease incidence reduced to near zero.7 , 28 In addition, MCC vaccines reduced carriage of the epidemic serogroup C ST-11 complex meningococci by around 80% over the first 2 years in the United Kingdom.29
This study demonstrates that although immune responses were not maintained by the majority of children, a substantial minority show evidence of boosting of antibody titers without additional doses of vaccine. A ≥4-fold rise in rSBA titers between 1 month and 10 years after vaccination was seen in 18.4% and 16.7% of children in Australian and the UK cohorts, respectively.
In both studies, children received a single dose of a licensed MCC vaccine as toddlers; however, the children in the UK cohort were slightly older at the time of vaccination, and this difference persisted to later blood draws, which may explain the slightly different results between the 2 cohorts. We are unable to exclude similar patterns between the 2 cohorts in “peaks” in the proportion of children with a rise in their rSBA titers because intervals between vaccination and blood draws were different between the 2 cohorts, and data from the Australian cohort did not include follow-up beyond 5 years postvaccination and data from the United Kingdom did not include rSBA titers from the first 2 years postvaccination.
From the date ranges for which we have data, a ≥4-fold rise in rSBA titers occurred most commonly at around 4–5 years postvaccination in the UK cohort when children were around 7 years of age and at around 3 years postvaccination in the Australian cohort when children were around 4 years of age, with a second smaller peak in the proportion of “boosters” occurring around 5 years postvaccination when children were around 6 years of age. The lower percentage of children who showed evidence of boosting 4 years postvaccination in the Australian cohort may be related to the longer time interval between compared blood draws for this time point. One year time intervals were compared between 1 and 2 years, 2 and 3 years and 4 and 5 years postvaccination; however, because of the unavailability of paired blood results from the same laboratory between 3 and 4 years postvaccination, comparisons could only be made between 1 and 4 years or 1 month and 4 years postvaccination for this time point. The high proportion of children with rSBA rise of ≥4-fold at visits between the mean ages of 48.5 to 85 months in both cohorts may be caused by increased social mixing as a result of daycare, preschool and school entry at these ages.
This natural boosting in rSBA titers may occur for several reasons, including exposure to carried MenC or to cross-reactive antigens, as well as host genetic differences or may simply be caused by stochastic changes. MenC is known to asymptomatically colonize the upper airways of individuals, and mucosal colonization with meningococci is typically an immunizing event, producing a bactericidal antibody response against capsular and noncapsular antigens.36 , 37 However, even before the introduction of MCC vaccines, there was little carriage of MenC,29 although this may be because MenC are often only carried for a short time and so, not detected. Thus, it is possible that even very brief episodes of exposure in previously immunized children will allow for boosting of antibody levels. In addition, identification of boosting in a subset of children may in fact identify those who are susceptible to acquisition of MenC given the relatively low rSBA GMTs in blood drawn in the visit immediately before the boost, with the majority of these children having undetectable rSBA titers before boosting.
This raises concern that there is still ongoing circulation of MenC that is not adequately identified in cross-sectional carriage studies. This could mean that ongoing herd immunity may not be well-maintained in the long-term and supports the recent decision by the UK Joint Committee on Vaccination and Immunisation to introduce an adolescent booster dose of MCC vaccine in 2013 (subsequently replaced with a tetravalent MenACYW conjugate vaccine since 2015). Other potential factors associated with an increase in the carriage rate of MenC that may contribute to this rise in rSBA titers, such as exposure to smokers, crowded living conditions or presence of adolescents in the same household, could not be investigated in these cohorts because of the retrospective nature of the analysis. Exposure to other carried organisms or other meningococci (cross-reactive antigens) is theoretically possible; however, to our knowledge, this has not been definitively demonstrated to produce bactericidal antibody responses.
Alternatively, there may be subtle differences in the immune responses of different individuals that determine the rapidity of waning of antibody or a potential for a rise in antibody titers. The initial antibody response to vaccination may provide a clue to these host genetic differences. It is possible that children who had a better initial antibody response “used up” most of their pool of B cells to become antibody-secreting cells and, therefore, were less likely to boost as well subsequently in response to further stimulation, that is, a greater proportion of B cells differentiated into plasma cells at the expense of priming memory B cells. A similar phenomenon has been noted previously with children who had an initial greater bactericidal antibody response to primary MCC vaccines, having lower postbooster antibody responses.38 , 39
Four children showed a delayed response to vaccination with a ≥4-fold rise in rSBA titers between 1 month and 1 year after immunization. This may be early evidence of boosting or may simply be evidence of a slow response to vaccination. The peak antibody response is thought to occur between 4 and 6 weeks after immunization; however, there is evidence that the germinal center reaction after vaccination may continue longer than expected with B cells maturing and differentiating for a longer time. MenC-specific memory B cells have been shown to increase between 5 months and 1 year after primary vaccines in the absence of booster vaccine doses,40 which may also explain the rise in antibody titers in a small number of children in this study within the first 1–2 years after vaccination.
In conclusion, a substantial minority of children immunized with MCC vaccine in early childhood had a rise in bactericidal antibody titers in the years after immunization in the absence of booster vaccine doses. This raises interesting questions about host genetic variability in initial and ongoing immune responses to vaccines with evidence that a greater initial immune response may result in a lower likelihood of subsequent boosting (and therefore persistence) of the antibody response. Interestingly, the age at which most of these children showed evidence of boosting occurs most commonly at around 6 or 7 years of age corresponding to school entry and greater social mixing. This may be evidence of exposure to carriage of MenC. Along with the known waning of immunity in the majority of immunized children, this may lead to a resurgence in disease rates, and though this has not yet been observed, this phenomenon raises some concern for maintenance of herd immunity, particularly in Australia where there is currently no adolescent MCC vaccine booster on the national immunization schedule.
We thank the Oxford Vaccine Group for providing access to the raw data for the UK cohort and Dr S. DiNatale and Dr Andrea McCracken from GlaxoSmithKline for providing data for the Australian cohort. We also thank the children and families who participated in both original studies from which these data are drawn.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
bactericidal antibody titer; meningococcal serogroup C conjugate vaccine; natural boosting; Neisseria meningitidis; rabbit complement serum bactericidal assay