Prevalence of Serum Bactericidal Antibody to Serogroup C Neisseria
meningitidis in England a Decade after Vaccine Introduction
David A. Ishola, Jr.,a,eRay Borrow,b,cHelen Findlow,bJamie Findlow,bCaroline Trotter,dand Mary E. Ramsaya
Immunisation Department, Health Protection Agency, Colindale, London, United Kingdoma; Vaccine Evaluation Unit, Health Protection Agency North West, Manchester
Royal Infirmary, Manchester, United Kingdomb; University of Manchester, Inflammation Sciences Research Group, School of Translational Medicine, Manchester, United
Kingdomc; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdomd; and Centre for Infectious Disease Epidemiology, Department of
Infection and Population Health, University College London, United Kingdome
at 2, 3, and 4 months of age. During 2000, a phased catch-up
campaign was implemented for young people up to the age of 18
had an early and marked impact on the incidence of serogroup C
disease (16). Within the first 2 years, there was an overall reduc-
tion in incidence of 87% in the targeted age groups and there was
a decrease in attributable deaths from 67 in 1999 to 5 in 2001 (2).
A reduction in the prevalence of nasopharyngeal serogroup C
ing the introduction of the MCC vaccine (14), providing a basis
for indirect protection (herd immunity). Reduced carriage rates
were sustained (13), and there was an estimated 67% fall in the
herd immunity (19). By 2002, the overall direct vaccine effective-
ness was estimated at well over 90% (19).
infant immunization. Field effectiveness of the initial 3-dose vac-
wane rapidly (22), and serological studies found that only 36% of
children were still protected (defined as a serum bactericidal an-
tibody [SBA] titer of ?8, with rabbit complement) 18 months
after infant vaccination (20, 23). In 2006, the immunization
3, 4, and 12 months. The expectation was that the booster dose in
toddlers would provide improved and extended individual pro-
tection. Disease incidence rates have remained at very low levels,
with the UK Health Protection Agency (HPA) reporting fewer
n 1999, the United Kingdom was the first country to introduce
meningococcal serogroup C conjugate (MCC) vaccines, incor-
since 2005 up until 2010 (11).
ment disease surveillance. Serological surveillance has been uti-
lized for a considerable time in the United Kingdom to inform
vaccine policy for several diseases, such as measles (10) and infec-
tion with Haemophilus influenzae type b (24). Therefore, the aim
of this study was to assess the population levels of immunity in
England to serogroup C meningococci, using measurements of
specific functional antibody levels in age-stratified sera. Specific
study objectives were to assess the current age-stratified levels of
population immunity to the infection (measured approximately
10 years after vaccine introduction), to compare the current im-
munity levels to historical time points before and shortly after
vaccine introduction, and to determine whether the change in
vaccine schedule (introduction of a booster dose at age 12
months) has had a beneficial effect. The study’s findings also pro-
vide population data for subsequent mathematical modeling to
guide future decisions on MCC vaccine scheduling in the United
Received 30 November 2011 Returned for modification 27 February 2012
Accepted 22 May 2012
Published ahead of print 30 May 2012
Address correspondence to David A. Ishola, Jr., email@example.com.
Copyright © 2012, American Society for Microbiology. All Rights Reserved.
cvi.asm.org Clinical and Vaccine Immunologyp. 1126–1130 August 2012 Volume 19 Number 8
MATERIALS AND METHODS
Source of sera. Serum samples were obtained from the HPA Seroepide-
miology Unit. The Unit maintains a depository of anonymized residual
sera from routine diagnostic testing at participating laboratories. There is
no record of the indication for blood testing, but immunocompromised
individuals are not included. The age and sex of the anonymous donors
and year of collection are collated on the database, as well as the location
of the source laboratory (17). Sera collected in 2009 were used for this
study, it being approximately 10 years since the introduction of MCC
vaccine in England.
Serological methods. The age-specific susceptibility to serogroup C
meningococcal infection was estimated by measuring the levels of stan-
dardized SBA, using baby rabbit complement (Pel-Freeze Incorporated,
Rodgerson, AZ) to serogroup C Neisseria meningitidis strain C11 (C:16:
P1.7-1,1) as previously described (15). Assays were conducted at the lab-
at 60 min. Titers of ?8 were taken as the putative protective level of
protection against disease (4). Titers of ?4 were assigned a value of 2 for
computational purposes, being half of the value of the lowest limit of
Sampling and statistical methods. Samples were selected from a
range of age bands that were intended to fit with the various vaccine
schedules since introduction of the serogroup C meningococcal vaccine
and also to enable comparison with previous studies as described below.
11 to 14 years, 15 to 19 years, 20 to 23 years, 24 to 27 years, 28 to 40 years,
reasonable precision around the 95% confidence intervals (95% CIs) of
proportions with SBA titers of ?8 within the strata of interest. For exam-
ple, a 50% proportion would have 95% CI of 40 to 60%. To achieve these
numbers, all samples in the ?1-year age group and a random selection of
determined, along with exact binomial 95% CIs of proportions. Geomet-
ple collection. In lieu of this, and as coverage with each schedule has been
high, the age of each serum donor in years and months was used to esti-
mate the vaccination schedule they would have been eligible for (16).
Protection was then compared according to the applicable vaccination
schedule by age and, within this, over time.
ing samples collected in 2009) were compared with historical data from
two previously published, similarly designed studies of age-specific pro-
duction (2000 to 2004) (23) periods. Both of these previous studies were
conducted in the same laboratory as the present study.
Ethical approval. The HPA Seroepidemiology Unit holds ethical ap-
proval (05/Q0505/U5) to carry out serological surveillance in support of
the Joint University College London/University College London Hospi-
tals (UCL/UCLH) Committees on the Ethics of Human Research.
In the 2009 survey, results were available for 1,174 samples, of
which 415 (35%; 95% CI, 33 to 38%) had evidence of seroprotec-
tion (shown by attaining putatively protective SBA titers of ?8).
to MCC introduction (in 1996 to 1999) and shortly after intro-
duction of MCC (in 2000 to 2004) (21, 23) (Fig. 1). This showed
high levels seen in adolescent age groups in 2000 to 2004 (repre-
band at the time of the two postvaccine surveys are shown below the graphs. pre-sch, preschool.
Immunity to Serogroup C Meningococcal Infection
August 2012 Volume 19 Number 8cvi.asm.org 1127
senting those eligible for catch-up vaccination from primary
school age forwards) has shifted into the older age groups. Thus,
Among the adults, seroprotection levels had seemed to decline
seroprotection levels that are very similar to those of the prevac-
In further analysis according to vaccine schedule (Table 1),
cohorts that were eligible for single-dose catch-up vaccination at
the outset of the MCC program in 1999 and 2000 showed declin-
ing levels of antibody in all age groups. The percentage decline in
GMTs from 2000 to 2004 to 2009 was highest in the cohorts with
CI, 66 to 122) (n ? 394) to 28.3 (95% CI, 19 to 42) (n ? 101) in
those eligible for vaccination at secondary school, from 104.2
in those eligible for primary school vaccination, and from 12.6
those eligible for preschool vaccination (Table 1). Seroprotection
levels remained much higher in those who were eligible for vacci-
nation at primary or secondary school age (born between 1982
and 1994 and approximately between 6 and 18 years old at the
time of the catch-up campaign) compared to those eligible for
to 1997 and 3 to 5 years old during that period). Protection was
especially low in children born in 1998, who were eligible for the
1 year old then.
Those 4 to 10 years old at sampling in 2009 (born in 1999 to
(before the addition of a booster to the schedule in 2006). Only
about a quarter of these subjects had protective antibody levels
(26.0%; 95% CI, 20 to 33%).
Children born between 2006 and 2008 (approximately 1 to 3
schedule of two infant primary doses plus a booster at age 12
months, also had only modest seroprotection, with less than one-
third showing a protective SBA titer (31.6%; 95% CI, 24 to 40%).
sampling) showed notable seroprotection levels, but as they were
current schedule, they were not readily comparable to other
GMTs followed a similar pattern to that described for propor-
tions of seroprotection (Table 1 and Fig. 2), across all of the vac-
cinated and the older unvaccinated age groups. GMT levels re-
as older children than those who were eligible for the routine
schedules. Similar to the seroprotection proportions, high GMTs
in infants of 2000 to 2004 fell sharply—as seen in the comparator
5- to 9-year-old band of 2009.
Between the ages of 1 and 3 years, antibody levels were sim-
ilar in children eligible for vaccination according to both the
old schedule (doses at 2, 3, and 4 months) and the current
schedule (3, 4, and 12 months). At the ages of 1, 2, and 3 years,
respectively, GMT measurements in the 2000-to-2004 survey
were 13.7 (95% CI, 9 to 20) (n ? 138), 7.5 (95% CI, 5 to 11)
(n ? 109), and 5.7 (95% CI, 4 to 8) (n ? 83), compared to 13.1
TABLE 1 Proportions of samples with protective levels of antibody by birth cohort and vaccination schedule
Vaccination schedule for birth cohort
2000–2004 survey2009 survey
SBA titer ?
8 (95% CI) GMT (95% CI) n
SBA titer ?
8 (95% CI) GMT (95% CI)
Current routine schedule
No vaccination yet (age ?3 mo at
time of sampling)
Incomplete (below age for 3rd dose) 2009
3, 4, and 12 mo
NA27 25.9 (11–46) 4.8 (3–9)
56.5 (34–77) 25.9 (10–70)
31.6 (24–40) 7.0 (5–10) 2006–2008 92
Old routine schedule (2, 3, and 4 mo) 2004–2005 91
11 (2004 only)
30.2 (19–43) 5.7 (4–9)
29.0 (19–41) 4.8 (3–7)
8.1 (7–10)3.7 (2–6)
Single–dose catch–up for various birth
cohorts at vaccine introduction in
Catch–up in 2nd yr of life
Primary school catch–up
Secondary school catch–up
31.7 (23–42) 7.2 (5–11)
56.1 (47–65) 27.5 (18–43)
55.8 (48–63) 28.3 (19–42)
None (most persons ?18 yr not
included in catch–up)
Pre–1982 NA 55012.5 (10–16)3.4 (3–4) 369 27.1 (23–32) 6.1 (5–7)
Total2,391 41.2 (39–43) 15.26 (14–17) 1,174 35.4 (33–38) 8.9 (8–10)
aNA, not applicable.
Ishola et al.
cvi.asm.org Clinical and Vaccine Immunology
(95% CI, 7 to 25) (n ? 49), 6.1 (95% CI, 3 to 11) (n ? 51), and
3.3 (95% CI, 2 to 5) (n ? 33) in 2009.
Within a year and around 2 years after vaccination, antibody
for a single-dose catch-up in the second year of life (without hav-
12 months. In the 1998 birth cohort (eligible for single-dose
2 to 9) (n ? 40). This compared with 6.1 (95% CI, 3 to 11) (n ?
51) in the 2007 birth cohort (eligible for the 12-month booster in
2008 and sampled in 2009). Around 2 years after vaccination, the
levels in the catch-up group (born in 1998, eligible for a single-
dose catch-up in 2000, and sampled in 2002) were higher (13.4;
95% CI, 7 to 26; n ? 43) than in those eligible for the current
routine schedule (born in 2006, eligible for the 12-month booster
in 2007, and sampled in 2009) (3.3; 95% CI, 2 to 5; n ? 33).
This report presents the results of a cross-sectional survey of SBA
to serogroup C N. meningitidis in England, carried out a decade
after the introduction of MCC vaccination in 1999. The findings
of this study suggest that protective antibody levels have declined
markedly in all immunized cohorts since the time of vaccination.
ary school age (from approximately 5 years) than in those eligible
as toddlers or at preschool age (between 1 and 4 years). The aging
of these cohorts over time explains the shift seen in the age group
with peak antibody levels between 2000 to 2004 and 2009. This is
probably mainly due to the higher antibody levels achieved in
those vaccinated at an older age—there was no clear evidence of a
higher rate of decline of antibody in those vaccinated earlier in
childhood. Furthermore, there was no evidence that the extended
routine vaccination schedule has had any substantial impact on
SBA GMT levels were significantly higher in those eligible for the
booster dose has had a very limited short-term benefit over the
rent routine schedule achieve similar GMT levels to those eligible
for catch-up vaccination in the second year of life, suggesting that
the priming vaccination in infancy does not improve the longer-
term persistence of antibody from the 12-month dose.
The major limitation of this study lies in the use of banked
anonymous serum samples from the HPA Seroepidemiology
Unit, which lack information on the actual vaccination status of
the individuals that the samples were obtained from. However,
age in England (25), and this form of convenience sampling has
been shown to provide similar results to more conventional ran-
bank has proven to be a valuable resource for a variety of infec-
tions, supporting research and contributing to successful vaccine
policy interventions in the United Kingdom (17). As the United
icy decisions on vaccination in England and elsewhere.
This study’s findings are consistent with previous evidence of
poor antibody persistence following MCC vaccination in young
children (5, 9). Separately, Snape and colleagues, in an observa-
tional study of people 11 to 20 years old who were previously
immunized between the ages of 6 and 15 years, found that anti-
body levels remain higher some years after immunization at an
levels of serological protection are associated with vaccination
above the age of 5 years (8). Furthermore, Perrett and colleagues
Campbell et al. that in children vaccinated under the routine in-
(6). It has been postulated that age-dependent vaccine responses
may be due to greater immune maturation with increasing age
(20); although prior exposure to meningococci may also contrib-
the previous exposure history of children offered vaccination at
therefore respond as if completely naïve.
low (11), and modeling studies suggest that indirect protection is
population without individual protection is increasing each year.
There is therefore a clear need to consider introducing a booster
dose in older childhood. This study suggests that this dose should
be given at age 5 years or above. Further evidence from clinical
trials of MCC booster doses given to children 6 to 12 years of age
showed that although responses were good across all age groups,
there was an age-dependent trend whereby the best boost re-
sponses occurred among the 12-year-olds (18). The response in
older children may depend, however, on age, prior exposure, and
choice of vaccine used. For example a better booster response to
Menitorix (containing a tetanus MenC conjugate) has been
shown in those primed with tetanus conjugates in infancy (3).
Such studies would need to be repeated in older age groups and
may also consider boosting with quadrivalent conjugate vaccines
FIG 2 Geometric mean titer (GMT) of serum bactericidal antibody (SBA)
against group C meningococci. Shown are current levels (2009) compared
with the period shortly after vaccine introduction (2000 to 2004).
Immunity to Serogroup C Meningococcal Infection
August 2012 Volume 19 Number 8cvi.asm.org 1129
thatalsoofferprotectionagainstserogroupsA,Y,andW135.Such Download full-text
vaccines are now licensed, although the burden of disease due to
these other serogroups in this age group is also currently very low
(11). In the United States, quadrivalent vaccine is currently rec-
ommended for routine use at ages 11 to 12 years, followed by a
second dose at 16 years, aiming for optimal protection in the crit-
ical high-risk period of the late teen years (1).
Boosting at or after 12 years of age in the United Kingdom
would offer the potential additional advantage of alignment with
existing routinely scheduled vaccines, such as the tetanus, diph-
theria, and polio (Td/IPV) booster, currently offered to young
people between ages 13 and 18, or the human papillomavirus
(HPV) vaccine, currently available to girls 12 to 13 years old. Giv-
ing the booster in adolescence might also ensure that antibody
levels remain high going into the secondary peak risk period for
meningococcal disease in the late teen years and early twenties.
These age groups are also those that represented the peak in car-
riage in the prevaccine era (7), and therefore, delaying booster
vaccination until adolescence has potential to provide a larger
herd immunity benefit.
Many thanks to Elaine Stanford, HPA Seroepidemiology Unit, Man-
chester, for selection of serum samples.
This work was supported by the Health Protection Agency (HPA).
D.A.I. is supported by a National Institute for Health Research (NIHR)
1. ACIP. 2011. Updated recommendations for use of meningococcal conju-
gate vaccines—Advisory Committee on Immunization Practices (ACIP),
2010. MMWR Morb. Mortal. Wkly. Rep. 60:72–76.
2. Balmer P, Borrow R, Miller E. 2002. Impact of meningococcal C conju-
gate vaccine in the UK. J. Med. Microbiol. 51:717–722.
3. Borrow R, et al. 2010. Kinetics of antibody persistence following admin-
istration of a combination meningococcal serogroup C and haemophilus
dom primed with a monovalent meningococcal serogroup C vaccine.
Clin. Vaccine Immunol. 17:154–159.
4. Borrow R, Balmer P, Miller E. 2005. Meningococcal surrogates of pro-
tection—serum bactericidal antibody activity. Vaccine 23:2222–2227.
5. Borrow R, et al. 2002. Antibody persistence and immunological memory
at age 4 years after meningococcal group C conjugate vaccination in chil-
dren in the United Kingdom. J. Infect. Dis. 186:1353–1357.
6. Campbell H, Andrews N, Borrow R, Trotter C, Miller E. 2010. Updated
postlicensure surveillance of the meningococcal C conjugate vaccine in
England and Wales: effectiveness, validation of serological correlates of
protection, and modeling predictions of the duration of herd immunity.
Clin. Vaccine Immunol. 17:840–847.
7. Christensen H, May M, Bowen L, Hickman M, Trotter CL. 2010.
Meningococcal carriage by age: a systematic review and meta-analysis.
Lancet Infect. Dis. 10:853–861.
8. de Voer RM, et al. 2010. Immunity against Neisseria meningitidis sero-
group C in the Dutch population before and after introduction of the
meningococcal c conjugate vaccine. PLoS One 5:e12144. doi:10.1371/
9. De Wals P, Deceuninck G, Lefebvre B, Boulianne N, De Serres G. 2011.
Effectiveness of serogroup C meningococcal conjugate vaccine: a 7-year
follow-up in Quebec, Canada. Pediatr. Infect. Dis. J. 30:566–569.
10. Gay NJ, Hesketh LM, Morgan-Capner P, Miller E. 1995. Interpretation
of serological surveillance data for measles using mathematical models:
implications for vaccine strategy. Epidemiol. Infect. 115:139–156.
11. Health Protection Agency. 2011. Laboratory confirmed cases of all
invasive meningococcal disease by serogroup, age and epidemiological
year, England and Wales, 2000–01 to 2009–10. (Last reviewed, 2 Au-
gust 2011.) http://www.hpa.org.uk/web/HPAweb&HPAwebStandard
/HPAweb_C/1234859710351?printable?true. Accessed 15 September
12. Kelly H, Riddell MA, Gidding HF, Nolan T, Gilbert GL. 2002. A random
cluster survey and a convenience sample give comparable estimates of
immunity to vaccine preventable diseases in children of school age in
Victoria, Australia. Vaccine 20:3130–3136.
vaccines on carriage and herd immunity. J. Infect. Dis. 197:737–743.
14. Maiden MC, Stuart JM. 2002. Carriage of serogroup C meningococci 1
year after meningococcal C conjugate polysaccharide vaccination. Lancet
15. Maslanka SE, et al. 1997. Standardization and a multilaboratory compar-
ison of Neisseria meningitidis serogroup A and C serum bactericidal as-
says. The Multilaboratory Study Group. Clin. Diagn. Lab Immunol.
16. Miller E, Salisbury D, Ramsay M. 2001. Planning, registration, and
rogroup C disease in the UK: a success story. Vaccine 20(Suppl 1):S58–
17. Osborne K, Gay N, Hesketh L, Morgan-Capner P, Miller E. 2000. Ten
years of serological surveillance in England and Wales: methods, results,
implications and action. Int. J. Epidemiol. 29:362–368.
18. Perrett KP, et al. 2010. Antibody persistence after serogroup C menin-
gococcal conjugate immunization of United Kingdom primary-school
children in 1999–2000 and response to a booster: a phase 4 clinical trial.
Clin. Infect. Dis. 50:1601–1610.
19. Ramsay ME, Andrews NJ, Trotter CL, Kaczmarski EB, Miller E. 2003.
Herd immunity from meningococcal serogroup C conjugate vaccination
in England: database analysis. BMJ 326:365–366.
20. Snape MD, et al. 2008. Seroprotection against serogroup C meningococ-
cal disease in adolescents in the United Kingdom: observational study.
21. Trotter C, Borrow R, Andrews N, Miller E. 2003. Seroprevalence of
meningococcal serogroup C bactericidal antibody in England and Wales
in the pre-vaccination era. Vaccine 21:1094–1098.
22. Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME. 2004.
Effectiveness of meningococcal serogroup C conjugate vaccine 4 years
after introduction. Lancet 364:365–367.
23. Trotter CL, et al. 2008. Seroprevalence of antibodies against serogroup C
24. Trotter CL, McVernon J, Andrews NJ, Burrage M, Ramsay ME. 2003.
Antibody to Haemophilus influenzae type b after routine and catch-up
vaccination. Lancet 361:1523–1524.
25. Trotter CL, Ramsay ME, Kaczmarski EB. 2002. Meningococcal sero-
impact of the campaign. Commun. Dis. Public Health 5:220–225.
Ishola et al.
cvi.asm.org Clinical and Vaccine Immunology