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Transcript
Vaccine 31 (2013) 4477–4486
Contents lists available at ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Effectiveness of meningococcal serogroup C vaccine programmes
Ray Borrow a,∗ , Raquel Abad b , Caroline Trotter c , Fiona R.M. van der Klis d ,
Julio A. Vazquez b
a
Vaccine Evaluation Unit, Public Health England, Clinical Sciences Building, Manchester Royal Infirmary, Manchester, UK
Laboratorio de Referencia de Meningococos, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
University of Cambridge, Department of Veterinary Medicine, Madingley Road, Cambridge, UK
d
National Institute of Public Health and the Environment, Bilthoven, The Netherlands
b
c
a r t i c l e
i n f o
Article history:
Received 28 May 2013
Received in revised form 2 July 2013
Accepted 30 July 2013
Available online 9 August 2013
Keywords:
Meningococcal serogroup C vaccine
Monovalent glycoconjugate vaccine
Children
Vaccine effectiveness
Immunologic memory
a b s t r a c t
Since the introduction of monovalent meningococcal serogroup C (MenC) glycoconjugate (MCC) vaccines
and the implementation of national vaccination programmes, the incidence of MenC disease has declined
markedly as a result of effective short-term vaccination and reduction in acquisition of MenC carriage
leading to herd protection. Monovalent and quadrivalent conjugate vaccines are commonly used vaccines
to provide protection against MenC disease worldwide. Studies have demonstrated that MCC vaccination
confers protection in infancy (0–12 months) from the first dose but this is only short-term. NeisVac-C® has
the greatest longevity of the currently licensed MCC vaccines in terms of antibody persistence, however
antibody levels have been found to fall rapidly after early infant vaccination with two doses of all MCC
vaccines – necessitating a booster at ∼12 months. In toddlers, only one dose of the MCC vaccine is required
for routine immunization. If herd protection wanes following catch-up campaigns, many children may
become vulnerable to infection. This has led many to question whether an adolescent booster is also
required.
Crown Copyright © 2013 Published by Elsevier Ltd. All rights reserved.
Contents
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4477
1.1.
Incidence and epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4477
Concepts of vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4478
MCC vaccines: the clinical evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4478
3.1.
Maternal immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4479
3.2.
Priming of infants (0–12 months) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4479
3.3.
Booster in the 2nd year of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4481
Toddler priming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4481
4.1.
Clinical experience of using a quadrivalent vaccine in infants and toddlers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4481
4.2.
Studies in adolescents (11–18 years) and adults (18 years onwards) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4482
4.3.
Impact of national vaccination programmes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4482
4.4.
Guidelines and recommended immunization practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4483
Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4484
Author disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4484
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4484
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4484
1. Introduction
1.1. Incidence and epidemiology
∗ Corresponding author at: Vaccine Evaluation Unit, Public Health England, Clinical Sciences Building, Manchester Royal Infirmary, Manchester M13 9WZ, UK.
Tel.: +44 161 276 8850; fax: +44 161 276 6792.
E-mail address: [email protected] (R. Borrow).
Bacterial meningitis is a life-threatening disease that is caused
by bacterial infection of the meninges. Neisseria meningitidis is the
most common cause of bacterial meningitis and a major cause of
0264-410X/$ – see front matter. Crown Copyright © 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2013.07.083
4478
R. Borrow et al. / Vaccine 31 (2013) 4477–4486
septicaemia [1–3]. In Europe, the US and other developed countries,
meningococcal disease incidence is typically between 1 and 10
per 100,000 population, with occasional ‘hyperendemic’ periods
of persistent disease caused by particular strains. The incidence
of meningococcal disease is highest among infants; the rates drop
after infancy but increase during adolescence and early adulthood.
There are 12 serogroups of N. meningitidis, defined on the basis
of different immunochemical variants of the polysaccharide capsule that surrounds the bacteria but only six (A, B, C, W, X, Y) cause
life-threatening disease [4]. While large meningococcal serogroup
A outbreaks have been prevalent in Africa, serogroup B and C
meningococci cause most disease in Europe, where most cases are
sporadic, with small case clusters periodically occurring [5]. In 2008
(n = 4978) and in 2009 (n = 4637), a total number of 9615 cases of
invasive meningococcal disease were reported in Europe with an
overall notification rate of 0.99 per 100,000 population in 2008 and
0.92 in 2009 [6].
A major advance in meningococcal disease prevention has
been the development of meningococcal glycoconjugate vaccines
including meningococcal serogroup C (MenC) glyconjugate (MCC)
vaccines. MCC vaccines were implemented to combat the increase
in serogroup C disease due to the ST11 clonal complex which,
before reaching the UK, had spread through Canada, Spain and the
Czech Republic [7]. The UK was the first country to introduce MCC
vaccination in 1999, incorporating MCC vaccines into the routine
infant schedule at 2, 3 and 4 months of age. An extensive singledose catch-up campaign was implemented for 1- to 18-year olds
[7]. Other European countries, Australia and Canada followed suit
and have all subsequently observed substantial reduction in MenC
disease [8–12]. In addition to MCC vaccines, quadrivalent conjugate vaccines against serogroups A, C, Y, and W are available and
recently, a four-component recombinant serogroup B vaccine has
been licensed in Europe.
2. Concepts of vaccination
Several underlying concepts of vaccination (summarized in
Table 1) are important for fully understanding the impact of MCC
vaccination programmes. Within medical communities in some
territories there is a danger that the current low incidence of MCC
disease may lead to a misconception that scheduled vaccination
programmes can be halted or scaled back. This view is erroneous
and there is a need to increase awareness of MCC vaccination and
emphasize the importance of continued vaccination. Vaccination
programmes have been associated with a significant reduction in
disease incidence but continued vaccination is essential to sustain
this (Fig. 1).
A widely accepted correlate of protection for MenC disease is the
outcome of a serum bactericidal antibody (SBA) [13] assay because
complement mediated bacterial killing by serum antibodies is the
primary mechanism of protection against meningococcal disease.
The original assay used complement preserved human serum but,
due to ease of availability, it is now accepted that 3- to 4-week
old baby rabbit serum may be used as an alternative complement
source for the SBA assay [14]. Serum bactericidal antibody titres
of ≥4 with human complement (hSBA) and ≥8 with baby rabbit
complement (rSBA) are indicative of protective efficacy [15]. High
circulating levels of SBA are important because the onset of the
disease is so rapid that the production of antibodies in response to
infection is too slow a process to be protective [16].
Catch-up campaigns have been employed by many countries
implementing national vaccination programmes. These are onetime programmes targeting the age groups at highest risk of
disease.
The primary outcome measures of vaccination trials relate to
the individual protection of immunized individuals, however, this
focus may underestimate the impact of a vaccine programme on a
population. While vaccines provide direct protection for the immunized population, they can also benefit unvaccinated individuals.
Disease transmission can be interrupted when a large proportion
of the population is immune. The more individuals in a given population there are with immunity, the lower the likelihood for a
susceptible person coming into contact with an individual carrying
the bacterium. This concept is known as herd protection [17,18].
Herd protection is of great importance in vaccination campaigns as
it provides indirect protection, with reductions in disease rates in
unimmunized individuals, however, herd protection can only usually occur if vaccination programmes achieve a large-scale coverage
of a population.
3. MCC vaccines: the clinical evidence
Commercially available vaccines that contain serogroup C
comprise monovalent conjugate vaccines, quadrivalent conjugate
vaccines, polysaccharide vaccines and a combination MenCHaemophilus influenzae type b (Hib) conjugate vaccine. Their
formulation, adjuvants used and antigenic content are summarized
in Table 2.
Polysaccharide vaccines are effective in the short term but are
not used in routine vaccination campaigns because they do not
induce a T-cell-dependent immune response, and are therefore
poorly immunogenic in young children and only confer short-term
protection [4]. Conjugate vaccines elicit B- and T-cell responses
and induce immunity and immune memory in infants <2 years of
age [18,19]. Three MCC vaccines were first licensed in the UK in
1999/2000, two conjugated to CRM197 , a mutated diphtheria toxoid
(Menjugate® (MCC-CRM197 , Novartis), Meningitec® (MCC-CRM197 ,
Pfizer), and one to tetanus toxoid (NeisVac-C® (MCC-TT, Baxter).
Quadrivalent meningococcal conjugates are Menactra® (ACWYDT, Sanofi Pasteur) licensed in the US for 2–55 years and given to
11–18 year olds [20], Menveo® (ACWY-CRM197 , Novartis Vaccines),
which is licensed in Europe and the US for ≥2 years (until 55 years in
US) and Nimenrix (ACWY-TT, Glaxo SmithKline) licensed in Europe
for individuals 12 months of age and older.
Meningococcal–Haemophilus influenzae type b (Hib) combination vaccines are available in form of Menitorix® (MCC-TT/Hib-TT,
GlaxoSmithKline), which is routinely given as a booster vaccines
in toddlers in the UK, and MenHibrix® (MenCY-TT/Hib-TT, GlaxoSmithKline), licensed in the US.
Different MCC vaccines produce different immune responses,
which may have an impact on vaccination programmes [21,22].
Different conjugates have been found to induce different antibody
avidity and with varying capabilities to prime for immunologic
memory [23,24]. Formulations using different carrier proteins have
similarly been shown to demonstrate varying avidity [25].
The polysaccharide capsule of MenC has been integral to vaccine
development. While Menjugate® and Meningitec® vaccines contain the O-acetylated (OAc+) form of polysaccharide, some MenC
strains have de-O-acetylated (OAc−) polysaccharide, which may
affect antibody specificity and functional activity when used in a
vaccine. NeisVac-C® contains a de-O-acetylated (OAc−) oligosaccharide and has been shown in clinical studies to demonstrate
greater immunogenicity than Menjugate and Meningitec [26]. The
reason for the improved immunogenicity is not clear, it may arise
from several factors including the O-acetylation, the TT conjugate,
the conjugate chemistry, the length of polysaccharide constituents
or adjuvants. It should be noted, however, that there is a general
waning of protection in all age groups independent of the vaccine
used.
R. Borrow et al. / Vaccine 31 (2013) 4477–4486
4479
Table 1
Vaccination definitions and concepts.
Vaccine immunogenicity
Vaccine effectiveness
Antibody persistence
Immune memory
Herd protection
Catch-up immunization
The ability of the vaccine to elicit an immune response. Greater vaccine antigenicity leads to an
enhanced host response. For MenC vaccines the accepted correlate of protection is serum bactericidal
antibody [13] which measures functional antibodies against the meningococcus.
The capability of MCC vaccines to provide protection from disease in an immunized individual.
SBA persistence in the host following vaccination.
The capacity of the host to raise an enhanced immune response at short or long time intervals after
initial priming. Memory B cells persist and can be reactivated to generate functional antibodies against
the MenC bacterium. In previous clinical studies the immune memory was assessed by either
challenging with plain polysaccharide vaccines or the use of avidity indices.
The concept that even susceptible (unimmunized) individuals can be indirectly protected against
infection if the proportion of immune (vaccinated) individuals is high enough. This is an important
benefit of the MCC vaccine where catch-up campaigns were performed.
A process that involves immunizing large cohorts of the population – in addition to routine use of the
vaccine in infants or toddlers. Provision of catch-up vaccination programmes has resulted in the
induction of herd protection by preventing the acquisition of carriage and hence increased and
prolonged the preventive effect of immunization.
Fig. 1. Introduction of vaccination programmes in 1999 has resulted in a significant and sustained decrease in meningococcal serogroup C disease. (Source: Meningococcal
Reference Unit, Health Protection Agency, UK).
20
15
10
Because infants (i.e., those under 12 months of age) are
the age group most often affected by meningococcal disease,
<1
1-4
5-9
10-14
15-19
20-24
>25
2009
2008
2007
2006
2005
2004
2003
2002
3.2. Priming of infants (0–12 months)
2000
0
2001
5
1999
Maternal-derived antibodies may influence the vaccine antibody responses in infants. The presence of maternal antibodies can
inhibit the development of an infant humoral response to vaccines.
In a recent study, anti-MenC antibody concentrations were found to
be equal in maternal and cord blood samples [27]. However, despite
placental transfer, cord blood anti-MenC antibody concentrations
were low, possibly placing neonates at risk before they receive their
primary vaccinations [27]. As MCC-vaccinated women reach childbearing age the protection of their neonates against MenC is likely
to improve. However, the estimated half-life of maternal IgG in
infants is just 5–6 weeks and consequently antibody levels at birth
are not sufficient to provide protection if the first vaccination is
given in the second year of life. However, most infants are currently
indirectly protected through herd protection [28,29].
clinical studies have focused on this age group. The implementation
of MCC programmes in infancy has significantly reduced the incidence of MenC disease [16,30] (Fig. 2). Following initial licensure of
MCC vaccines, the infant posology consisted of three vaccine doses.
incidence rate per 100,000
3.1. Maternal immunity
All Ages
Fig. 2. Incidence of meningococcal serogroup C disease by age group (England and
Wales) Source of plotted data: Ref. [54].
4480
R. Borrow et al. / Vaccine 31 (2013) 4477–4486
Table 2
Polysaccharide and conjugate vaccines for the prevention of meningococcal serogroup C disease.
Monovalent conjugated MenC vaccine
Menjugate® (MCC-CRM197 , Novartis)
Adjuvants/Amount of oligosaccharide
Vaccine composition
10 ␮g MenC oligosaccharide conjugated to
12–25 ␮g CRM197
Aluminium hydroxide adjuvant
Menjugate is a monovalent MCC vaccine with an
oligosaccharide backbone derived from serogroup C
conjugated to the non-toxic CRM197 derivative of diphtheria
toxoid.
Meningitec is a monovalent MCC vaccine with an
oligosaccharide backbone derived from serogroup C
conjugated to the non-toxic CRM197 derivative of diphtheria
toxoid.
A de-O-acetylated oligosaccharide conjugated directly to the
tetanus toxoid. Clinical studies of NeisVac-C demonstrate a
greater immunogenicity than the two CRM197 conjugated
vaccines (Menjugate and Meningitec) [26,34].
Meningitec® (MCC-CRM197 , Wyeth/Pfizer)
10 ␮g MenC oligosaccharide conjugated to
15 ␮g CRM197
Aluminium phosphate adjuvant
NeisVac-C® (MCC-TT, Baxter)
10 ␮g MenC polysaccharide conjugated to TT
Aluminium hydroxide adjuvant
Quadrivalent conjugated MenC vaccines
Menactra® (quadrivalent, MCV4, Sanofi
Pasteur)
Menveo® (quadrivalent vaccine,
MenACWY-CRM197 , Novartis)
Nimenrix® (quadrivalent, MenACWY,
GlaxoSmithKline)
Other conjugate and polysaccharide vaccines
Menitorix® (MCC-TT/Hib-TT,
GlaxoSmithKline)
4 ␮g each of MenA, C, Y and W135
oligosaccharides conjugated to approximately
48 ␮g of CRM197
No adjuvant
10 ␮g of MenA, and 5 ␮g each of Men C, Y and
W oligosaccharides conjugated to
approximately 48 ␮g of CRM197
No adjuvant
5 ␮g of MenA, and 5 ␮g each of Men C, Y and W
oligosaccharides conjugated to 44 ␮g of
tetanus toxoid carrier protein
New quadrivalent vaccine Menactra containing serogroups A,
C, Y and W135 conjugated to diphtheria toxoid is currently
only licensed for use in individuals aged 2–55 years in the US
and Canada [64].
Quadrivalent vaccine Menveo containing serogroups A, C, Y
and W conjugated to CRM197 . Menveo has recently been
licensed to protect adolescents and adults and induces an
immune response non-inferior to Menactra [48]
Quadrivalent vaccine, Nimenrix containing serogroups A, C, Y
and W conjugated to tetanus toxoid [71] and was recently
licensed in Europe to protect individuals from 12 months of
age and has shown good immunogenicity and safety in adults
and children.
5 ␮g Hib PRP + 12.5 ␮g TT + 5 ␮g MenC.
PSC + 5 ␮g TT powder
No adjuvant
Menitorix is prepared by separate conjugation of Hib and
meningococcal serogroup C polysaccharides to a tetanus
toxoid carrier.
Polysaccharide vaccines, especially against MenC, are not
immunogenic in young children, nor do they induce immune
memory. These vaccines are effective in children older than 2
years as well as adults.
Polysaccharide vaccines
CRM197, Cross-reacting material of diphtheria toxoid as a carrier protein; Hib-TT, Haemophilus influenzae type b conjugate vaccine with tetanus toxoid as carrier protein;
MCC, Meningococcal serogroup C conjugate vaccine; TT, tetanus toxoid.
during adolescence in 2010 owing to the effects of herd protection
[21]. The study concluded that NeisVac-C and Menjugate showed
good immunogenicity after a single dose at 2 months of age and
should be investigated further in single-dose priming strategies.
Another study consolidated the view that there is a difference
in antibody persistence depending on the priming vaccine used.
This was a randomized, multicentre, open-label clinical trial infants
(n = 389) aged 14–18 months who had been previously primed
with either three doses of MCC-CRM197 conjugate or two doses of
NeisVac-C were randomized to receive a booster with either vaccine and dosed with the DTaP-IPV-Hib vaccine at the same time.
% subjects with SBA titers ≥ 8
During the pre-licensure studies of NeisVac-C, the seroprotection
rate was 100% after the first of three doses, a proportion that was
maintained after the second and third doses. By 12–14 months
of age, SBA titres had dropped significantly, being protective in
only 47% of infants. All infants given booster doses of NeisVacC had significant antibody responses, providing strong evidence
that NeisVac-C adequately primes for immunologic memory [31]. A
high seroprotection rate observed after the first dose in infants was
observed in further studies, suggesting that the number of primary
doses of NeisVac-C could be reduced [32–34].
A study of NeisVac-C delivered concomitantly with the diphtheria, tetanus, three component acellular pertussis and Hib conjugate
vaccine delivered to infants (n = 106) at 2, 3 and 4 months confirmed that a reduced vaccination schedule of NeisVac-C could be
used [35].
A comparison of three MCC vaccines has been performed with
vaccination occurring at 2 and 3 or 2 and 4 months of age [35]. Following the first dose of NeisVac-C, 97% of infants acquired an rSBA
titre of ≥8, compared with 80% and 53%, respectively, for Menjugate
and Meningitec. Following the two doses of NeisVac-C, Menjugate
or Meningitec, 98–100% of infants achieved protective antibody
levels. Two years after the booster dose, a follow-up of the same trial
showed that the proportions of subjects with putatively protective
rSBA titres of ≥8 for children who previously received NeisVac-C,
Menjugate and Meningitec were 43%, 22% and 23%, respectively.
The proportion of subjects in each of these groups who achieved
rSBA titres ≥8 at the prebooster visit and 1, 2, 12 and 24 months
after receiving a booster dose of Menitorix at 12–14 months of age,
are given in Fig. 3. Further boosting was not deemed necessary
100
80
60
40
20
0
Pre-Booster
month 1
Meningitec
month 2
Menjugate
month 12
month 24
NeisVac-C
Fig. 3. Percentages of subjects with SBA titres ≥8 before and 1, 2, 12, and 24 months
following administration of Menitorix at 12–14 months of age, by priming MCC
vaccine. Source of plotted data: Ref. [21].
percent subjects with SBA
titers ≥ 8
R. Borrow et al. / Vaccine 31 (2013) 4477–4486
4481
100
80
60
40
20
0
SBA > 8
1 month post
dose
SBA > 8
12 month post
dose
SBA > 128
1 month post
dose
SBA > 128
12 month post
dose
MCC-CRM prime + MCC-CRM boost
MCC-CRM prime + MCC-TT boost
MCC-TT prime + MCC-CRM boost
MenC-TT prime + MenC-TT boost
Fig. 4. Percentages of subjects with SBA titres ≥8 or ≥128 at 1 month and 12 months
after MCC-CRM or MCC-TT primary doses followed by MCC-CRM or MCC-TT booster
doses. Source of plotted data: Ref. [22].
Children primed with NeisVac-C had higher SBA geometric mean
titres (GMT) than those primed with MCC-CRM197 (SBA GMT 6520
[95% CI, 5359–7932] vs. 1903 [95% CI, 1600–2260]) irrespective of
which vaccine was used as the booster [36]. A 12-month follow-up
study revealed that seroprotection in the group primed and boosted
with NeisVac-C was 92.8% compared with 61.5% for those primed
and boosted with MCC-CRM197 conjugate. This indicated longer
antibody persistence in those primed with NeisVac-C [22], a factor
that can be considered important for future changes in vaccination
schedules involving priming vaccines (Fig. 4).
Infant vaccination with NeisVac-C or Meningitec (in combination Infanrix® hexa, GlaxoSmithKline) followed by a booster dose of
Menitorix demonstrated robust and persistent responses [37,38].
The conclusions from infant studies are that a high level of protection is acquired from first dose and that priming with the correct
vaccine is important. Priming with NeisVac-C gives the greatest
longevity in terms of maintaining antibody titres of the currently
licensed vaccines.
3.3. Booster in the 2nd year of life
A booster dose is an extra administration of a vaccine after an
earlier dose, resulting in re-exposure to the immunizing antigen.
This boosting aims to restore immunity back to protective levels
after it has decreased over a specified period of time. This topic is
discussed in greater detail later in this article.
Following the implementation of MCC vaccination in the UK
in 1999, the long-term effectiveness of MCC vaccines was studied. In a report of the effectiveness of MCC vaccination in the UK 4
years after its introduction into the routine immunization schedule at 2, 3 and 4 months, it was found that vaccine effectiveness in
infants following routine vaccination appeared to wane rapidly, and
cohorts vaccinated at older ages in a catch-up campaign seemed to
have better and longer-lasting protection than those vaccinated in
infancy. It was concluded that a dose later in infancy or in the second
year of life may improve long-term protection [11,12]. A Spanish
study also showed that vaccine effectiveness decreases over time
when given in infancy in a 2, 4, 6 month schedule. High short-term
vaccine effectiveness values were found in the 4 years following its
introduction, but there was loss of effectiveness with time among
children vaccinated in infancy [9].
MenC antibody persistence data are important in indicating the
duration of protection in otherwise vulnerable groups and the point
at which booster doses become necessary. For example, in one
study in the UK, 1 year after a course of 3 doses of MCC vaccine
at 2, 3, and 4 months of age, 54% of children had an SBA titre of
≥8 but this had decreased to 12% after 4 years. This indicates that
MenC SBA titres in infants rapidly wane, eventually to a level that
is not considered protective [39–41].
Fig. 5. Seroprevalence of SBA titres ≥8 in The Netherlands pre- and post-MCC vaccination. Source of plotted data: Ref. [28].
Based on these observations, the official recommendation
included in the Summary of Product Characteristics of all MCC vaccines has been that a booster dose should be given in the second
year of life after completion of the primary infant immunization
series.
4. Toddler priming
In a study of toddlers (n = 226) aged 12–18 months, a single
dose of the three licensed MCC conjugate vaccines resulted in a
high SBA GMT and rates of SBA ≥8. NeisVac-C induced higher
SBA GMTs and higher seroprotection rates, 1 month and 6 months
after vaccination. Challenge with a plain AC polysaccharide vaccine
demonstrated the induction of immunologic memory of all three
vaccines. Again the NeisVac-C group reached a significantly higher
SBA GMT [26].
In 2002, a single MCC (NeisVac-C) vaccination at the age
of 14 months was implemented for all newborns in the Dutch
national immunization programme (NIP). The reason to include
MCC vaccination in the NIP was the rapidly progressive increase
in the incidence of MenC disease in 2000–2001. This programme
also included a catch-up group of individuals aged 14 months
to 18 years. After introduction of vaccination, a sharp rise in
MenC-specific IgG and functional antibodies was observed in the
age-cohort 15–23 months. However, after this peak in antibody
levels, a steep decline in IgG antibodies was observed, and IgG
concentrations had decreased to pre-MCC introduction era levels
in children between 23 and 72 months of age. In older children,
who were vaccinated in the catch-up programme between 9 and
18 years of age, MenC-specific IgG and SBA titres increased gradually with age and were significantly higher than in the pre-MCC
introduction era (Fig. 5) [28]. It can be concluded from these studies
that only one dose of vaccine is required in toddlers, together with
a suitable catch-up campaign, for successful routine immunization.
4.1. Clinical experience of using a quadrivalent vaccine in infants
and toddlers
Infants and toddlers are the two age groups that are immunized under the current vaccination programmes and where the
primary immune response is understood. A recent randomized
controlled multicentre trial investigated the use of Menveo (ACWYCRM197 ) in infants. After immunization with ACWY-CRM197 at 2,
3, and 4 months of age, the percentage of participants with hSBA
titres ≥4 after three doses were: serogroup A, 93%; C, 96%; W135, 97%; and Y, 94% [42]. A recently approved conjugated vaccine,
ACWY-TT (NimenrixTM ; GlaxoSmithKline), has been shown to have
good effectiveness and to have a clinically acceptable safety profile in toddlers over 1 year of age and older children [43]. This
was shown in a study that included 240 toddlers who were 12–14
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R. Borrow et al. / Vaccine 31 (2013) 4477–4486
months of age, 1 month after vaccination with differing formulations of ACWY-TT, 88.1–92.7% had rSBA-Men C titres of ≥128
compared with 87.0% of controls and 97.6–100% of ACWY-TTvaccinated toddlers had rSBA titres of ≥128 against serogroups
A, W and Y compared with no more than 35.9% of controls [43].
More recently, a variety of other studies have also shown the
good efficacy, safety and tolerability of quadrivalent meningococcal conjugate vaccines in infants and toddlers [44–47]. Whilst these
studies show promising results, some investigators comment that
persistence of antibodies may be a more appropriate correlate of
long-term protection for meningococcal conjugate vaccines than
the ability to generate a booster response after exposure to the
pathogen [48].
A study in 382 infants in the UK and Canada investigated the
persistence of immunity following different priming- and booster
schedules with ACWY- or MCC vaccines. At 5 years of age, a decrease
in SBA activity against all serogroups was observed. Substantially
better persistence was observed in children primed with MCC vaccine, as compared to the quadrivalent vaccine [49].
4.2. Studies in adolescents (11–18 years) and adults (18 years
onwards)
All licensed MCC vaccines have a good response in adolescents.
They are currently routinely administered to this age group only in
the USA (quadrivalent) and Canada (MCC), but adolescent boosters should be considered elsewhere. In a recent study assessing
SBA responses in adolescents 22 months after vaccination with
a single dose of Menveo or Menactra, the immune response was
found to be sustained [48]. In a study in which a booster dose
of either a polysaccharide vaccine or MCC-CRM197 was administered to adolescents previously immunized with the conjugate
vaccine, the booster dose produced significantly raised (P < 0.0001)
SBA titres that remained elevated 1 year later. Introduction of an
adolescent booster of MCC vaccine might provide enhanced longterm population control of the disease [48,50]. The immunogenicity
of a single dose of NeisVac-C has been investigated in vaccinenaive adults (n = 73) compared with adults previously vaccinated
with a meningococcal serogroup A-C polysaccharide MACP vaccine (n = 40). Before vaccination, seroprotection was significantly
higher in previously vaccinated adults (P < 0.001). Both at one week
and 1 month after vaccination, seroprotection was still slightly
higher in those previously vaccinated but, 6 months after vaccination, seroprotection was higher in adults who had originally
been vaccine-naive [51]. This study showed that NeisVac-C is safe
and immunogenic in naive and adults previously vaccinated with
bivalent AC polysaccharide vaccine, although the magnitude and
persistence of post-vaccination SBA responses in the latter group
were lower.
4.3. Impact of national vaccination programmes
The UK implemented a national MCC vaccination programme
at the end of 1999. MCC vaccines were incorporated into the routine infant immunization schedule at 2, 3 and 4 months of age, and
a catch-up campaign targeting all those aged up to 18 years was
launched. The vaccine was well accepted and routine coverage has
been consistently above 90%. Uptake in the catch-up campaign varied by age group, with over 75% of preschool children and over 85%
of school children aged 5–16 immunized. The catch-up campaign
was carried out over 12 months, with older teenagers and young
children, i.e., those assessed to be at highest risk of disease, targeted
first. The winter of 2000/2001 was therefore the first opportunity to
observe the full effect of the vaccine campaign. Cases of MenC disease declined rapidly: by 2007/2008, fewer than 30 cases occurred,
a decrease of over 97% compared with 1998/1999. In an assessment
Fig. 6. Herd protection effects on meningococcal serogroup C disease in England
and Wales. Figure redrawn with permission from Ref. [16].
of surveillance data 4 years after the introduction of the vaccination
programme, MCC vaccine effectiveness remained high in children
vaccinated in the catch-up campaign (aged 5 months to 18 years).
However, for children vaccinated in the routine infant immunization programme, the effectiveness of the MCC vaccine fell to low
levels after only 1 year [11]. As a result, the vaccination scheduling
was changed; two doses of MCC conjugate vaccine are now given
at 3 and 4 months with a booster at 12 months [7,12].
Further seroprevalence analysis found that the proportion with
SBA titres ≥8 was higher in cohorts receiving MCC immunization at
5–17 years (n = 1009) as part of a catch-up campaign than it was in
children offered the vaccine at 1–4 years (n = 610) [52]. Protective
titres in children offered routine immunization were initially high
(75%), however, these titres fall to much lower levels (36%) beyond
18 months post immunization [53]. Antibody persistence has also
been found to be poor in individuals less than two years of age in
the catch-up campaign [53].
Despite these findings, the impact on MenC disease has been
sustained, with the lowest recorded incidence (0.02 cases per
100,000 population in the 2008/2009 epidemiological year) [54].
The population impact on MenC disease has been maintained as a
result of herd protection resulting from the catch-up vaccination
programme [54,55].
The scale of the herd protection effect on MenC disease in
England and Wales is illustrated in Fig. 6, which compares the
observed number of cases of MenC disease with the predicted number of cases for models that do and do not include a parameter
that reduces the risk of MenC acquisition in vaccinated individuals. Clearly, the model that does not include this herd protection
greatly overestimates the number of cases of disease (Fig. 6) [16,56].
The high coverage during the catch up campaign has led to a low
incidence of MenC for over a decade.
In The Netherlands routine vaccination has been administered
at 14 months as a single dose with no observed reduction in vaccine
effectiveness over time. In the same year as routine immunization
was introduced, a catch-up campaign was implemented for all children and adolescents between 1 and 18 years of age, who were
given a single dose of NeisVac-C (overall vaccine coverage 94%).
Soon after implementation of The Netherlands’ programme, MenC
disease significantly decreased in vaccinated persons, and a sharp
decline was observed in non-immunized cohorts. These reductions
were most likely a consequence of herd protection [57]. No primary vaccine failures have been reported but clinical data up to
R. Borrow et al. / Vaccine 31 (2013) 4477–4486
2011 show that there have been three secondary vaccine failures
of which two were in immunodeficient patients [58]. Only sporadic cases of MenC disease in non-immunized age-cohorts have
occurred, indicating low transmission due to the herd effect. However, monitoring the persistence of vaccine-induced protection in
various age categories after a single immunization remains relevant since widespread introduction of the conjugate vaccine has
led to reduced circulation, leading to a lack in natural boosting,
eventually resulting in possible waning immunity in vaccinated and
non-vaccinated age-cohorts. After introduction of vaccination, the
prevalence of SBA titres ≥8 in infants between 15 and 23 months of
age was 92.6%. However, this peak was followed by a decline in SBA
levels although they remained well above the SBA levels observed
in the pre-introduction era (P < 0.0001). Individuals who had been
vaccinated during the catch-up campaign in 2002 were 5–22 years
of age during the post-MCC introduction study in 2006/2007. The
prevalence of functional SBA titres was higher in the age-cohort
6–9 years compared with the pre-introduction era (P < 0.05). SBA
titres increased gradually with age for children vaccinated between
5 and 18 years of age and were significantly higher than in the
pre-MCC introduction era (P < 0.0001). SBA titre ≥8 prevalence had
increased from 45.2% to 95.5% in the age-cohorts 9–10 and 19–21
years, respectively. The prevalence of SBA titres ≥8 in the post-MCC
introduction era in cohorts over 25 years of age was comparable to
the pre-MCC introduction era: 21% and 23%, respectively. In all age
categories combined, the overall seroprevalence of SBA titres ≥8
was higher after wide-spread introduction of MCC vaccination than
before, 43.0% vs. 19.7%, respectively [28]. The vaccination campaign
has been highly successful; by 2006 there were only four reported
cases of MenC disease. However, administration of a booster dose
early in adolescence is being investigated to provide protection
during this period of increased risk of meningococcal disease and
to maintain antibody levels in sufficient numbers of individuals to
sustain herd protection [59].
Spain implemented a nationwide MCC vaccination campaign
(including 16 out of the 19 autonomous Spanish regions) in autumn
1997 using a plain polysaccharide vaccine in a target population
aged 18 months to 19 years [59,60] with an overall estimated vaccine coverage of 76.3%. This reduced the overall incidence of MenC
by 45%. A reduction was seen in all age groups; the number of
MenC cases in the target group fell by 76% in comparison with
the year before vaccination was used for that specific intervention.
However, the incidence of MenC disease continued to increase in
the years following vaccination, a foreseeable circumstance given
the limitations in the immunogenicity of polysaccharide vaccine
[61,62]. Conjugate vaccines became available in Spain in 2000, and
were included in the infant vaccination schedule involving a 3 dose
primary series at 2, 4 and 6 months of age. A catch-up campaign was
then implemented among children and young adults in Spain but
the coverage and duration varied by region. Four regions did not
implement additional catch-up campaigns, 10 autonomous communities implemented the catch-up campaign for those under 19
years old and three regions included children under 15–16 years
of age as the target population. Additional catch-up campaigns
were implemented in different years and using different strategies; some were completed in 1 year, others were undertaken over
2–3 or 4 years. [60]. The risk of suffering from MenC disease during 2002/2003 was 25% less than the previous year and 58% less
compared with the year before vaccination. The risk of MenC disease was lower compared with that observed during each of the
previous years except for 2000/2001 [60].
A decrease in the number of MenC cases in children under ten
years was observed during the last three seasons in this study.
These children were either born after the conjugate vaccine was
included in the routine vaccination schedule or were part of the
target group for the catch-up campaign. In the epidemiologic year
4483
2002/2003, 38 cases due to MenC (1.0/100,000) were reported in
children under 10 years, compared with 254 cases (6.6/100,000)
during the season before MCC vaccine was introduced, which represents an 85% reduction in the incidence at this age. There was
increased incidence in the 10–14 year age group, although not statistically significant. At the time of the study, only about 35% of the
population in this group had been vaccinated [60]. Spain had therefore not experienced the same level of herd protection as the UK
and The Netherlands; the result being that the campaign did not
immunize all adolescents, in whom carriage prevalence is highest
[9]. In fact, the number of MenC cases is still higher than in most
other countries with national programmes [6]. There is therefore a
need to revise current vaccination guidelines in Spain.
In Canada, in a MCC vaccination campaign designed to control
an emerging epidemic, vaccinations were given to 82.1% of those
aged 2 months to 20 years. After the campaign, the number of
cases of MenC disease decreased from 58 in 2001 to 27 in 2002,
and the incidence fell from 7.8 per million to 3.6 per million. Vaccine effectiveness was found to be 96.8% (95% confidence interval,
75.0–99.9%)[63]. An adolescent booster has now been introduced
[64]. In Australia the MCC vaccination campaign offered a single
dose at 12 months of age and catch-up vaccination for those aged
under 20 years. This initiative achieved a 75% reduction in MenC
cases between 2002 and 2005 and a booster dose in adolescents
has now been implemented.
Mathematical models have enhanced our understanding of herd
protection [65]. However, it is not clear how long herd protection
will persist and whether changes in the current immunization programmes will be necessary to maintain these effects in the longer
term. Long-term strategies to include a booster dose in adolescents to maintain antibody levels therefore need to be considered
[10,16,56].
4.4. Guidelines and recommended immunization practices
Many countries are now considering the need for a MCC booster
in adolescents to counter the decline in titre after initial and subsequent vaccine doses. It has been reported that if herd protection
starts to decline many children will be vulnerable. Falling levels of immunity against MenC have been reported in Greece, The
Netherlands, UK and Spain. Several countries, including Austria,
Canada and Switzerland, have already introduced booster vaccinations for teenagers [66].
In the US, the latest recommendations from the Advisory Committee on Immunization Practices [67] state that adolescents
should be vaccinated at 11 or 12 years, with a booster dose at
16 years of age. They also recommend a 2-dose primary series
administered 2 months apart for persons aged 2–54 years having persistent complement component deficiency and functional
or anatomic asplenia, and for all adolescents with human immunodeficiency virus (HIV) infection [67].
Brazil has recently introduced routine vaccination with MCC
vaccine, the first time it has been used in a country in which most of
the MenC isolates do not belong to the ST11 clonal complex. It will
be important to follow the evolution in this country to determine
whether current knowledge of the ST11 and MCC vaccine can be
extrapolated to other strains. This is of importance due to the high
rates of capsule expression of the ST11 clonal complex [55].
In England, a recent Joint Committee on Vaccination and Immunization advised that for MenC vaccination, an adolescent booster
should be given and the course decreased to a single dose in infancy.
It is expected that Spain and The Netherlands may adapt their
routine meningococcal vaccine recommendations; however, each
region has its own advisory committee and all proposed changes
are likely to depend on epidemiology as well as other reasons.
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R. Borrow et al. / Vaccine 31 (2013) 4477–4486
5. Concluding remarks
Acknowledgments
A considerable body of evidence exists for the clinical effectiveness of MCC vaccines and the success of routine vaccination
programmes. All of the available MCC vaccines, however, show
significantly greater long-term effectiveness when administered
to toddlers than to infants. Of the currently licensed MCC vaccines, NeisVac-C shows the greatest longevity of immune response.
However, the protective antibody titre of all MCC vaccines has
been found to drop within 18 months of vaccination, raising the
question as to whether a booster dose is needed in teenagers
to maintain protection into adolescence. To address this, several factors need to be considered such as herd protection
(including the likely persistence of herd protection), age of vaccination, epidemiology, monovalent or quadrivalent booster, and
cost (since most governments now have cost-effectiveness criteria).
A question mark remains over how to maintain low levels of
MenC disease in Europe. Many European countries are now using
MCC vaccines but using different schedules and targeting different
age groups. Because of this, there are many ‘islands’ of susceptible
populations within Europe, where MenC circulation may be able to
(re-)establish. Because the incidence rate in general is low, there are
few possibilities that one MenC strain will arrive at the susceptible
islands but, when one strain does arrive, there are no immunologic
barriers against colonization and transmission, which is likely to
produce invasive cases [68]. If elevated protective antibody levels
can be maintained in teenagers, Europe will probably uphold low
levels of MenC disease.
Conjugate vaccines have proven effective, but even quadrivalent
preparations can only cover the minority of disease-causing strains.
Whether or not protection of adolescents should be extended
to serogroups A, W and Y in addition to C depends on the epidemiology of the country in question. For example in the UK
there are high levels of meningococcal serogroup Y carriage in
adolescents [69] but relatively low levels of disease, therefore
introducing a meningococcal serogroup-Y-containing vaccine may,
theoretically, be detrimental and should only be considered when
there is further evidence explaining how this may affect carriage and disease. Decisions to introduce conjugate vaccinations
should be informed by disease surveillance data. There is, however, a continuing need for a comprehensive childhood MCC
vaccination programme even when the incidence of disease is
low.
Future developments in meningococcal vaccination will include
the use of a recently licensed vaccine against serogroup B disease [70], development of new vaccines (including those with
the potential to protect against serogroups B and X), worldwide
vaccination programmes to improve global coverage and revised
vaccination programmes to improve adolescent and adult protection.
This paper was supported by an educational grant from Baxter Healthcare. Representatives of Baxter Healthcare had no role
in gathering, analysing, or interpreting the information presented.
Editorial assistance was provided by Touch Medical Communications.
Author disclosures
RB has performed contract research on behalf of Pubic Health
England (formerly Health Protection Agency) that was funded
by Pfizer, Novartis Vaccines, Baxter Bioscience, GlaxoSmithKline,
Sanofi Pasteur, Alexion Pharmaceuticals Inc., Emergent Europe, and
Merck. JAV has acted as a consultant for and received travel support from GlaxoSmithKline, and Sanofi Pasteur, and has undertaken
contract research on behalf of the National Institute of Health Carlos III, Madrid, Spain, for GlaxoSmithKline, Novartis, Pfizer, Merck,
and Sanofi Pasteur. The other authors declare that they have no
conflicts of interest.
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