Review of Meningococcal Vaccines

12/12/2018 Review of meningococcal vaccines with updates on immunization in adults
Hum Vaccin Immunother. 2014 Apr; 10(4): 995–1007. PMCID: PMC4896590

Published online 2014 Feb 5. doi: [10.4161/hv.27739] PMID: 24500529
Review of meningococcal vaccines with updates on immunization in

adults
Yorgo C Zahlanie,1 Moza M Hammadi,1 Soha T Ghanem,2 and Ghassan S Dbaibo1,*
1Center for Infectious Diseases Research; Division of Pediatric Infectious Diseases; Department of Pediatrics
and Adolescent Medicine; American University of Beirut Medical Center; Beirut, Lebanon
2Department of Pediatrics; Makassed General Hospital; Beirut, Lebanon
*Correspondence to: Ghassan S Dbaibo, Email: gdbaibo@aub.edu.lb
Received 2013 Nov 3; Revised 2013 Dec 31; Accepted 2014 Jan 6.
Copyright © 2014 Landes Bioscience
Abstract
Meningococcal disease is a serious and global life-threatening disease. Six serogroups (A, B, C, W-
135, X, and Y) account for the majority of meningococcal disease worldwide. Meningococcal
polysaccharide vaccines were introduced several decades ago and have led to the decline in the burden
of disease. However, polysaccharide vaccines have several limitations, including poor immunogenicity
in infants and toddlers, short-lived protection, lack of immunologic memory, negligible impact on
nasopharyngeal carriage, and presence of hyporesponsiveness after repeated doses. The chemical
conjugation of plain polysaccharide vaccines has the potential to overcome these drawbacks.
Meningococcal conjugate vaccines include the quadrivalent vaccines (MenACWY-DT, MenACWY-
CRM, and MenACWY-TT) as well as the monovalent A and C vaccines. These conjugate vaccines
were shown to elicit strong immune response in adults.
This review addresses the various aspects of meningococcal disease, the limitations posed by
polysaccharide vaccines, the different conjugate vaccines with their immunogenicity and reactogenicity
in adults, and the current recommendations in adults.
Keywords: meningococcal conjugate vaccine, adults, meningococcal disease, Neisseria meningitidis,

meningococcal polysaccharide vaccine, recommendations
Introduction
N meningitidis is a gram-negative, aerobic diplococcal bacterium, and member of the family
Neisseriaceae.1,2 There are at least 13 serogroups of N meningitidis based on the immunochemistry of
the polysaccharide capsule.3 Globally, 6 serogroups (A, B, C, W-135, X, and Y) account for over 90%
of cases of meningococcal disease.4N meningitidis is a commensal organism in the human nasopharynx
and is pathogenic only in humans.1 It most commonly causes asymptomatic nasopharyngeal carriage
and rarely leads to invasive disease.5 It is transmitted by direct contact with saliva or inhalation of
large-droplet inocula.6,7
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896590/ 1/28
History
Epidemic meningitis was first described in Geneva during 1805 then in Massachusetts over the
following year.8 In 1887, the organism was first isolated by Weichselbaum and was named
Diplococcus intracellularis meningitidis.9 In 1913, serum therapy (intrathecal injection of equine anti-
serum) was shown to reduce mortality associated with meningococcal meningitis but was then replaced
by sulfonamide therapy in 1937.8-10 However, the subsequent appearance of sulfa-resistant
meningococci in 1963 led to the preference of β-lactams and the development of polysaccharide
vaccines against N meningitidis.3,5
Epidemiology
N meningitidis has become the leading cause of bacterial meningitis in children beyond the neonatal
period and in young adults due to reduction in the incidence of S pneumoniae and Hib infections
achieved by the introduction of conjugate vaccines against these pathogens.11,12 Among the different
pathogens causing bacterial meningitis, it is the sole bacterium capable of generating large outbreaks of
meningitis.13 Approximately 500 000 cases of invasive meningococcal disease occur annually
worldwide, resulting in more than 50 000 deaths.14 The rate of meningococcal disease peaks in infancy
and then shows a smaller peak in late adolescence.12,15 Epidemics are usually characterized by the
predominance of a single meningococcal serogroup, higher incidence rates, and a shift toward older
age groups.16 Epidemics occur more frequently during winter and spring in temperate areas and during
the dry season in tropical areas.17 Around 97–98% of cases of meningococcal disease are sporadic and
do not occur in the context of outbreaks.18,19 Despite advances in prompt diagnosis and antimicrobial
therapy, the case-fatality rate is 10–15%.3 Permanent sequelae occur in up to 20% of survivors (e.g.,
neurodevelopmental disabilities, hearing loss, visual impairment, seizure disorder, skin scarring, and
amputation).5,20 Disease incidence and serogroup distribution vary significantly among different
geographic locations.21
North America
The rate of meningococcal meningitis in the United States has dropped from 16–59 per 100 000 in
1930 to around 0.3 per 100 000 between 2005 and 2011.9,18 Even before the implementation of the
meningococcal conjugate vaccine in 2005, the annual incidence of meningococcal disease started to
decline.18 In the mid-1990s, serogroup Y had emerged to become major disease-causing isolate in the
United States.2 Serogroups B, C, and Y dominate in the United States, each accounting for
approximately one-third of cases, with B predominant among young infants less than 1 y and C, W, and
Y predominant among persons older than 11 y.22
Europe
The incidence of meningococcal disease throughout Europe varies from 0.3 per 100 000 in Italy to 0.6
per 100 000 in France and 3.6 per 100 000 in England and Wales.14 Serogroup B is the most common
disease-causing isolate in industrialized countries, particularly in Europe.8 The incidence of
meningococcal C disease showed a dramatic decline in all European countries that have implemented
routine MCC vaccination.23 Overall, the incidence of meningococcal disease in Europe has declined
from 1.9 per 100 000 in 1999 to 0.92 per 100 000 in 2009.24
Africa
In 1963, Lapeysonnie described the “meningitis belt” of sub-Saharan Africa in which occurs the
greatest burden of meningococcal disease worldwide.10 This region compromises 22 countries,
stretching from Ethiopia in the east to Senegal in the west.25 The incidence rate in the “meningitis bet”
can exceed 1% of the population during epidemics.26 The largest epidemic occurred in 1996–1997 with
>25 000 resulting deaths.26 Large epidemics occur mainly during the dry season (from December to
June).27
Meningococcal A disease is a public health concern in the “meningitis belt” and other developing
countries.28 Following the introduction of meningococcal A conjugate vaccine in the “meningitis belt,”
there was an epidemiologic shift in the predominant circulating serogroup from A to W-135, although
the total number of meningococcal cases has dramatically decreased.25 Over the past years, serogroup
X has also led to several local outbreaks in other parts of Africa.26,29
Asia
Serogroup A has historically been responsible for epidemics, most recently in India and the Philippines
in 2005 and possibly in Bangladesh between 2002 and 2004.30 Moreover, other serogroups have
caused local outbreaks, including serogroup C in China since 2002, serogroup W-135 in Singapore in
2000–2001, and serogroup Y in Taiwan between 2001 and 200330. Since 1984, there was a shift in
serogroup predominance from A to C in China, probably due to the introduction of meningococcal A
polysaccharide vaccine.24
Annually, over 2 million Muslim pilgrims visit the cities of Mecca and Medina in Saudi Arabia during
a short period of time, around one week, called the Hajj. An outbreak related to serogroup A occurred
during the 1987 Hajj season.31 Serogroup A vaccine was then required in 1988 for all pilgrims for
entry into Saudi Arabia.32 Serogroup W-135 was the predominant pathogen in subsequent outbreaks
during 2000 and 2001.32-34 Pilgrims had acquired W-135 nasopharyngeal carriage or disease and
imported the serogroup to their household contacts in their home countries.35 Fortunately, no further
outbreaks have occurred due to the shift in vaccination to the quadrivalent (A, C, W-135, and Y)
polysaccharide vaccine as a Hajj visa requirement in 2002.31,36,37
Australia and New Zealand

Serogroups B and C predominate in Australia with a prolonged serogroup B epidemic in New Zealand
during the 1990s.3 In the mid-1990s, there were a rise in cases of meningococcal C disease in
Australia.26 As a result of the introduction of MCC in Australia in 2003, the incidence of
meningococcal C disease dropped from 1.15 per 100 000 in 2002 to 0.07 per 100 000 in 2009.24
Disease incidence has also declined in New Zealand from 13 per 100 000 during 1996–2003 to 2.6 per
100 000 in 2007 due to the introduction of meningococcal B vaccine in 2004.26
Risk Factors
The risk of invasive meningococcal disease is dependent on organism, host, and environmental factors.
Organism
The polysaccharide capsule helps the bacterium evade opsonization, phagocytosis, and complement-
mediated bacteriolysis.38 Non-capsulate mutants of N meningitidis are serum sensitive and non-
virulent.7,8,39 Encapsulated strains are pathogenic and cause increased incidence of morbidity and
mortality in a population.18
Host factors
Factors that impair integrity of nasopharyngeal mucosa and lead to invasive disease include recent
Mycoplasma pneumoniae or viral upper respiratory tract infection and both active and passive
smoking.40 Disease rates are higher among black and poor persons in the United States, although race
and socioeconomic status are likely to be markers for other risk factors (e.g., smoking, household
crowding, and urban residence).2,18 Patients who have complement component deficiency (e.g., C3
and C5-C9) are also prone for recurrent invasive meningococcal disease, often with unusual capsular
strains.41 Although patients with anatomical or functional asplenia appear to be at increased risk for
meningococcal disease, the data are less compelling than that of their increased risk for pneumococcal
disease.18 HIV does not appear to be an independent risk factor for meningococcal infection even if the
rate of meningococcal disease is elevated in HIV patients.18,42,43
Environmental factors
Crowded living conditions (such as in college dormitories, military camps, or Hajj pilgrimage) and
close and prolonged contact (such as kissing, sneezing, or coughing) increase person-to-person
transmission, and thus the risk of invasive disease.27,28 The current risk of meningococcal disease
among US military members is comparable to background levels due to the adoption of meningococcal
vaccination in the military.44 Travelers to regions where meningococcal disease is epidemic or
hyperendemic, such as sub-Saharan Africa or Saudi Arabia, are also at increased risk.37,45 Other
groups at risk are microbiology laboratory workers routinely exposed to live cultures of N
meningitidis.46 Health care workers are not in general considered as high-risk individuals unless they
are exposed to the respiratory secretions of patients with meningococcal disease.18,47
Pathogenesis
N meningitidis may cause asymptomatic colonization in the nasopharynx or result in invasive disease.
Colonization The rate of nasopharyngeal carriage increases throughout childhood to reach a peak in 19-
y-old individuals (23.7%) then declines into older adulthood.48 More than 50% of the strains isolated
from asymptomatic carriers lack capsules and are not serogroupable.21 Colonization is a natural
immunizing event by which carriers develop SBA against pathogenic and non-pathogenic strains of N
meningitidis.49 Following meningococcal A polysaccharide vaccination, persistence of group A SBA
titers was more evident in Sudanese vaccinees compared with North American vaccinees due to the
higher rate of serogroup A carriage in Sudan.50
Invasion In most cases, invasion occurs 1–14 d after colonization with a novel meningococcal strain.8
Bacterial adhesion to the mucosal cells of the nasopharynx is facilitated by adhesins, which include pili
and opacity-associated proteins.2,3 This is followed by endothelial phagocytosis and then invasion into
the bloodstream.42 SBA or cross-reactive antibodies directed at the polysaccharide capsule may
preclude further disease progression.12 Adolescents and young adults who failed to form antibodies
against N meningitidis during their childhood are especially at risk in the second peak of
meningococcal disease.12 Goldschneider et al. showed that most military recruits who acquired
meningococcal disease were deficient in antibodies against the pathogenic strains of N meningitidis.51
In the absence of host immunity, the infection can result in any of these clinical syndromes: meningitis,
meningococcemia (petechiae, purpura, adrenal hemorrhage), pneumonia, and other infections
(pharyngitis, conjunctivitis, endophthalmitis, pericarditis, myocarditis, arthritis, urethritis, and
epididymitis).5,12,52,53
Diagnosis
Although isolation of N meningitidis from a normally sterile fluid (e.g., blood or CSF) is the gold
standard for diagnosis of meningococcal disease, the sensitivity of culture might be decreased,
especially in antibiotic-pretreated patients.1,2,19 Polymerase chain reaction has the ability to detect
serogroup-specific meningococcal DNA and does not require viable organisms.2,8 Since
meningococcal disease can be severe, it is critical to start treatment as soon as infection is suspected
without delays in laboratory confirmation.22
Treatment
Penicillin and ampicillin are the first-line treatment for N meningitidis.11,52,54 Alternatively, extended-
spectrum cephalosorins (ceftriaxone or cefotaxime) can be used in case of resistance or uncertain
diagnosis.52,54,55 Although few studies have described reduced susceptibility to penicillin, the clinical
significance remains unclear.11 In addition, patients with poor prognostic signs might need
hemodynamic resuscitation, mechanical ventilation, and renal replacement therapy, as indicated, in a
fully equipped critical care facility.6,52
Antimicrobial Prophylaxis
In order to prevent secondary cases, chemoprophylaxis should be given to close contacts ideally <24 h
and not >14 d after identification of an index case.56 In a Cochrane review, ceftriaxone, rifampin and
ciprofloxacin were the most effective antibiotics for eradication of N meningitidis from the
nasopharynx.57 Rifampin is usually the drug of choice, but in view of circulation of resistant strains,
ciprofloxacin, and ceftriaxone are recommended.57 Unlike ciprofloxacin, ceftriaxone is safe in children
and pregnant women.57,58 Since fluoroquinolone resistance was reported in the United States in 2008,
the CDC recommends the use of ceftriaxone, rifampin, and azithromycin to eradicate carriage in areas
where resistance has been identified.47
Meningococcal Vaccines
There are three types of meningococcal vaccines available:
1) MPV which are available in bivalent (A and C), trivalent (A, C and W-135), and tetravalent (A, C,
W-135 and Y) formulations
2) MCV which are available as movovalent (A or C) and tetravalent (A, C, W-135, and Y)
3) Vaccines against serogroup B using OMV preparations27
Polysaccharide Vaccines (Table 1)
Table 1. Meningococcal quadrivalent vaccines18,101,145
Trade Licensed Age

Formulation Type Manufacturer Dose (s) Serogroups
name year group
MPV-4 Polysaccharide Menomune Sanofi Pasteur 1981 ≥2 y 1
MPV-4 Polysaccharide Mencevax GlaxoSmithKline ≥2 y 1
11–55
2005 1
y
MenACWY-
Conjugate Menactra Sanofi Pasteur 2007 2–10 y 1
DT
9–23
2010 2
mo
11–55 A, C, W,
2010 1
y and Y
2011 2–10 y 1
MenACWY-
Conjugate Menveo Novartis 4 (if 2–6
CRM
2–23 mo)
2013
mo 2 (if 7–
23 mo)
MenACWY- ≥12
Conjugate Nimenrix GlaxoSmithKline 2012 1
TT mo
Background
In the 1970s, the first MPV were developed against serogroups A and C (MACP) in response to
meningitis epidemics among military recruits in the United States.13,59 In 2003, the emergence of
serogroup W-135 in the “meningitis belt” prompted the development of trivalent then tetravalent
polysaccharide vaccines.13 Until mid-2000, the only available quadrivalent meningococcal vaccines
were non-conjugated polysaccharide vaccines manufactured by Sanofi Pasteur (Menomune) and
GlaxoSmithKline Biologicals (Mencevax).47,60
Immunogenicity and effectiveness

During late 1960s, the introduction of meningococcal C polysaccharide vaccine into US army recruits
reduced the rate of meningococcal C disease by 89.5%.61 In a study conducted in Texas, MPV-4 had an
efficacy of 85% in reducing the rate of meningococcal C disease in a population aged 2–29 y.62 In a
Cochrane review, the efficacy of meningococcal A polysaccharide vaccine was 95% in adults and
children above 5 y.63 In general, MPV has over 85% efficacy against serogroups A and C in school-age
children and adults.64,65 Vaccination with W-135 and Y polysaccharides induces the production of
SBA, although clinical protection has not been documented.66,67 Shao et al. showed that MPV-4 is
immunogenic against all four serogroups in at least 93% of young adults in Taiwan.64 Although no
difference in SBA titers was detected in adults receiving either MACP or corresponding conjugate
vaccine, antibodies in the polysaccharide group had lower bacteriolysis ability and were less effective
in conferring passive immunity than those in the conjugate group.68 The antibody response to each of
the four polysaccharides is serogroup-specific and independent.66
Limitations
Although serogroup A polysaccharide provides some immunity as early as 3 mo of age, serogroup C
polysaccharide is poorly immunogenic in children <18–24 mo.69 Other shortcomings of MPV include
short-lived protection, lack of immunologic memory, negligible impact on nasopharyngeal carriage,
and presence of hyporesponsiveness after repeated doses.59
Duration of protection Polysaccharides are T-cell-independent antigens that stimulate B lymphocytes.65

This humoral response is short-lived and does not possess an anamnestic response, explaining the
relatively short duration of protection and lack of immunologic memory of MPV.61,65 Thus, repeat
vaccination is required every 3–5 y, but this might induce hyporesponsiveness.70 In infants and young
children, antibody concentrations against serogroup A and C polysaccharides decrease during the first
2–3 y after polysaccharide vaccine has been administered.71,72 Although antibodies can still be
detected up to 10 y in healthy adults, their ability to neutralize the invading organism may decrease
with time.39 In a study conducted on 20 laboratory staff workers who are regularly exposed to N
meningitidis and who previously received MPV-4, the average duration of SBA titers to the 4
serogroups exceeded 10 y.46 However, about 23% of adults may not retain immunity against serogroup
W-135 for 5 y, the time suggested for a repeat dose.46
Hyporesponsiveness Hyporesponsiveness refers to the reduction of the antibody response with

repeated doses of MPV as compared with the initial dose.59,73,74 Lashkman et al. showed that
administration of MACP booster dose induced hyporesponsiveness to serogroup C following
polysaccharide primary dose.75 In 2 other studies, re-immunization with MACP induced
hyporesponsiveness to serogroup C, but MCC overcame this hyporesponsiveness.76,77 A study
conducted in Saudi Arabia showed hyporesponsiveness to serogroup C but a boosted response for
serogroup A with repeated exposures to MACP.62 Similarly, MPV-4 induced hyporesponsiveness to
serogroup C in healthy adults previously immunized with MPV-4 as compared with subjects who were
either vaccine-naive or primed with MenACWY-CRM.78 The antibody response of serogroup C to
MCC is also decreased after use of polysaccharide vaccine.79,80
Hyporesponsiveness is clearly documented for polysaccharide C, but only limited data exists for other
serogroups. Borrow et al. showed hyporesponsiveness to polysaccharide A following revaccination
with MACP.81 However, revaccination with MACP was still protective as the post-revaccination SBA
titer for group A was higher than that in naïve subjects.81 Initial MPV-4 immunization also induced
hyporesponsiveness to all four serogroups following a subsequent dose of MenACWY-TT in subjects
aged 4.5–34 y, although the response remained protective.82
Both natural immunity from exposure to N meningitis or cross-reacting bacteria as well as vaccination
with MCV induce a T-cell response and thus the development of memory B cells.47,74 Upon exposure
to a polysaccharide antigen, these primed B cells are terminally differentiated into antibody-producing
plasma cells without regenerating this lymphocyte population.47,74 Unless the B-cell pool is re-
expanded by exposure to a T-dependent antigen, revaccination with MPV leads to a further decrease in
antibody response.83 A previous dose of meningococcal polysaccharide vaccine may, therefore,
predispose to meningococcal disease with subsequent doses of plain or conjugate vaccine. However,
this theoretical increase in disease susceptibility lacks clinical trial data.84
Carriage Since acquisition of nasopharyngeal carriage is not substantially reduced with MPV, person-
to-person transmission of N meningitidis via respiratory route is not interrupted, and thus, herd
immunity cannot be provided in the unvaccinated population.34,85,86 Hassan-King at al. found that a
national vaccination campaign with MACP following an outbreak during 1982–1983 in the African
Gambia had little influence on the rate of nasopharyngeal carriage of serogroup A.86 Following the
Hajj-related outbreak of meningococcal disease in the United States during 1987, the rate of serogroup
A carriage also did not appear to be different between vaccinated and unvaccinated pilgrims returning
to their home country.85 Similarly, MPV-4 did not influence the acquisition of serogroup W-135 in
Turkish Hajj pilgrims as well in their household contacts.87 On the contrary, meningococcal
polysaccharide vaccine was effective in preventing colonization in Kuwait pilgrims.88 However, these
pilgrims were required to take one dose of ciprofloxacin, which eradicates nasopharyngeal carriage.88
A systemic review in 2007 showed that MPV had a positive impact on the rate of nasopharyngeal
carriage in high-risk individuals, such as military recruits, at least for a limited period of time.84 On the
other hand, most studies in the low-risk population showed that MPV had negligible impact on
colonization.84 The reduction of nasopharyngeal carriage seems to be greatest for enclosed populations
such as military recruits and lowest for open populations such as sub-Saharan Africa.47
Safety
Most of the adverse events related to MPV are usually mild.89 The most commonly reported events are
tenderness and erythema at the injection site lasting for 1–2 d.47,89,90 Transient low-grade fever occurs
in <5% of vaccinees.47 Severe adverse events include allergic reactions, seizures, and paresthesias but
occur in a small percentage of recipients (<0.1 per 100 000 doses).91
Glycoconjugate Vaccines
Background
In the 1970s, multiple studies demonstrated that polysaccharide antigen is poorly immunogenic in
children <2 y of age.12 Due to the high incidence of disease caused by N meningitidis, S pneumonia,
and Hib in these children, a different type of vaccine was needed.12 Hib and S pneumoniae conjugate
vaccines were first introduced in 1990 and 2000, respectively, for mass immunization of infants in the
United States and had dramatically reduced the incidence of disease caused by these pathogens.12
Chemical conjugation of Hib and S pneumoniae antigens to carrier proteins converted T-cell
independent polysaccharides into T-cell dependent antigens, allowing development of memory B cells
and consequent anamnestic responses.61
Diphteria toxoid, non-toxic mutant of diphtheria toxin (CRM197), and tetanus toxoid have been used as
protein moieties for meningococcal vaccines.61
Advantages
Unlike MPV, MCV are immunogenic in infancy (the age group with the highest incidence of
meningococcal disease), induce higher levels of SBA, provide long-lasting protection, reduce the rate
of nasopharyngeal colonization, provide herd immunity, and do not induce hyporesponsiveness after
repeated dosages.4,12,63 In other words, MCV have the potential to overcome the limitations of MPV.
Meningococcal C Conjugate Vaccine (Table 2)
Table 2. Meningococcal monovalent C vaccines16,19,95
A
Formulation Type Trade name Manufacturer Serogroup
MCC-TT Conjugate Neisvac-C Baxter Healthcare
MCC-CRM Conjugate Menjugate Kit Novartis C
MCC-CRM Conjugate Meningitec Pfizer
B
Licensed year Age group Dose (s)
1999 2–4 mo 3
1999–2000 5–11 mo 2
1999–2000 1–18 y 1
2002 20–24 y 1
2006 12 mo 1 (with Hib)
Background
Based on the successful experience with Hib and S pneumoniae conjugate vaccines, MCC was
developed and evaluated in several clinical trials in response to the increased incidence of
meningococcal C disease in the 1990s.61,92 MCC was first introduced into the routine immunization
program in the United Kingdom in November 1999 as a three-dose series administered concomitantly
with routine primary immunizations given at 2, 3, and 4 mo of age.16 Observed waning of antibody
titers within one year of vaccination has led the UK National Health Service in 2006 to recommend a
booster dose of MCC in the second year of life.65
Between November 1999 and December 2000, a catch-up campaign was targeted for all children >4
mo and <18 y of age.16 Children 5–11 mo of age received two doses of MCC, and those from 1–18 y
received one dose.16 In 2002, the catch-up campaign was extended to include all adults <25 y of age.93
As a result of this vaccination program, meningococcal C disease has fallen by >95% in the United
Kingdom.93 This is due to both individual direct protection and indirect protection by herd immunity.93
This successful vaccine campaign experience in the United Kingdom encouraged other countries,
including the Netherlands, Ireland, Spain, Australia, and Canada, to introduce MCC into their routine
immunization schedules.61 Surveillance in all age groups has suggested an effectiveness of 95% at 1 y,
with significant waning over a period of 4 y.70 MCC is available as MCC-TT (Neisvac-C) and MCC-
CRM (Meningitec or Menjugate Kit).94,95
Safety
The majority of adverse events related to MCC is self-limiting and resolves within the follow-up
period.94,96 Across all age groups, injection site reactions (including redness, swelling, and
tenderness/pain) were very common.94,96 Transient injection site tenderness was reported in 70% of
94 96
94,96
adults in clinical trials. Myalgia, artharlgia, headache, and somnolence were also commonly
reported in adults.94,96
Quadrivalent Conjugate Vaccines (Table 1)
MenACWY-DT
Background In January 2005, MenACWY-DT (Menactra), manufactured by Sanofi Pasteur, was
licensed by the US FDA for persons aged 11–55 y.18 The FDA extended the age of vaccination in 2007
to include 2- to 10-y-old children, and in 2011, infants 9–23 mo of age were also included in the
immunization schedule.31 MenACWY-DT is approved as a two-dose series for children aged 9–23 mo
and as a single dose in people aged 2–55 y.60
Immunogenicity and effectiveness In adults aged 18–55 y, non-inferiority of MenACWY-DT to MPV-4

was assessed by the similar proportion of participants with at least 4-fold rise in SBA titers against each
of the 4 serogroups.97 Studies for assessment of the duration of protection showed persistence of
antibody titers against all vaccine serogroups at 3 y post-vaccination.12,65 Three years following
revaccination with MenACWY-DT, antibody titers were higher among people primed with
MenACWY-DT as compared with those primed with MPV-4.12,65 Five years following the
introduction of MenACWY-DT for use in pre-adolescents in the United States, there was a significant
reduction in the number of cases of serogroup C and Y disease among early adolescents (11–14 y) with
a minimal reduction in older adolescents (15–18 y).98 However, breakthrough cases of meningococcal
disease were observed when MenACWY-DT was administered at 11–12 y of age because the vaccine
did not provide protection for >5 y or throughout the full period of highest risk.98 Almost 50% of the
11- to 18-y-old vaccinees had serum antibody concentrations similar to non-vaccinated people five
years after receiving the vaccine.98 The waning immunity and breakthrough cases underscored the
need for booster vaccination in this age group.98
Concomitant vaccinations MenACWY-DT may decrease the antibody response to PCV13, and it is
recommended (at least in the United States) that MenACWY-DT should be given ≥4 wk after
completion of all PCV13 doses in patients with anatomic or functional asplenia due to their high risk
for invasive pneumococcal disease.99 Concomitant administration of MenACWY-DT with Td in
adolescents aged 11–17 y or typhoid vaccine in adults aged 18–55 y did not affect the immunogenicity
of either vaccine.18
Safety Documented local and systemic adverse reactions were similar or slightly higher for
MenACWY-DT as compared with MPV-4.9,12 For example, reported pain that limited movement in the
site of injection was higher in MenACWY-DT recipients (11–13%) as compared with 3% in MPV-4
recipients.65 Fever of ≥100 °F was also more frequently observed with MenACWY-DT (2–5%) than
MPV-4 (3%).64
MenACWY-DT is contraindicated in case of severe allergic reaction (e.g., anaphylaxis) after a previous
dose of a meningococcal capsular polysaccharide-, diphtheria toxoid- or CRM-containing vaccine, or
to any component of MenACWY-DT.97
In 2006, correlation between GBS and MenACWY-DT was studied after reporting 17 cases of GBS
following MenACWY-DT vaccination.65 The risk of GBS was estimated to be 0.4–1.3 per million
doses, but the beneficial effect of MenACWY-DT in preventing invasive meningococcal disease was
significantly higher than potential risks.56 Persons previously diagnosed with GBS may be at increased
risk of GBS following receipt of MenACWY-DT, and thus should not receive MenACWY-DT unless
they are at high risk of meningococcal disease.100
MenACWY-CRM
Background In February 2010, MenACWY-CRM (Menveo), manufactured by Novartis Vaccines, was
approved by the FDA for use in subjects 11–55 y of age.18 Over the following year, the covered age
group was extended to include 2- to 55-y-old individuals.18 In August 2013, the ACIP extended its
recommendation to 2- to 23 mo-old children who are considered at high risk for meningococcal
disease.101
Immunogenicity and effectiveness Prior to licensure of MenACWY-CRM, a large-scale comparative

trial in adults showed that both MenACWY-DT and MenACWY-CRM induced immune responses to
serogroups A, C, W-135, and Y, with the post-vaccination antibody titers being consistently higher for
MenACWY-CRM.102 In 2010, Stamboulian et al. showed that healthy adults who received
MenACWY-CRM had more robust immune responses to all four serogroups as compared with subjects
who were vaccinated with either MenACWY-DT or MPV-4.103
Concomitant vaccinations Concomitant administration of MenACWY-CRM with other age-appropriate

adult vaccines was studied by Gasparini et al., and it was shown that MenACWY-CRM did not affect
the immune responses to diphtheria and tetanus antigens when Tdap was concomitantly
administered.104 In contrast, MenACWY-CRM appeared to moderately attenuate the immune
responses to two out of three of the pertussis antigens.104
Safety Common solicited adverse reactions among adolescents and adults were pain at the injection site
(41%), headache (30%), myalgia (18%), malaise (16%), and nausea (10%).105 The reactogenicity
profile and rates of adverse events among subjects aged 56–65 y who received MenACWY-CRM were
similar to those observed in younger vaccinees aged 11–55 y.106
It is contraindicated to administer MenACWY-CRM in case of severe allergic reaction (e.g.,

anaphylaxis) to a previous dose of meningococcal vaccine, to any vaccine that contains DT or CRM, or
to any component of MenACWY-CRM.106
MenACWY-TT
Background MenACWY-TT (Nimenrix), manufactured by GlaxoSmithKline Biologicals, is the first
meningococcal quadrivalent conjugate vaccine to be approved in Europe in 2012 as a single dose for
immunization of individuals from 12 mo of age.107 This vaccine is unavailable in the United States.
Tetanus toxoid was selected as a carrier protein based on the broad experience with Hib and MCC
tetanus toxoid conjugate vaccines.21
Immunogenicity and effectiveness Phase II and III studies showed that a single dose of MenACWY-TT
was highly immunogenic in toddlers, children, adolescents, and adults one month following
vaccination.108 MenACWY-TT showed non-inferiority to MPV-4 in terms of immunogenicity to the 4
serogroups in adults aged 18–55 y, with significantly higher antibody titers against serogroups A, W-
135, and Y one month post-vaccination.30,109 In subjects 10–25 y of age, SBA titers were also higher
for these 3 serogroups in recipients of MenACWY-TT compared with MenACWY-DT.110 In late
adolescents aged 15–19 y receiving either MenACWY-TT or MPV-4, SBA was consistently higher in
the MenACWY-TT group.110 In the Philippines and Saudi Arabia, MenACWY-TT also proved to be
non-inferior to the licensed MPV-4 in terms of both immunogenicity and safety endpoints in a
randomized controlled trial conducted in subjects aged 11–55 y.111 The persistence of antibodies was
evaluated in a study conducted by Ostergaard et al. where higher immunogenicity against serogroup W-
135 at 42 mo (3.5 y) following vaccination was demonstrated in 15- to 19-y-old individuals who
received MenACWY-TT as compared with MPV-4.111 In fact, the immune response induced by
MenACWY-TT against serogroups A, C, W-135, and Y persists up to three years after vaccination.112
Limited data are available about assessment of MCV use in adults aged >55 y. Dbaibo et al.
demonstrated that a single dose of MenACWY-TT given to healthy adults ≥56 y induced a vaccine
response rate ≥76% with ≥93% of vaccinees achieving rabbit SBA (rSBA) titers ≥1:128 against all four
serogroups.113 This is the first study that evaluated MenACWY-TT in an elderly population and is one
of the few studies that provided information on immunogenicity of meningococcal conjugate vaccine in
this age group.113
Concomitant vaccinations Co-administration of MenACWY-TT with seasonal influenza vaccine

(Fluarix) in adults showed non-inferiority of antibody titers for all serogroups, except for serogroup
C.114 Overall, >97% of subjects had rSBA titers ≥1:128 one month following vaccination without
affecting the response to influenza antigens.114 These data support the co-administration of these two
vaccines in adult travelers.114 Infanrix hexa (DTaP-HBV-IPV/Hib vaccine), Priorix tetra (MMR-
Varicella combined vaccine), and Synflorix (PCV10) in toddlers aged 12–23 mo as well as Twinrix
(combined hepatitis A and B vaccine) in adolescents aged 11–17 y did not affect the immunogenicity
of the co-administered MenACWY TT.110 Unlike Prevnar (PCV13), Infanrix hexa, Priorix tetra,
ProQuad (a similar product as Priorix tetra but manufactured by Merck), and Synflorix are unavailable
in the United States.
Safety MenACWY-TT showed well-tolerated local and systemic solicited adverse events in toddlers,
children, adolescents, and adults in all phase III trials.60,108 In adults, the most frequently reported
local adverse events were pain (25.3%), redness (10.3%) and swelling (8.5%), and general adverse
events were headache (15.8%) followed by fatigue (13%), gastrointestinal symptoms (4.7%), and fever
(4%).110 Studies in 10- to 25-y-old subjects receiving either MenACWY-TT or MenACWY-DT
showed that pain and headache were the most commonly reported solicited local and general adverse
events, respectively, occurring at a similar rate in both groups.115 Both local and general solicited
symptoms were reported in no more than 3% of vaccinees aged 56 y and older, with no serious adverse
events related to vaccine.113 MenACWY-TT showed greater local reactogenicity but similar rates of
systemic symptoms when compared with a licensed polysaccharide vaccine in adults aged 18–55 y.109
Finally, the acceptable safety profile of MenACWY-TT in healthy adults was not affected by co-
administration with seasonal influenza vaccine.114
Meningitis Vaccine Project (Table 3)
Table 3. Meningococcal monovalent A vaccine25,118
Formulation Type Trade Manufacturer Licensed Age Dose Serogroup

name year group
MenA-TT Conjugate MenAfriVac Serum Institute of 2010 1–29 y 1 A
India
The WHO previously recommended the use of polysaccharide vaccines in the “meningitis belt” to
control epidemics caused by different serogroups.116 For many years, serogroup A was the
predominant serogroup causing meningococcal epidemics in this part of the world. Due to the lack of
progress in the introduction of the more effective meningococcal A conjugate vaccine, the Meningitis
Vaccine Project, a partnership between the WHO and the Program for Appropriate Technology in
Health, was established in 2001, with its goal to eliminate epidemics of group A meningitis in sub-
11 118
Saharan Africa through the development and licensure of meningococcal A conjugate vaccine.117,118
MenA-TT (MenAfriVac) was licensed in 2010 as single dose in individuals 1–29 y of age.25,118 Large-
scale immunization campaigns started in December 2010.119 Burkina Faso was the first country to
introduce MenAfriVac, with national coverage reaching 95.9%.120 Its impact during the next epidemic
season has been excellent since no case of meningococcal A disease occurred in any vaccine
recipient.119 Overall, a low incidence of meningococcal A disease was observed in Burkina Faso
during 2011.121 Whether MenAfriVac will completely eliminate meningococcal A disease is yet to be
determined in the following years.
Recommendations in Adults (Tables 4, 5, and 6)
Table 4. Recommendations in adults in United States18
Age
Vaccine Dose (s) Risk (s) Booster
group
-Microbiologists routinely exposed to N meningitidis
-Military recruits
2–55
MenACWY- 1 dose -Travel to hyperendemic or epidemic area
y
DT -First-year college students living in residence halls (up
or to 21 y if not vaccinated >16 y) Every 5 y if
MenACWY- 2 doses (2 2–55 -Terminal complement deficiency continued risk
CRM mo apart) y -Asplenia/hyposplenia
2 doses (2
>18 y HIV (if 2-dose series not given between 11–18 y)
mo apart)
MPV-4 1 dose ≥56 y Same as above
Table 5. Recommendations in adults in United Kingdom43,95
Vaccine Dose (s) Age group Risk (s) Booster

1 dose 10–25 y If unvaccinated
1 dose of
MCC/Hib
and
-Terminal complement deficiency -
1 dose of ≥1 y
Asplenia/hyposplenia
MCV-4
MCC
(1 mo
apart)
No booster
<25 y or any age if at risk for -HIV if unknown or previous
1 dose needed
meningococcal disease immunization
<25 y or any age if at risk for -HIV if unknown or previous
2 doses
meningococcal disease immunization with asplenia
MenACWY-
CRM
Travel to hyperendemic or
or 1 dose ≥11 y
epidemic area
MenACWY-
TT
Table 6. Recommendations in adults in Saudi Arabia31,130
Vaccine Dose (s) Age group Risk (s) Booster

MCV-4 or MPV-4 1 dose Any age ≥10 d and <3 y prior to travel to Hajj Every 3 y if frequent travel
Whenever possible, a meningococcal conjugate vaccine is preferred because of its higher

immunogenicity, immune memory, lack of hyporesponsiveness and impact on carriage and herd
immunity as compared with polysaccharide vaccine.47 However, MPV can be given in case of allergy
to the conjugate vaccine, age >55 y, unavailability or high expenses of MCV, and travel for a limited
period of time to a hyperendemic or epidemic area.31 However, its use is limited in the case of routine
use in the general population.122,123 The ACIP of the CDC recommends the use of MPV-4 in adults
>55 y.18 There is lack of data on the use of MCV in this age group, except for the study that was
conducted by Dbaibo et al. and demonstrated the immunogenicity of MenACWY-TT above age of 55
y.47,113 MenACWY-TT is approved in Europe for use in this age group.107
High-risk groups
United States The ACIP recommends MCV-4 (MenACWY-DT or MenACWY-CRM) for all persons
aged 11–18 y and for persons aged 2–55 y at increased risk for meningococcal disease.18,90,124,125
The ACIP recommends the use of a single dose of MCV-4 for high-risk individuals aged 2–55 y such
as microbiologists routinely exposed to isolates of N meningitidis, military recruits, or first-year college
students up to age of 21 y who are living in dormitories if they were not vaccinated beyond the age of
16 y, with a booster dose every 5 y if at continued risk.18,22,126 The ACIP also recommends the use of
a two-dose series of MCV-4 for persons aged 2–55 y, 2 mo apart, in case of terminal complement
deficiencies and asplenia/hyposplenia, followed by a booster dose every 5 y.18,22,127 HIV patients
should receive a two-dose series of MCV-4, 2 mo apart, if this series was not provided at 11–18 y of
age.18,126
United Kingdom The JCVI in the United Kingdom recommends routine MCC vaccination at age of 3
mo, 12–13 mo (with Hib), and 14 y.95 Neisvac-C or Menjugate Kit should be used for infants at 3 mo
of age because they provide a good immune response after one dose under 1 y of age and strong
immune responses when boosted as Hib/MCC vaccine at 12–13 mo.93 Meningitec is less immunogenic
under 1 y of age.93 All three MCC can be used in adolescents.93 In individuals aged 10–25 y, one dose
of MCC should be given if no previous MCC was given, but no further vaccination is required if MCC
was given since reaching 10 y of age.95 The JCVI recommends one dose of Hib/MCC and one dose of
MCV-4, one month apart, for patients with terminal complement deficiency or asplenia/hyposplenia for
individuals ≥1 y.95 The BHIVA recommends MCC vaccination for HIV-infected adults <25 y of age in
case of unknown immunization history or no previous immunization, and at any age if at risk for
meningococcal disease.43 One dose of MCC is usually given to HIV patients, but 2 doses are
administered in case of concomitant asplenia.43
Travel
Meningococcal disease is rare in travelers (0.4 per 100 000 per month) as compared with other vaccine-
preventable travel-related infectious diseases.128
United States
The ACIP recommends one dose of MCV-4 for travelers to countries where meningococcal disease is
hyperendemic or epidemic, particularly if prolonged stay or contact with local population are expected
(e.g., schools, hospitals, military barracks…).18,37,58,129 For example, vaccination against
meningococcal disease is recommended for persons who travel to or reside in the “meningitis belt,”
especially during the dry season (from December to June).18,36,58,129 Travelers require a booster dose
every 5 y, if still indicated.18,37,58 Prior to travel, unvaccinated patients with anatomical or functional
asplenia, complement deficiency, or HIV should receive a two-dose series of MCV-4 (if <56 y), 2 mo
apart, or a single dose of MPV-4 (if ≥56 y).18,58
United Kingdom
The JCVI recommends one dose of MenACWY-CRM or MenACWY-TT in individuals ≥11-y-old
traveling to hyperendemic or epidemic areas, even if they have been previously vaccinated with
MCC.95 Vaccination is recommended for travelers to sub-Saharan Africa, particularly if prolonged
stay, contact with local population, or backpacking are expected.95 The BHIVA addresses the same
recommendations for HIV-affected travelers, with a booster dose every 5 y if still indicated.43
Saudi Arabia
Immunization against meningococcal disease is not a prerequisite for entry into any country except for
Hajj/Umrah pilgrims to Saudi Arabia, where the quadrivalent polysaccharide or conjugate vaccine is
required by the government of Saudi Arabia for all Hajjis and needs to be administered ≥10 d and <3 y
31 130
31,130
prior to arrival. The conjugate vaccine is preferred for use in Hajj pilgrims due to concerns of
hyporesponsiveness with repeated doses of MPV as many individuals participate in repeat
pilgrimages.131 Seven to 10 d post-vaccination are required to develop appreciable antibodies and
achieve protection against meningococcal disease.54,58
For other countries, the small risk of travel-related diseases for the general traveler coupled with the
unpredictable nature of epidemics make it difficult to provide evidence-based meningococcal vaccine
recommendations for travelers.132
Pregnancy and Breastfeeding

No randomized, controlled trials have evaluated the safety of MPV-4 or MCV-4 in pregnant or lactating
women.18,133 Yet, Vaccine Adverse Event Reporting System (VAERS) reports of exposure to MPV-4
or MCV-4 during pregnancy did not raise any maternal, fetal, or infant safety concerns.18,134 The
ACIP recommends the use of MenACWY-DT in pregnant women, if they are at risk for meningococcal
disease.134
Placental transport would likely be improved with conjugate vaccine through induction of IgG1-
subclass of maternal antibodies, resulting in longer protection in newborns and young infants.133
Maternally-derived antibodies might interfere with the antibody response to vaccines received in early
infancy by forming immune complexes with the vaccine antigen and hiding it from B lymphocytes.135
However, Rohner et al. showed lack of a consistent negative correlation between maternal antibodies
and post-immunization antibodies in infants primed with MenACWY-CRM.135
Meningococcal B Vaccines
Meningococcal quadrivalent vaccines do not contain serogroup B polysaccharide and thus, do not
confer protection against serogroup B, which is the predominant serogroup in developed countries.
Even when coupled to a carrier protein, serogroup B capsule is poorly immunogenic because of the
structural similarity to the polysialylated form of the neural cell adhesion molecule in the fetal
tissues.16,59,136,137 Anticapsular antibodies against group B have poor bactericidal activities.137,138
Furthermore, the use of serogroup B polysaccharide vaccine carries the theoretical risk of
autoimmunity due to molecular mimicry.137,139 Currently, there is no vaccine licensed in the United
States against serogroup B disease.18
OMV-based vaccines have been successfully used in Cuba, Norway, and New Zealand but do not
provide cross protection with non-homologous group B variants.70
In January 2013, the European Commission approved Bexsero, which is manufactured by Novartis
Vaccines, for use in persons starting at age of 2 mo, and the European Union members will evaluate
this vaccine for its possible inclusion into the immunization schedules.140 The components of Bexsero
are OMV and the recombinant N meningitidis group B antigens: heparin-binding antigen, adhesin A
protein, and factor H binding protein.141 An evaluation of >1000 meningococcal B strains from five
European countries predicted that 63–90% would be covered by this vaccine.141 Both recombinant
meningococcal B vaccines (with and without OMV) induce substantial immune responses against
genetically diverse strains and have an acceptable safety profile in adults.142 Although Bexsero is not
licensed in the United States, the CDC recommended its use at the Princeton University after reporting
8 cases of meningococcal B disease among Princeton students since March 2013.143 Another four-case
outbreak was reported at the University of California, and officials are considering whether to provide
Bexsero in the university to prevent further spread of the outbreak.144
Glossary
Abbreviations:
ACIP Advisory Committee on Immunization Practices
BHIVA British HIV Association
CDC Centers for Disease Control and Prevention
CRM197 diphtheria cross-reacting material, a nontoxic variant of diphtheria toxin
DT diphtheria toxoid
FDA Food and Drug Administration
GBS Guillain–Barré syndrome
HBV hepatitis B vaccine
Hib Haemophilus influenzae type b
IPV injectable polio vaccine
JCVI Joint Committee on Vaccination and Immunization
MACP meningococcal polysaccharide bivalent A/C vaccine
MCC meningococcal C conjugate vaccine
MCV meningococcal conjugate vaccine
MMR measles-mumps-rubella vaccine
MPV meningococcal polysaccharide vaccine
MenACWY meningococcal conjugate quadrivalent vaccine
N meningitidis Neisseria meningitidis
OMV outer membrane vesicles
PCV pneumococcal conjugate vaccine
S pneumonia Streptococcus pneumoniae
SBA serum bactericidal antibody
Td combined tetanus and diphtheria vaccine
Tdap combined tetanus, diphtheria and acellular pertussis vaccine
TT tetanus toxoid
Notes
10.4161/hv.27739
Disclosure of Potential Conflicts of Interest

G.S.D. has served on Advisory Boards, received grant support through his institution, and received
honoraria for lectures from GlaxoSmithKline, Merck Sharpe and Dohme, Sanofi-Aventis, and Pfizer.
All other authors have no interests to declare.
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Review of Meningococcal Vaccines

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12/12/2018 Review of meningococcal vaccines with updates on immunization in adults

Hum Vaccin Immunother. 2014 Apr; 10(4): 995–1007. PMCID: PMC4896590

Review of meningococcal vaccines with updates on immunization in

Copyright © 2014 Landes Bioscience

Keywords: meningococcal conjugate vaccine, adults, meningococcal disease, Neisseria meningitidis,

Australia and New Zealand

3) Vaccines against serogroup B using OMV preparations27

Polysaccharide Vaccines (Table 1)

Table 1. Meningococcal quadrivalent vaccines18,101,145

Trade Licensed Age

Immunogenicity and effectiveness

Duration of protection Polysaccharides are T-cell-independent antigens that stimulate B lymphocytes.65

Hyporesponsiveness Hyporesponsiveness refers to the reduction of the antibody response with

Meningococcal C Conjugate Vaccine (Table 2)

Table 2. Meningococcal monovalent C vaccines16,19,95

Quadrivalent Conjugate Vaccines (Table 1)

Immunogenicity and effectiveness In adults aged 18–55 y, non-inferiority of MenACWY-DT to MPV-4

Immunogenicity and effectiveness Prior to licensure of MenACWY-CRM, a large-scale comparative

Concomitant vaccinations Concomitant administration of MenACWY-CRM with other age-appropriate

It is contraindicated to administer MenACWY-CRM in case of severe allergic reaction (e.g.,

Concomitant vaccinations Co-administration of MenACWY-TT with seasonal influenza vaccine

Meningitis Vaccine Project (Table 3)

Table 3. Meningococcal monovalent A vaccine25,118

Formulation Type Trade Manufacturer Licensed Age Dose Serogroup

Recommendations in Adults (Tables 4, 5, and 6)

Table 4. Recommendations in adults in United States18

Table 5. Recommendations in adults in United Kingdom43,95

Vaccine Dose (s) Age group Risk (s) Booster

Table 6. Recommendations in adults in Saudi Arabia31,130

Vaccine Dose (s) Age group Risk (s) Booster

Whenever possible, a meningococcal conjugate vaccine is preferred because of its higher

Pregnancy and Breastfeeding

ACIP Advisory Committee on Immunization Practices

BHIVA British HIV Association

CDC Centers for Disease Control and Prevention

CRM197 diphtheria cross-reacting material, a nontoxic variant of diphtheria toxin

FDA Food and Drug Administration

GBS Guillain–Barré syndrome

HBV hepatitis B vaccine

Hib Haemophilus influenzae type b

IPV injectable polio vaccine

JCVI Joint Committee on Vaccination and Immunization

MACP meningococcal polysaccharide bivalent A/C vaccine

MCC meningococcal C conjugate vaccine

MCV meningococcal conjugate vaccine

MMR measles-mumps-rubella vaccine

MPV meningococcal polysaccharide vaccine

MenACWY meningococcal conjugate quadrivalent vaccine

N meningitidis Neisseria meningitidis

OMV outer membrane vesicles

PCV pneumococcal conjugate vaccine

S pneumonia Streptococcus pneumoniae

SBA serum bactericidal antibody

Td combined tetanus and diphtheria vaccine

Tdap combined tetanus, diphtheria and acellular pertussis vaccine

Disclosure of Potential Conflicts of Interest

6. Koyfman A, Takayesu JK. Meningococcal disease. Am J Emerg Med 2011; 1:174 - 8

46. Elias J, Findlow J, Borrow R, Tremmel A, Frosch M, Vogel U. Persistence of antibodies in

57. Prasad K, Karlupia N. Prevention of bacterial meningitis: an overview of Cochrane systematic

http://dx.doi.org/10.1093/infdis/140.5.690; PMID: 118997 [PubMed] [CrossRef]

73. Bröker M, Veitch K. Quadrivalent meningococcal vaccines: hyporesponsiveness as an important

84. Dellicour S, Greenwood B. Systematic review: Impact of meningococcal vaccination on pharyngeal

95. Chapter 22 Meningococcal. Green Book, 2013: p. 235-59. Available at

97. Package insert available at