Review of meningococcal vaccines with updates on immunization in adults

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

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 vaccines^18,101,145

Formulation	Type	Trade name	Manufacturer	Licensed year	Age group	Dose (s)	Serogroups
MPV-4	Polysaccharide	Menomune	Sanofi Pasteur	1981	≥2 y	1	A, C, W, and Y
MPV-4	Polysaccharide	Mencevax	GlaxoSmithKline		≥2 y	1
MenACWY-DT	Conjugate	Menactra	Sanofi Pasteur	2005	11–55 y	1
				2007	2–10 y	1
				2010	9–23 mo	2
MenACWY-CRM	Conjugate	Menveo	Novartis	2010	11–55 y	1
				2011	2–10 y	1
				2013	2–23 mo	4 (if 2–6 mo) 2 (if 7–23 mo)
MenACWY-TT	Conjugate	Nimenrix	GlaxoSmithKline	2012	≥12 mo	1

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 vaccines^16,19,95

A
Formulation	Type	Trade name	Manufacturer	Serogroup
MCC-TT	Conjugate	Neisvac-C	Baxter Healthcare	C
MCC-CRM	Conjugate	Menjugate Kit	Novartis
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 adults in clinical trials.^94,96 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 vaccine^25,118

Formulation	Type	Trade name	Manufacturer	Licensed year	Age group	Dose	Serogroup
MenA-TT	Conjugate	MenAfriVac	Serum Institute of India	2010	1–29 y	1	A

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-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

Vaccine	Dose (s)	Age group	Risk (s)	Booster
MenACWY-DT or MenACWY-CRM	1 dose	2–55 y	-Microbiologists routinely exposed to N meningitidis -Military recruits -Travel to hyperendemic or epidemic area -First-year college students living in residence halls (up to 21 y if not vaccinated >16 y)	Every 5 y if continued risk
	2 doses (2 mo apart)	2–55 y	-Terminal complement deficiency -Asplenia/hyposplenia
	2 doses (2 mo apart)	>18 y	HIV (if 2-dose series not given between 11–18 y)
MPV-4	1 dose	≥56 y	Same as above

Table 5. Recommendations in adults in United Kingdom^43,95

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

Table 6. Recommendations in adults in Saudi Arabia^31,130

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 prior to arrival.^31,130 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

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

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.

10.4161/hv.27739