Meningococcal Capsular Group A, C, W, and Y Conjugate Vaccines

Clinical Description and Manifestations

The clinical features of meningococcal disease are highly variable. Classic clinical features of meningococcal disease are fever, rash, and meningitis, but initial presentation is often non-specific and therefore may be indistinguishable from those of other bacterial, rickettsial, or viral infections. ^, In fact, many serious cases of meningococcal disease are initially misdiagnosed as a benign viral illness, which can have devastating consequences because rapid progression to life-threatening disease may follow within hours.

The most common clinical manifestation is acute bacterial meningitis. Older children and adults typically have an abrupt onset of fever, headache, photophobia, myalgias, and malaise. Seizures occur in approximately 20% of patients. Signs of altered consciousness, such as hyperactivity or lethargy, can be prominent. Nuchal rigidity is a common sign except in infants in whom a more gradual onset of fever, poor feeding, and lethargy are the typical initial complaints, and a bulging fontanel may be the major sign of central nervous system involvement. A rash is present in the majority of cases of meningococcal disease, which consists of typical petechiae or purpuric lesions that usually are most apparent on the chest, upper arms, and axillae. Maculopapular rashes also are common and may occur early in the absence of petechiae.

Among patients with meningococcal disease, 10%–20% have severe sepsis or meningococcemia. Meningitis may be absent, but the organism is widely disseminated in the bloodstream and in multiple organs. Spreading purpura heralds signs and symptoms of septicemia with rapid onset of hypotension and signs of multiple organ failure, although not all patients with shock or hypotension have purpura. White blood cell counts may be very high, normal, or low, and a prominence of immature band forms is often present. At the time of autopsy, acute adrenal hemorrhage may be present (Waterhouse-Friderichsen syndrome). The case fatality rate from severe meningococcemia can be as high as 40%. More commonly, the course of meningococcal disease is less fulminant.

Up to 15% of patients with meningococcal disease have pneumonia, which is most commonly associated with capsular group Y strains. In the absence of a characteristic rash and bacteremia, the cause of the pneumonia may go unrecognized: the clinical microbiology laboratory may not report isolation of N. meningitidis from oropharyngeal secretions because it is considered normal flora.

Gastrointestinal symptoms are common in IMD but rarely dominate the initial presentation. However, there have been recent reports of group W IMD patients presenting with predominantly gastrointestinal symptoms. For example, during the United Kingdom outbreak of capsular group W IMD, seven teenagers presented with symptoms such as abdominal cramps, abdominal pain, vomiting, and diarrhea. The clinical importance of these cases is that some of these patients were initially sent home with a diagnosis of gastroenteritis; five of the seven patients died. Similarly, 14 of 58 cases during a group W outbreak in Chile initially received a diagnosis of gastroenteritis, of which 8 died. Gastrointestinal symptoms as the initial presentation in group W infection have been reported in other countries as well.

Less common manifestations of meningococcal disease include myocarditis, endocarditis, pericarditis, arthritis, conjunctivitis, pharyngitis, and cervicitis. Late in the course of treated disease, arthritis, or pericarditis may occur as a result of immune complex formation. A nongroupable meningococcal strain emerged in 2015 and caused outbreaks of urethritis predominantly among heterosexual men in several United States cities and has also recently been identified in the United Kingdom.

Complications of Meningococcal Disease

Approximately 10%–20% of patients who survive meningococcal disease have permanent physical, neurologic, and/or psychologic sequelae, resulting in substantial declines in health-related quality of life among survivors and their caregivers. A systematic review published in 2018 found that 3%–8% of meningococcal disease survivors had amputations and 2%–55% had skin scars. These physical sequelae were most common among patients who developed meningococcemia. Patients with meningococcal meningitis who do not develop septic shock are less likely to die or have physical sequelae, but 2%–20% may develop neurosensory hearing loss, mild to moderate cognitive deficits, or seizure disorders. Both meningococcemia and meningitis survivors can also have psychological or behavioral sequelae, including post-traumatic stress disorder and anxiety. Despite this high burden of sequelae, the risk of neurologic complications with meningococcal meningitis is generally lower than that of patients with meningitis caused by Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae .

Bacteriology and Molecular Epidemiology

Weichselbaum was the first to culture N. meningitidis from patients with meningitis in 1887. The organism is a Gram-negative, oxidase-positive, diplococcus that naturally infects only humans. Many meningococcal strains express a polysaccharide capsule. Thirteen serologically distinct meningococcal capsular groups were reported on the basis of the immunochemistry of the polysaccharide. ^, However, what had been designated as group D was found to be an unencapsulated variant of group C; therefore, there are 12 known meningococcal capsular groups: A, B, C, E (formerly known as 29E), H, I, K, L, W (formerly known as W-135), X, Y, and Z. Organisms with capsular groups A, B, C, W, X, or Y are responsible for almost all cases of disease.

For determination of meningococcal genetic lineage, multilocus sequence typing (MLST) is a commonly used method. MLST capitalizes on nucleotide sequence analysis to index variation based on polymorphisms in seven housekeeping genes to define the meningococcal sequence type (ST); STs are considered to belong to the same clonal complex (CC) if they share the same allele for at least four of the seven MLST loci. ^, Despite the capacity of N. meningitidis for horizontal gene transfer, a relatively small number of MLST-defined genetic lineages cause most invasive meningococcal disease (IMD).

Meningococci can be further classified on the basis of the outer membrane proteins PorA and PorB. Historically this classification was based on serologic methods, which have largely been replaced by DNA sequence-based approaches. Another outer membrane protein—FetA, an enterobactin receptor—has also been used for typing. Sequencing of the meningococcal factor H (fH) binding protein (FHbp) gene provides additional evolutionary ^, and genomic epidemiologic information about meningococcal strains, as well as for information about potential coverage of vaccines that were developed for prevention of capsular group B disease (Chapter 39). Meningococci also can be divided into immunotypes on the basis of variation in the lipooligosaccharide structure.

Whole genome sequencing (WGS) has rapidly emerged as the primary method used for outbreak detection of N. meningitidis and in some situations has replaced traditional phenotypic testing methods for characterization of the organism. WGS is better able to discriminate meningococcal strains than other genomic epidemiologic methods, such as pulsed-field gel electrophoresis and MLST, facilitating outbreak detection and studies of transmission. WGS can be used for extensive strain characterization, including determination of ST, CC, capsular group, and the alleles of genes that encode for other antigens that are important for strain characterization such as PorA, PorB, and FetA, and FHbp. In addition, WGS can be used to monitor for emergence of antimicrobial resistance to, for example, penicillin and the fluoroquinolones. Finally, WGS data can be used to predict the coverage by vaccines that were developed for prevention of capsular group B infection by determining the alleles for the genes that encode for vaccine antigens including PorA, FHbp, Neisseria adhesin A (NadA), and Neisseria heparin binding antigen (NhbA) (refer to Chapter 39).

The meningococcus is naturally competent for transformation with DNA, which provides a mechanism for horizontal exchange of DNA. ^, As a consequence, the organism has a highly panmictic population structure and exchanges genes encoding key antigens that are used in the serologic characterization of isolates and as vaccine components. ^, The facility to exchange genes that encode for capsule and protein vaccine antigens has the potential to lead to vaccine escape by virulent clones. ^{, ,} The meningococcus has more than 100 putative phase-variable genes, which contributes to the antigenic variability and phenotypic adaptability of the organism.

Pathogenesis

As mentioned above, most IMD is caused by bacteria from a limited number of hypervirulent lineages. ^, Carriage isolates, in contrast, belong to a broader group of lineages, many of which have been rarely associated with disease. ^, These observations indicate that certain meningococci are genetically predisposed to cause disease. In addition, IMD is, with rare exception, caused by encapsulated strains, whereas carried strains often do not express capsule, which underscores the importance of the meningococcal capsule as a virulence factor. ^,

Following attachment to pharyngeal mucosal cells, the organism replicates and establishes a carrier state. Pili seem to be the most important adhesin, and two opacity-associated proteins (Opa and Opc), lipooligosaccharide, and interbacterial interactions (via PilX) facilitate subsequent tight attachment. Attachment to epithelial cells is mediated by specific receptors such as CD46 and carcinoembryonic antigen receptors. Attachment initiates loss of piliation by the bacteria as well as cytoskeletal rearrangements in the host cell that result in internalization of the bacteria within membrane-bound vesicles by endocytosis. ^, Once the organism has colonized the pharynx, the likelihood of acquiring IMD depends on the virulence of the particular isolate, host factors affecting innate susceptibility, and the presence or absence of serum bactericidal antibodies. Once the organism enters the bloodstream, the spleen is involved in bacterial clearance. Because of impaired clearance, patients with asplenia or hyposplenic function may be at increased risk of severe meningococcal disease.

The complement cascade is activated by serum antibodies via the classical pathway, which results in opsonization and bacteriolysis of meningococci. In the absence of specific antimeningococcal antibodies, these complement-mediated functions also can be activated by the alternative pathway. Given the central role of complement proteins in host defenses against invasive N. meningitidis disease, persons with underlying deficiencies of properdin, C3, or the late complement components (C5 through C9) are at greatly increased risk of developing meningococcal disease.

Some patients with meningococcal disease develop rapidly progressive cutaneous hemorrhage and skin necrosis, disseminated intravascular coagulation, and shock. Many factors contribute to overwhelming meningococcal disease, but the most important are the rapid doubling time of the bacteria and their propensity to release endotoxin-rich outer membrane vesicles (blebbing), which results in very high levels of endotoxin, porin proteins, and DNA in the circulation. These trigger various pattern recognition receptors expressed on monocytes and macrophages (see subsequent discussion), which results in proinflammatory cytokine release and activation of fibrinolytic and complement pathways. Endotoxin (lipooligosaccharide) is the most potent toxic molecule, and levels of lipooligosaccharide in the circulation correlate directly with severity of clinical manifestations and case fatality rate.

Transmission

The meningococcus colonizes only the pharynx of humans and has no other known environmental niche. The organism is usually a harmless commensal, and there are major differences in carriage rates by age, geography, and time. In Europe and countries with similar meningococcal epidemiology, such as the United States, carriage rates are usually highest among adolescents and young adults, whereas in the meningitis belt of Africa, carriage prevalence peaks at around age 10 years old and gradually declines among older adolescents. The duration of meningococcal carriage varies but typically the bacteria persist for weeks to months. ^, The vast majority of meningococcal carriers do not develop meningococcal disease; rather, carriage and disease represent distinct outcomes of meningococcal colonization.

Meningococci are transmitted person-to-person through respiratory secretions. Both meningococcal disease patients and asymptomatic carriers of the bacteria can serve as sources of transmission. Transmission requires close contact, such as living in a household with the infected person, intimate kissing, or other direct exposure to respiratory excretions.

Diagnosis

Confirmation of meningococcal disease is usually achieved through conventional cultures of blood, cerebrospinal fluid (CSF), or other infected sites. Gram staining to demonstrate the characteristic Gram-negative diplococcus also can be used to inform the diagnosis. Direct latex agglutination testing of serum or CSF for detection of meningococcal capsular polysaccharides can suffer from lack of sensitivity but is still widely used in some regions. ^,

Polymerase chain reaction (PCR) assays can be used to detect meningococcal DNA in normally sterile body fluids, which establishes the diagnosis and is particularly useful in the setting of negative cultures because of previous antibiotic use. There are several PCR-based commercial meningitidis/encephalitis panels that include detection of N. meningitidis . Capsular group-specific PCR assays are available to discriminate among capsular groups A, B, C, W, X, Y, Z, and E.

In Europe, a substantial proportion of meningococcal cases are detected using PCR. In the United Kingdom, for example, 55% of all cases were diagnosed based on positive PCR. ^, Using PCR for diagnosis of meningococcal disease has dual benefits: it provides a more accurate picture of disease burden and establishes the diagnosis in a greater proportion of cases.

Treatment

Ceftriaxone or cefotaxime are typically recommended for inclusion in antibiotic regimens for empiric bacterial meningitis treatment before the causative pathogen has been identified. Although many antimicrobial agents are effective for management of meningococcal disease, intravenous aqueous penicillin was traditionally considered the therapy of choice once meningococcal disease is confirmed. Recently, however, there has been emergence of penicillin-resistant, ceftriaxone-susceptible N. meningitidis. In addition, although the clinical importance is unknown, some meningococcal isolates from the United States have intermediate susceptibility to penicillin (minimum inhibitory concentration [MIC]: 0.1–1.0 µg/mL). ^, Reduced susceptibility to penicillin among meningococcal isolates has been commonly reported from other countries as well, along with infrequent reports of penicillin resistance. The recent emergence of penicillin resistance, uncertainty about the clinical significance of intermediate susceptibility to penicillin, and the more convenient dosing schedule and availability of generic ceftriaxone make it a reasonable option for therapy of meningococcal disease, even after the diagnosis has been established. In fact, in the United States penicillin is now recommended for treatment only if penicillin susceptibility has been confirmed ; ceftriaxone/cefotaxime are recommended for treatment of meningococcal disease in the United Kingdom. In resource-poor settings, single-dose intramuscular chloramphenicol in oil or ceftriaxone is effective but is rarely used.

Non-susceptibility of meningococcal isolates to third-generation cephalosporins has rarely been reported. Isolates from eight patients with capsular group A IMD in India were reported to have ceftriaxone MICs of 0.25–8 µg/mL, with penicillin MICs of 0.094 - >32 µg/mL; no further characterization of these strains was provided and N. meningitidis isolates with such high MICs to third-generation cephalosporins have never been described beyond this report from India. ^, In a study from France, 2% of invasive meningococcal isolates during 2013–2015 had reduced susceptibility to third-generation cephalosporins due to a penicillin binding protein mutation compared with isolates without the mutation, with cefotaxime MICs of 0.047–0.125 µg/mL. While these reports are concerning, ceftriaxone nonsusceptible N. meningitidis appears to be uncommon and has not been reported in the United States or elsewhere. Nevertheless, continued surveillance is warranted.

Early initiation of antibiotic therapy and attention to circulatory status in patients suspected of having meningococcal infection may decrease morbidity and mortality. ^, Because the clinical features of meningococcal disease can overlap those of bacterial meningitis or sepsis caused by other bacterial pathogens, depending on the age of the patient, clinical manifestations, exposure history, the results of Gram stains of CSF or petechial hemorrhages, and the presence or absence of other epidemiologic risk factors, broader initial empirical therapy is standard before the diagnosis is confirmed. Antibiotic treatment for 7 days is adequate therapy for most systemic meningococcal illnesses.

In a meta-analysis of 25 randomized trials involving children and adults with bacterial meningitis in both high- and low-income countries, adjunctive therapy with a glucocorticoid was associated with a reduction in mortality in patients with pneumococcal meningitis, but not meningitis caused by H. influenzae or meningococcus. In addition, corticosteroid therapy has been shown to decrease the rate of neurosensory hearing loss in infants and children with Hib meningitis. Based on these data, some experts recommend the use of dexamethasone in patients with suspected or confirmed pneumococcal or H. influenzae meningitis but suggest that dexamethasone does not need to be given or continued for patients with meningitis caused by other pathogens, including N. meningitidis . When given, the first dose of corticosteroid should be administered 10–20 minutes before or at least concomitant with the initiation of antibiotic therapy.

Chemoprophylaxis

Close contacts of a patient with meningococcal disease are at greatly increased risk of developing secondary cases of disease. The risk is greatest in household contacts and other close contacts exposed to oral secretions and in childcare center contacts. The risk of transmission to healthcare workers is low, but healthcare workers exposed to the respiratory secretions of meningococcal disease patients (e.g., persons performing mouth-to-mouth resuscitation or unprotected healthcare workers exposed during management of endotracheal tubes) should be considered close contacts. ^,

Rifampin, ceftriaxone, and ciprofloxacin eradicate nasopharyngeal N. meningitidis colonization, and these agents are recommended for chemoprophylaxis of close contacts. While ciprofloxacin is logistically the easiest of the three antibiotics to administer because it is given orally as a single dose, resistance to ciprofloxacin has been sporadically reported worldwide, including recent reports of resistance in a high proportion of meningococcal isolates from Shanghai, China, as well as among capsular group Y (NmY) isolates in the United States. ^, Based on one study suggesting that azithromycin can also eliminate meningococcal carriage, ceftriaxone, rifampin, or azithromycin have been recommended for eradication of meningococcal carriage in areas where ciprofloxacin resistance has been identified. ^,

Chemoprophylaxis should be offered to household members and to other persons with a history of prolonged close contact. Prophylaxis of child daycare contacts is recommended in the United States ; in the United Kingdom prophylaxis for these individuals is recommended only if they otherwise fulfill the definition of a close contact. Because the risk of disease in contacts is highest in the first week after onset of disease in the index patient, prophylaxis should be administered to contacts as soon as feasible, preferably within 24 hours of identification of the index patient. Because penicillin therapy does not reliably eradicate nasopharyngeal colonization, additional antimicrobial treatment is recommended at the time of hospital discharge for eradication of colonization in patients not treated with ceftriaxone or cefotaxime. Contacts who were previously immunized with meningococcal vaccines against the relevant capsular group should still receive chemoprophylaxis because primary vaccine failure, lack of serum antibody persistence, or both, may render vaccinated persons susceptible to disease.

Expanded chemoprophylaxis has been used in response to meningococcal disease outbreaks in an attempt to stop the outbreak through eradication of carriage from the population at risk. While administration of expanded chemoprophylaxis is sometimes associated with the emergence of antimicrobial resistance, particularly when rifampin is used, it may provide temporary protection to the individuals who receive prophylaxis. Settings in which expanded chemoprophylaxis is most likely to provide benefit include relatively small populations that have limited mixing with outside populations and in which high antibiotic coverage can rapidly be achieved. However, recent work has suggested that village-wide chemoprophylaxis might also help prevent meningococcal disease cases during epidemics in the meningitis belt of Africa. If undertaken, the antibiotic should be administered to all persons during the same time period to minimize the chance that recipients will be reinfected by other carriers within the population. Administration of expanded chemoprophylaxis should not delay or replace vaccination against the appropriate meningococcal capsular group if vaccination is feasible.

Incidence and Public Health Burden

The epidemiology of meningococcal disease is highly variable and dynamic, and is influenced by environmental, host, and pathogen variation, and immunization policy. The epidemiology varies substantially both geographically ( Fig. 39.1 ) and by capsular group.

Although meningococcal disease is a global problem that occurs in all countries, the highest burden of disease is in the meningitis belt of Africa, which extends from Senegal on the west coast to Eritrea on the east ( Fig. 39.2A ). In this region, meningococcal disease occurs primarily during the dry season, beginning generally in November or December and terminating abruptly with the onset of increased humidity and rain in June or July. The precise reasons for this epidemiologic pattern are unknown but most likely, environmental, host, and microbial factors in combination play a role.

Serogroup A N. meningitidis (NmA) was historically the major cause of epidemic and endemic meningococcal disease in the meningitis belt of sub-Saharan Africa. ^, The annual incidence of disease during group A epidemics in sub-Saharan Africa could exceed 1000 per 100,000 population, or 10,000-fold higher than the current incidence of meningococcal disease in the United States. The case fatality rate during group A epidemics in Africa varied between 10% and 15%. With the introduction of a monovalent group A conjugate vaccine in 2010, the incidence of NmA disease in the meningitis belt has dramatically declined and NmA epidemics have vanished; however, disease caused by capsular groups W (NmW), X (NmX), and, more recently, C (NmC), has emerged ( Fig. 39.2B ). Why disease caused by these capsular groups has increased in the sub-Saharan region is unknown.

The burden of endemic meningococcal disease in Europe is much lower than in the meningitis belt—0.6 cases per 100,000 population in 2017 —and has declined dramatically in countries that introduced group C meningococcal conjugate vaccines. In Europe and other temperate climates, rates of meningococcal infections are highest during the winter months. ^, This association may be a result of closer personal contact during the winter months, lack of ventilation, or an increase in upper respiratory infections, all factors that facilitate transmission of or invasion by the organism, or both.

The European countries with the highest reported incidence rates per 100,000 population in 2018 were Lithuania (2.4), Ireland (1.5), the Netherlands (1.2), and the United Kingdom (1.2). The overall capsular group distribution for meningococcal disease cases in Europe in 2017 was 51% capsular group B (NmB), 17% NmW, 16% NmC, and 12% NmY ( Fig. 39.1 ). Most cases of meningococcal disease in Europe are sporadic, but outbreaks of NmC meningococcal disease still occur in the region, including outbreaks among men who have sex with men.

Some countries particularly in western Europe have recently experienced an increase in disease caused by group W. Since 2009, the United Kingdom has experienced a rapid increase in group W disease, from 1.8% of cases in 2008–2009 to 28% of cases in 2017. A similar expansion in NmW occurred in the Netherlands and several other European countries. The increase was a result of clonal expansion of an ST-11 clonal complex strain. As a result of the increase and as discussed further below, a quadrivalent MenACWY immunization campaign for 14–18-year-olds was initiated in the United Kingdom in August 2015, with similar programs introduced in Italy in 2017 and the Netherlands in 2018. ^,

NmA strains rarely cause disease in western Europe. This capsular group does, however, circulate in Eastern Europe, with 41% of meningococcal disease cases in Moscow, Russia and 63% of cases in Almaty, Kazakhstan caused by NmA in 2018. Lower levels of NmA disease have been detected in other eastern European countries.

In the United States, the annual incidence of meningococcal disease has steadily declined since 2000, with a historically low incidence in 2018 of 0.10 per 100,000. ^, The decline preceded the widespread use of meningococcal conjugate vaccine in the United States. The reasons for the decrease are not known but are likely multifactorial and include decreases in active and passive tobacco smoking, changing patterns of antibiotic use, increased use of influenza vaccines, declines in meningococcal carriage, and lack of novel antigenic variants among virulent strains to which the population does not have immunity. Implementation of quadrivalent meningococcal conjugate vaccine in adolescents has also contributed to declining cases in this age group (see below, Public health considerations – epidemiological effects of meningococcal conjugate vaccines) .

NmB is the most common cause of meningococcal disease in the United States; in 2018, the incidence of capsular groups C, W, and Y combined was 0.05 per 100,000. However, in 2018, group C still accounted for approximately 30% of all meningococcal disease in the United States and in recent years has caused outbreaks among men who have sex with men ^{, , , , ,} and people experiencing homelessness (CDC unpublished data). NmA does not circulate in the United States, while NmW remains uncommon, accounting for only about 5% of meningococcal disease cases in 2018. Meanwhile NmY accounted for about 15% of cases, with the highest incidence in adults greater than 65 years of age.

In Latin America, the true burden of meningococcal disease is unclear due to reliance on passive sentinel surveillance in most countries. Capsular groups B and C predominate in many countries of the region; however, following group C conjugate vaccine introduction into the routine pediatric immunization schedule in Brazil, the incidence of group C disease has decreased. ^, An increase in disease caused by group W strains was reported from Brazil beginning in 2003, with spread to Argentina by 2008 and Chile by 2012. ^{, ,} Phylogenetic analysis demonstrates that the ST-11 NmW strain responsible for the increase in disease in South America is the likely ancestor of the NmW strains responsible for the more recent increases in Europe.

The strength of meningococcal disease surveillance varies substantially across the Asia-Pacific region, but there are dramatic differences in epidemiology by country. ^, In India, for instance, the vast majority of reported disease is caused by NmA; in China, NmC accounts for more than 40% of cases but groups A, B, and W also circulate; and in Japan, which had an extremely low meningococcal disease incidence of <0.03 cases per 100,000 in 2014, NmY predominates. ^, New Zealand, meanwhile, has one of the highest incidences of meningococcal disease in the region at 2.3 per 100,000 persons in 2019; 52% of these cases were caused by NmB and 30% by Nm W. In Australia, meningococcal disease cases began increasing in 2014 following over a decade of sustained declines, reaching 1.6 cases per 100,000 population in 2017. The increase is attributable to capsular groups W and Y, with NmW accounting for the largest proportion of meningococcal disease cases in 2016–2017. The highest burden of meningococcal disease in Australia occurs among indigenous children <10 years of age, particularly those aged <5 years.

Mass gatherings with attendees from many parts of the world can provide an optimal opportunity for meningococcal transmission and subsequent global spread. A notable example was in 2000–2001, when outbreaks of group W disease occurred among Hajj pilgrims in Mecca, Saudi Arabia, where several million pilgrims from around the world gather each year in crowded conditions. Cases linked to this outbreak were identified in numerous countries around the world—from England, to Singapore, to the United States—along with over 200 cases identified in Saudi Arabia. To prevent future outbreaks, Saudi Arabia now requires proof of quadrivalent meningococcal vaccination for Hajj and Umrah pilgrims.

The incidence of meningococcal disease varies by age, likely resulting from an interplay between the degree of immunity, variation in transmission patterns by age, and virulence of circulating strains. In many countries, disease incidence is highest among infants who have not yet acquired natural immunity. In the European Union, for example, the reported rate of meningococcal disease (primarily group B) during 2017 among children younger than 1 year of age and between 1 and 4 years of age were 8.2 and 2.5 cases per 100,000 population, respectively. Incidence in the United States is much lower but follows similar trends by age: in 2018 incidence was 0.83 and 0.18 per 100,000 population among children younger than 1 year of age and children 1–4 years of age, respectively. In the United States and Europe, there are additional peaks in incidence among adolescents and young adults and among the elderly. ^, Different capsular groups contribute to the peaks in disease in each age group, with NmB now being primarily responsible for the adolescent peak in the United States while groups Y and, in Europe, W, are the primary cause of disease in older adults (representative data for the United States are shown in Fig. 39.3 ). ^,

Risk Factors for Disease and Carriage

Epidemiologic factors: Viral respiratory infections, exposure to tobacco smoke or indoor firewood stoves, bar or discothèque patronage, and binge drinking ^, are all associated with increased rates of meningococcal carriage or disease. There are a variety of plausible mechanisms for the association between these environmental and behavioral factors and meningococcal infection. Respiratory viruses and tobacco smoking cause alterations in the mucosal surface that enhance bacterial binding or decrease the ability of the host to clear the organism from the nasopharynx. Bar patronage and binge drinking could increase transmission through crowding, coughing caused by exposure to tobacco smoke, and other close contact.

In the United Kingdom and the United States, being a university student, ^, a freshman living in a university residence hall, and intimate kissing with multiple partners ^, were associated with an increased risk of acquiring meningococcal carriage or disease. In the United States, the increased disease risk among college students has become specifically associated with meningococcal NmB following introduction and widespread use of conjugate group A, C, W, Y vaccines ; previously, NmC caused the largest share of cases among college students. However, recent outbreaks of NmC disease have occurred in the United States among men who have sex with men and people experiencing homelessness (CDC unpublished data); furthermore, high meningococcal disease incidence and frequent outbreaks were historically observed among military recruits. These data suggest that crowding and other close contact, rather than age or gender, is the main determinant of meningococcal carriage and increased disease risk.

There is a substantially increased risk of meningococcal disease among microbiology laboratory workers, primarily associated with processing liquid cultures on an open bench. In one report of 16 probable laboratory-acquired cases, 50% were fatal. For this reason, meningococcal vaccination is typically recommended for laboratory workers with occupational exposure to meningococcal isolates (see Recommendations for use of conjugate vaccines—groups at increased risk of disease , below).

Biological factors : In addition to presence of anti-meningococcal serum bactericidal antibodies, activation of the complement cascade and binding of complement components to the surface of N. meningitidis are critical host defenses against developing IMD. Deficiency of proteins in the complement cascade, particularly components of the membrane attack complex, such as C5, C6, or C7, has long been recognized as an important risk factor for IMD that can increase meningococcal disease risk by up to 10,000-fold. Studies vary widely in the proportion of meningococcal disease patients found to have underlying complement deficiency, from 0.3% of 297 patients with meningococcal disease in one study in the United Kingdom to more than 50% of 16 or 53 patients in studies from Japan and New Caledonia, respectively. In general, the percentage of meningococcal disease cases occurring in patients with complement deficiency increases as the population incidence of meningococcal disease decreases. Individuals with complement deficiency more frequently develop disease caused by capsular groups X, Y, Z, W, E or nongroupable meningococci ; some studies have found that 30% or more of patients with disease caused by these strains have complement deficiency. ^, In addition, complement-deficient patients frequently have recurrent episodes of IMD as teenagers or adults. Accordingly, complement deficiency should be considered in patients with recurrent meningococcal disease and patients with disease caused by nongroupable or capsular group X, Y, Z, W, or E strains.

A similar risk of meningococcal disease is observed when complement deficiency is induced with the C5 complement inhibitor eculizumab. As among those with inherited complement deficiencies, disease caused by nongroupable strains is common among eculizumab recipients. ^, The increase in risk is presumed to also apply to the newer C5 inhibitor ravulizumab. While MenACWY and MenB (see Chapter 39) vaccination are recommended for patients receiving C5 complement inhibitors, it is also clear that these patients can develop meningococcal disease caused by these capsular groups despite recent vaccination, highlighting the critical role of the complement cascade in meningococcal immunity.

While terminal complement component deficiency results in the greatest increase in IMD risk, deficiencies in serum levels of C3 or C4, properdin, or alternative complement pathway activation from factor D deficiency are also associated with increased risk of IMD. ^, However, mutations related to complement fH are associated with a lower risk of meningococcal disease. Polymorphisms in several other innate immune system components, such as mannose-binding lectin (MBL) ^, or toll-like receptor 4 (TLR4) have also been reported to be associated with meningococcal disease in some studies; however, data on these associations are conflicting and the potential increase in risk is vastly lower than the increased risk among individuals with terminal complement deficiencies. ^,

In addition to complement deficiency, patients with HIV infection are at increased risk of meningococcal disease. There are limited data on potential increased meningococcal disease risk among asplenic patients, but the risk is substantially lower than for S. pneumoniae . Finally, meningococcal disease risk is approximately 70-fold higher among survivors of meningococcal disease than in the general population, likely due largely to undiagnosed underlying complement deficiency or other immunodeficiency.

Significance

Meningococcal disease is a devastating illness with high rates of death and sequelae among those affected. While meningococcal disease incidence is low in most regions of the world, outbreaks and epidemics still occur particularly in the meningitis belt of Africa. The risk of disease is also substantially elevated among individuals with certain underlying conditions or other risk factors, such as occupational exposure. Because of the high toll of the disease among those affected, the substantial community and economic impact of outbreaks, and the tendency of the disease to strike young and otherwise healthy individuals, the disease causes significant public concern and remains of high public health importance despite relatively low global incidence. Meningococcal group A, C, W, Y conjugate vaccines, along with group B (MenB) vaccines (see Chapter 39), are important tools for prevention of this deadly illness.

History

Early meningococcal vaccines used killed whole bacterial cells. Between 1900 and 1940, several trials were conducted, but the studies frequently had inconclusive results in part because of low incidence among the control groups. Pursuit of a whole-cell vaccine was curtailed by excessive reactogenicity. Following the successful development of tetanus and diphtheria toxoid vaccines in the 1930s, the protective potential of crude meningococcal culture filtrates containing inactivated exotoxin was explored. ^, These preparations were immunogenic, but they were likely contaminated with capsular polysaccharide antigens, outer membranes, and endotoxin.

Enthusiasm for development of meningococcal vaccines waned when antibiotics proved effective for treatment and prevention of secondary cases. By the early 1960s, however, sulfonamide-resistant isolates of N. meningitidis were widespread and represented an important problem among military recruits during the Vietnam War era, prompting renewed interest in meningococcal vaccine development. ^,

Polysaccharide Meningococcal Vaccines

During the early 1940s, Scherp and Rake demonstrated that serum from horses immunized with group-specific capsular polysaccharides protected mice against lethal challenge with N. meningitidis, but purified preparations of capsular polysaccharide had failed to elicit antibody responses in humans. ^, The poor immunogenicity was attributed to the relatively low molecular size of the polysaccharide formulation tested, as studies showed that polysaccharide antigens of high molecular weight induced sufficient antibody responses in humans. ^, By the end of the 1960s, Gotschlich and colleagues had developed an alternative approach for the purification of high-molecular-weight meningococcal polysaccharides that were safe and immunogenic. ^, Vaccines based on these polysaccharides were rapidly deployed to control meningococcal disease in the United States Army resulting in a dramatic reduction in meningococcal disease incidence.

Although meningococcal polysaccharide vaccines were a critical tool for meningococcal disease control for much of the late 20th century, they have been replaced by conjugate vaccines in most settings because of the immunologic inferiority of the former. Although they have an acceptable safety profile and are immunogenic and effective in older children and adults, polysaccharide vaccines have substantial limitations relative to meningococcal polysaccharide-protein conjugate vaccines. They are poorly immunogenic in infants, do not provide a booster response, do not substantially decrease meningococcal pharyngeal colonization and therefore do not provide herd protection, and can induce the phenomenon of immunologic hyporesponsiveness. They are still used at times for outbreak control, particularly in the meningitis belt of Africa, but it is likely that they will eventually be phased out. For a comprehensive review of meningococcal polysaccharide vaccines, refer to this chapter in the 6th edition.

Meningococcal Polysaccharide-Protein Conjugate Vaccines

The chemical conjugation of polysaccharides to protein carrier molecules confers a T-cell–dependent immune response. The success of this approach was first demonstrated in humans with Hib vaccines in the 1980s. Subsequently, similar conjugate vaccines were investigated for the meningococcus for groups A, C, W, and Y (see Table 39.1 for polysaccharide structures). These conjugate vaccines elicit high serum bactericidal antibody titers and boostable immune responses, and overcome the limitations of polysaccharide vaccines discussed above.

TABLE 39.1

Meningococcal Polysaccharide Structures . Polysaccharide Chemical Structures Reproduced From McCarthy PC et al. 2018 (Article Published Under Creative Commons Attribution License Which Permits Unrestricted Use, Distribution, and Reproduction in any Medium, Provided the Original Work is Properly Cited)

Capsular Group	Polysaccharide Structure
A	N -acetyl mannosamine-1-phosphate
C	Alpha 2–9 N -acetyl neuraminic acid [NANA]
W	Copolymer of NANA with galactose
Y	Copolymer of NANA with glucose