Globally, Neisseria meningitidis is an important cause of vaccine‐preventable morbidity and mortality. 1 Each case requires urgent medical and public health intervention to prevent death, disability, and secondary transmission. Sporadic and endemic cases occur worldwide. The meningococcus is also the cause of epidemic meningitis. Epidemic meningococcal meningitis, first described by Vieusseux in Geneva in 1805, remains a public health concern and a challenge for reducing mortality in sub‐Saharan Africa.
The Organism and Clinical Presentation
Neisseria meningitidis is a Gram‐negative, oxidase‐positive, aerobic diplococcus. Encapsulated strains cause the great majority of cases of invasive disease. The meningococcal polysaccharide capsule is an important virulence factor, allowing evasion of opsonization and phagocytic and complement‐mediated killing. 2 Besides being a primary antigen to which bactericidal antibodies are induced during naturally acquired infection, the distinct composition of each meningococcal capsular polysaccharide provides the basis for serogrouping of isolates. Although 13 serogroups are described, 6 serogroups are currently recognized as the most common causes of disease (A, B, C, W‐135, X, and Y). 3
The meningococcus is acquired through direct contact with respiratory droplets. Humans are the sole reservoir, and the usual ecologic niche of the bacteria is the mucus membranes of the upper respiratory tract. 3 In most cases, disease‐causing strains are acquired through close contact with an asymptomatic carrier. 4 Carriage, or colonization of the upper respiratory tract mucosa, is a necessary but not sufficient cause of invasive disease. In populations, carriage varies substantially by age. Although occurring in less than 1% of infants, it may be found in up to 15% of healthy adolescents. 5 In most instances it is either transient or lasts for a period of days to weeks, but may last for months in the minority of persons. 3 Carriage is an immunizing event, affording some level of protection from the development of invasive disease. 6 Behaviors that facilitate contact with respiratory secretions, including intimate kissing or crowded settings such as military barracks and the Hajj pilgrimage, increase the incidence of carriage. 6–8
Although rare overall, the frequency with which disease results following acquisition is influenced by host, environmental, and pathogen factors. Factors that increase the susceptibility to disease include asplenia, complement deficiency, and certain immunocompromising conditions and genetic polymorphisms. 3,9 Damage to the respiratory mucosa resulting from smoking, viral or bacterial co‐infection, and environmental conditions may facilitate meningococcal invasion and development of disease. Most cases of meningococcal disease in industrialized countries are sporadic, occurring without secondary transmission, but persons who are at close contact with those with disease are at up to 800‐fold higher risk for developing disease than those without such exposure. 10 Certain bacterial lineages have increased propensity to cause disease. 11
Disease usually develops within 1 to 14 days following acquisition. 3 Initial symptoms may be nonspecific or resemble viral upper respiratory tract infections. Later symptoms reflect localization, and include intense headache, nausea, vomiting, stiff neck, and photophobia in the case of meningitis, and maculopapular, purpuric, or petecheal rash in the case of bloodstream infection. Delirium and coma often appear. 10 Meningococcal meningitis is the most commonly recognized presentation globally, accounting for 80% to 85% of all reported cases of meningococcal disease, although bloodstream infection may be under‐recognized. The remaining 15% to 20% of cases are most commonly bloodstream infection or pneumonia, but pericarditis, conjunctivitis, urethritis, and arthritis can also occur. 12 Meningitis can occur with or without septicemia. Meningococcal meningitis has a case‐fatality rate of 5% to 10% even with timely antibiotic therapy. 13 In addition, 12% to 19% of survivors develop long‐term neurologic sequelae. 10,14 Severe bloodstream infection, or meningococcemia, may present as purpura fulminans and is associated with an increased case‐fatality rate.
Meningococcal disease incidence is strongly influenced by age group, socioeconomic conditions, serogroup, and bacterial strain as determined by multilocus sequence type. Tremendous variability is observed in meningococcal disease incidence by country and region (Figure 1), and in recent years the implementation of vaccination programs in many countries has begun to reduce the incidence of meningococcal disease. Serogroups A, B, and C account for up to 90% of the disease globally, but with much global variation observed in the relative contribution of each. 15 In industrialized countries, implementation of chemoprophylaxis recommendations for persons in close contact with meningococcal disease case‐patients has effectively reduced the occurrence of secondary cases. 16 However, N meningitidis also causes epidemic meningitis. Meningococcal disease outbreaks are associated with higher case fatality than sporadic cases. 17 Clusters and small‐scale outbreaks pose a worldwide problem, but explosive outbreaks comprising hundreds of thousands of cases are unique to sub‐Saharan Africa. 18
The “meningitis belt” of sub‐Saharan Africa is a region at uniquely high risk for meningococcal disease. The epidemiology is characterized by an elevated baseline incidence of 10 to 20 cases per 100,000 population, annual epidemics coinciding with the dry season, and intermittent explosive epidemics in which attack rates can reach 1,000 per 100,000. 19 The last major serogroup A epidemic occurred in 1996 to 1997 and resulted in hundreds of thousands of cases and over 25,000 deaths. 1 The belt was first proposed by Lapeyssonnie, described as an area between latitudes 4° and 16° north with a high incidence and recurring epidemics. He recognized that disease occurred in areas receiving 300 to 1,100 mm mean annual rainfall, coinciding with much of semi‐arid sub‐Saharan Africa and including the Sahel. 20 Extending from Ethiopia to Senegal, the meningitis belt is now considered to include 12 epidemic prone countries. 21 Many other countries in Africa experience outbreaks, although less frequently and with lower interepidemic incidence.
Serogroup A is the predominant cause of outbreaks in the African meningitis belt. However, outbreaks of serogroups C, X, and W‐135 have been recorded. 22–25 Meningococcal outbreaks are effectively clonal, and are characterized by successive shifts in the predominant sequence type. Since the 1990s, ST‐5 complex strains have predominated, with the notable emergence of ST‐11 W‐135 in 2002 following the outbreak associated with the Hajj pilgrimage in 2000. 1,26,27
The epidemiology of meningococcal disease in South Africa has features both of industrialized and developing countries. Serogroups A, B, C, W‐135, X, and Y are each reported with appreciable frequency. In Western Cape Province (Cape Town), serogroup B predominates. 28,29 From 2000 to 2005 ST‐11 serogroup W‐135 emerged rapidly, replacing serogroup A as the most common cause of endemic disease in Gauteng (Johannesburg) and increasing the overall incidence in this province fivefold, to 4.0 cases per 100,000 population. 29
As in much of the world, in the pre‐World War II era the epidemiology of meningococcal disease in the Americas was characterized by intermittent serogroup A outbreaks with attack rates in the tens of cases per 100,000. Since World War II, serogroup A is effectively absent in the Americas, as it is across the industrialized world. Outbreaks and clusters of meningococcal disease persist, most commonly serogroup C. 17 Serogroup B outbreaks are notable for lower attack rates but prolonged duration. 30–32 The 1990s was witness to the emergence of serogroup Y disease in much of North America, in particular the United States but to a lesser degree Canada. 13,33 Recent vaccination programs have begun to change the epidemiology of serogroup C.
The annual incidence of meningococcal disease in the United States from 1998 through 2007 was 0.53 cases per 100,000 population. 34 This represents a two‐thirds decline in incidence, from 0.92 in 1998 to 0.33 cases per 100,000 in 2007. The highest incidence observed in the United States occurred in Oregon (1.52 cases per 100,000), resulting from ongoing hyperendemic serogroup B disease belonging to sequence type 41/44. 31 The serogroup‐specific incidence of B disease in Oregon was 1.01 cases per 100,000, compared with 0.15 cases per 100,000 in the other Active Bacterial Core Surveillance (ABCs) sites. Excluding Oregon isolates, the serogroup distribution of ABCs isolates is 28.8% C, 29.9% B, 34.8% Y, and 6.1% W‐135 and non‐groupable. Serogroups A, X, and Z accounted for 1, 2, and 4 isolates in ABCs, respectively. Infants are at highest risk, with a second incidence peak in late adolescence. Quadrivalent (A, C, Y, W‐135) meningococcal conjugate vaccine has been recommended for adolescents since 2005, but was implemented without a catchup campaign. 9 Among adolescents aged 11 to 19 years, 75% of cases are caused by serogroups contained in the quadrivalent vaccine. By 2007, coverage among adolescents reached 32.4%; however, the incidence of vaccine‐preventable serogroups remained stable between the periods from 2004 to 2005 and 2006 to 2007, suggesting little observable early impact of the vaccination program. 34,35 By 2008, coverage had increased to 41.8%. In infants, 57% of cases are serogroup B, for which no vaccine is licensed in the United States.
In Canada, serogroups B, C, and Y are the most common causes of meningococcal disease (Figure 1). 36 The overall incidence rates ranged from 0.62 in 2002 to 0.42 per 100,000 in 2006. 37 In 2004 and 2005, serogroup‐specific incidence was highest for serogroup B (0.27 and 0.30 per 100,000 persons, respectively). 38 The highest rates were in children 0 to 4 years, followed by adolescents 15 to 19 years. Rates of disease in infants observed during 1995 through 2004 (average 9.2 per 100,000 persons) were comparable to those observed in infants in the United States in the same period (9.2 per 100,000 during 1991 through 2002). 9,39 The occurrence of hyperendemic disease rates in children in certain provinces prompted implementation of serogroup C meningococcal conjugate vaccination programs. Subsequently, the incidence of serogroup C disease decreased from 0.23 in 2002 to 0.08 per 100,000 in 2006. In contrast, the incidence remained stable for serogroups B, Y, and W‐135. The decrease in serogroup C incidence occurred in provinces with the earliest immunization programs, and declines across all age groups suggest a herd immunity effect. 37 Sporadic and outbreak‐associated disease caused by ST‐11 complex serogroup C emerged during the 1990s. 40 Serogroup B disease caused by ST‐269 complex has also emerged in Canada, as in the UK and other parts of the world. 41
Published data are limited on incidence of meningococcal disease in Latin America. The reported incidence varies from less than 0.1 case per 100,000 inhabitants in countries like Mexico to two cases per 100,000 inhabitants in Brazil. 42 Serogroups B and C are the most prevalent causes of disease, and serogroup A is largely absent (Figure 1). 1 Outbreaks and hyperendemic disease of serogroups B and C have been reported from Chile, Brazil, and Cuba. 43–45 Serogroup B vaccines have been implemented in the latter two countries. 46,47 More recently, serogroups Y and W‐135 have been reported from Argentina and Colombia. 48,49
Despite its relative rarity, the incidence of meningococcal disease varies widely across Europe and it remains prominent on the European public health agenda as a target for new and existing vaccines. 50 Since 1999, the countries of Europe have contributed to a collaborative surveillance system for meningococcal disease. First through the European Union Invasive Bacterial Infections Surveillance Network (EU‐IBIS) and subsequently the European Centre for Disease Prevention & Control (ECDC), 27 countries now participate. In 1999, the incidence across Europe ranged from a low of less than 1 per 100,000 in Poland, Estonia, France, Germany, Slovenia, and Italy to a high of 14.3 per 100,000 in Ireland. 50 As in other industrialized countries, incidence is highest in young children with a second, smaller peak in adolescents. In 2001 the incidence of culture‐confirmed meningococcal disease varied between 0.2 and 6.5 per 100,000 across collaborating countries, and similar variability was observed in reports in 2007, with the incidence of confirmed and probable cases ranging from 0.3 to 4.2 per 100,000. 51,52 Serogroup B has been the most important cause of disease (Figure 1), although the epidemiology of serogroup C disease has prompted the implementation of vaccination programs in many European countries. No fewer than eight countries in Europe have implemented routine meningococcal C conjugate vaccination programs in varying schedules for children and, in some cases, adolescents and young adults, and all have observed substantial declines in incidence. The earliest and most comprehensive such programs was implemented in the UK beginning in 1999, and has resulted in substantial reductions in disease burden through direct protection of vaccinated persons and through reduction in carriage and herd immunity.53,54 Although significant reductions in serogroup C disease were observed, serogroup B remains a substantial contributor to the overall burden of meningococcal disease in Europe, with notable clonal outbreaks documented. 55–57
Asia and The Pacific
The contrast in epidemiology of meningococcal disease is perhaps nowhere more apparent than in Asia and The Pacific. Incidence rates of 3.0 per 100,000 and notable serogroup C clusters prompted vaccination programs in Australia, with subsequent declining incidence. 58–60 New Zealand observed the emergence of an ST‐41/44 serogroup B lineage with incidence rates sustained above 10 per 100,000 for several years in the 1990s and early 2000s. 61 Children and indigenous populations were disproportionately affected. Substantial declines in incidence were observed following introduction of a clone‐specific outer membrane vesicle vaccine. 62 In contrast, serogroup A disease remains a threat in China and India. 63,64 Serogroup C disease has recently emerged in China. 65,66 In response, bivalent (A, C) polysaccharide vaccine was introduced into the Expanded Program on Immunization. 67 Meningococcal disease is reported rarely in Japan. 68 Among 2,600 patients presenting with meningitis to four hospitals in Bangladesh over a 2‐year period, 189 (24%) had a confirmed bacterial etiology, among which 72% were N meningitidis. Serogroup A accounted for 87% of meningococcal disease cases. 69
Special Settings: Outbreaks During the Hajj
Crowded conditions increase the risk of meningococcal disease transmission, and travel can facilitate introduction of new strains into susceptible populations. Two major outbreaks of meningococcal disease occurred in recent years associated with the annual Hajj pilgrimage to Mecca, Saudi Arabia. 7,70,71 The first international outbreak of meningococcal disease associated with the Hajj occurred in 1987 and was caused by N meningitidis serogroup A. 72 This outbreak resulted in an attack rate of 640 per 100,000 American pilgrims. Subsequently, Saudi Arabia required vaccination against N meningitidis serogroup A as a condition for receiving a Hajj visa. In March and April 1992, the health surveillance system in Saudi Arabia detected increasing numbers of cases of N meningitidis serogroup A, but further spread was not detected. 71 Serogroup W‐135 was identified in 6.4% of 483 confirmed cases of meningococcal disease admitted to Mecca hospitals from 1987 through 1997. 73 In the 2000 Hajj, more than 400 cases of W‐135 infection in pilgrims and their close contacts were reported from 16 countries. 26,71,74–76 Attack rates in returning pilgrims of 25 to 30 per 100,000 were reported from several countries. 71,77,78 The outbreak was determined to have resulted from expansion of a hypervirulent lineage. 26 Subsequently, quadrivalent vaccine has been required for entry into Saudi Arabia for the Hajj.
The epidemiology of meningococcal disease exhibits remarkable diversity across the globe, with incidence rates ranging from less than one case per 100,000 in many industrialized countries to attack rates of 1% during meningitis belt epidemics. Meningitis remains prominent in the public consciousness both in industrialized settings and in the developing world. A limited number of countries have successfully implemented meningococcal conjugate vaccination programs, but more remains to be accomplished. No broadly protective serogroup B vaccines are yet available, and the countries of the African meningitis belt await a conjugate vaccine developed to end epidemic meningitis as a public health concern. 79 Even as meningococcal disease epidemiology is described, the risk to travelers is incompletely understood. However, the increasing frequency and ease of travel may increase the risk of acquiring meningococcal disease for travelers, and of introducing new strains into susceptible populations.
Declaration of interests
The authors state they have no conflicts of interest to declare.