The Global Evolution of Meningococcal Epidemiology Following the Introduction of Meningococcal Vaccines

Journal of Adolescent Health 59 (2016) S3eS11

www.jahonline.org Review article

The Global Evolution of Meningococcal Epidemiology Following the Introduction of Meningococcal Vaccines Stephen I. Pelton, M.D. * Maxwell Finland Laboratory for Infectious Diseases, Boston, Massachusetts

Article history: Received November 12, 2015; Accepted April 8, 2016 Keywords: Meningococcal disease; Epidemiology; Vaccine; Immunization

A B S T R A C T

Invasive meningococcal disease (IMD) caused by Neisseria meningitidis is associated with high morbidity and mortality. Although IMD incidence is highest in infants, a second peak occurs in adolescents/young adults. The incidence of IMD and the predominant disease-causing meningococcal serogroups vary worldwide. Epidemiologic data have guided the development of meningococcal vaccines to reduce the IMD burden. In Europe, serogroup C IMD has been substantially reduced since the introduction of a serogroup C conjugate vaccine. Serogroup B predominates in Europe, although cases of serogroup Y IMD have been increasing in recent years. In the United States, declines in serogroup C and Y disease have been observed in association with the introduction of quadrivalent (serogroups ACWY) meningococcal conjugate vaccines; serogroup B persists and is now the most common cause of outbreak associated disease. In the African meningitis belt, a conjugate vaccine for serogroup A has been effective in decreasing meningitis associated with that serogroup. Outbreaks of the previously rare serogroup X disease have been reported in this region since 2006. In recent years, outbreaks of serogroup B IMD, for which vaccines have only recently been approved by the U.S. Food and Drug Administration and the European Medicines Agency, have occurred in Europe and the United States. Targeting meningococcal vaccination to adolescents/young adults may reduce the morbidity and mortality associated with IMD and has the potential to impact the larger community through herd benefits. Ó 2016 Society for Adolescent Health and Medicine. All rights reserved.

Invasive meningococcal disease (IMD) is a condition, too often fatal, caused by invasion of the bacterium Neisseria meningitidis into the blood stream and subsequent development of septic shock and purpura fulminans in a subset of patients. When the bacterium gains access to the central nervous system, meningitis

Conflicts of Interest: S.I.P. has received honorarium for participation on vaccine advisory boards, including those on meningococcal vaccines and for participation in vaccine symposiums for Sanofi, Novartis, and Pfizer. He has had Investigator Initiated Research funding from Pfizer. He received no payment for his participation in the development of this manuscript. Disclaimer: Publication of this article was supported by Pfizer, Inc. The opinions or views expressed in this supplement are those of the authors and do not necessarily represent the official position of the funder. * Address correspondence to: Stephen I. Pelton, M.D., Maxwell Finland Laboratory for Infectious Diseases, 670 Albany Street, 6th Floor, Boston, MA 02118. E-mail address: [email protected]. 1054-139X/Ó 2016 Society for Adolescent Health and Medicine. All rights reserved. http://dx.doi.org/10.1016/j.jadohealth.2016.04.012

results. The morbidity and mortality resulting from either condition is substantial, with a case-fatality rate (CFR) approximating 10% in developed countries [1e3]. Many survivors experience permanent debilitating sequelae such as hearing loss, neurologic impairments, or limb loss [3,4]. The incidence of IMD varies by geographic region and ranges from <.5 to .9 cases per 100,000 population in North America and Europe to 10 to 1,000 cases per 100,000 population in the African meningitis belt. Incidence is highest in infants and young children, with a second smaller peak in adolescents and young adults (Figure 1) [8,9]. Colonization of the nasopharynx is a prerequisite for IMD, and humans are the only host for this organism. Colonization is typically asymptomatic; however, N. meningitidis can translocate from the nasopharynx to the blood stream, resulting in disease. Transmission may occur following close contact with an infected or colonized individual.

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A

United States 1998–2007

Incidence

15 10 5 0

5.38

<1

1.04

0.38

0.78

0.28

0.69

1–4

5–14

15–24

25–64

≥65

Age Group

B

Europe 2011

15

Incidence

12.3 10

4.1

5

0

<1

1–4

0.8

1.3

5–14

15–24

0.2

0.3

0.4

25–49

50–64

≥65

Age Group

C

Burkina Faso 2011

Incidence

15

10

5 2.0 0

<1

2.0

1.5 1–4

5–14

0.7

0.3

15–29

≥30

Age Group Figure 1. Universality of meningococcal epidemiology: highest incidence in infancy with second peak during adolescence (all serogroups). (A) Invasive meningococcal disease in the United States, 1998e2007, cases per 100,000 population [5]; (B) invasive meningococcal disease in Europe after introduction of MenCC, 2011; cases per 100,000 population [6]; (C) meningococcal meningitis in Burkina Faso after introduction of MACV, 2011, cases per 100,000 population [7].

N. meningitidis is a gram-negative diplococcus in which most pathogenic isolates are encapsulated [10,11]. The major categorization of N. meningitidis is by capsular polysaccharide serogroup, of which there are 13. Most cases of IMD are caused by serogroups A, B, C, W-135 (referred to as serogroup W herein), X, and Y [12], with serogroup prevalence differing according to geographic region (Figure 2). A more detailed molecular characterization scheme termed multilocus sequence typing is derived from the analysis of seven housekeeping genes and groups isolates into sequence types and sets of related sequence types called clonal complexes [14,15]. The ability to characterize strains by multilocus sequence typing and sequence types is important for characterizing outbreaks to determine if they are due to a single strain circulating within the community and for identification of hypervirulent strains. Because of rapid bacterial multiplication in the bloodstream and the subsequent progression of disease, immediate antibiotic treatment and hospital admission with supportive care of

patients is required when IMD is suspected [16]. In addition to antibiotic prophylaxis for secondary prevention in close contacts, vaccination may also be of value in controlling meningococcal outbreaks [17]. Effective vaccines are available for serogroups A, C, W, and Y [18], and vaccines for serogroup B (MnB) have recently been approved [19]. Although it is well documented that infants experience high rates of IMD, meningococcal carriage rates in infants in western countries are relatively low, rising as high as 25%e33% by young adulthood in the United Kingdom [20,21]. In the African meningitis belt, carriage rates are highest in individuals aged 5e14 years (5%) [22]. Although carriage isolates are genetically heterogeneous in nature, isolates that cause IMD usually represent a subset of those carried [14]. The properties that make these hyperinvasive strains more pathogenic have not yet been completely identified, but it has been postulated that the presence of viral genetic material incorporated and expressed by N. meningitidis (a bacterial prophage) [23,24] may be a virulence

S.I. Pelton / Journal of Adolescent Health 59 (2016) S3eS11

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A,C B,C B,C,Y

A,W-135,C,X

B,C

B,C

Figure 2. Predominant serogroups associated with invasive meningococcal disease worldwide [13].

factor. As well, host genetic factors [25] may contribute to susceptibility to disease. Introduction of serogroup-specific vaccines for N. meningitidis has been shown to reduce the prevalence of IMD. To maximize the benefit of these vaccines, it is imperative to understand the local epidemiology of IMD in specific geographic areas where they will be used. A number of recent articles have examined the epidemiology of IMD globally [12,26] and in individual countries [1,27e33]. However, meningococcal epidemiology evolves over time due to secular trends and vaccine pressure. It is the intent of this supplemental review article to present the most recent epidemiologic data and to assess the changes that have occurred since the introduction of meningococcal vaccines. Invasive Meningococcal Disease by Geographic Region United States In the United States, the quadrivalent ACWY vaccine (MenACWY) was recommended by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention in 2005 for individuals aged 11e12 years [34]. A 2011 update from ACIP recommended administration of a booster dose at age 16 [35]. In the United States, ACIP also recommended (in 2015) an MnB vaccine series which may be administered to adolescents and young adults aged 16 through 23 years to provide short-term protection against most strains causing serogroup B meningococcal disease; the preferred age for vaccination is 16 through 18 years [36]. ACIP also recommends vaccination with an MnB vaccine in at-risk persons aged 10 years and older [19]. Currently approved MnB vaccines in the United States are bivalent rLP2086 (Trumenba; MenB-FHbp) and 4CMenB (Bexsero; MenB-4C). Even before the recommendation for universal immunization of adolescents with meningococcal vaccines, the rate of IMD in the United States began to steadily decrease in the year 2000 after a high in 1999 of 1.1 per 100,000 population (Figure 3).

A comparison of periods before (2000e2005) and after (2006e2010) the introduction of the quadrivalent vaccine found that serogroups B, C, and Y were most frequently associated with IMD both before and after MenACWY introduction [39]. In the most recent reporting year (2013), 556 cases of meningococcal disease were reported to the National Notifiable Disease Surveillance System (.18 cases/100,000 population); serogroup B and C accounted for most cases [37]. Although the genetic composition of isolates varied, strains of N. meningitidis from cases of IMD before and after the introduction of universal adolescent immunization with meningococcal quadrivalent vaccine remained genetically similar [39]. There was evidence of capsule switching (strains with genetic markers that were previously associated with one capsule type now found with a different capsule type) during both periods. Outbreaks of meningococcal disease (multiple cases due to the same strain of N. meningitidis in the same “community”) account for approximately 2% of cases; in the last 4 years, outbreaks on college campuses have been reported primarily due to serogroup B and in the men having sex with men communities primarily due to serogroup C [40,41]. Data suggest that infection with influenza virus may be a predisposing factor for the development of IMD because seasonal peaks in IMD routinely occurred 2 weeks after peaks in hospitalization for influenza [42]. This suggests that increased use of influenza vaccines in the United States may also impact IMD incidence. Between 2003 and 2013, the rate of meningococcal meningitis decreased from .61 per 100,000 to .18 per 100,000 in the United States [37]. Data from National Vital Statistics Reports indicate that deaths from meningococcal infection have decreased almost every year between 1997 (309 deaths) and 2013 (59 deaths) (Figure 3) [38]. Europe As in the United States, many European countries have seen reductions in IMD cases in recent years. For example, substantial

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Deaths

Deaths

Incidence

350

0.7

300

0.6

250

0.5

200

0.4

150

0.3

100

0.2

50

0.1

0

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

0

Incidence per 100,000 population

S6

Year Figure 3. Incidence and deaths from meningococcal disease in the United States. Incidence data per 100,000 population from the National Notifiable Diseases Surveillance System [37]. Deaths from meningococcal disease from the National Vital Statistics System [38].

decreases in IMD rates have been observed in the Netherlands (from 4.5 to .6 per 100,000 population between 2001 and 2012) [43], Germany (from .94 to .47 per 100,000 population between 2003 and 2010) [44], and England and Wales (from 5.37 to 2.21 per 100,000 population between 1998/1999 and 2008/2009) [45]. Among the combined 29 European Union countries reporting surveillance data, the rate of IMD cases dropped from 1.9 per 100,000 population in 1999 to 1.1 per 100,000 population in 2007 [46]. Recently, however, an increase in IMD has been reported in Sweden, as cases rose from .6 per 100,000 population in 2010 to .95 per 100,000 population in 2012 [47]. In Europe, serogroups B and C were responsible for most cases of IMD at the beginning of the 21st century [43]. Because of an increased number of cases and deaths seen in the 1990s, a conjugate vaccine for N. meningitidis serogroup C (MenCC) was approved in the United Kingdom in 1999 [48], followed by incorporation of this vaccine into the national immunization programs (NIPs) of a number of other European countries [49]. Consequent reductions in IMD cases associated with serogroup C occurred in all countries where MenCC was used [50], and cases of IMD associated with serogroup C have proportionately decreased in the years following MenCC introduction [46]. Thus, as of 2011, serogroup B remains the most prominent cause of IMD among most countries of Europe (73.6% of IMD cases) with serogroup C associated with only 14.4% of cases [6]. In recent years, the proportion of serogroup Y IMD cases has increased in a number of European countries. In particular, in 2013, the Scandinavian countries (with the exception of Denmark) all had proportions of serogroup Y IMD greater than 10% of all IMD cases in which the serogroup was determined. In Sweden, serogroup Y was the predominant serogroup from 2011 to 2013, with approximately 50% of serogrouped IMD cases caused by serogroup Y each year [51]. During this period, the incidence of IMD was .6 per 100,000 population in 2010 and 2011 and rose to .95 per 100,000 population in 2012 [47]. In England and Wales, although the overall incidence of IMD declined between 2007 and 2009, the proportion of cases caused by serogroup Y increased each year [52]. The increase in serogroup Y cases in Europe may be partially due to the preferential use of MenCC as opposed to the quadrivalent serogroup ACWY vaccine. Although neither serogroup A nor serogroup W cause an appreciable number of IMD cases in Europe [6], the incidence of serogroup W disease has been increasing in England and Wales since 2009 [53]. In 2013/2014 serogroup W was associated with 15% of IMD cases [53]. In response to this increase, the Joint Committee on Vaccination and Immunisation of Public Health England has recommended that individuals aged 14e18 years be vaccinated

with the quadrivalent conjugate ACWY vaccine with the goal of generating herd immunity in the overall population against serogroup W disease [54]. In 2007, 23% of IMD cases in Europe were meningitis and 23% were septicemia (of a total of 5,491 IMD cases), with 11% being both meningitis and septicemia and 42% being of unknown clinical presentation [46]. In 2011, there were proportionately more meningitis and septicemia cases (43% and 33%, respectively, of a total of 1,824 IMD cases), with 18% being meningitis and septicemia. The apparent increases may actually be the result of more complete reporting as there were no cases classified as “unknown” for that year [6]. The CFR in Europe was 8.1% in 2007 and varied considerably among the reporting countries. The highest CFRs in 2007 were in Hungary (16.3% of 43 IMD cases) and Poland (14.0% of 335 IMD cases) [46]. In 2011, the CFR in Europe was 8.7%, with the highest rates occurring in Slovakia (40.0% of 20 cases) and Hungary (17.9% of 67 cases) [6]. Latin America The incidence of IMD varies among the Latin American countries, with incidence rates ranging from .6 per 100,000 in Argentina (1990e2003) and Chile (2009) to 3.4 per 100,000 in Uruguay (Canelones, 2001e2002) [55]. Because of the large geographic area that encompasses Latin America, the predominant serogroups that cause IMD vary by location. Serogroup C has been predominant in the regions of Mexico, Central America, the Caribbean, and Brazil, whereas serogroup B has predominated in the Andean region and the Southern Cone region (Argentina, Chile, and Uruguay) [56]. However, even within a country as large as Brazil, serogroup C has recently been the most common serogroup associated with IMD across internal regions, gaining in prominence (Federal District) or overtaking serogroup B (Amazonas) [33,57]. Recently, there has been an increase in cases of serogroup W IMD reported in the Southern Cone [58]. In Brazil and Argentina, an increased percentage of IMD cases has been caused by serogroup W since the mid-2000s [58]. In Chile, the percentage of serogroup W IMD cases has increased every year between 2009 (1.8%) and 2012 (58.3%), and it is now the predominant serogroup in that country [59]. Increases in the percentage of serogroup W IMD cases between 2010 and 2011 were observed in the <1-year (25% vs. 62.5%) and >20-year (6.6% vs. 27.7%) age groups [60]. Most of the serogroup W isolates in South America belong to single sequence type [57], similar to the virulent strains identified in Hajj pilgrims in 2000 [60]. Currently, meningococcal vaccines are rarely included in the NIPs in Latin American countries. The exceptions are Cuba, which,

S.I. Pelton / Journal of Adolescent Health 59 (2016) S3eS11

beginning in the 1980s, has vaccinated infants with a combination serogroup C polysaccharide conjugate and serogroup B outer membrane vesicle vaccine, and Brazil, which, beginning in 2011 has vaccinated infants with a serogroup C conjugate vaccine [55]. Meningococcal vaccines have also been used in other age groups in response to outbreaks of IMD [61,62]. A case-control analysis following administration of the serogroup C conjugate vaccine following one of these outbreaks found an overall vaccine effectiveness of 98% [63]. The effect of the vaccine was also assessed in the Federal District of Brazil where the overall incidence of IMD was reduced by 68% and an 80% decline occurred in serogroup C IMD after vaccine introduction [57]. Africa The rate of meningococcal meningitis in regions of subSaharan Africa greatly exceeds that occurring in other regions of the world [64]. Meningococcal disease epidemics in the African meningitis belt typically occur during the dry season from January through June when the incidence can reach as high as 1,000 cases per 100,000 population. In periods between outbreaks, the rate of endemic disease remains relatively high at 10 to 25 cases per 100,000 population [65]. In the decades between 1990 and 2010, the predominant serotype associated with outbreaks in the meningitis belt has been serogroup A [66], with specific sequence types causing many of the meningitis cases [67,68]. This high incidence of serogroup A meningitis led to the development of a serogroup A polysaccharide conjugate vaccine (MACV) [69] that was administered in 2010 to nearly 100% of the population of Burkina Faso between the ages of 1 and 29 years [70]. Since that time, immunization campaigns with MACV have been conducted in a number of countries within the meningitis belt with generally high coverage rates reported [71e73]. In the period between 1995 and 2004, an estimated 60,000 deaths occurred during meningococcal outbreaks in this region [66]. In 2005, before the introduction of MACV, the CFR among countries in the meningitis belt ranged from 4% in Mali to 26% in Benin [66]. Since introduction of MACV, the overall CFR in the surveillance countries has been relatively stable at 8.5%, 9.1%, and 9.1% in 2012, 2013, and 2014, respectively [71e73]. Widespread use of MACV has been accompanied by an overall reduction in epidemic activity among countries in the meningitis belt that have reported surveillance data [71,73]. In Burkina Faso, more meningitis cases were reported during the 2012 meningitis season than in the 2011 season, primarily because of an increase in serogroup W cases [74]. In contrast, in regions of Chad where MACV was not used, serogroup A still predominated [75], demonstrating the shift in serotypes in communities in countries with a successful vaccination program. Among meningitis cases in 2012 through 2014 from which the serogroup has been determined, W is now the most common serogroup (76%, 72%, and 81% of meningococcal isolates identified) [71e73]. Analysis of serogroup W isolates from cases in Niger in 2010 and 2011 and Burkina Faso in 2012 found a single sequence type was dominant [74,76]. Although rare in other parts of the world, meningococcal meningitis associated with serogroup X has been documented in a number of African countries [77]. In 2006, serogroup X meningitis outbreaks occurred in Niger, Kenya, and Uganda [77]. Although the incidence of serogroup X meningitis is still relatively low, the number of cases, as well as the lack of an effective vaccine, warrants continued surveillance of meningococcal disease associated with this serogroup.

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Asia and Western Pacific The paucity of surveillance data from most countries in the Asian and Western Pacific regions makes confidence in epidemiologic trends in this area difficult. In general, meningococcal vaccines are not included in the NIPs of countries in this region. In China, serogroup A was the predominant serogroup associated with IMD until the early 2000s [78]. A serogroup A polysaccharide vaccine introduced in 1982 led to a stabilization of IMD cases in China at .2 to 1 case per 100,000 population. However, an increase in serogroup C cases in 2002/2003 led to a vaccination program with a combined serogroup A/C polysaccharide vaccine in 2004. Data from the city of Hefei, in Anhui Province, found that the incidence of IMD peaked in 2005 at 8.43 cases per 100,000 and then decreased to 2.32 cases in 2010. There was a concomitant shift in the percentage of serogroup C IMD cases from 83% in 2005 (with 13% of cases identified as serogroup A) to 40% in 2010 (with 49% of cases identified as serogroup A) [78]. The CFR of serogroup C IMD was roughly double that of serogroup A IMD from 2000 to 2010. Because IMD is rare in Japan, a study to assess the characteristics of meningococcal isolates examined those collected between 1974 and 2003 [79]. The predominant serogroups among these isolates were serogroups B (57%) and Y (21%). No meningococcal vaccines are currently approved for use in Japan [80]. As in Japan, IMD is uncommon in Korea [81]. Data from isolates collected from IMD cases in 2002/2003 found that serogroup Y was the most common among this small sample (9 of 11 isolates, 81.9%) [81]. Among 16 N. meningitidis isolates collected from the cerebrospinal fluid of children with bacterial meningitis aged <5 years in Jeonbuk Province (2001/2002), nine were serogroup X (56.3%) and six were serogroup Y (37.5%) [82]. Following an outbreak of IMD at a military training center in 2011, Korean authorities recommended that beginning in 2012, new military recruits receive the quadrivalent ACWY conjugate vaccine [83]. Beginning in 1994, Australia has conducted an annual survey of IMD (the Australian National Neisseria Network). The number of IMD cases recorded in the most recent National Neisseria Network report (2013) was 143, the lowest number since the surveillance system started. The number of IMD cases has been declining in Australia since 2002, due in part, to the introduction of the serogroup C conjugate vaccine to the NIP in 2003 (single vaccination at 12 months of age with a catch-up program for individuals aged 1e19 years) [84]. In 2002, serogroups B and C accounted for 55.8% and 41.5% of IMD cases, respectively [85]. Most cases in 2013 were associated with serogroup B (72.7%) with serogroup Y associated with 10.5% [86]. Similar to the situation in Australia, the incidence of IMD has generally been declining in New Zealand since 2002 [87]. The incidence of IMD in 2013 was 1.5 per 100,000 population, which is the lowest it has been for 20 years. The predominant serogroup in 2013 was serogroup B (52.6% of IMD cases), followed by serogroup C (29.8%) [87]. A prolonged epidemic of IMD associated with serogroup B led to the development and administration (beginning in 2003) of a serogroup B outer membrane vesicle vaccine specific for the endemic New Zealand strain [88]. Despite this restricted specificity, the high vaccine coverage (83%) and effectiveness (77% vs. the unvaccinated population) [89] are likely to have been factors in the decline of IMD rates observed in New Zealand in recent years.

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Age Group Considerations The incidence of IMD is highest in infants aged <1 year and remains relatively high until approximately age 5 years. Although the incidence tends to decrease in older children, it usually spikes again during adolescence and young adulthood when individuals are living in close quarters. Incidence again tapers off in older adults. This pattern has been observed at both the regional [1,6,46,64] and country levels [1,5,30,44] and with individual serogroups [27,45] (Figure 1). The CFR of IMD is sometimes higher in infants than in older children [30,44,64] but is routinely highest in adults aged
65 years [1,30,44,64,90,91]. As with IMD incidence levels, high CFRs among older adults are observed when rates associated with individual serogroups are examined [27,30]. General trends can also be observed when examining the prevalence of serogroups in the various age groups. In North America and Europe, serogroup B is the most common serogroup associated with IMD in infants [1,5,6,27e29,44,46], with incidence also routinely spiking during adolescence and young adulthood [27,44,92] in the current era of universal immunization with MenACWY in adolescents. Recent surveillance data from Europe indicate that serogroup B is the causative agent for at least 70% of IMD cases in all age groups up to 24 years [6]. The proportion of IMD cases caused by serogroup B generally declined with age but remained relatively high in individuals at or older than 65 years. There has been a substantial reduction in serogroup C IMD in all age groups in the Netherlands [43,49] and in England and Wales [45] after the introduction of the serogroup C vaccine. This suggests that the protection of the older and/or nonvaccinated population likely results from herd protection induced by the vaccine [45,49]. Likewise, in the United States, the incidence of IMD associated with serogroups C, W, and Y among the 11- to 19-year-old population has been declining since the introduction of the quadrivalent vaccine [92]. In Europe, substantial increases in serogroup Y IMD have been observed in the <1-, 1- to 4-, and 25- to 49-year age groups between 2008 and 2011 [6]. In England and Wales, the highest incidence of serogroup Y IMD in 2009 was in those aged 15e19 years, 45e64 years, and
65 years [52]. Serogroup Y IMD in the United States is typically seen in older individuals, although cases in infants have become more common in recent years [93]. Meningococcal Carriage and the Effect of Vaccines N. meningitidis is a common constituent of the human nasopharyngeal microbiota, and carriage is a necessary precursor to the development of IMD. Although IMD rates are highest in infants and young children, carriage rates typically peak in late adolescence/young adulthood and then decline [22,94]. Recent studies have found carriage rates of 4.5% in infants, 23.7% in those aged 19 years, and 7.8% in 50-year olds in countries where serogroups B and C were predominant (such as in Europe) [94]. Overall N. meningitidis carriage rates in 2012 among university students in Chile were 4% [95]. In the African meningitis belt, the carriage rate of N. meningitidis was 1.8% in infants, 4.9% for those aged 5e14 years, and 2.6% for individuals
30 years [22]. Relatively low N. meningitidis carriage rates of 3.2%e4.0% were found in the U.S. states of Georgia and Maryland in 2006e2007 [96], indicating the variations in carriage rates may be observed between different geographic areas. This is a substantial decrease

compared with a similar study conducted in Georgia in 1998 in which the carriage rate was 6.1%e7.7% [97]. The high transmissibility of N. meningitidis is demonstrated by the rapid increase in carriage rates when students begin living in university dormitories [98,99] and in the acquisition of serogroup W in pilgrims to the Hajj as well as in their household contacts [100]. Prevention of N. meningitidis serogroup C carriage and subsequent herd effect leading to reduction in IMD in unimmunized individuals is an important benefit of immunization programs. The reduction in meningococcal carriage following vaccination appears limited to the polysaccharide-conjugate formulations and is rarely seen with polysaccharide-only formulation [101]. Administration of a meningococcal A/C polysaccharide vaccine during an outbreak in Brazil had no effect on overall carriage rates. In contrast, meningococcal conjugate C (capsular polysaccharideprotein) vaccines have routinely demonstrated a serogroupspecific reduction in carriage. In the United Kingdom, administration of the serogroup C conjugate vaccine led to a substantial reduction in serotype C carriage in university students for up to 2 years after vaccine administration [102]. Conversely, the carriage rate of meningococcal serogroup Y has been increasing in a cohort of university students in the United Kingdom [98]. In Burkina Faso, carriage studies 2 years after widespread use of the serogroup A conjugate vaccine have shown that carriage of serogroup A has been nearly eliminated [98].

Recent Meningococcal Outbreaks The introduction and widespread use of meningococcal vaccines for serogroup C in Europe and for serogroups A, C, W, and Y (with growing use in Europe) have led to reductions in IMD associated with these serotypes. Until recently, the lack of a vaccine targeting serogroup B has meant that individuals were vulnerable to this pathogen. Accordingly, a number of outbreaks caused by serogroup B have occurred in recent years. Because of the contagious nature of N. meningitidis, these outbreaks often occur among those interacting in classrooms, residence halls, or the workplace. The U.S. Centers for Disease Control and Prevention defines an MnB organizational outbreak as one in which more than one case occurs that are “linked by a common affiliation other than a shared, geographically delineated community” [103]. Since 2010, there have been five MnB outbreaks (Table 1) in the United States [104,107,108,110,111], one in Ireland [105], and one in the United Kingdom [106]. The outbreaks in the United States, in which 2e10 confirmed cases per outbreak were identified, have all involved students at universities or contacts of those students. Analysis of isolates from patients indicates that different MnB clones (as determined by sequence type) were recovered from several of the outbreaks [104,107,108,110,111]. The recent U.S. Food and Drug Administration approval of vaccines for MnB and recommendations for use in 16- to 18-year old individuals as well as during outbreak situations may serve to prevent the morbidity and mortality resulting from MnB outbreaks. MnB vaccines have been used (in consultation with the U.S. Food and Drug Administration) before approval in some of the U.S. outbreaks described here [108,109] and were associated with halting of the outbreak. Laboratory analysis indicates that antisera from subjects vaccinated with bivalent rLP2086 are bactericidal for MnB isolates from recent university outbreaks in the United States [112], and pooled sera from adolescents and

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Table 1 Invasive meningococcal disease outbreaks associated with serogroup B since 2010 Location

Dates

Number of cases

Serotypes/clonal complexes

Reference

Ohio, USA Irelanda Warwickshire, UKa New Jersey, USAa California, USA Oregon, USA Rhode Island, USA

January 2008eNovember 2010 March 2010eNovember 2013 February 2013eJune 2013 March 2013eMarch 2014 November 2013 January 2015 February 2015

10 8 5 8 4 7 2

ST-269/ST-269 ST-6697/ST-41/44 ST-1194/ST-41/44 ST-409/ST-41/44 ST-32/ST-32 Not available ST-9069

[104] [105] [106] [107] [108] [109] [110]

a

Associated with the same sequence type serogroup B strain.

infants vaccinated with 4CMenB are bactericidal for strains associated with recent IMD outbreaks worldwide [113]. Outbreaks of serogroup C disease in men having sex with men have been reported since 2013 in three European countries: Germany, France, and Belgium [114]. This strain is related to the outbreak strain identified in New York City from 2010 to 2013. Most recently, eight cases of meningococcal disease have been reported from the United Kingdom and Sweden in youth returning from the 23rd World Scout Jamboree and their contacts [115]. In two of the cases in the United Kingdom, a serogroup W strain was isolated as the causative agent and which is identical to a strain already circulating in the that country. Two large outbreaks of meningococcal serogroup C IMD are currently occurring in Africa. Between January and May 2015, Niger’s Ministry of Public Health notified the World Health Organization of 8,500 suspected cases of meningococcal meningitis, including 573 deaths [116]. This is the first large-scale meningitis outbreak caused by N. meningitidis serogroup C to hit any country in Africa’s meningitis belt. During a similar period (January 2015 through March 2015), Nigeria notified the World Health Organization of 652 suspected cases of meningococcal disease, including 50 deaths, apparently due to serogroup C [117]. Both of these outbreaks emphasize the potential for serotype shifts following introduction of meningococcal conjugate vaccines with limited coverage of clinically relevant isolates. Summary and Future Considerations Studies of the epidemiology of meningococcal disease demonstrate significant differences in serogroup distributions by geographic regions. The introduction of MenCC vaccines in Europe, MenACWY in the United States and Canada, and MACV in Africa appear to be associated with declines in vaccine type disease and shifts in serotype distributions in those geographic regions. Serogroup B has become the major cause of outbreaks as well as endemic disease in Europe and North America. Serogroup X and W demonstrate increasing importance in Africa and serogroup Y is more prevalent in Scandinavia and United Kingdom. Regional epidemiologic considerations have guided the development and use of meningococcal vaccines, which have been effective in the serogroup-specific reduction of IMD in areas where those vaccines have been used. Although evidence of capsular switching has not been extensive thus far, an increased prevalence of serogroups either not covered in existing vaccines (e.g., serogroup X in Africa) or contained in vaccines that are not in common use (e.g., serogroup Y in Europe) has been observed. Because infants, adolescents, and young adults are a population at increased risk for IMD, and serogroup B is one of the most predominant serogroups in the United States, the recently

approved MnB vaccines are particularly applicable to these age groups. The MnB vaccine licensed in the European Union was added to the NIP of England in September 2015 [118]. Epidemiologic surveillance will continue to be important in providing data on which national and regional health authorities can base vaccination policies. Further reductions in the morbidity and mortality associated with IMD may be achieved with the introduction of serogroup appropriate vaccines informed by epidemiologic data. Acknowledgments Medical writing support was provided by Daniel E. McCallus, Ph.D., of Complete Healthcare Communications, LLC, and was funded by Pfizer Inc. The sponsor of the supplement had no role in content of this manuscript. Funding Sources This supplement was supported by Pfizer Inc. References [1] Baccarini C, Ternouth A, Wieffer H, et al. The changing epidemiology of meningococcal disease in North America 1945-2010. Hum Vaccin Immunother 2013;9:162e71. [2] Sadarangani M, Scheifele DW, Halperin SA, et al. The impact of the meningococcal serogroup C conjugate vaccine in Canada between 2002 and 2012. Clin Infect Dis 2014;59:1208e15. [3] Stein-Zamir C, Shoob H, Sokolov I, et al. The clinical features and longterm sequelae of invasive meningococcal disease in children. Pediatr Infect Dis J 2014;33:777e9. [4] Pace D, Pollard AJ. Meningococcal disease: Clinical presentation and sequelae. Vaccine 2012;30(Suppl 2):B3e9. [5] Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998-2007: Implications for prevention of meningococcal disease. Clin Infect Dis 2010;50:184e91. [6] European Centre for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe. Available at: http://ecdc.europa.eu/ en/publications/Publications/invasive-bacterial-diseases-surveillance-2011. pdf. Accessed April 13, 2015. [7] Novak RT, Kambou JL, Diomande FV, et al. Serogroup a meningococcal conjugate vaccination in Burkina Faso: Analysis of national surveillance data. Lancet Infect Dis 2012;12:757e64. [8] Australian Government Department of Health. Meningococcal - Australian meningococcal surveillance programme annual reports. Available at: http://www.health.gov.au/internet/main/publishing.nsf/Content/cda-pubsannlrpt-menganrep.htm. Accessed August 18, 2015. [9] Centers for Disease Control and Prevention. Active bacterial core surveillance (ABCs) surveillance reports. Available at: http://www.cdc.gov/ abcs/reports-findings/surv-reports.html. Accessed August 18, 2015. [10] Harrison OB, Claus H, Jiang Y, et al. Description and nomenclature of Neisseria meningitidis capsule locus. Emerg Infect Dis 2013;19:566e73. [11] Rouphael NG, Stephens DS. Neisseria meningitidis: Biology, microbiology, and epidemiology. Methods Mol Biol 2012;799:1e20. [12] Jafri RZ, Ali A, Messonnier NE, et al. Global epidemiology of invasive meningococcal disease. Popul Health Metr 2013;11:17.

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