GLOBAL EPIDEMIOLOGY OF CAPSULAR GROUP W MENINGOCOCCAL
DISEASE, 1970-2014: EMERGENCE AND PERSISTENCE OF HYPERVIRULENT ST11 LINEAGE
by
Mustapha Munir Mustapha
MBBS, Bayero University, Nigeria 2007
Submitted to the Graduate Faculty of
Department of Epidemiology
Graduate School of Public Health in partial fulfillment
of the requirements for the degree of
Master of Public Health
University of Pittsburgh
2015
UNIVERSITY OF PITTSBURGH
Graduate School of Public Health
This essay is submitted
by
Mustapha Munir Mustapha
on
December 1st, 2015
and approved by
Essay Advisor:
Lee H. Harrison, MD
Professor,
Departments of Epidemiology and Medicine
Graduate School of Public Health and School of Medicine
University of Pittsburgh
Essay Reader:
Maria Mori Brooks, PhD
Associate Professor,
Department of Epidemiology
Graduate School of Public Health
University of Pittsburgh
Essay Advisor:
Jane W Marsh, PhD
Research Associate Professor,
Department of Medicine
School of Medicine
University of Pittsburgh
ii
Copyright by Mustapha Munir Mustapha
2015.
iii
Essay Advisor: Lee H Harrison, MD
GLOBAL EPIDEMIOLOGY OF CAPSULAR GROUP W MENINGOCOCCAL
DISEASE, 1970-2014: EMERGENCE AND PERSISTENCE OF THE HYPERVIRULENT
ST-11 LINEAGE
Mustapha M Mustapha, MPH
University of Pittsburgh, 2015
ABSTRACT
Following an outbreak in Mecca Saudi Arabia in 2000, meningococcal strains expressing
capsular group W (W) emerged as a major cause of invasive meningococcal disease (IMD)
worldwide.
The Saudi Arabian outbreak strain (Hajj clone) belonging to the ST-11 clonal complex (cc11) is
similar to W cc11 causing occasional sporadic disease before 2000. Since 2000, W cc11 has
caused large meningococcal disease epidemics in the African meningitis belt and endemic
disease in South America, Europe and China. Traditional molecular epidemiologic typing
suggested that a majority of current W cc11 burden represented global spread of the Hajj clone.
However, recent whole genome sequencing (WGS) analyses revealed significant genetic
heterogeneity among global W cc11 strains. While continued spread of Hajj-related strains
occurs in the Middle East, the meningitis belt and South Africa have co-circulation of the Hajj
clone and other unrelated W cc11 strains and South America, the UK and France share a
genetically distinct W c11 strain. Other W lineages persist in low numbers in Europe, North
America and the meningitis belt. In summary, WGS is helping to unravel the complex genomic
epidemiology of group W meningococcal strains. Wider application of WGS and strengthening
iv
of global IMD surveillance is necessary to monitor the continued evolution of group W lineages.
There is need for a vaccine that is protective against group W in the meningitis belt.
Public Health relevance: This essay presents a critical review of studies reporting IMD
surveillance data spanning four decades and places in context the recent findings of WGS studies
to the epidemiology of group W IMD. This report will be of use to Public Health surveillance
and policy professionals in several countries currently facing a rise in number of W cc11 cases
and persistence of sporadic group W cases. Data presented in this review also provides evidence
in support of introduction of group W in the African meningitis belt.
v
TABLE OF CONTENTS
BACKGROUND AND SIGNIFICANCE ................................................................................................. 1
Neisseria Meningitidis .......................................................................................................................... 1
Public Health Significance .................................................................................................................... 2
Aims ...................................................................................................................................................... 4
MOLECULAR CHARACTERISTICS OF GROUP W ......................................................................... 6
Multilocus sequence typing (MLST) .................................................................................................... 6
Outer membrane proteins (OMP), PorA, PorB, and FetA. ................................................................... 6
Whole Genome Sequencing (WGS) ..................................................................................................... 7
Factor H binding protein (FHbp) .......................................................................................................... 8
16S ribosomal RNA gene (16S)............................................................................................................ 9
“Capsular switching” ............................................................................................................................ 9
GLOBAL INCIDENCE OF MENINGOCOCCAL GROUP W DISEASE ........................................ 10
Group W IMD incidence, 1970 – 1999................................................................................................... 10
Group W incidence: 2000 and beyond .................................................................................................... 13
Saudi Arabia (Hajj) 2000-2001 .......................................................................................................... 13
Middle East: endemic W following Hajj epidemics. ........................................................................... 14
Africa: emergence of W cc11 epidemics ............................................................................................. 14
USA and Canada................................................................................................................................. 17
Asia ..................................................................................................................................................... 18
Australia and New Zealand................................................................................................................. 19
DISCUSSION ............................................................................................................................................ 21
CONCLUSION ......................................................................................................................................... 22
vi
BIBLIOGRAPHY ..................................................................................................................................... 23
vii
LIST OF FIGURES
Figure 1: Meningitis belt, 2006 ...................................................................................................... 3
Figure 2: Molecular typing of invasive capsular group W N. meningitidis in Brazil, 1990-2005..
....................................................................................................................................................... 12
Figure 3: Distribution of confirmed N. meningitidis in Taiwan, 1996-2002.. .............................. 13
Figure 4. Distribution of capsular groups among confirmed invasive meningococcal disease
cases, meningitis belt 2003-2015. ................................................................................................. 16
Figure 5. Global occurrence of capsular group W cc11 meningococcal disease, 2000-2014. ..... 20
viii
BACKGROUND AND SIGNIFICANCE
Neisseria Meningitidis
Neisseria meningitidis (meningococcus), an important cause of bacterial meningitis and sepsis
worldwide shows dynamic changes in strain distribution over time [1]. The 13 African countries
of the ‘meningitis belt’ have the highest incidence of endemic disease and periodic epidemics
occur in this region (Figure 1) [2]. The major meningococcal virulence factor is the
polysaccharide capsule, which is the target of capsular group-specific vaccines [3] Capsular
groups A, B, C, W (formerly W-135), Y and X cause almost all invasive meningococcal disease
(IMD). Other virulence factors include major outer membrane proteins (OMP) PorA, PorB,
FetA, FHbp and lipooligosaccharide [4, 5]. N. meningitidis undergoes genetic change through
point mutation, phase variation, homologous recombination and acquisition of genetic material
from both within and outside Neisseria species [4, 6]. These phenomena result in substantial
genetic variability even among meningococcal isolates of the same lineage and facilitate
emergence and persistence of virulent lineages [7, 8].
N. meningitidis capsular group W (W) was first observed among military recruits in the United
States in the late 1960s [9, 10]. The pathogenic potential of group W was recognized by the midlate 1970s [11, 12]. W emerged as a major global cause of IMD following a global outbreak that
began among Hajj pilgrims in Mecca, Saudi Arabia in 2000 which resulted in over 400 cases and
52 deaths; previously, group W had not been known to cause outbreaks [13]. The Hajj outbreak
strain was characterized as clonal complex (cc) 11, PorA antigen gene type P1.5,2, with a
distinct pulsed field gel electrophoresis (PFGE) pattern and 16S ribosomal RNA (16S) type 31
[14]. Since 2000 several W epidemics have occurred in the meningitis belt and case clusters have
1
been reported in South Africa, South America, Europe, United States and China [15-21].
Surveillance studies have shown that group W strains are associated with high high case fatality
[18, 22], younger age groups [21, 23-28], and atypical clinical features such as arthritis and
pericarditis [20, 29-34]. For example, the median age of patients with group W IMD in South
Africa 2000-2005 was 5 years compared to 21 years among cases with group A disease [21]. In
Burkina Faso in 2002 – 2003, 62% of W cases were in children <5years old compared to 7% of
group A cases [35].
Molecular surveillance studies using traditional genotyping techniques suggested that the current
global burden of W cc11 represented continued spread of the epidemic Hajj clone [36, 37].
However, recent data based on whole genome sequencing (WGS) suggest that the molecular
epidemiology of W cc11 is more complex [38]. In this review, we examine the global
distribution and molecular characteristics of group W from 1970-2015 with emphasis on the
emergence of endemic and epidemic W cc11 disease since 2000.
Public Health Significance
IMD is often a fatal disease; mortality rates range between 5-10% with survivors suffering from
long term sequelae such as hearing loss and other neurologic deficits, limb amputation, and renal
damage [39, 40]. Transmission is through close contact with airway droplets of
asymptomatically colonized individuals. Risk factors for IMD are close contact with an IMD
patient, cigarette smoking, kissing, immune complement deficiency and crowding in bars,
dormitories or large human gatherings [1].
Jafri et al [41] classified global meningococcal disease incidence pattern into countries with
epidemic and/or high endemic disease with incidence rates >10 cases per 100,000 population that
2
comprise most African countries, Uruguay, New Zealand and Mongolia. The highest incidence
rates of 100-1000 per 100,000 are witnessed during occasional epidemics across 21 countries
[42] in Africa collectively referred to as the ‘meningitis belt’ (Figure 1) [2]. Moderate endemic
rates are between 2-10 cases per 100,000 population and occur in South Africa, some European
countries, Brazil, Cuba and Australia. Remaining countries have low endemic rates
(<2/100,000).
Figure 1: Meningitis belt, 2006
(Source: U.S. Centers for Disease Control and Prevention)
The epidemiologic pattern of meningococcal disease differs by capsular group over time [43].
Capsular group A is most common cause of epidemic meningitis; for example, an outbreak of
group A meningococcal disease in 1996 in the meningitis belt resulted in over 250,000 cases and
3
25,000 deaths [44]. Group B causes sporadic disease and small outbreaks in low to moderate
endemic countries [45, 46] but is very uncommon in the meningitis belt. Group C also causes
sporadic disease and small case clusters globally [47], although group C strains occasionally
cause large epidemics in the meningitis belt [48]. In recent decades, groups W and Y have
emerged to cause significantly higher number of meningococcal disease cases globally [13, 17,
20, 49-52] while smaller group X [53, 54] epidemics have occurred in the meningitis belt.
IMD is a rapidly progressive disease that can cause death within 24-48 hours in previously
healthy individuals or may lead to serious sequelae among survivors [55]. Additionally,
outbreaks of meningococcal disease cause substantial economic cost and societal disruption [56,
57].
Vaccines remain the primary control strategy against meningococcal disease [58]. Laboratory
surveillance of circulating meningococcal strains is critical for monitoring trends, informing
vaccine policy, timely detection of outbreaks, and understanding the emergence of new IMD
strains.
Aims
This essay reviews the global distribution of group W meningococcal disease across five decades
with a focus on the recent emergence of the W cc11 in recent decades as a major cause of
meningococcal disease globally. A comparative review of current and historic molecular typing
approaches used to classify group W strains is also presented. The aim is to provide Public
Health personnel, microbiologists and epidemiologists with a reference framework that will
assist in critical evaluation and interpretation of local meningococcal incidence and surveillance
reports in order to make sound evidence-based public health decisions.
4
Surveillance data presented in this essay, combined with the recent success with the control of
group A disease in the meningitis belt [59], make a compelling case for the introduction of a
multivalent protein conjugate vaccine that covers group W strains in the meningitis belt where
several thousand cases of IMD are caused by W strains. We also propose strengthening global
meningococcal disease surveillance and broader application of whole genome characterization
given the limitation of conventional genotyping approaches in discriminating group W strains.
5
MOLECULAR CHARACTERISTICS OF GROUP W
Multilocus sequence typing (MLST)
MLST is the method of choice for determining the genetic lineage of N. meningitidis [60].
Strains of the same sequence type (ST) share a common lineage and closely related STs are
grouped under the same clonal complex (cc). Cc11 is a globally widespread, hyperinvasive cc
comprised of strains expressing capsular groups B, C, W and Y [61, 62]. Historically, cc11 was
more commonly associated with capsular group B in the 1960s [63, 64] and with group C from
the early 1970s [65, 66]. Group W strains represented only a very small proportion of cc11
strains in the 1970s-1990s [61]. Following the Hajj 2000 epidemic [13], cc11 became the
predominant W lineage globally and the only group W lineage associated with epidemic disease.
Sporadic group W belonging to other clonal complexes have occurred at low levels globally [36,
67] including cc22 in North America [46, 68] and Europe [37, 69, 70]; cc175 in the meningitis
belt [54, 71, 72] and cc174 in Brazil [36].
Outer membrane proteins (OMP), PorA, PorB, and FetA.
PorA and PorB are virulence determinants and the basis of serologic classification of
meningococci. Meningococcal serotype and serosubtype are based on antigenic properties of
PorB and PorA respectively [61]. Serologic classification has been superseded by gene sequence
typing curated by the PubMLST database (pubmlst.org/neisseria/) [73]. Sequence variation
within the porA gene, combined with MLST is a powerful tool for molecular surveillance [73,
74]. The porB [75] and fetA [76] genotypes are often used to further characterize invasive
meningococcal strains. The W cc11 lineage is characterized by a remarkably stable outer
membrane allelic profile P1.5,2:F1-1:2-2 (PorA VR1,VR2:FetA:PorB) despite global spread and
6
different epidemiologic patterns over four decades [14, 15, 17, 21, 37, 70, 77, 78]. Although the
P1.18 porA allele predominates among W cc22 strains [46, 69, 70, 79], OMP allelic profile
variability among W cc22 isolates is consistent with non-clonal, sporadic disease
(http://pubmlst.org/neisseria/) [37, 46].
Pulse field gel electrophoresis (PFGE):
PFGE [80] has been used by some molecular epidemiologic studies [14, 36, 81, 82] to
discriminate W cc11 Hajj outbreak strains from endemic strains. Six of 19 (32%) sporadic preHajj W cc11 isolates were indistinguishable by PFGE from the Hajj clone with remaining 13
isolates having >85% PFGE similarity to the Hajj clone [14]. Also, non-Hajj related W cc11
from Cameroon in 1999-2000 had 2-3 band differences from Hajj clone by PFGE [82]. It was
not clear whether strains with ≥3 PFGE band differences compared to the Hajj clone isolated
from France [37], Burkina Faso [83] and Brazil [36] in 2000-2003 represented continued
expansion of the Hajj clone. Thus, PFGE was able to discriminate between W isolates belonging
to different clonal complexes but was less discriminatory for epidemic and sporadic W cc11
strains. Despite this limitation, PFGE has been utilized to describe W strains as likely
descendants of the Hajj clone [36, 83].
Whole Genome Sequencing (WGS)
WGS data are now publically available for several hundreds of genomes and are increasingly
applied to the study of molecular epidemiology of global meningococcal lineages [87, 88]. Indepth genomic comparison of group B, C and W cc11 strains using genome-wide allelic
profiling [89, 90] revealed that W cc11 strains were phylogenetically distinct from C and B
strains. Phylogenetic studies [38, 90] also show that the W cc11 forms a distinct branch within
7
cc11, suggesting that a majority of current and historic W cc11 strains shared a common origin,
likely through a historic capsular switching event [91]. WGS studies have further discriminated
W cc11 strains into a number of distinct phylogenetic clusters. Based on allelic profiles of 1546
core genomes, Lucidarme et al [90] classified W cc11 into Anglo-French Hajj strains; Burkina
Faso/North Africa strain and South American/UK strain (Table 1). Similarly, based on antigenic
profiles, SNP and core genome phylogenetic analyses, Mustapha et al [91] discriminated W cc11
strains linked to the Hajj outbreak from non-Hajj related endemic clusters and showed that the
Hajj cluster acquired a number of unique virulence factors through allelic exchange. In summary,
these studies demonstrate significant genetic diversity within W cc11 lineage and that genetically
distinct sub-lineages were associated with different geographic and epidemiologic settings.
Factor H binding protein (FHbp)
FHbp is a meningococcal surface protein and one of the polysaccharide capsule-independent
antigens used in vaccines that were developed for prevention of group B disease [5]. There is
marked variability in the fHbp gene among W cc11 strains globally. The Hajj clone and
descendant strains shared FHbp protein 9 (variant group 1); non-Hajj related W cc11 strains
shared FHbp proteins belonging to variant groups 2 and 3; FHbp 22 is predominant among nonHajj strains in Chile, Argentina, and Europe while strains from Africa and Brazil shared FHbp 23
and 151 respectively (http://pubmlst.org/neisseria/) [18, 20, 38, 92, 93]. Substantial fHbp gene
diversity could be a common characteristic shared by cc11 strains regardless of capsular group
given that group C cc11 strains from Canada were recently shown to exhibit extensive fHbp gene
diversity [94].
8
16S ribosomal RNA gene (16S)
16S sequencing showed promise in discriminating the Hajj clone from sporadic W cc11. The
Hajj clone contained 16S type 31 while sporadic W cc11 had 16S types 13 and 14 [14, 36].
“Capsular switching”
The expression of a different polysaccharide capsule through allelic exchange of capsular genes,
has been linked with an increased incidence of meningococcal disease [84, 85]. In 1970-1999,
cc11 genetic lineage was most commonly associated with invasive group C strains [61, 86]. This
observation suggested that W cc11 strains arose through C→W capsular switch, although the
true direction of the genetic exchange is unknown.
9
GLOBAL INCIDENCE OF MENINGOCOCCAL GROUP W DISEASE
Group W IMD incidence, 1970 – 1999
Capsular group W was associated with sporadic IMD cases globally in the 1970s through the
mid-1990s. However, some surveillance data from the African meningitis belt, UK, Brazil and
Taiwan suggest an increase in W cc11 in the mid- to late 1990s, predating the Hajj 2000
epidemic.
Active surveillance in the United States identified W in 3% and 4% of invasive meningococcal
isolates from 1989-1991 [95] and 1992-1996 [96] respectively. In Canada W caused 3-6% of
annual reported IMD cases in 1997-1999 [97] and <1% of IMD cases in Quebec, 1991-1992
[98]. In Australia 6% of 66 IMD isolates in 1971-1980[99] and 8.2% of 110 IMD isolates in
1977-1987 [100] belonged to group W. In Netherlands, W strains predominantly with PorB
serotype 2a, represented <2.5% of all IMD isolates in 1959-1983 [101, 102] and 19801990[103]; W strains with phenotype 2a:P1.2,5 caused 3.5% of IMD in Poland, 1995-1996
[104]. In Italy, W strains represented 3.6% of 56 confirmed IMD cases in Italy 1994 [105] and
<1% in 1999-2001 [106] Sporadic W cases caused <8% of IMD cases in Norway and Denmark
in the 1970s [107]; in Greece, 1996-1997 [108]; East Germany, 1971-1984[109] and Scotland
1972-1982 [110]. In England and Wales, average annual W cases increased to 42 cases/year in
1996/97-1998/99 compared to 18 cases/year in 1993/94-1995/96 [47] Some sporadic W strains
from 1970-1999 from UK [14], France [37], Netherlands and Sweden [70] were found to be
genetically similar to the Hajj clone by various molecular typing methods [14, 37, 70]. In
Sweden, P1.18 subtype, associated with cc22 was also common among sporadic W strains [70].
10
In summary, diverse W strains, including strains genetically similar to the Hajj clone caused a
small proportion of IMD cases across Europe and North America during 1970-1999.
In the African meningitis belt, W cc11 was identified in 3.1% of 349 endemic meningococcal
disease strains from Senegal and Niger in 1981-1982 [111] and 7.3% of 41 strains from the
Gambia [112]. In 1992-1995, an unexpectedly high proportion of W cc11 (43%) was observed in
a small sample of 14 endemic case isolates in Gambia [113]. In Brazil, W represented <2% of all
meningococcal disease isolates from 1990-2001 [36]. The proportion of Brazilian W cc11
isolates increased from 35% of 63 W isolates in 1990-1995 to 80% of 56 W isolates in 19961999 [36], while the proportion of cc174 declined from 52% to 16% among W isolates (Figure
2). All 67 W cc11 strains from Brazil in 1990-1999 were indistinguishable from the Hajj clone
by porA and fetA genotyping but differed from the Hajj clone by both16S and PFGE [36].
Laboratory surveillance in Taiwan identified W cc11 among 30% (16/53) of confirmed IMD
cases in 1996-1999 (Figure 2B) [114] while rare W cases were reported from Malaysia [115],
Indonesia[14] and Thailand [116] in the 1980s and 1990s. W strains have been identified among
disease isolates in Saudi Arabia throughout the 1990s [117-119]. Group W comprised 13% of
IMD case isolates in Saudi Arabia in 1994-1999 [119] and a small proportion (<10%) of IMD
isolates in Egypt [120], Israel [121] and Kuwait [122] in the 1980s and 1990s. These data
demonstrate that W strains were endemic to the Middle East and W cc11 cases existed in parts of
Asia since the 1980s.
11
Figure 2: Molecular typing of invasive capsular group W N. meningitidis in Brazil, 1990-2005.
Based on data from Lemos et al [36].
12
Figure 3: Distribution of confirmed N. meningitidis in Taiwan, 1996-2002.
Based on data from Chiou et al [114].
Group W incidence: 2000 and beyond
Saudi Arabia (Hajj) 2000-2001
During the Hajj 2000 outbreak, over 400 cases of W cc11 disease were recorded among pilgrims
and their close contacts across 16 different countries in Europe, Africa, Middle East, Southeast
Asia and the United States (Figure 5). This represented the first known outbreak of group W
disease [13, 22, 123, 124]. In 2001, a similar outbreak among pilgrims from Saudi Arabia
occurred with 106 meningococcal cases reported that were indistinguishable from the 2000 Hajj
clone by MLST, porA and fetA genotyping [22, 125] and by PFGE [14, 37, 70]. In 2002, a
quadrivalent polysaccharide vaccine that covers W capsular antigen was made a visa requirement
13
for all pilgrims traveling to Saudi Arabia, where no subsequent W outbreaks have been reported
[22, 125].
Middle East: endemic W following Hajj epidemics.
Following the 200-2001 epidemics in Saudi Arabia, W became a leading cause of endemic
meningococcal disease across the Middle East [126]. While Saudi Arabia witnessed a decline in
meningococcal disease from 338 cases in 2000 to 6 cases in 2009, reports from Qatar, Oman,
Kuwait and United Arab Emirates indicated that W was the most commonly identified
meningococcal group in 2001-2009 [122, 126]. It is unclear whether these endemic W cases
represented spread and persistence of the Hajj clone. Laboratory surveillance of IMD strains
identified W cc11 in 4.5% of 67 IMD isolates from Egypt, 1998-2003 [120] and 38.1% of 333
confirmed pediatric IMD cases in Turkey, 2005-2012 [127]. WGS studies demonstrate that
endemic W cc11 strains from Turkey represent continued spread of the Hajj clone [90].
Africa: emergence of W cc11 epidemics
Cases of W cc11 among Hajj pilgrims and their contacts were reported across Africa in
Morocco, Sudan, Chad, Central African Republic, and Burkina Faso in 2000 and 2001 [42, 124].
In 2001, disease caused by W cc11 was equally as common as group A in a non-representative
sample of cases from outbreaks in Burkina Faso and Niger [128]. In 2002, the largest known W
epidemic occurred in Burkina Faso, with over 12,000 cases and 1,400 deaths [78]. More than
80% of cases were due to W cc11 strains [56] with antigenic type P1.5,2 similar to the Hajj clone
[78]. In 2003-2008, W cc11 epidemics subsided despite persistence of endemic cases [25, 42]
[129]. Also, a substantial proportion of endemic W disease in the meningitis belt was caused by
W cc175 [67, 81, 130]. These data demonstrate the presence of other clonal W lineages in the
meningitis belt post Hajj. Further W cc11 epidemics were recorded across the meningitis belt in
14
2009-2014 [17, 24, 42, 131] making W the most commonly isolated capsular group across the
meningitis belt in 2010-2014 (Figure 4). Genomic analyses [20, 38, 90] reveal that W cc11 in the
meningitis belt were heterogeneous, with persistence of both the Hajj clone and strains unrelated
to the Hajj outbreak. Hajj related W cc11 shared FHbp allele 9 while FHbp alleles 23 and 151
were predominant among non-Hajj endemic strains in the meningitis belt [38, 92]. Given the
limited number of isolates characterized by whole genome sequencing, the relative contribution
of the Hajj clone to W cc11 epidemics across the region is difficult to assess [17, 23, 132, 133].
The introduction of a highly effective group A polysaccharide-protein conjugate vaccine
(MenAfriVac) in 2010 – 2014 led to a dramatic reduction in group A meningococci both in
disease cases and asymptomatic carriage [59, 134] that could lead to elimination of group A
epidemics within the region and underscores the importance of the recent emergence of W
disease.
15
Figure 4. Distribution of capsular groups among confirmed invasive meningococcal disease
cases, meningitis belt 2003-2015.
On average, 9.3% of suspected meningitis cases had their cerebrospinal fluid (CSF) tested for
common bacterial pathogens in 2005-2010 compared to 25.5% in 2011-2015. Others* depict all
confirmed cases that were not group A or W in 2004-2009. Data from 2005 covers only weeks 118 while 2015 data covers the first 35 weeks of the year when most meningococcal disease cases
occur. Based on publically available data from WHO
(http://www.who.int/csr/disease/meningococcal/en/) [42].
Outside the meningitis belt, W strains, predominantly belonging to cc11, represented 9% of 350
IMD strains from South Africa in 1999-2002 [135]. In 2005, South Africa witnessed a doubling
16
of meningococcal disease incidence due to an increase in W cc11 [21]. Similarly,
meningococcal disease incidence attributed to W cc11 increased in neighboring Mozambique
from 2005-2008 [136]. Similar to the meningitis belt, South Africa also has co-circulation and
persistence of non-Hajj endemic W cc11. More than 72% of W cc11 cases in South Africa in
2003-2013 were caused by strains representing continued spread of the Hajj clone [38] while
28% were phylogenetically diverse, non-Hajj related isolates that shared FHbp alleles 22, 151
and 4 (http://pubmlst.org/neisseria/) [38]. Genetic heterogeneity among non-Hajj W cc11 strains
in South Africa could represent evolution of a historical strain over several decades or may be a
result of multiple introductions of global W cc11 lineages.
South America: Emergence of endemic W cc11 clusters.
Southern Brazil, Argentina and Chile witnessed the emergence of W cc11 as a major cause of
endemic meningococcal disease after 2003 [137]. Case clusters first appeared in southern Brazil
where W represented 17.8% of all invasive strains in 2003-2005 compared to 3.2% in 1995-2002
[138]. In Argentina, W cases increased from 7% in 2006 to 50% of all isolates in 2008-2011
[49]. Similarly, the proportion of W cc11 increased in Chile from 6.6% in 2010 to 58.3% in 2012
[18]. Similar to UK, and France, W cc11 from Chile and Argentina also shared FHbp allele 22
[18, 90] while Brazil W cc11 strains had FHbp allele 151.
USA and Canada
No increase in endemic W in the United States was observed despite presence of Hajj related W
cc11 cases in 2000 [14]. W made up 2.3% (48/1979) of all isolates identified through sentinel
surveillance in the United States during 2000-2010 [46, 79]; cc22 predominated with only 2
cases of W cc11. However, a cluster of 14 W cc11 cases was reported in 2008-2009 in Florida
[15]. WGS reveals that W cc11 from Florida were most genetically similar to South American
17
strains [38]. Low incidence rates of W disease (0.01-0.05 per 100,000) have persisted in Canada
from 1990-2011 accounting for 5% of all IMD cases [139]. In Quebec 2009-2013, W cc22
represented 3.8% of 263 confirmed IMD cases [68].
Europe: emergence of endemic W cc11 clusters and persistence of sporadic W cc22
Cases of W cc11 among returning pilgrims and their close contacts were reported across several
European countries in 2000 and 2001 [22, 123]. An overall increase in W disease occurred in
France [140]. Among 101 W case isolates in France 45% (45/101) belonged to cc11 among
which 32% (32/101) were indistinguishable from the Hajj clone by serotyping and PFGE [37]. In
2006-2008, W cc11 cases declined and were replaced by cc22 [29]. A cluster of imported W
cc11 cases from the meningitis belt was reported in France during 2012 [16]. A similar increase
in W cases related to the Hajj outbreak was seen in the England and Wales 2000-2002 [47]; W
cases returned to pre-2000 levels in 2003 – 2008 and then increased again in 2009-2014, with
15% of all meningococcal disease cases in 2013-2014 being group W.[20] Over 67% of all W
cases in the UK 2010-2013 belonged to cc11 while cc22 persisted as a cause of sporadic disease
[20]. In Spain, W cc22 strains represented 1.6% of IMD cases in the Basque region, 1990-2004
[141]. Likewise in Italy, W persisted as a cause of sporadic IMD causing for 2.6% of IMD cases
in 2006-2014 [142, 143] where cc22 predominated with fewer W cc11 isolates [69].
Recent W cc11 case clusters from the UK, Ireland and France 2009-2015 formed a common
phylogenetic cluster with strains from Brazil, Chile and Argentina [90]. These data suggest that
European W cc11 clusters represent continuing spread of the South American strain.
Asia
In Singapore, Hajj related and endemic W cc11 cases were reported in 2000-2002 [144] but have
not been reported since 2003 suggesting disappearance of endemic W cc11 [144]. In Taiwan
18
2000-2001, average W cc11 case isolates increased to 34 cases/year compared to 4 cases/year in
1996-1999 [114]. Also, endemic W cc11 cases emerged in China (2011-2012) where 24.4%
(11/45) confirmed IMD in 2011 -2012 cases were W cc11 [19]. Rare group W cases belonging to
cc4821 have also occurred in China [145]. It is unclear whether W cc11 in Taiwan and China
represent expansion of local endemic strains or continued global spread of the Hajj clone. A few
W cases (<4) were also reported in Malaysia [115], India [146] and Japan [147]. In Korea, a
cluster of three of W cc11 cases whose OMP genotype (P1.5-1,2-2:F3-9) differed from that of
other global W cc11 strains was identified among military recruits [148]. These data demonstrate
the complex molecular epidemiology of W strains, and the need to strengthen molecular
surveillance of N. meningitidis in parts of Asia.
Australia and New Zealand
In Australia, W caused 1.5-5% of annual IMD cases in 1997-2012; group W isolates were of
diverse porA genotypes including a few with P1.5,2 genotype similar to that found in global W
cc11 strains [149]. Disease caused by W continued to be rare in New Zealand, accounting for
3.5% of 700 reported IMD cases in 2008-2013 [45]. One case of W:P1.5,2:cc11, identical to
global W cc11 strains, was reported in New Zealand, while a cluster of W cc11 P1.7-2,4 cases
genetically distinct from global W cc11 was reported in 2003 [85]. A New Zealand W cc11 P1.72,4 strain was shown to have arisen through capsular switching between locally endemic group C
and a carriage group W strain.[85].
19
Figure 5. Global occurrence of capsular group W cc11 meningococcal disease, 2000-2014.
Blue boxes represent W cc11 strains with known epidemiologic and/or genetic link to the Hajj
2000 outbreak; red boxes represent W cc11 strains not linked to the Hajj outbreak and gray
boxes represent W cc11 clusters with unknown link to the Hajj outbreak.
20
DISCUSSION
Epidemic W cc11 IMD began with the 2000 Hajj outbreak. However, an upward trend in W cc11
sporadic cases occurred in the mid to late 1990s in the meningitis belt [82, 113], Brazil [36], UK
[47] and Taiwan [114]. Application of WGS to molecular surveillance of meningococcal disease
revealed that several W cc11 case clusters arose independent of the Hajj epidemic consistent
with global multifocal emergence of W cc11 [20, 38, 90]. W cc11 was found to comprise a
number of genetically and geographically diverse sub-lineages and different sub-lineages could
coexist within the same country at the same time. W cc22 in Europe and North America and
cc175 in Africa have persisted as a cause of a minority of disease cases.
The Hajj, an annual gathering of over 2 million people from around the world is an ideal setting
for the selection and rapid global dissemination of virulent meningococci. For example, in 1987,
a Hajj-related meningococcal outbreak facilitated the spread of virulent group A cc5
meningococci from south Asia to sub-Saharan Africa [150]. Excessive crowding during the Hajj
may have facilitated rapid, intense transmission of an antigenically novel strain within an
immunologically naïve population [86]. The Hajj clone and its descendants shared a number of
recombination events leading to allelic exchange within fHbp gene and metabolic genes, nor and
aniA. These methobolic genes may be involved in nasopharyngeal survival of meningococci and
could have played a role in increased virulence of the Hajj clone. It is also hypothesized that the
polysaccharide group A/C vaccine requirement for Hajj pilgrims in the 1990s could have led to
selection of a group W strain that had undergone capsular switching [86, 151]. Existence of
multiple endemic clusters caused by strains unrelated to the Hajj epidemic suggests that different
21
genetic and/or environmental factors could be responsible for emergence and persistence of
different sub-lineages in different epidemiologic settings.
CONCLUSION
Group W strains belonging to clonal complex (cc) 11 have emerged during the past 15 years as a
major cause of global meningococcal disease. The recent success with the control of group A
disease in the meningitis belt has led to the predominance of W as the cause of meningococcal
disease in the region [59]. This, in combination with the emergence of disease caused by
capsular groups X [54, 152] and C [48], underscore the need for polyvalent vaccines for the
meningitis belt. Strengthened global meningococcal disease surveillance and broader application
of whole genome characterization is needed given that conventional molecular typing does not
sufficiently discriminate W cc11 strains.
22
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