Annual Hajj pilgrimages of 2000 and 2001: first international W meningococcal outbreak

The Hajj 2000 international outbreak

An international emergency was reported following the annual Hajj season in Saudi Arabia in March 2000 [Reference Mayer6, Reference Popovic9], leading to secondary clusters in Muslim communities around the world as pilgrims returned to their countries of origin, demonstrating the epidemic potential of this serogroup [Reference Hahné10, Reference Taha11]. More than 400 W invasive cases were confirmed worldwide among pilgrims and their close contacts in at least 16 countries (Belgium, Denmark, Finland, France, Germany, Indonesia, Kuwait, Morocco, Norway, Oman, Saudi Arabia, Singapore, Sweden, The Netherlands, UK, USA) [Reference Mayer6, Reference Popovic9] (Fig. 1).

Fig. 1. World map showing the extent of known cases associated with serogroup W in countries reporting a significant proportion of cases and outbreaks.

How did the situation evolve after Hajj 2000?

A significant number of W cases were reported towards the end of the 2001 epidemic season in Burkina Faso and Niger [Reference Taha12] and in January 2002 the first major epidemic of meningococcal disease caused by serogroup W began in Burkina Faso, with more than 12 000 cases and 1400 deaths [Reference Koumaré13], confirming the potential of W isolates to cause major epidemics in African countries as suggested by Kwara et al. in 1998 [Reference Kwara8] (Fig. 1).

This association with major epidemics suggests a high capability for transmission. In fact, consistent high levels of asymptomatic carriage of W ST11/ET37 strains (5·5% prevalence in children aged 5 years) were found in 1996 during a study in children in The Gambia [Reference MacLennan14] and also recently in Burkina Faso [Reference Kristiansen15], suggesting the capability for that clone both to persist and to be transmitted among susceptible populations. Wilder-Smith et al. [Reference Wilder16] found that 15% of returning pilgrims to Hajj 2000 carried a single W clone and 55% were still carriers 6 months later, emphasizing that W ST11/ET37 CC strains are highly transmissible and persistent, thus constituting a potential risk not only to their close contacts but also for the community in general. These data were later confirmed by Nicolas et al. in 2005 [Reference Nicolas17], who analysed carriage of this clone in pilgrims and their family contacts in Morocco, Oman and Sudan, with W strains persisting for several months. More recently, a study conducted in Turkey in pilgrims travelling to the Hajj shows an important prevalence of W strains among carriers (around 11%) before the trip and a significant percentage of acquisition of the epidemic strain W when they returned from the pilgrimage, also suggesting a high rate of transmission among their household contacts [Reference Ceyhan18]. The duration and high prevalence of serogroup W in carried strains might favour the dissemination to the population in general (not only to the household contacts), resulting in an increasingly wider reservoir.

Owing to the observed high persistence and transmissibility, new reports of the increase and spread of W strains have appeared in literature [Reference Caugant5, Reference Wilder-Smith, Chow and Goh19, Reference Parent du Châtelet, Barboza and Taha20]. In a recent study, W ST11/ET37 CC strains were identified in almost all the countries in the African meningitis belt from 2004 to 2010, mainly associated with sporadic cases and small epidemics [Reference Caugant5]. The W ST11/ET37 CC strains seemed to disappear from Burkina Faso after 2006 and the sporadic W isolates found in this country belonged to ST175 CC, which has not been associated with major epidemics and is responsible for endemic disease cases. However, W ST11/ET37 CC re-emerged in carriers as well as patients, after the country-wide mass vaccination with A conjugate vaccine [Reference Kristiansen15]. In Chad serogroup W strains became predominant during most of the period 2004–2008, where the strains belonged to either ST11/ET37 CC or ST175 CC. This shows the contribution of other CCs in serogroup W emergence in Africa and other geographical regions, suggesting the continuous emergence of new W genetic lineages [Reference Taha11]. An increased number of W cases was observed in Niger in 2010 and the isolates belonged to ST11/ET37 CC [Reference Collard21]. The study shows a continuous spread of W strains in the African meningitis belt. Whether the introduction of a new serogroup A conjugate vaccine (PsA-TT) [Reference Frasch, Preziosi and LaForce22] in a nationwide mass vaccination campaign in the African meningitis belt starting in Burkina Faso in December 2010 will have some effect in other non-A serogroup epidemic strains, particularly in W strains, is something to be evaluated in future studies. Looking at the current situation, during the first quarter of 2012 [23], alerts for meningococcal disease were reported in 10 countries of the African meningitis belt (Fig. 1). The outbreaks were mainly associated with W strains. In spite of tremendous success in controlling epidemics for serogroup A in the region [Reference Djingareya24, Reference Daugla25], enhanced surveillance needs to be maintained to monitor the evolution of serogroups in the region both in patients and in asymptomatic carriers. There is no evidence for serogroup replacement with serogroup C conjugate vaccines, but this is not demonstrated for other serogroups like A or W. Recent studies show a strong impact of MenAfriVac vaccination on serogroup A in carriers [Reference Kristiansen15, Reference Kristiansen26] and there is not yet strong evidence for serogroup replacement [Reference Kristiansen15], in either the disease or its carriers.

In South Africa, a country located outside the African meningitis belt, serogroup W was established as the predominant cause of endemic disease in 2008 [Reference von Gottberg27]. This situation currently looks rather stable [Reference von Gottberg28] and is associated with a high mortality rate. A similar situation, with serogroup W appearing as predominant and becoming endemic, has been observed in Saudi Arabia, where the tetravalent conjugate vaccine has been recommended in the National Immunization Schedule for children at the age of 9 months since 2012 [29] underlining the need for flexible and current public health interventions.

The travel of W strains to the South Cone in Latin America: spreading and becoming endemic in some countries

Although there have been no reports of serogroup W cases from Latin American countries associated with Hajj 2000 [Reference Mayer6, Reference Popovic9], this may be due to the absence of well-established surveillance for invasive meningococcal disease (IMD) in many countries in the region. A hypothetical association with the Muslim communities located in the region is no more than speculation because, as has been mentioned, there is no epidemiological information to establish that association. However, the emergence of serogroup W meningococcal cases has been observed in the South Cone (a geographical region composed of the southernmost areas of South America, south of the Tropic of Capricorn, including Argentina, Southern Brazil, Chile, Paraguay, Uruguay) in the last decade. This geographical area seems to be, for now, the last stage of the spread of serogroup W. The trends observed in the region suggest that serogroup W might become endemic in some countries of the region. This observation is a large change compared to with past situations (with serogroup W just associated with large epidemics or local outbreaks), highlighting the need to consider the inclusion of this serogroup in any vaccination strategy for the region.

Tracking the expansion of W strains: molecular characterization

As mentioned elsewhere in this review, many studies have been made characterizing W isolates both phenotypically and genetically in an effort to get a better understanding of the evolution, not only of serogroup W but particularly of those strains belonging to ST11/ET37 CC (Table 1). Genetic drift should be driving the evolution of the Hajj-related strains after the 2000 outbreak. High rates of W strains in carriers and persistence among them allows the W strains to evolve and, emerging genetic variants hinder analysis of the evolution of the epidemic strains. In this sense fine characterization of W isolates is critical for tracking their spread and following the evolution.

Table 1. Methods used for characterization of W strains in different studies found in the literature

MLST, Multi-locus sequence type; CC, clonal complex; MEE, multi-enzyme electrophoresis; PFGE, pulsed-field gel electrophoresis; MLDF, multi-locus DNA fragment typing;

WGS, whole genome sequence.

* Reference according to the numbers used in this paper.

However, the level of characterization already used in different studies is rather heterogeneous and it is difficult to compare findings among them (Table 1). Most of the authors define at least the genosubtype (PorA variable regions) and sequence type; then all strains characterized as P1·5,2 belonging to the ST11/ET37 CC are referred to as Hajj 2000 or closely related strains [Reference Efron37, Reference Sorhouet-Pereira38, Reference Barra40, Reference Taha46]. However, the inclusion of additional markers shows that several genetically related subgroups are present in W ST11/ET37 CC, suggesting that fine characterization is needed to fully understand trends in transmission and spread [Reference Harrison, Trotter and Ramsay1, Reference Caugant5, Reference Taha11]. Only Mayer et al. in 2002 [Reference Mayer6] compared the use of two phenotypic (serotyping and serosubtyping) and six molecular markers [16S, PFGE, MEE, VR-1 VR-2, multi-locus sequence typing (MLST), multi-locus DNA fragment typing (MLDF)] for characterization of W strains, defining sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for all molecular subtyping methods for identifying the Hajj outbreak-associated strains. The authors concluded that 16S sequencing, PFGE, and MEE provided the best specificity (98%, 86%, 80%, respectively) and PPV (96%, 79%, 72%, respectively), and a combination of PFGE and MEE resulted in a specificity of 90% and a PPV of 84%. The sequence of fetA variable region has also been used later, but there is no specific analysis of its specificity and/or PPV values [Reference Efron37, Reference Taha47]. Some authors have shown that other genetic lineages among W strains (ST2495 and ST22) might be expanding, contributing to the genetic diversification of the meningococci associated with serogroup W [Reference Taha11]. N. meningitidis is subject to horizontal DNA transfer and re-assortment of genes between different strains producing genetic variants. Therefore, characterization of invasive meningococcal strains by several fine molecular typing approaches is essential to monitor and understand the evolution of the situation. As an example, there was a cluster of W cases in southeastern Florida [Reference Doyle48], in which the authors used PFGE and MLST for characterization of the isolates (7/12), with all W strains belonging to ST11 CC with an indistinguishable (or closely related) band pattern profile by PFGE. With this microbiological information the authors suggest that ‘The dominant clonal complex observed in the Florida cluster matches the dominant type recently observed in Argentina and Brazil, raising the possibility of introduction to Southeastern Florida from South America.’ However, at that time there was no information about PFGE patterns in W strains isolated in the South Cone in Latin America, so we only know that the strains isolated in both Florida and the South Cone belonged to ST11 CC which is not enough to support the suggestion. A minimal consensus about what molecular markers should be used might help to be able to compare definitely different findings in different geographical areas and reach a conclusion as to whether we are observing the emergence of W ST11 CC strains in different geographical areas or, on the contrary, the Hajj 2000 strains are still spreading globally.

W ST11/ET37 CC strains: where do they come from?

Because of the sporadic isolation of ST11/ET37 W strains in different geographical locations and years, it has been suggested that the 2000 outbreak associated with the Hajj might have been the result of spreading of a pre-existing, although not well known, W ST11/ET37 CC strain, after an amplification effect possibly enhanced by favourable environmental circumstances [Reference Mayer6], rather than emergence of a new W strain.

Immunological pressure might have had an important role in this history. The annual Muslim pilgrimage to Saudi Arabia had been previously associated with outbreaks of meningococcal disease in returning pilgrims [Reference Jones and Sutcliffe49]. After the first pandemic of meningococcal serogroup A infection during Hajj 1987, Saudi Arabian authorities required vaccination with a bivalent serogroups A+C vaccine for all pilgrims arriving in the country [Reference Al-Gahtani50]. Since the mid-1990s, because of that visa requirement for all pilgrims entering the country, millions of doses mainly of meningococcal A + C polysaccharide vaccine have been administered (although some countries were using the quadrivalent meningococcal A + C + W135 + Y polysaccharide vaccine), allthough those A + C polysaccharide vaccines offer no protection from W strains. Since 2002 the quadrivalent meningococcal vaccine (A + C + Y + W) has been required to obtain the Hajj visa.

Similarities in both molecular and phenotypic markers have been suggested when comparing W with serogroup C strains, both belonging to ST11/ET37 CC [Reference Mayer6, Reference Wang51]. In addition to being a member of the ST11/ET37 complex, additional molecular and phenotypic markers of this W clone are very similar to those of serogroup C strains of the ST11/ET37 complex that are associated with outbreaks and sporadic cases of meningococcal disease. The question is whether W ST11/ET37 CC strains have derived from serogroup C strains of the same CC through a capsular-switching event, often described in meningococcal strains involving different serogroups [Reference Castilla52] or both W and C ST11/ET37 CC represent two separate and distinct evolutionary lines with a distant common ancestor that subsequently differentiated into different serogroups. The data already discussed in this review and presented in several studies show that an increasing numbers of W strains were reported in Saudi Arabia every year from 1990 to 2000 [Reference Mayer6, Reference Wang51] suggesting some circulation of W strains before Hajj 2000. This finding is confirmed by the isolation of a similar W strain in a patient from Indonesia who was a pilgrim returning from the 1996 Hajj. Additionally, very similar strains have been recovered worldwide at least since 1970 [Reference Mayer6], suggesting that the hypothetical capsular-switching event (from C to W or in the opposite direction) took place possibly before 1970 [Reference Mayer6].

Carriers, transmission and persistence data already commented upon in this review [Reference MacLennan14–Reference Ceyhan18, Reference Daugla25, Reference Kristiansen26] might indicate that W ST11/ET37 CC strains appear to be significantly more transmissible than C ST11/ET37 CC isolates and it has been suggested that the modification of this capability might be related to the serogroup switch [Reference Kristiansen26]. However, this different characteristic might also suggest that in fact W and C ST11/ET37 CC represent two separate and distinct evolutionary lines among the ST11/ET37 CC.

The question then is whether this clone has the potential to settle in the population maintaining adequate rates of transmission to be associated with endemic or epidemic situations or whether the situation at the beginning of this century is a one-off and temporary. A recent report shows recent transmission of W ST11/ET37 CC in southeastern China [Reference Zhou54], suggesting that the strains might be still globally spreading. The global distribution of reports of W increases is shown in Figure 1 and it might only reflect part of the extension of serogroup W, and those geographical areas with no apparent effect could be associated with poor surveillance systems. How this situation evolve in the next future is one of the most important topics for those people involved in prevention and control of meningococcal disease worldwide.