Meningococcal Disease and Immunization Activities in Hajj and Umrah Pilgrimage: a review

As well as a Graphical Plain Language Summary, an audio narration of this feature from the authors is also available. To access the audio narration alongside the Graphical Plain Language Summary for this article, go to https://​doi.​org/​10.​6084/​m9.​figshare.​19298804.

Mass gatherings and those associated with religious events such as the Hajj and Umrah pilgrimages to Makkah, Kingdom of Saudi Arabia (KSA), are well recognized risk factors for Neisseria meningitidis (meningococcal) transmission and subsequent invasive meningococcal disease (IMD) outbreaks [1‐4]. The annual Hajj pilgrimage lasts for 5 days (from day 8 to day 12 or 13 during the 12th month of the Islamic lunar calendar). Over 1.5 million external pilgrims (from more than 184 countries) enter the KSA to attend each year, with 1.86 million external pilgrims visiting in 2019 [2, 5, 6]. For Umrah, visitors attend in far greater numbers (7.2 million in 2019), although attendance is across a longer period with a peak during the month of Ramadan (almost 2 months before Hajj season) [7]. The often intense crowding that exists in the Hajj and Umrah setting, with large group congregation for prayers and with pilgrims sharing accommodations and dining facilities, and the broad mix of individuals from diverse geographical origins and the local KSA population all contribute to enhanced risk of meningococcal transmission [8, 9].

While 12 N. meningitidis serogroups have been identified [10], six serogroups are responsible for the great majority of IMD (serogroups A [MenA], B [MenB], C [MenC], W [MenW], X [MenX] and Y [MenY]) [11‐13]. Substantial geographical variation exists in the relative importance of specific serogroups in local population carriage and IMD epidemiology. Consequently, the admixture of pilgrims from different countries attending the Hajj is associated with the circulation and exposure to a diverse range of serogroups across the broader pilgrim population. Due to the different epidemiological patterns within their country and disease unpredictability, some serogroups will be relatively unfamiliar to pilgrims from certain countries (in the sense of pilgrims’ local prevalent epidemiology), with the potential for carriage acquisition of unfamiliar meningococcal serogroups and subsequent onward transmission to their broader local population upon their return [5, 14]. Obviously, there is also the potential for IMD outbreaks, either at and during the Hajj or in the pilgrims’ homeland upon their return.

Previous IMD outbreaks associated with Hajj events have substantially impacted the global IMD epidemiology. Notably, the outbreaks in 2000 and again (although of lesser magnitude) in 2001, due predominantly to MenW, resulted in substantial pilgrim mortality [15]. They also served as the origin of subsequent intercontinental spread via pilgrims acting as a transmission vector on their return home. Indeed, this was the principal step in the emergence of MenW (previously of relatively limited concern) as an important global IMD serogroup [16‐18], compounded by the emergence of a separate South American strain in 2003 [18].

This, in turn, has led to the implementation of comprehensive vaccination strategies (via quadrivalent MenACWY vaccine for pilgrims entering KSA and also for KSA residents) and other measures such as chemoprophylaxis to mitigate further outbreak risk [19]. As we outline below, while these have led to considerable success, some limitations remain in the current immunization approaches, and there remains an ongoing risk for future outbreaks arising at or from the Hajj [5, 20].

In the present manuscript, we provide a narrative overview of key lessons from past pilgrim IMD outbreaks and studies of meningococcal carriage, and then we focus on relevant epidemiologic aspects of IMD and carriage in those countries from which the majority of external pilgrims originate. This provides a perspective on the existing immunization strategies and how these could be strengthened to provide broader and more complete protection for pilgrims.

As a first step, we utilized data reported by the KSA Ministry of Health for the 2019 Hajj [6], where additional information supplied indicates that nearly two-thirds of visiting pilgrims arrive from 13 countries chiefly from across Southeast Asia and the Middle East and North Africa (MENA) region; Indonesia, India, Pakistan, Bangladeshi, Iran, Egypt, Turkey, Iraq, Algeria, Nigeria, Morocco, Sudan and Malaysia. We then searched PubMed to identify relevant literature on IMD and N. meningitidis carriage associated with Hajj or Umrah pilgrimage from these countries, along with articles reporting on these same characteristics within each of these countries. The search strategy included a range of free-text and Medical Subject Headings (MeSH) search terms, e.g., “Hajj”, “Umrah”, ‘‘meningococcal”, ‘‘N. meningitidis” and “carriage” and specific countries in various combinations. The identified articles were supplemented by snowball sampling of relevant citations from the identified papers (including a large number of comprehensive, systematic reviews). Our search covered the period through March 2020, and although comprehensive, our approach was not systematic per se; we did not have specific selection criteria or specific publication date limitations. Our aim was to identify the most relevant data for each specific country. Although for some, the available literature is limited and often rather outdated, whenever possible we focus on the more recent published data for each country.

In compliance with ethical guidelines, this article is based on previously conducted studies and reported data and does not contain any studies with human participants or animals performed by any of the authors.

IMD outbreaks during the Hajj and responsive immunization strategies for at-risk pilgrims have been reviewed extensively [5, 14‐16, 19‐21]; a schematic of key events is shown in Fig. 1.

Awareness of the significance of Hajj as a focus for local disease and subsequent international spread was raised following MenA outbreaks in 1987 [22, 23]. This prompted the introduction of mandatory immunization against MenA for pilgrims arriving from the high-risk sub-Saharan meningitis belt countries in 1987, using a bivalent MenA-C vaccine, a measure extended in 1988 to include all visiting Hajj pilgrims [19]. In the same year, mass chemoprophylaxis with ciprofloxacin for pilgrims from sub-Saharan meningitis belt countries to reduce meningococcal nasopharyngeal carriage was also introduced (and continues to the present time). Following Umrah-related MenA outbreaks in 1992 (chiefly in unvaccinated pilgrims) [23], mandatory immunization was implemented for all pilgrims entering KSA [19]. Nevertheless, IMD outbreaks due to various serogroups continued to occur. In their extensive analysis of IMD surveillance within KSA across 1995–2011, Memish and colleagues reported that between 1995 and 1999, a total of 265 IMD cases occurred within KSA, of which 60 involved Hajj pilgrims and 46 involved Umrah pilgrims; most IMD was due to MenA (49% of serogrouped cases), although MenB (26%) and MenW (20%) were also noted [15].

The subsequent 2000 and 2001 outbreaks involved a total of 654 IMD cases, of which 249 (38.1%) occurred in external pilgrims, involving 223 Hajj pilgrims and 26 Umrah pilgrims, with the remainder chiefly occurring in KSA citizens/residents [15]. The IMD case fatality ratio (CFR) was substantially higher in external pilgrims than in KSA citizens/residents, and so the majority of IMD deaths in the 2000–2001 outbreaks were in visiting external pilgrims. This may be due in part to the delay in diagnosis and medical care in pilgrim patients on pilgrimage, and also the generally greater age of pilgrims than that of affected residents [15]. Although the great majority of IMD cases in 2000–2001 were due to MenW (78% of serogrouped cases), IMD due to MenA was also reported (accounting for 20% of serogrouped cases). Most MenA cases were observed in 2000, where in reality there was a MenA outbreak at the same time as the larger MenW outbreak. Six cases of MenB were also reported during these years [15]. These latter outbreaks led to greater reinforcement of the existing immunization requirements. Immediately following the 2000 outbreak, a shift towards a broader protection policy utilizing the quadrivalent MenACWY vaccine was partially implemented, but supply issues seriously hampered availability for pilgrims (which may have contributed to the later 2001 Hajj outbreak). Use of the MenACWY vaccine was compulsory from 2002 onwards for all pilgrims, and while initially only available as a polysaccharide vaccine, the use of a conjugated MenACWY vaccine has been widely available since 2010 (although, as we describe below, pilgrim uptake is low). In tandem with the external pilgrimage policy, expansion of immunization activities for all KSA citizens/residents with pilgrim interactions and introduction of infant quadrivalent MenACWY vaccination has occurred [19, 24].

At the present time, while both polysaccharide and conjugated ACWY vaccines are valid for external pilgrims, policy differences exist in the duration of validity of the vaccination. While pilgrims immunized with conjugated MenACWY vaccines must show evidence of vaccination within the past 5 years, those receiving the polysaccharide vaccine must show evidence of immunization within the past 3 years [4]. The requirement for chemoprophylaxis for all pilgrims arriving from the sub-Saharan meningitis belt countries remains in place. These protocols, along with continued expansion and widespread availability of conjugated MenACWY immunization for all at-risk KSA citizens/residents, have led to substantial success in curtailing further disease outbreaks amongst Hajj/Umrah pilgrims, with no outbreaks since 2001 [19]. This has been accompanied by a substantial decline in IMD cases within the KSA population over the past two decades [15, 24]. However, one cannot be complacent, for a number of reasons.

Firstly, although outbreaks have been curtailed, sporadic cases continue to occur, with 14 IMD cases reported in pilgrims attending Hajj between 2002 and 2011 [15]. Onward transmission from pilgrims is also observed, most recently with reports in 2019 of meningococcal infection due to a ciprofloxacin-resistant non-groupable N. meningitidis strain in two Umrah pilgrims returning to the United Kingdom (UK). A further close contact in the UK subsequently developed IMD due to this same strain [25, 26].

Secondly, the current strategies require strengthening. Conjugated MenACWY vaccines are preferable to polysaccharide vaccines (due to the induction of immunologic memory and the potential for reduction in nasopharyngeal carriage acquisition and onward transmission [27, 28]). Expert groups have called for the use of conjugated vaccines by pilgrims to be made a priority, especially for those pilgrims making regular visits, as repeated polysaccharide immunization may lead to weaker immune responses [29, 30]. However, this has not been formally actioned, and data indicate that most pilgrims receive the polysaccharide vaccine. In their 2014 study (published in 2017), Memish et al. reported that 98.2% of the 1055 arriving pilgrims (most from countries we also describe below) had received the polysaccharide vaccine, and the remainder had received a conjugate vaccine [31]. A more recent 2017 study (published in 2021) involving 2973 pilgrims arriving from a wide range of countries reported that between 60 and 70% of vaccinated pilgrims arriving from low- and middle-income countries (LIMCs) had received polysaccharide MenACWY vaccine [32]. Perhaps more worrying was the high proportion of unvaccinated pilgrims from LIMCs (20–25%) [32]. An earlier survey from 2009 reported that only 75% of pilgrims had received meningococcal vaccination before travel [33], while a more recent survey involving 1012 Umrah pilgrims visiting in 2019 reported that only 41.3% had actually received meningococcal vaccination [34]. While other data report 100% compliance in pilgrims from most countries surveyed in 2013 and 2014 [31, 35], these more recent data suggest a need to strengthen oversight of the existing regulations for pilgrims [32]. Domestic pilgrim vaccination (i.e., in KSA residents/citizens attending the Hajj) is also suboptimal. A recent study of immunization status in external and domestic pilgrims reported that 81.7% of domestic pilgrims had confirmed meningococcal vaccination status compared with 93.5% of overseas pilgrims [36]. Vaccine uptake by healthcare workers (HCWs) working/volunteering at the Hajj is inadequate, with one study reporting only 76.1% of HCWs surveyed between 2015 and 2017 indicating receipt of MenACWY [37].

Another issue is the role of chemoprophylaxis in pilgrims attending from sub-Saharan Africa, where concerns have been raised regarding the risk–benefit trade-off in continuing this policy, especially in light of increasing antimicrobial resistance [19, 31, 38]. Finally, there remains the potential for future Hajj IMD outbreaks and ongoing intercontinental spread due to serogroups not currently covered by current mandatory immunization (i.e., MenB and MenX) [14, 39]. Protein-based vaccines (4CMenB and MenB-FHbp) against a range of subcapsular antigens conferring protection against MenB are now available [12, 40, 41], although MenB vaccination is not included in current immunization strategies for individuals entering KSA for Hajj and Umrah pilgrimage [4, 20, 42].

The intense social crowding and congregation that accompany the Hajj are recognized factors associated with higher rates of meningococcal transmission and carriage acquisition [30]. A recent review of carriage studies reported that meningococcal carriage is higher in the holy cities of Mecca and Medina compared to other KSA cities (e.g., Riyadh), and in general, carriage is greater in Hajj pilgrims compared with Umrah pilgrim populations [9]. This same review also noted that most studies in pilgrim populations report comparable carriage rates to those reported in other settings, although factors influencing carriage such as antibiotic use will have an impact [9]. Onward transmission to close contacts of returning pilgrims is well documented, with household contact carriage rates ranging between 8 and 25% [9]. While substantial temporal variation exists in carriage of specific serogroups, the broad picture is the predominance of MenW and MenB in carriage isolates [9].

Quantifying the impact of Hajj attendance on carriage is complex. A number of studies conducted in 2001, 2014 and 2017 specifically examined carriage rates in pilgrims before and after Hajj participation [31, 32, 43]. Carriage patterns from pilgrims in specific countries are described later, but these studies report overall carriage rates ranging from 3.4 to 8.0% in pilgrims prior to Hajj attendance, and between 1.2 and 10.4% in departing pilgrims. Two of these studies analysed carriage loss and acquisition during the Hajj using a paired-sample approach. In the earlier 2001 study, a broad pattern of higher carriage rates was seen in departing pilgrims, with some evidence of increased acquisition in pilgrims from countries with low carriage prior to the Hajj, such as among Malaysian and Indonesian pilgrims. MenW accounted for a far higher proportion of isolates identified in pilgrims after the Hajj prior to their departure home than that identified from pilgrims on arrival for the Hajj (44.2% and 5.3%, respectively) [43]. This is in keeping with the understanding that acquisition and onward transmission of MenW carriage was the principal driver of subsequent intercontinental spread. The later 2014 study found higher carriage among pilgrims arriving from countries with high endemic disease (although the 6.3% carriage rate was considered low) and generally lower carriage in departing pilgrims [31]. An important observation from this later study was that, while carriage was relatively low, there was a high prevalence of MenB isolates, accounting for 66.7% of all positive samples on arrival and for 100% of those from departing pilgrims [31]. A second important point is that antibiotic use during Hajj either as a compulsory prophylaxis or taken for other reasons, including illness, and as a general precautionary measure during the pilgrimage is high [44], and this can impact/reduce carriage rates [31, 45]. Recent data indicate that 55.8% of pilgrims report antibiotic use during the Hajj [32].

In 2019, a total of 2,489,406 pilgrims participated in Hajj activity, which included 1,855,027 external pilgrims [6]. Of these we selected those 13 countries that account for the greatest numbers of pilgrims travelling to KSA: Indonesia, India, Pakistan, Bangladesh, Iran, Egypt, Turkey, Iraq, Algeria, Nigeria, Morocco, Sudan and Malaysia (Fig. 2). These account for 65.4% of all external pilgrims. For each country, we describe the relevant epidemiological aspects, including principal IMD causative serogroups (Table 1), and available data for meningococcal carriage in the local resident population (Table 2) and in pilgrims from these countries before or after attending the Hajj (Table 3). While our purpose was to report all relevant serogroups, we also wanted to evaluate patterns of MenB disease or carriage, and so relevant data for MenB are presented in bold across these tables. Where possible, we focus on the most recent data, although for some countries data are sparse and epidemiologic data are often outdated.

It should be noted that routine meningococcal vaccine programmes vary widely in those countries. In most countries there is no formal national immunization policy, the exceptions being Egypt (infant polysaccharide MenA–C vaccine) and Sudan and Nigeria (infant conjugated MenA vaccine as part of the broader regional efforts, although coverage data are lacking). Consequently, it is chiefly only those pilgrims from these countries participating in Hajj or Umrah activities who receive any form of meningococcal vaccine, and as outlined earlier, the great majority receive polysaccharide MenACWY [31, 32].

The data reported across these countries highlight substantial geographical and temporal heterogeneity patterns in IMD and meningococcal carriage. For some countries, data are sparse and limited, and often from some time ago, including those countries contributing substantial pilgrim numbers such as Indonesia, India and Pakistan. Efforts should be made to generate and publish more robust data on both the local IMD epidemiology and the relevant pilgrim characteristics, to allow a greater understanding of the current IMD landscape in such countries. Greater information is available for other countries such as Turkey and countries in North Africa. As a consequence, while much of the data we describe above are, to some extent, outdated, we believe that reporting across countries that contribute the great majority of Hajj pilgrims provides an additional perspective to the risk of future IMD outbreaks that have been the focus of previous and often comprehensive reviews [2, 3, 5, 9, 14, 19, 20, 29, 30].

Although such limitations mean we must be cautious about over-interpreting these data, some additional observations can be made. While a broad range of meningococcal serogroups are carried by and circulate among pilgrims attending Hajj and Umrah events, MenW and more recently MenB are important serogroups in some countries [9, 31]. Of the 13 selected countries, the available data indicate that MenB was the predominant IMD causative serogroup in Turkey [83], Iran [69] and across much of the MENA region; Morocco [94], Algeria [93, 94] and Egypt [77] (although with the caveat that recent data exist only for Turkey and Morocco). There is some, albeit limited, evidence for MenB carriage acquisition during the Hajj, although this is inconsistent, and patterns are undoubtedly influenced by factors such as antibiotic use [31, 45].

The existing immunization regulations for Hajj/Umrah pilgrims remain relatively unchanged since their development and introduction in 2001. These were implemented in response to the IMD disease patterns and vaccine options available at that time, and to some extent may not account for more recent IMD patterns [109] and the more recent development of MenB vaccines [110, 111]. Although effective in reducing IMD, there is limited evidence that MenB vaccines have any effect on N. meningitidis carriage [110‐113], and so are unlikely to prevent any onward transmission of MenB. Novel pentavalent vaccines are in clinical development. These include a pentavalent vaccine targeting MenX (i.e., MenACWY and X), principally to address MenW emergence in sub-Saharan Africa [114, 115], and vaccines combining 4CMenB or MenB-FHbp vaccine components with MenACWY elements as MenABCWY formulations [116‐118]. These pentavalent vaccines are in the latter stages of clinical development and could be available within the next 5 years. Although data are lacking for the specific benefits of use in pilgrim populations, existing MenB vaccines and novel pentavalent vaccines could offer additional immunization options for further consideration.

The introduction of mandatory MenACWY immunization for Hajj and Umrah pilgrims entering the KSA has realized substantial benefits in reducing IMD outbreaks and subsequent spread in returning travellers. While this represents a substantial achievement, the sustained success of immunization activities may require further actions. Continued emphasis on the value of conjugated ACWY vaccines is needed, along with greater monitoring of vaccine compliance. The use of conjugated MenACWY vaccines in place of polysaccharide vaccines in immunization protocols could reduce the requirement for chemoprophylaxis in pilgrims from sub-Saharan Africa, and so may reduce antibiotic use and antimicrobial resistance. The introduction of additional immunization options such as MenB vaccination could also be considered. The Graphical Plain Language Summary summarizes the context, outcomes and impact of this study for healthcare professionals.