The Epidemiology of Invasive Meningococcal Disease in the Kingdom of Saudi Arabia: A Narrative Review with Updated Analysis

IMD surveillance in KSA is based on immediate mandatory reporting of all clinically suspected meningitis cases to the regional health authority, which is responsible for immediate preventive measures (antibiotic prophylaxis of close contacts through contact tracing), and which oversee clinical and laboratory confirmation. Case confirmation for bacterial meningitis is on the basis of isolation of a causative organism (N. meningitidis, S. pneumoniae, H. influenzae, etc.) from the cerebrospinal fluid (CSF) or by blood culture, and/or detection of bacterial antigens in the CSF via latex agglutination. Increasingly, polymerase chain reaction (PCR) technologies are used to identify organisms from CSF and blood samples (particularly useful in culture-negative samples). For IMD, causative serogroups are determined using latex agglutination and PCR. For each case, all relevant clinical, microbial, and demographic aspects (age, gender, resident status, etc.) are recorded on a case-reporting form, and then shared by the regional health authority with the MoH [40]. These data form the basis of data published by the MoH in their statistical yearbooks [41]. While these datasets are publicly available, there are some limitations to the data. For example, while the surveillance parameters outlined above clearly allow for identification and categorization of different clinical forms (i.e., meningococcal meningitis, meningococcal bacteremia/septicemia, or meningococcal meningitis plus bacteremia) and rarer presentations (e.g., septic arthritis), such information is not reported in the statistical yearbooks.

Over the past 25 years, there have been substantial increases in the overall population of KSA, rising from 18.5 million in 1995 to 27.5 million in 2011 [40], and to 35.2 million in 2019 [41]. Illustrative population demographics are shown in Tables S1 and S2. A substantial number of residents are non-Saudi nationals living and working in KSA, representing 30–40% of the overall population, and accounting for 38% of the total population in 2019 [41]. While the Saudi national population comprises similar numbers of males and females, there are approximately twice the number of resident (non-Saudi) males than females, and so at present males constitute approximately 58% of the overall KSA population [41].

In 2019, individuals aged from 15 to 64 years constitute 72.3% of the population, 16.2% are aged from 5 to 14 years and 8.3% are children < 5 years of age [41]. At present, 25.3% of the population reside in Riyadh; other important regional population centers are Jeddah (14.3%), Mecca (7.2%), and Medina (6.5%) (Table S2).

Immunization strategies implemented by the KSA MoH have been heavily influenced by disease epidemiology within KSA itself (including IMD outbreaks associated with the Hajj pilgrimage), and also by the development and introduction of available vaccines. These strategies address protection in the local KSA resident population and also for pilgrims entering KSA for Hajj or Umrah purposes. The evolution of IMD immunization approaches and key policy changes has been comprehensively reviewed by Yesli and colleagues, from which we describe the key developments [35].

Initially, immunization was introduced in response to an outbreak of MenA disease in 1987, after which mandatory immunization with the bivalent MenAC vaccine was introduced for all pilgrims attending the Hajj, along with vaccination initiatives directed towards KSA residents in the major pilgrimage sites of Mecca and Medina. For those pilgrims attending from the high-risk Sub-Saharan meningitis belt, an additional step was compulsory use of oral ciprofloxacin on arrival in KSA in order to reduce N. meningitidis nasopharyngeal carriage. A broader protective policy was implemented in 2002, following significant outbreaks due to serogroup W in 2000 and 2001, again associated with Hajj gatherings (both within KSA and in pilgrims returning to their country of origin), with compulsory vaccination with the polysaccharide quadrivalent MenACWY vaccine required by all citizens/residents in and around Mecca/Medina and all Hajj pilgrims ≥ 2 years of age, as well as immunization of all healthcare workers, and personnel involved in pilgrimage activities. In 2010, the use of conjugated MenACWY vaccine was introduced within KSA for use in individuals aged 2–55 years, while the polysaccharide ACWY vaccine remains valid for older citizens/residents and all external pilgrims [35]. Since 2013, the NIP has included infant vaccination with conjugated MenACWY vaccine (at 9 and 12 months), and more recently has since 2020 recommended a single dose to be given at 18 years of age [44, 45]. Vaccination against other important causes of infant meningitis (S. pneumoniae and H. influenzae) is also included in the NIP (with pneumococcal immunization given at 2, 4, 6, and 12 months of age, and Hib at 2, 4, 6, and 18 months) [45]. Although infant MenACWY vaccination coverage is not reported within the publicly available MoH datasets, the uptake of other recommended infant vaccines is reported to be high (> 95%) in recent years for hexavalent (diphtheria, pertussis, tetanus, Hib, hepatitis B, and polio) pneumococcal and measles–mumps–rubella vaccines [41]; one might assume that infant MenACWY coverage is also high.

At the present time, external pilgrims are required to show evidence of prior meningococcal vaccination before entry into the country (within the past 5 years for those immunized with conjugated MenACWY vaccines, and within the past 3 years for polysaccharide MenACWY vaccines) [46]. Similar requirements also apply to all citizens/residents in Mecca/Medina, all internal pilgrims, and all staff working with the pilgrims; compliance is facilitated by annual vaccination campaigns offering primary and booster dosing as necessary [35]. While MenB vaccines are now available and used in a number of other countries in their national immunization schedules [1, 10, 11], Men B vaccination is not included in current immunization strategies in KSA, or for individuals entering the country for the Hajj and Umrah pilgrimages [36, 46, 47].

Two key surveillance studies have reported on IMD within KSA across this period, each of which is based on data reported in MoH sources. The first study reported on all IMD cases for the years 1999–2002, a period covering disease outbreaks due to serogroup W associated with overseas pilgrims attending for Hajj or Umrah in 2000 and 2001 [39]. A subsequent and more comprehensive review by Memish et al. evaluated surveillance across a broader period, from 1995 to 2011 [40], from which we describe key aspects.

Over this 1995–2011 period, 1103 IMD cases were reported, of which 645 occurred in KSA citizens or residents (Fig. 1). Note that no distinction between the different clinical forms of IMD (meningococcal meningitis, septicemia, or meningitis plus septicemia) was reported. For KSA citizens/residents, the highest cumulative incidence across 1995–2011 was seen in children < 5 years of age (12/100,000); cumulative incidence was 2/100,000 in those aged 5–14 years, and approximately 1/100,000 in both the 15–64 and ≥ 65 years age-groups.

Looking at specific timeframes; 265 cases occurred between 1995 and 1999 [of which 139 (52.4%) occurred in KSA citizens or residents], 654 cases in the 2000–2001 period which included the Hajj-related IMD outbreaks [372 (56.9%) in KSA citizens/residents), and 184 cases from 2002 to 2011 [134 (72.8%) in KSA citizens/residents] [40]. In the 2002–2011 period, while approximately 50 cases were reported in KSA residents in 2002 and 2003, in later years the annual case numbers declined to around 10 cases each year. Surveying the population-adjusted annual incidence rates for KSA citizens/residents for these periods, between 1995 and 1999, the mean annual incidence in the overall population was 0.20/100,000, rising to 1.42/100,000 and 1.32/100,000 in the peak 2000 and 2001 years, respectively, and then declining from 0.21/100,000 in 2002 to 0.01/100,000 in 2010 [40].

From a geographical perspective, approximately 49% of all cases in 2000 occurred in Mecca and Medina during Hajj (and approximately 31% of all cases in 2001), while, in the 2002–2011 period, these cities together accounted for only 8.1% of reported cases occurring during the Hajj seasons [40]. This would seem to reflect the decreasing impact of outbreaks associated with mass gatherings, with no IMD outbreaks occurring within KSA since 2001.

To some extent, the age-related epidemiology across this period reflects the age demographics of at-risk populations, where broadly speaking the mean age of non-Saudi nationals is higher than Saudi national citizens and higher still in visiting pilgrims. The mean age of IMD cases across the entire 1995–2011 period was lowest in Saudi national citizens (9.6 years), higher in non-Saudi national residents (14.4 years), and much higher in Hajj-pilgrims (48.9 years). In addition, the mean age of IMD cases was also higher during Hajj seasons, and, in cases occurring in Mecca and Medina compared to other times of the year or regions, in part reflecting the influence of cases in (generally) older pilgrims. Finally, the general pattern across this whole period was that of a decrease in the age of IMD cases, falling from a mean age of 31 years in 1995–1999 to 18 years in 2002–2011, which in part reflects the increasing contribution of KSA citizens/residents to the total IMD case numbers and the relative decline in case numbers in pilgrims.

Mortality due to IMD was high, with 198 deaths across 1995–2011, and an overall case fatality rate (CFR) of 18.0% [40]. The majority of deaths (125, 63.1%) occurred in external pilgrims visiting for Hajj or Umrah, and the CFR was substantially higher (28.9%) in external pilgrims than in KSA citizens/residents (10.4%); CFRs were also higher in IMD cases occurring during the Hajj season (28.6%) than at other times (10.0%). This in part may reflect delay in diagnosis and medical care in patients on pilgrimage, and also the generally greater age of pilgrims. Looking at age-related IMD mortality, most occurred in older age groups, with 85 deaths in those aged > 45 years and 72 deaths in those aged 15–45 years; 8 IMD deaths occurred in children < 1 year of age, 20 deaths in those aged 1–4 years, and 13 in those aged 5–14 years. Higher CFRs were seen with increasing age, being lowest in infants < 1 year (6.8%), 9.4% in individuals aged between 1 and 4 years, 9.3% in those aged 5–14 years, 19.4% in those aged 15–45 years, and 32.6% in those > 45 years. However, this pattern also changed over time. While the annual mean CFR in children < 5 years of age was relatively similar in 1995–1999 and in 2002–2011 (13.6% and 12.4%, respectively), the CFR in patients aged ≥ 5 years fell from 20.7% in 1995–1999 to 8.7% in 2002–2011 [40], which may reflect the generally lower mean age of non-infant cases in this latter period that we outline above.

For the complete 1995–2011 period, a total of 656 cases (59.5%) had serogroup data [40]. Of these cases, 11.3% occurred in infants < 1 year, 21.8% in those aged 1–4 years, and 13.1% in those aged 5–14 years. The greatest number of cases were due to MenW (57.2%) and MenA (29.4%), while MenB accounted for 10.1% of cases. However, serogroup distribution varied across this period (Fig. 1). Between 1995 and 1999, MenA and MenB were the most prevalent serogroups, while in 2000–2001, the high numbers of MenW and MenA cases reflect the impact that the disease outbreaks in these years associated with the Hajj (chiefly a MenW outbreak, although a MenA outbreak also occurred in 2000). Subsequently, between 2002 and 2011, of the 115/184 IMD cases (62.5%) with serogroup data, 40.0% were MenW, 35.7% were MenA, and 16.5% were due to MenB, with a few cases due to other serogroups (i.e., MenY, MenX, and MenZ). There were no notable differences in CFRs associated with the principal causative serogroups: MenA (21.8%), MenB (21.2%), and MenW (19.7%), although a higher CFR was seen in the small number of cases due to MenY (33.3%) [40].

Our updated surveillance data for subsequent years are outlined as follows. Between 2012 and 2019, there was a total of 2050 meningitis cases reported by the MoH [41]. Of these, the great majority were categorized as ‘other’, a group that includes culture-negative disease and viral and ‘aseptic’ meningitis, accounting for 1875 cases (91.5%) (Table 1; Fig. 2a). Looking at specific years in this period, more cases were reported in 2017 than other years, with 415 meningitis cases due to any cause, with the highest numbers of identifiable bacterial meningitis cases also reported in 2017 (Fig. 2a). The majority of all meningitis cases due to any cause occurred in children and adolescents < 15 years of age (62.5%); approximately one-third of all cases occurred in infants < 1 year of age (Fig. 2b). A total of 175 confirmed bacterial meningitis cases were reported for 2012–2019, and the most common identifiable pathogen was S. pneumoniae (99 cases; 56.6% of all bacterial meningitis cases), followed by N. meningitidis (44 cases; 25.1% of all bacterial meningitis cases), and H. influenzae (32 cases; 18.3% of all bacterial meningitis cases) (Table 1; Fig. 2c). As described earlier, while such information is captured during surveillance, reporting limitations preclude reporting on the relative prevalence of different clinical forms of IMD (meningococcal meningitis or meningococcemia sepsis, or both together). Across 2012–2019, of the 44 IMD cases reported, the greatest number of IMD cases occurred in 2017 (n = 10) and 2018 (n = 9), while 65.9% occurred in children and adolescents < 15 years of age and 31.8% in children < 5 years of age. Most cases were reported in Saudi citizens (n = 31) with 13 cases reported in non-Saudi residents, and 27 cases occurred in males; these latter numerical differences are generally consistent with the population demographics outlined above. The mean IMD incidence rate in the overall population for 2012–2019 was 0.02/100,000 (Table 1; Fig. 2c–e). The highest number of reported IMD cases was recorded in Medina (n = 11) and Riyadh (n = 10), while four cases were reported from Mecca (Fig. 3). No specific seasonal pattern to IMD cases was apparent (Fig. S1).

A limitation of reporting from this more recent MoH yearbook data for IMD is the lack of information on causative serogroup or mortality, while recent serogroup data reported from other sources are limited. Although Yesli et al. have reported that disease due to MenW, MenA, MenB, and MenY have all been reported to the MoH in the years 2012–2015, absolute numbers are lacking [26].