Laboratory-confirmed invasive meningococcal disease : effect of the Hajj vaccination policy , Saudi Arabia , 1995 to 2011

Z Memish (zmemish@yahoo.com)1,2, R Al Hakeem1, O Al Neel1, K Danis3,4, A Jasir5, D Eibach5,6 1. Public Health Directorate, WHO Collaborating Center for Mass Gathering Medicine, Ministry of Health, Riyadh, Kingdom of Saudi Arabia 2. College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi Arabia 3. European Programme Intervention Epidemiology Training (EPIET), European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden 4. Institut de Veille Sanitaire, Paris, France 5. European Public Health Microbiology Training Programme (EUPHEM), European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden 6. Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, University of Lyon, Lyon, France


Introduction
Invasive meningococcal disease (IMD) is caused by the gram-negative coccoid bacterium Neisseria meningitidis [1,2].Transmission via respiratory droplets can lead to bacterial meningitis and septicaemia in the persons who get infected.Six serogroups (A, B, C, W135, X and Y) differentiated by their polysaccharide capsule, account for the majority of IMD cases [3].IMD primarily affects children below five years of age, causing an estimated 500,000 cases and 50,000 deaths annually worldwide [4].Polysaccharide and conjugated vaccines are available for serogroups A, C, W135 and Y [5].One vaccine for serogroup B has been licensed in Europe in January 2013 and other serogroup B vaccines have been used in New Zealand, Cuba and France to control epidemics [6].
In Saudi Arabia (SA), the annual Hajj and the yearround Umrah pilgrimage lead to a particular high risk of outbreaks with invasive N. meningitidis.The Hajj pilgrimage is held on every 12th month of the Islamic calendar (2011 attendance: 2.9 million pilgrims, including 1.8 million from >140 foreign countries), making it one of the largest mass gathering events worldwide [7][8][9].About 45,000 pilgrims arrive from the European Union each year [7].Compared to the Hajj, the Umrah pilgrimage includes slightly different rituals and can be undertaken at any time of the year.Foreign pilgrims generally arrive by air in the city of Jeddah and continue to the pilgrimage sites in Mecca, Mina, Mount Arafat and Muzdalifah.Many end the journey with a visit to the holy sites in Medina [7].Extreme congestion with populations from diverse geographical areas appears to promote a high prevalence of asymptomatic N. meningitidis carriage, with up to 80% reported for Mecca pilgrims [10,11].In comparison carriage prevalence between 3% and 30% has been shown for the African meningitis belt and in a Norwegian randomised study, 9.6% of Norwegian volunteers harboured N. meningitidis [12,13].The United States (US) Centers for Disease Control reported five to 10% of adults as asymptomatic nasopharyngeal carriers [14].
Following an outbreak of serogroup A IMD among pilgrims in 1987, Saudi Arabian health authorities implemented three interventions: (i) the compulsory vaccination before entering SA with bivalent AC vaccine for all Hajj pilgrims, (ii) annual vaccination campaigns for all residents in the proximity of pilgrimage sites and (iii) compulsory oral ciprofloxacin upon entering SA to pilgrims from sub-Saharan Africa to eradicate nasal carriage [11,15,16].
In response to two large IMD outbreaks caused by N. meningitidis serogroup W135 in the 2000 and 2001 Hajj seasons [15,17], the SA Ministry of Health (MoH) adjusted their vaccination policy.In 2002, they required a polysaccharide quadrivalent non-conjugated ACWY meningococcal vaccine for (i) children and adults aged above two years living in Mecca and Medina, (ii) Hajj pilgrims aged above two years from within and outside of SA, (iii) healthcare workers in SA and (iv) government personnel serving the pilgrims [18].Since 2010, a conjugated polysaccharide quadrivalent ACWY meningococcal vaccine is given to the same target groups aged from above two to 55 years.The vaccines are administered during annual vaccination campaigns in Mecca and Medina in a single dose with boosters every three years.As of 2013 no meningococcal vaccines are included in the SA national childhood immunisation schedule (NCIS).This study aims to describe the epidemiology of IMD in Saudi Arabia for the years 1995 to 2011, with a focus on changes in incidence and case fatality ratio (CFR) after the introduction of the polysaccharide quadrivalent ACWY vaccine in 2002, in order to evaluate the effect of this Hajj vaccination policy change.

Methods
A confirmed IMD case was defined as either isolation of N. meningitidis from cerebrospinal fluid (CSF) or blood or detection of capsular antigen in CSF by latex agglutination assay [19].An IMD surveillance system was started in 1994 in SA based on recommendations of the World Health Organization (WHO) [20].Since then, the Preventive Medicine Directorate at the MoH requires laboratories from all 20 health regions in SA to anonymously report confirmed IMD cases.The casebased reporting form collects information on age, sex, nationality, SA residency status, vaccination status, date of onset of symptoms (by Gregorian and Islamic calendar), clinical status and place of laboratory confirmation (health region).Information on the capsular groups, determined by latex agglutination, is also collected on the reporting form.
For the purposes of this study, all IMD cases in the surveillance database from 1 January 1995 to 31 December 2011 were extracted.This included cases among Saudi citizens and residents, foreign pilgrims and illegal immigrants.A citizen was considered a person in possession of the Saudi Arabian nationality, and a resident a person originating from outside SA but residing and working in SA.A foreign pilgrim was defined as a person holding a special visa for the Hajj or Umrah pilgrimage, whereas an illegal immigrant was an unregistered person devoid of any valid entry permit for SA.Hajj-related cases were specified as IMD cases with dates of disease onset during the Hajj season in the cities of Mecca or Medina.

Statistical analysis
Age group-, sex-and region-specific annual and cumulative disease incidences were calculated for IMD cases among Saudi citizens or residents.Age group-(0-4; 5-14; 15-64; >65 years of age) and year-specific population denominators were obtained from the United Nations Development Programme (UNDP) website [21].To calculate the cumulative incidence over several years, mid-period population estimates were used as a denominator.The Ministry of Hajj, Saudi Arabia [22] provided the numbers of foreign and domestic Hajj pilgrims.For foreign Hajj pilgrims, no age or sex specific incidences have been calculated, as no age or sex specific Hajj pilgrim numbers were available.In the absence of a population register to calculate rates, illegal immigrants were excluded from any incidence calculations.
From all cases, regardless of citizenship and nationality, numbers of Hajj-related IMD cases as well as year, age and region specific CFRs were calculated.Relative risks for death from IMD were identified by calculating ratios of case-fatalities and their 95% confidence intervals (95% CIs) for the residence status, seasons, age groups and sex.The Student's t-test was used to compare means (age, CFRs and number of cases) between the pre-epidemic (1995-1999) and post-epidemic (2002-2011) periods, excluding the outbreak years (years 2000, 2001), and linear regression models were fitted to describe trends.A p-value <0.05 was considered statistically significant.Surveillance data were computerised using Excel programme (Microsoft, USA) and statistical analysis was performed with Stata 12 (Statacorp, Texas, USA) software.

Study population
During the study period, the population of SA rose from 18,491,845 in 1995 to 27,448,000 persons in 2011, the latter of which comprises 68% SA citizens and 32% residents of foreign origin [21].In 2011, children less than five years-old and adults above 65 years of age accounted for 10%, and 3% of the population, respectively.The largest population increase has been recorded for the 15 to 64 years age group, which comprised 66.7% of the population in 2011 (compared to 56.1 in 1995).Forty-five percent of the population were female.There were 1,936,124 and 1,858,490 persons registered in the health districts of Mecca and Medina in 2011 respectively, representing 14% of the population in SA.During the study period the number of Hajj pilgrims increased by 57% from 1,865,234 (1,080,465 from outside SA) in 1995 to 2,927,717 (1,828,195 from outside SA) in 2011 [22].

Annual and cumulative invasive meningococcal disease incidences
Between 1995 and 2011, 1,103 cases of IMD were reported to the MoH in SA (Table 1).Of those, 645 cases were Saudi citizens/residents and 299 were foreign Hajj pilgrims.Of the remaining cases, 82 were illegal immigrants (not included in incidence calculations), 73 were foreign Umrah pilgrims and four had unknown identity (combined cumulative incidence of IMD among citizens, residents and foreign Hajj pilgrims: 3.92/100,000 population).Between 1995 and 1999, the mean annual incidence was 0.20/100,000, ranging from 0.25/100,000 in 1995 to 0.06/100,000 in 1999 (Figure 1A).In the two outbreak years of 2000 and 2001, the annual incidence increased to 1.42 and 1.32/100,000, respectively.In the post-epidemic period, the mean annual incidence did not exceed 0.06/100,000, ranging from 0.21/100,000 in 2002 to 0.01/100,000 in 2010, a significant decrease compared to the pre-epidemic period (p=0.02)(Figure 1A).
In an analysis restricted to SA citizens and residents, the cumulative incidence between 1995 and 2011 (2.85 cases/100,000) was lower compared to rates including Hajj pilgrims.Outside the outbreak periods the annual incidence followed the same trend described above (Figure 1A).

Age, sex and region specific incidence for Saudi Arabia citizens and residents
For SA citizens and residents, in the study period, the age group including less than four year-olds had the highest cumulative incidence, with both sexes equally affected (12.3 cases/100,000; Figure 2).Above four years of age, males had a higher cumulative incidence.Among those between 15 and 64 years of age, cumulative incidence among males (1.8 cases/100,000) was three times higher than among females (0.6 cases/100,000).
In the period between 1995 and 2011, citizens and residents in the main Hajj pilgrimage destinations had a high cumulative incidence (Mecca: 9.04 cases/100,000 n=175; Medina: 4.52 cases/100,000 n=84 and Jeddah: 2.28 cases/100,000 n=88), whereas urban regions, not visited by the Hajj pilgrims, such as the capital city Riyadh (1.85 cases/100,000 n=131) had lower cumulative incidences.

Distribution of mean age
In the period between 1995 and 2011, among SA citizens and residents, the age group comprising those younger than four years had the highest disease incidence.However, the mean age of all IMD cases, including pilgrims, between 1995 and 2011 was 25.8 (SD: 0.7) years.The mean age decreased from 31 years (SD: 1.3) in the pre-epidemic period to 18 years (SD: 1.4) in the post-epidemic period (p<0.01;b coefficient -1.27, Figure 3).
The mean age of IMD cases during the Hajj season (37.0 years; SD: 1.0) was higher (p<0.01)than among cases outside this season (17.4 years; SD: 0.8).

Serogroup distribution
Serogroup results were available for 59% of all cases reported between 1995 and 2011.In 33% (369/1,103) the serogroup could not be determined and in 7% (78/1,103) no information was submitted (

Discussion
According to the present study and confirming previous reports, the Hajj season constitutes a special opportunity that is very favourable to IMD epidemics [7,9,10].
The high morbidity and fatality for pilgrims during the Hajj season might be largely explained by epidemiologically unfavourable conditions (e.g.crowding, delayed clinical and laboratory diagnosis).Our study indicates that the incidence of IMD decreased in SA following the introduction of the ACWY vaccine in 2002.More specifically, Hajj-related IMD cases declined after the introduction of the vaccine compared to pre-epidemic years.The results suggest that the compulsory use of the ACWY vaccine for pilgrims and residents of Mecca and Medina may have played a role in reducing not only Hajj-related IMD cases, but also the overall disease incidence in SA.
Children under five, predominantly affected by serogroup B and W135 infections, suffered the highest agespecific incidence of IMD throughout the study period.This is consistent with experience from the United Kingdom (UK), the US and Germany, where B is the most prevalent serogroup in children below five years [23][24][25].The mean age of cases decreased during the study period.Two factors may explain this evolution.First, there could have been a decrease in IMD in adolescent or adult Hajj pilgrims since 2002 because of the vaccine introduction for all Hajj pilgrims.Second,  [10].However, those incidence rates cannot be compared to those in SA, as the serogroup distribution in those countries differs, which changes the disease impact completely.Differences in case definitions, which include different laboratory methods as well as clinical and epidemiological criteria, impede international comparisons, as examples from European and Australian guidelines illustrate [30,31].In the future, introduction of new sensitive polymerase chain reaction (PCR) methods for the detection of N. meningitidis in SA, could enable laboratories to confirm a higher number of suspected IMD cases [32,33].
In the current IMD surveillance database, it proved difficult to distinguish between Hajj related cases and non-Hajj cases.We used the time of disease onset and the region to infer a potential connection to the pilgrimage.As per our criteria, cases outside of Mecca and Medina with contact to Hajj pilgrims, or Hajj pilgrims moving outside both cities, would not be identified as Hajj-related.As this information could be used to implement public health control measures, reporting health personnel should verify the Hajj-related status of every case.
The majority of outbreak-related cases were caused by N. meningitidis serogroup W135.The responsible clone was later found to belong to the ST-11/ET-37 complex [34].Genetic analysis of the clone suggested that a capsular switch from serogroup C to serogroup W135 may have occurred years before the onset of the outbreak [34].The same hypervirulent clone caused serogroup C disease in Belgium, Iceland, Ireland, the Netherlands, Portugal and the UK in the late 1990s and early 2000s [10].Concerns had been raised that mass immunisation with vaccines that do not protect against all serogroups could lead to an increase in incidence of meningococcal disease due to strains not included in the vaccine [35,36].Following the introduction of ACWY vaccines, this phenomenon of serotype replacement, or a major emergence of non-vaccine serotypes, has not been reported in Mecca and Medina, or elsewhere.
Vaccine coverage data are needed to determine whether the vaccine contributed to reduced morbidity.While no coverage data are available for foreign Hajj pilgrims, the entry requirement that is enforced through border checks suggest that coverage should be high.In comparison, compliance among Saudi pilgrims may be poorer, since Saudi citizens do not have to provide proof of vaccination at border controls or check points.In 2006, a study of 134 British and 109 Saudi Hajj pilgrims reported that vaccine coverage was lower among local residents (64%) than among British pilgrims (100%) [37].According to this study, 50% of local pilgrims residing in Mecca and Jeddah had been

Conclusion
Saudi-Arabian IMD surveillance data highlight the shift from Hajj-related cases towards non-Hajj related ones, following the introduction of the ACYW vaccine in 2002.The number of cases and the CFR also declined, suggesting a potential positive effect of the current Hajj vaccination policy, among other factors.On the basis of our investigations, we can formulate a number of recommendations.First, regular monitoring of vaccination coverage would help interpret trends of IMD.Second, the surveillance system could be improved through notification of clinically suspected and epidemiologically-linked cases as well as including more sensitive molecular biology based diagnostic methods.Third, inclusion of information on possible links to the Hajj could be considered for the surveillance form.Continued surveillance with annual data analysis remains necessary to drive adapted public health measures and avoid future IMD epidemics during the Hajj seasons of the coming years.

Figure 2 Figure 3
Figure 2Cumulative incidence of invasive meningococcal disease for citizens and residents of Saudi Arabia by age group and sex, 1995-2011 (n=645)

Table 1
Confirmed invasive meningococcal disease cases by residency status in Saudi Arabia,1995-2011 (n=1,103)In the 2000 and 2001 outbreak years, IMD cases from Mecca and Medina during the Hajj accounted for 49% and 31% of all notified annual IMD cases, respectively (Figure1B).In contrast, between 2002 and 2011, only a mean annual 8.1% (standard deviation (SD): 10.1) of all IMD cases were reported from Mecca or Medina during the Hajj season.Since 2006, during Hajj seasons, Medina reported only one case of IMD.The mean numbers of Hajj-related cases was higher (13.4 cases/year; SD: 9.3) during the pre-epidemic than during the postepidemic years (1.7 cases/year; SD: 2.3; p=0.02).
IMD: invasive meningococcal disease; SD: standard deviation.aUnless otherwise specified.bFor the period considered, only the number of citizens and residents combined are available.No reliable numbers for Umrah pilgrims and persons with illegal residency status are available.Hajj-related cases

Table 2
Distribution of serogroups for all typed isolates (n=656) among invasive meningococcal disease cases (n=1,103) and stratification by time periods, age groups, and outcome, Saudi Arabia Of 1,103 isolates from cases of invasive meningococcal disease 369 isolates were not typable and for 78 isolates serogroups were not reported.The CFR for cases with untypable isolates was 9.8% (36 deaths).
CFR: case fatality ratio; IMD: invasive meningococcal disease.a Pre-epidemic period.b Epidemic period.c Post-epidemic period.d CFR=Deaths/total number of confirmed IMD cases.

Table 3
Mortality, case fatality ratio and relative risk of dying from invasive meningococcal disease by residency status, Hajj season, age group and sex, Saudi Arabia, 1995-2011 (n=1,103) CFR=(Number of deaths /Number of confirmed IMD cases) in each category.b The relative risk of dying from invasive meningococcal disease is calculated by dividing the CFR of the relevant row by the CFR of the reference row. a

Table 4
Annual mean case fatality ratio (CFR) by age groups, Saudi Arabia, 1995-2011 CFR = (Number of deaths /Number of confirmed IMD cases) in each category.vaccinated,compared with 71% from the rest of the country.Overall, a larger vaccine coverage study would obviously help interpret results of IMD surveillance data. a