Impact of Haemophilus influenzae Type b Conjugate Vaccine in Mongolia:Prospective Population-Based Surveillance, 2002-2010Susana Scott, PhD1, Dorjpurev Altanseseg, MD, PhD2, Demberelsuren Sodbayer, MD, MPH3,

Pagvajav Nymadawa, MD, PhD, DSc2, Davaadash Bulgan, MD, PhD2, Jamsran Mendsaikhan, MD, PhD3,

James P. Watt, MD, MPH4, Mary P. E. Slack, MA, MBBChir, FRCPath5, Maria G. Carvalho, PhD6, Rana Hajjeh, MD6,

and Karen M. Edmond, MBBS, MSc, MTPH, FRACP1,7

Objectives Bacterial meningitis is associated with high mortality and long-term complications. This study as-sessed the impact of Haemophilus influenzae type b (Hib) conjugate vaccine on childhood bacterial meningitis inUlaanbaatar, Mongolia.Study design Prospective, active, population-based surveillance for suspected meningitis in children aged 2-59months was conducted (February 2002-January 2011) in 6 hospitals. Clinical data, blood, and cerebrospinal fluidwere collected. The impact of Hib conjugate vaccine was assessed by comparing Hib and all cause meningitisdata in the 3 years preceding pentavalent conjugate vaccine implementation (2002-2004) with 3 years postimple-mentation (2008-2010).Results Five hundred eleven cases of suspected meningitis were identified from 2002-2011. Pentavalent conju-gate vaccine coverage in December 2005 in Ulaanbaatar city was 97%. The proportion of suspected cases con-firmed as Hib meningitis decreased from 25% (50/201) in the prevaccination era to 2% (4/193) in thepostvaccination era (P < .0001). The annual incidence of Hib decreased from 28 cases per 100 000 children in2002-2005 to 2 per 100 000 in 2008-2010 (P < .0001).Conclusions This article demonstrates the marked impact of Hib conjugate vaccine introduction onmeningitis in Mongolia. It is important to sustain this surveillance system to monitor the long-term impactof Hib conjugate vaccine, as well as other interventions such as pneumococcal and meningococcal vaccines.(J Pediatr 2013;163:S8-11).

Bacterial meningitis continues to be associated with high rates of death and long-term complications in children <5 yearsof age.1 Many studies in Europe, North and South America, and Africa2-6 have shown that the introduction ofHaemophilus influenzae type b (Hib) conjugate vaccine into childhood immunization programs results in a dramatic

decrease in both Hib disease and suspected bacterial meningitis without confirmed etiology.2,3

Data on Hib conjugate vaccine impact in Asian countries are limited.7,8 Mongolia was one of the few countries in Asiato have baseline Hib burden of disease data. These data were available as a result of a population-based active surveil-lance system that was established in February 2002 at the National Center of Communicable Diseases (NCCD), Ministryof Health, Mongolia. The incidence of Hib meningitis was reported as 28/100 000 in children aged <5 years from 2002-2004.9 Mongolia was also one of the first countries in Asia to introduce Hib conjugate vaccine and introduced the com-bined Diphtheria-Tetanus-Pertussis-Hepatitis B-Hib (pentavalent; Quinvaxem, Berna Biotech Korea, Seoul, South Ko-rea) conjugate vaccine in January 2005. The primary objective of this study was to assess the impact of this vaccineon childhood bacterial meningitis using the NCCD surveillance system.

From the 1Department of Infectious DiseaseEpidemiology, London School of Hygiene and TropicalMedicine, London, United Kingdom; 2National Center ofCommunicable Diseases, Ministry of Health; 3WorldHealth Organization, Ulaanbaatar, Mongolia; 4JohnsHopkins Bloomberg School of Public Health, Baltimore,MD; 5Respiratory and Vaccine Preventable BacteriaReference Unit, ReferenceMicrobiology Services, PublicHealth England, London, United Kingdom; 6Division of

Methods

Prospective, active, population-based surveillance for suspected meningitis inchildren aged 2-59 months was conducted from February 2002-January 2011(2002-2010) in 6 sites (the NCCD, the National Center of Maternal and ChildHealth, Khan-Uul District Hospital, Songinkhairhan District Hospital, Sukhbaa-tar District Hospital, and Bayanzurkh District Hospital). These are the onlyhospitals that admit children with meningitis in Ulaanbaatar, the capital of

Bacterial Diseases, National Center of Immunization andRespiratory Diseases, Centers for Disease Control andPrevention, Atlanta, GA; and 7School of Pediatrics andChild Health, University of Western Australia, Crawley,Australia

Please see the Author Disclosures at the end of thisarticle.

0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc.

All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.03.024

CSF Cerebrospinal fluid

Hib Haemophilus influenzae type b

NCCD National Center of Communicable Diseases

PCR Polymerase chain reaction

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Vol. 163, No. 1, Suppl. 1 � July 2013

Mongolia. Trained clinical staff ascertained clinical details ofall children admitted to these hospitals and completed datacollection forms from 2002-2010. Full details about thesurveillance system and methods have been previouslypublished.9

Case Identification and DefinitionsOnly hospitalized children aged 2-59 months of age were in-cluded in the study. A suspected clinical case of pediatricmeningitis was defined as a sudden onset of fever ($38�C)plus 1 or more of the following: neck stiffness, bulgingfontanelle, altered or reduced level of consciousness,convulsions, poor sucking and irritability, prostration,lethargy, toxic appearance, petechial or purpuric rash, or se-vere vomiting. Clinicians were encouraged to perform lum-bar puncture on all suspected meningitis patients. Adiagnosis of purulent bacterial meningitis was made if thecase fulfilled the clinical criteria for a suspected case plusthe cerebrospinal fluid (CSF) had 1 of the following abnor-malities: (1) turbid or cloudy in appearance; (2) CSF whiteblood cell count >100 cells/mm3; or (3) CSF white bloodcell count 10-99 cells/mm3 plus CSF glucose <40 mg/dLand CSF protein >100 mg/dL. Confirmed bacterial meningi-tis was defined as a suspected or purulent bacterial meningitiscase with a pathogenic organism including Hib, Streptococcuspneumonia, orNeisseria meningitidis. The organisms could beisolated from CSF or blood by microbiological culture tech-niques or could be identified from the CSF by latex aggluti-nation or real time polymerase chain reaction (PCR).Methods remained consistent over the 9-year period andare described in our earlier article.9 All specimens were ana-lyzed using culture, latex agglutination, and real time PCR.

Vaccination CoverageRoutine immunization services are provided in all largehealth facilities including family clinics and district health of-fices in Ulaanbaatar (43 health facilities in total). Outreachservices are provided by nurses to both urban and remote dis-tricts. The private sector does not play a major role invaccination programs. The liquid-lyophilized pentavalentconjugate vaccine was introduced in January 2005 with sup-port from United Nations Children’s Fund and Global Alli-ance for Vaccines and Immunization. Three doses of the

Table I. Distribution of cases of meningitis in children aged

Type of case

2002-2004 200

No ofchildren

Age, mo,mean (SD)

No deaths(%)

No ofchildren

Agmea

All suspected 201 12.9 (13.1) 23 (11.4) 117 10.Incomplete data 22 13.2 (12.8) 3 (13.6) 6 15.Negative 52 11.7 (10.6) 4 (7.7) 18 12.Purulent, not confirmed 32 19.2 (16.8) 4 (12.5) 24 12.Hib 50 8.4 (4.8) 8 (16.0) 8 8.Streptococcus pneumoniae 19 18 (15.6) 3 (12.5) 16 4.Neisseria meningitidis 24 8.4 (8.4) 1 (5.3) 38 15.Other confirmed bacterial infection 2 10.8 (6.0) 0 (0.0) 7 11.

*Both cases had group B streptococcus.

Impact of Haemophilus influenzae Type b Conjugate Vaccine in MSurveillance, 2002-2010

vaccine were provided to all children aged 2, 3, and 4months.Pentavalent conjugate vaccine replaced DTP andmonovalenthepatitis B vaccine and nationwide coverage of pentavalentconjugate vaccine achieved by 2008. The first phase of intro-duction in Ulaanbaatar city and 5 rural provinces was com-plete by the end of 2005. Coverage of the third dose ofpentavalent conjugate vaccine in Ulaanbaatar city was re-ported to be 97% in December 2005 in children aged 12months.10 Supplies of the vaccine have been consistent withno reported problems or interruptions of supply throughoutthe surveillance period (2002-2010).In this study, all families were asked for their child’s immu-

nization card when the child was admitted to hospital. Fam-ilies were asked to bring the card from home if it was notavailable at the first request. All data were cross checkedwith Ministry of Health, World Health Organization,and United Nations Children’s Fund records to ensurecompleteness. Families were only asked if their child hadreceived any pentavalent conjugate vaccines from birth untilthe time of presentation to hospital and the answer wasrecorded as “yes/no.” The number of doses of pentavalentconjugate vaccine was not recorded.

Data AnalysesOnly Ulaanbaatar residents were included in the surveillancesystem. Residency was determined by interviewing familymembers and reviewing identification cards. The populationof children aged 2-59 months in Ulaanbaatar was 60 047 in2005.11 Annual incidence rates per 100 000 children aged 2-59 months were calculated by dividing the number of casesof meningitis in residents by the population in Ulaanbaatarin this age group. All analyses were performed in Stata SE12.0 (StataCorp LP, College Station, Texas).

Results

From February 2002-January 2011 (2002-2010), a total of510 cases of suspected meningitis were identified from the6 Ulaanbaatar hospitals in children aged between 2 and 59months. Of these children 477 (93%) were Ulaanbaatar resi-dents (Table I) and 51% (245) were male, with a median ageof 10.2 months (SD 6.1). Forty seven (9.8%) of the suspectedmeningitis cases died.

2-59 months in Ulaanbaatar, Mongolia, 2002-2010

5-2007 2008-2010 Total

Totaldeaths (%)

e, mo,n (SD)

No deaths(%)

No ofchildren

Age, mo,mean (SD)

No deaths(%)

Total no ofchildren

8 (5.3) 15 (12.8) 139 9.1 (10.9) 9 (4.7) 477 47 (9.8)3 (6.9) 2 (33.3) 8 14.2 (11.3) 1 (12.5) 36 6 (16.6)1 (6.5) 3 (16.7) 22 12.3 (11.8) 1 (4.5) 92 8 (8.7)1 (4.6) 4 (16.7) 39 15.6 16.5) 1 (2.5) 95 9 (9.5)0 (7.4) 1 (12.5) 4 7.4 (3.9) 0 (0.0) 62 9 (14.5)3 (2.7) 2 (12.5) 28 16 12.5) 3 (10.7) 63 8 (12.7)5 (7.6) 2 (5.3) 47 6.1 (7.3) 2 (4.3) 109 5 (4.6)0 (5.2) 1 (14.3) 11 7.3 (5.0) 1 (9.0) 20 2* (10.0)

ongolia: Prospective Population-Based S9

In

cid

en

ce

per 1

00 000

Haemophilus influenzae type b

Streptococcus pneumoniae

Neisseria meningitidis

Purulent, not confirmed

Figure. Annual meningitis incidence in children aged 2-59months in Ulaanbaatar, Mongolia, 2002-2010.

THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 163, No. 1, Suppl. 1

Of the cases of suspected meningitis, 349 (73%) met thecase definition of purulent meningitis. Of the purulent men-ingitis cases, 234 (69%) were confirmed with Hib, pneumo-coccus, or meningococcus; 62 Hib (26%), 63 S pneumoniae(27%), and 109 N meningitidis (47%). In addition, 10 wereconfirmed with group B streptococcus (Table I). Therewere no cases of non-type B Haemophilus influenzae menin-gitis. Twenty-four (9.4%) children with confirmed bacterialmeningitis died (Table I).

The Figure and Table II display the annual incidence ofsuspected, purulent, and confirmed bacterial meningitis inthe study population from 2002-2010. The annual incidenceof confirmed meningitis decreased from 52 cases per 100 000children in 2002-2005 to 43 per 100 000 in 2008-2010(P = .10, P for trend .17). The annual incidence of Hibdecreased from 28 cases per 100 000 children in 2002-2005 to2 per 100 000 in 2008-2010 (P < .0001), and there were nocases of Hib meningitis by 2010. In contrast the incidence ofS pneumoniae slightly increased from 11 cases per 100 000children in 2002-2005 to 16 per 100 000 in 2008-2010(P = .09, P for trend .08). The incidence of N meningitidisincreased from 13 cases per 100 000 children in 2002-2005 to

Table II. Annual cases of meningitis and incidence in childre

Number of total meningiti

2002 2003 2004 2005

All suspected 70 (116.6) 77 (128.2) 54 (89.9) 47 (78.Incomplete data 11 (18.3) 5 (8.3) 6 (10.0) 0 (0.0Negative 22 (36.6) 24 (40.0) 6 (10.0) 5 (8.3Purulent, not confirmed 9 (15.0) 12 (20.0) 11 (18.3) 13 (21.Hib 12 (20.0) 19 (31.6) 19 (31.6) 6 (10.Streptococcus pneumoniae 7 (11.7) 8 (13.3) 4 (6.7) 7 (11.Neisseria meningitidis 8 (13.3) 9 (15.0) 7 (11.7) 14 (23.Other confirmed bacterial infection 1 (1.7) 0 (0.0) 1 (1.7) 2 (3.3

S10

26 per 100 000 in 2008-2010 (P = .07, P for trend .05) due toan outbreak of serogroup A meningococcus in 2008.There was no significant change in the annual incidence of

suspected meningitis from 2002-2005 (112 cases per 100 000)to 2008-2010 (88 per 100 000) (P = .09, P for trend .10). Inaddition, the annual incidence of purulent non confirmedmeningitis increased from 18 cases per 100 000 children in2002-2005 to 21 per 100 000 in the postvaccination periodfrom 2008-2010 (P = .99, P for trend .87). However, the2008-2010 postvaccination data included cases of suspectedand purulent meningitis from the 2008 meningococcal out-break, which was a temporal anomaly unrelated to the useof Hib conjugate vaccine. Thus, we repeated the suspectedand purulent analyses excluding the 2008 data. We founda statistically significant decrease in the annual incidence of-suspected meningitis in 2009-2010 (54 per 100 000, P = .04)compared with the 2002-2005 data. We also found a statisti-cally significant decrease in the annual incidence of purulentmeningitis in 2009-2010 (6 per 100 000, P = .03) comparedwith 2002-2005 data.The proportion of suspected cases identified through the

surveillance system, which were confirmed as Hib meningitisdecreased from 25% (50/201) in 2002-2005 to 2% (4/193)2008-2011 (P < .0001).

Discussion

The introduction of Hib conjugate vaccine in Ulaanbaatar,Mongolia, resulted in a marked decrease in the incidence ofconfirmed Hib meningitis. Before vaccine introduction in2005, Hib was the leading cause of childhood bacterial men-ingitis with an estimated annual incidence of 28 per 100 000children.9 This decreased to 10 per 100 000 children in thefirst year of Hib conjugate vaccine introduction and furtherdecreased to zero as coverage increased in the study popula-tion. These observations are consistent with other studies,which have reported dramatic declines in Hib pediatricmeningitis following the introduction of Hib conjugate vac-cine.2-4,6 In addition to reducing hospitalization, Hib conju-gate vaccine has also substantially reduced the disablingsqueal following bacterial meningitis.5,12,13 Our findings aresimilar to other studies from low- and middle-income coun-tries, which have shown decline in Hib meningitis and nochange in pneumococcal meningitis; including reportsfrom Africa (The Gambia,3 Senegal,4 Uganda2) and Latin

n aged 2-59 months in Ulaanbaatar, Mongolia, 2002-2010

s cases (Incidence in cases per 100 000 child population)

2006 2007 2008 2009 2010 Total

3) 24 (40.0) 46 (76.6) 94 (156.5) 32 (53.3) 33 (55.0) 477 (158.9)) 2 (3.3) 4 (6.7) 4 (6.7) 4 (6.7) 0 (0.0) 36 (12.0)) 2 (3.3) 11 (18.3) 2 (3.3) 10 (16.6) 10 (16.6) 92 (30.6)6) 5 (8.3) 6 (10.0) 32 (53.3) 4 (6.6) 3 (5.0) 95 (31.6)0) 1 (1.7) 1 (1.7) 3 (5.0) 1 (1.7) 0 (0.0) 62 (20.6)7) 5 (8.3) 4 (6.7) 11 (18.3) 6 (10.0) 11 (18.3) 63 (20.9)3) 6 (10.0) 18 (30.0) 37 (61.6) 4 (6.7) 6 (10.0) 109 (36.3)) 3 (5.0) 2 (3.3) 5 (8.3) 3 (5.0) 3 (5.0) 20 (6.7)

Scott et al

July 2013 SUPPLEMENT

America.5,6 There have been few studies from Asia, althoughour findings are also consistent with studies from Bangla-desh,7 which reported significant decrease in Hib disease fol-lowing use of pentavalent conjugate vaccine.

There are several limitations to this study. Cases may havebeen missed due to children with bacterial meningitis notreaching hospital. However, bacterial meningitis is a severedisease and requires hospitalization for treatment. Healthcare is freely provided to all children in Mongolia, and thenetwork of district hospitals in Ulsan Baatar is easily accessi-ble. Under these circumstances, we do not believe that thiswas a major source of underestimation of cases of meningitis.The selective criteria used by Mongolian physicians to diag-nose meningitis also may have resulted in some childrenwith meningitis not being ascertained by the surveillance sys-tem. However, this was an active surveillance system withhigh quality reporting and laboratory procedures, and allhospital admissions were checked on a regular basis to min-imize missing any suspected cases. Another limitation wasthe relatively small area under surveillance, which made mea-suring the impact of pentavalent conjugate vaccine on the in-cidence of suspected bacterial meningitis difficult because oflocal trends in meningitis pathogens other than Hib. The ef-fect of the 2008 serogroup A meningococcal outbreak was es-pecially marked. However, we were able to repeat analysesexcluding these data, and significant impacts on both sus-pected and purulent meningitis were detected.

Almost 50% of children with bacterial meningitis were re-ported to have received antibiotic treatment prior to collec-tion of CSF. This limited the number of cases confirmed byculture as it is difficult to isolate causative organisms fromthe CSF of children who have received antibiotics. However,latex tests, PCR, and blood cultures were also used for bacte-rial confirmation which increased the sensitivity of the diag-nosis of Hib, S pneumoniae, and N meningitidis.

This study also found high incidence of S pneumoniae andNmeningitidismeningitis inMongolia and provides evidenceto support the introduction of pneumococcal and meningo-coccal vaccines.14

Pediatric bacterial meningitis surveillance is routine inmany high income countries and has several uses: providingclinical data to doctors and nurses, monitoring changes inepidemiology of bacterial infections, providing early warningof pathogen re-emergence, and investigating the long-termimpact of vaccination programs. In the United Kingdom,there was an increase in the number of cases of Hib despitelong-term sustained high Hib vaccination coverage of 3 dosesbefore 12 months of age. This led to an introduction ofa booster dose in children older than 12 months.15 Ourhigh-quality bacterial meningitis surveillance system wasused to monitor the marked impact of Hib conjugate vaccineintroduction in Ulaanbaatar. This system will be used tomonitor the long-term impact of Hib conjugate vaccineand other interventions such as pneumococcal andmeningo-coccal vaccines inMongolia. TheWorld Health Organizationis introducing regional sentinel surveillance in key centersthat can provide high quality surveillance in low-and mid-

Impact of Haemophilus influenzae Type b Conjugate Vaccine in MSurveillance, 2002-2010

dle-income countries. This surveillance is important for on-going assessment of Hib, as well as the impact ofpneumococcal and meningococcal vaccine in low-and mid-dle-income countries. n

Author Disclosures

M.S. has received financial assistance from vaccine manufac-turers to attend medical conferences and speak at scientificmeetings. The remaining authors declare no conflicts of in-terest, real or perceived.

Reprint requests: Susana Scott, PhD, Department of Infectious Disease

Epidemiology, London School of Hygiene and Tropical Medicine, Keppel

Street, London WC1E 7HT, UK. E-mail: susana.scott@lshtm.ac.uk.

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