Approaches to prevent acute bacterial meningitis indeveloping countries*P.F. Wright1

Endemic acute bacterial meningitis of childhood appears to be neglected as a cause of morbidity andmortality in developing countries, probably because it has been overshadowed by the dramatic epidemics ofmeningococcal disease in sub-Saharan Africa. The available data based on reviews of hospitalized patientssuggest that endemic meningitis is mostly a disease of young infants, Streptococcus pneumoniae andHaemophilus influenzae type b being the most important etiologic agents. The epidemiological patternappears to be different in developing countries, compared with northern Europe or the USA, and closelyresembles the early age of onset and high incidence of meningitis observed among the native Americanpopulations in Alaska.

The mortality from meningitis appears to be much higher in developing countries than in industrializedcountries. The availability of vaccines against the pneumococcus and haemophilus, particularly those inwhich the bacterial polysaccharide is conjugated to a protein, promises protection against systemic bacterialinfection from these organisms. The assessment of the efficacy ofsuch vaccines will have to include a closeexamination ofmeningitis as an outcome. It is suggested that before such vaccines become available carefulclinical and epidemiological studies ofmeningitis will help both to define the impactofthis disease andhow todesign an intervention strategy.

IntroductionAcute bacterial meningitis is a pyogenic infection ofthe meninges due to colonization of the nasopharnyxand invasion of the nasal mucosa, followed by bac-teraemia and entry of bacteria into the cerebrospinalfluid and meninges, most often at the choroid plexus.The illness is usually seen in the first two years of lifebut can occur at any age. The organisms primarilyresponsible, which have been well characterized, areHaemophilus influenzae type b, Streptococcus pneu-moniae, and Neisseria meningitidis. Although otherbacteria may be implicated, particularly in neonatalmeningitis, most cases in both industrialized anddeveloping countries are due to these three organisms.However, the differential diagnosis of the clinicalsyndrome of meningitis in developing countries hasa broader spectrum of etiologies, including malaria,tuberculous meningitis, and a wide range of viralencephalitides, than in the more developed countries.

The diagnosis of meningitis is dependent on notonly the physician's skill and motivation, but also theperformance of a lumbar puncture and the laboratory'scapability to examine and culture the cerebrospinalfluid (CSF). A definite etiological diagnosis can bedifficult, if not impossible, if the patient had previously

* A resum6 of this article appears on pages 484-485.'Professor of Pediatrics, Vanderbilt University, Nashville, TN37232, USA. Former Consultant, Expanded Programme on Immu-nization, World Health Organization, Geneva, Switzerland.

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been treated with antibiotics. Epidemiological assess-ment of the impact of meningitis further demands thatall such cases within a given population base beascertained, which, to the best of our knowledge, hasnever been carried out in a developing country.However, the present review of the available fragment-ary data defines the impact of epidemic and endemicchildhood meningitis in the developing world. Specialattention is given to meningitis caused by Haemophilusinfluenzae type b (Hib), especially in developing coun-tries, because promising new vaccines, consisting ofthepolysaccharide coat of Hib coupled with a proteincarrier, could protect even during the first six monthsof life against systemic infections due to Haemophilus.With these bacterial pathogens, meningitis is only onepossible manifestation because the bacteraemia couldlead to pneumonia and other focal infections.

Epidemiology

Epidemic meningitisThe historical literature on meningitis in developingcountries mostly describes the dramatic epidemics ofmeningococcal A disease across sub-Saharan Africa(1). Although the epidemiology has been well defined,the reasons for the characteristic epidemic patterns arenot fully understood (1). Prevention of meningococcaldisease has been attempted by the administration ofmeningococcal A and C polysaccharide vaccines, and

Bulletin of the World Health Organization, 67 (5): 479-486 (1989) © World Health Organization 1989 479

P.F. Wright

there is evidence supporting the efficacy of groupA vaccine from a number of African countries (3) andthe group C component (4) from Brazil in children over24 months of age. The relative infrequency ofepidemicsand the necessity to give vaccine at an age not includedin the immunization schedule of the Expanded Pro-gramme on Immunization (EPI) have hampered thedevelopment of a uniform vaccination policy. Nocountry is at present regularly vaccinating childrenwith meningococcal vaccines. An apparent sparing ofchildren under two years of age in epidemics anda duration of protection of at least four years in olderchildren suggest that vaccination of children at two-year intervals and adults every 4-6 years might bea reasonable policy (5). Evidence that a single dose ofchloramphenicol is curative means that the disease, ifrecognized early, may be relatively easily treated (6).

Endemic childhood meningitis

Owing to the emphasis on the epidemics of meningo-coccal disease, the impact of endemic childhoodbacterial meningitis in developing countries has beenoverlooked. In the developed world the impact ofchildhood meningitis is well documented and appreci-ated. In North America, Hib accounts for the majorityof meningitis cases (Table 1), which in England andFrance are frequently due to meningococcus (typesB and C). The importance of the latter in Europe,compared with the USA, is unexplained epidemiolog-ically.

As regards Hib infection in industrialized coun-tries, sections of the American population have beenidentified with enhanced susceptibility at an early age;they include American Indians, Eskimos, children withsickle-cell disease, and children in day-care centres.Both the incidence and age distribution of the diseasewithin these groups differ from that in the remainder ofthe United States population. Another feature of Hibmeningitis in Europe was that a higher proportion ofcases occurred in children between 18 months and5 years of age. The age distributions from somedeveloping countries are also summarized in Table 2.

The available data on mortality from Hib menin-gitis (Table 2) for the USA and Europe are populationbased; for the developing countries they representa very limited sampling of university hospitals, wherethere may be some bias since only the very sickchildren were brought to these hospitals. In spite ofthese limitations, the figures reflect a very high mor-tality associated with meningitis in the developingcountries; in contrast, proper management of Hibmeningitis cases (by intensive care and rapid initiationof parenteral antibiotic therapy) has helped the indus-trialized countries to achieve the current low mortalityfigures. Not included in this assessment are the neuro-logical sequelae of meningitis with delayed mortality,which pose a substantial burden for families trying tocare for these children.

In several developing countries meningitis hasbeen documented to account for a substantial number

Table 1: Causes of bacterial meningitis, Including H. Influenza. type b (Hib), In children les than 5 years of age

Population and country Percentage of cases caused by:

Hib Pneumococcus Meningococcus Other organisms

EuropeanEngland (17)' 37 12 48 3France (18) 41 19 37 3

North AmericanUSA (19) 70 17 10 3

AfricanSenegalb 41 39 10 10Nigeria (20) 40 39 8 13Cameroon (7) 42 43 3 12

African (meningitisbelt)Egypt (21) 25 36 20 19Ethiopia (22) 41 22 25 12

AsianPapua New Guinea (8) 49 43 5 3

South AmericanChile (23) 63 29 6 2

' Figures in parentheses indicate the reference to the study.Trevoux, C. Etude statistique de 1052 cas de meningite purulente observde Dakar. Thesis, University of Lyon, 1972.

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Approaches to prevent acute bacterial meningitis In developing countries

Table 2: Age distribution of Hib meningitis and mortality In various populations

Population and country Age group Mortality (%)

< 1 year 1-2 years 2-5 years 5-15 years

EuropeanFinland (24)' 25 35 34 6 3Sweden (25) 31 23 36 10 1.4England (17) 30 25 36 9 5.7

North AmericanUSA (19) 53 30 11 6 6Alaska (non-native) (26) 50 30 18 2 Not availableAlaska (native) (26) 67 24 6 3 6Navaho (Indian) (27) 77 - 22- 1 8

AfricanSenegalb 75 14 11 0 33Nigeria (20) 84 8 4 8- 26Cameroon (7) 55 25 17 3 24

AsianPapua New Guinea (8) 92 8 0 0 30

South AmericanChile (23) 82 13 4 1 11

' Figures in parentheses indicate the reference to the study.b See footnote b in Table 1.

ofin-hospital deaths, e.g., 8.5% in the paediatric unit inYaounde (Cameroon) and 15% in Goroka Hospital inthe Papua New Guinea highlands (7, 8).

In summary, four different epidemiological andclinical patterns of Hib systemic disease are evident.

(1) In northern European countries Hib infectionoccurs at a late age and with a low incidence;epiglottitis is an important component of the diseasespectrum, accounting for 23% of the total Hib diseasein Finland (9).

(2) In the USA and in non-native Alaskan popu-lations there is an intermediate pattern ofHib infectionwith earlier onset than in Europe but with lowmortality.

(3) In other populations in the Americas, as

shown by data from Chile, Jamaica, and the Eskimoand Navaho populations, there is very early onset anda high incidence of Hib infection.

(4) In some African and south-east Asian coun-tries (Cameroon, Nigeria, Papua New Guinea andSenegal), there is very early onset of Hib disease witha high incidence and striking mortality; however,pneumococcal disease is relatively more prominenttogether with other organisms, chiefly Gram-negativeenteric bacteria including salmonella species; epiglot-titis is rarely recognized clinically.

The data on the incidence of meningitis are

fragmentary in the developing countries (Table 3), thereported cases being mostly hospital based. However,

none of the 147 meningococcal meningitis patients ina rural area of the Gambia was seen in a hospital (2);the two estimates from Senegal and Papua NewGuinea are based on patients presenting from popula-tions known to be served by hospitals. No one hasattempted the very difficult task of identifying casesthat are not admitted for care.

The available epidemiological facts, particularlythe very young age of onset, would suggest that the

Table 3: Attack rate of Hib meningitis (cases per year per1000 children less than 5 years of age)

Population and country Rate

EuropeanEngland (17)' 0.11Finland (24) 0.32

AmericanUSA (19) 0.19-0.63Alaska (non-native) (26) 0.69Alaska (native) (26) 2.8Navaho (Indian) (27) 1.7

AfricanSenegalb 0.36

AsianPapua New Guinea (8) 2.6

a Figures in parentheses indicate the reference to the study.See footnote b in Table 1.

P.F. Wright

incidence and mortality will be found to resemble orexceed those in identified high-risk groups such asnative Alaskans. If one assumes that there are 2.0 casesper thousand children per year under five years of agewith a mortality of 30%, this leads to a worldwideestimate ofone million cases ofHib meningitis per yearin developing countries with 300 000 deaths and 200 000children with neurological damage.

In planning interventions the impact of menin-gitis and other systemic Hib disease (epiglottitis,septicaemia, septic arthritis, cellulitis and pneumonia)should be much more precisely defined. In Papua NewGuinea, H. influenzae species were the most commonorganisms recovered from the lung aspirates andblood of children with pneumonia (10). Although notall of these were type b, approximately 20% of thecultures that grew significant bacteria were Hib,suggesting that other forms of systemic disease shouldbe taken into consideration in assessing the effective-ness of Hib and other polysaccharide-conjugate vac-cines.

Prevention

Polysaccharlde vaccine developmentThere was early recognition that the age-relatedincidence of Hib meningitis rose following the initialdecay of maternal antibody and then declined in thesecond year of life with the gradual acquisition ofnatural antibody through pharyngeal carriage, sys-temic infection or exposure to cross-reacting antigens.The concept that circulating antibody was the criticaldeterminant of the host's defence against Hib gainedfurther credence from animal experiments, from sparingof disease in patients on replacement gamma-globulinfor immune deficiency, and from use of prophylacticgamma-globulin (11). The critical antigen was identi-fied early in the understanding of Hib to be thecapsular polysaccharide-polyribosyl ribitol phos-phate, PRP. This antigen shares the characteristic ofmany carbohydrate antigens of eliciting a T-cellindependent immune response in which there is delayin the infant's ability to mount a response, which isoften of the IgM phenotype and does not boost onrepeat immunization.

Polysaccharide vaccines that were developed fora number of encapsulated bacteria have been evalu-ated in adults and children, the findings amply confirm--ing the difficulties in their use as immunogens but withencouraging signs. Pneumococcal polysaccharides,particularly the types common as pathogens, aretypically poorly immunogenic in young children; inspite of this, a study from Papua New Guinea sugges-ted efficacy in prevention of deaths from respiratoryillness (12). This study must be repeated since logical

interpretation of the data is difficult without evidenceof induction of an antibody response. Pneumococcalvaccines are, however, licensed in the USA for use inthe elderly to prevent pneumonia. As described earlier,meningococcal A and C vaccines are efficacious inchildren and may have a role to play in epidemic andendemic childhood meningococcal disease. However,meningococcal B vaccine which has N-acetylneura-minic acid (as its capsular substance) is poorly anti-genic in all ages.

Finally, a large trial with Hib in Finland demon-strated efficacy ofthe vaccine in children over approxi-mately 24 months old (13). Based primarily on theefficacy in Finland, the polysaccharide Hib vaccinewas licensed for use in the USA in 1985 in children at24 months of age. After introduction of the vaccine,surveillance was started to determine the vaccine'sefficacy, estimates ofwhich vary in different studies butappear to be less than optimal, perhaps in the order of50% (14). No benefit would be expected from suchunconjugated polysaccharide vaccines in developingcountries because their use is restricted to childrenover two years of age.

Following the lack of immediate success of poly-saccharide vaccines in the prevention of childhoodillness, efforts were begun to couple the polysaccharideto a protein carrier, thus changing the nature of theimmune response to a T-cell dependent responsewhich can be invoked at an earlier age. The choice ofprotein carrier, coupling agent, and formulation of thepolysaccharide have all been varied in an effort toachieve optimal immunogenicity. The resulting vac-cines have been evaluated in a number of phase-I andphase-2 safety and immunogenicity trials, and an Hibpolysaccharide-diphtheria toxoid vaccine has under-gone field trials in Finland and Alaska. In Finland thevaccine was given at 3, 4, 6, and 14 months toapproximately 30000 infants, 80% of them havinga serum antibody response after the third dose. After9 months of follow-up, the vaccine efficacy was 87%with confidence limits of 50-96% (15). The Alaskantrial has been completed and is being analysed; theinitial results are far less promising than those fromFinland (J.I. Ward, personal communication, 1988). InDecember 1987, the Hib-diphtheria toxoid vaccinewas licensed for use in the USA. Other Hib vaccineshave used as conjugates a nontoxic variant (CRM197)of diphtheria toxin, the outer membrane proteins of N.meningitidis, and tetanus toxoid. It appears that thesedifferent structures are not likely to behave in anidentical fashion as immunogens.

Thus, among the currently evaluated series ofvaccines against Hib infection, only one conjugateappears to have high efficacy, based on the Finnishdata. However, the epidemiology of Hib disease inFinland is very different from that in the developing

Approaches to prevent acute bacterial meningitis In developing countries

countries where the available data suggest that 80% ofrecognized Hib illness occurs in the first year of life. Inevery population surveyed, the first two months of lifeare almost completely spared of disease and the peakincidence of disease remains in the second six monthsof life. Immunization would therefore have to beeffective by six months of age.

Analysis of a second important trial from Alaskawill be completed shortly. It will be of more relevanceto developing countries because ofthe similar early ageof onset of disease. Further information is expectedfrom post-licensing surveillance in the USA whichshould establish the efficacy of the Hib-conjugatevaccines for children older than 18 months; if thesevaccines prove successful in this age group, they willundoubtedly be evaluated for inclusion in the primaryseries of immunizations in the first six months of life.

Preliminary strategiesWith this background one can now consider how todemonstrate whether the conjugated Hib vaccine hasa sufficiently high efficacy and cost-benefit ratio indeveloping countries to deserve consideration forinclusion in the EPI. The following clinical studies aresuggested that should lead towards that goal.

(1) Definition of maternal antibody levels of Hibantibody and the patterns of antibody decay andacquisition in the first two years of lifeIf the pattern of acquisition of disease is reflected in theserum antibody levels, the height of maternal serumantibody levels might be expected to reflect the age ofonset of susceptibility of the infant. With early onset ofdisease one would expect either that maternal levelsare low, placental transfer is ineffective, and/or antibodydecay is more rapid, or that exposure is so intense thata moderate level of passive antibody can be overcome.The subsequent rate of acquisition of antibody shouldbe a reflection of the intensity of exposure. Significantquestions exist about the duration of maternal anti-body in developing countries and capability of theinfant in this setting to respond to antigenic challenge.Studies on 50 children, with serum samples every twomonths for the first six months of life and every fourmonths thereafter until two years of age, at each offourgeographically diverse sites would help to answer thesequestions. For each of these children a matchedmaternal serum sample should be drawn at the time ofthe birth of the child. Comparative data are publishedfrom the USA and from the Eskimo population.

(2) Comparison of vaccine safety and immunogenicityin developing countries

Another step is to do immunogenicity trials with

Hib-conjugate vaccines given in a schedule that isconsistent with incorporation into EPI. Safety ofthesevaccines is not a major issue, but their immunogenicitymust be established in developing countries. This isimportant not only for the PRP vaccines mentionedabove, but as a prototype for vaccines against otherencapsulated bacteria. Age and interval between dosesmay be very important with these vaccines. It mustbe demonstrated that they can be combined withdiphtheria-tetanus-pertussis (DTP) vaccines withoutloss of potency and without giving excessive amountsof carrier protein, particularly if there is alreadya vaccine component such as diphtheria or tetanus.Duration of the antibody will also be a significantconcern with these vaccines. A primary series mustprovide protection until the initiation of a strongresponse to natural exposure.

Vaccine and control groups (with 50 children ineach) for studies at two to three representative sitesthroughout the developing world might be sufficient toestablish immunogenicity. The determination of anti-body levels should be done in a reference laboratory ina developed country to ensure standardization of theresults. Similar trials from the USA would providecomparative data.

It must be recognized that the immunogenicity ofdifferent conjugated polysaccharides may vary. Al-though relevant data will be generated in the USA andelsewhere as to the optimal preparation for use inindustrialized countries, these findings will have to bereplicated in developing countries. The Alaskan dataappear to confirm the need for this approach.

(3) Definition ofthe age-specific attack rate ofmeningitisSites would have to be chosen providing a high qualityof clinical care and bacteriology services to a definedpopulation base. Prospectively all cases of meningitiswould be identified for a one-year period. Simultan-eously a retrospective one-year review would giveinteresting comparative information. The identifica-tion of cases that presented to the hospital would haveto be coupled with an effort to assign a cause of deathto those children who do not reach medical care.Meningitis can be a fulminant disease with deathoccurring within 24 hours of the onset of symptoms.

Three possible categories of meningitis are (1)bacteriologically proved, (2) antigen-positive withevidence ofCSF changes, and (3) clinically diagnosed.A recent study has demonstrated good sensitivity andspecificity of the antigen detection method in Ethiopia(16) but this could not substitute for a lumbar punctureor for good bacteriological techniques.

Given that 20% of the population in a developingcountry is under 5 years old and that an estimated rateofHib meningitis in this age group might be 2 per 1000

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per year, a total population of 38 000 people wouldhave to be under surveillance for one year to establishthat this was a real rate + 1 per 1000. We believe it isnot unrealistic that such information might be obtain-able from selected centres in the developing world.

There is also the question ofwhether by interview-ing parents shortly after a child's death an accuratecause of death can be established by their descriptionof, for example, a febrile illness with neurological signssuch as stiff neck or seizures. As virtually all untreatedcases of meningitis are fatal, these records combinedwith the clinic and hospital records might give a rela-tively complete case ascertainment. Such investiga-tions might be conducted initially in a region free ofmalaria which may be the major confounding cause ofsudden febrile illness leading to death. A counterargument for performing at least one study in centralAfrica is that sickle-cell disease and other haemoglo-binopathies clearly increase the risk of systemic infec-tion with encapsulated bacteria. If a cause of deathsurvey could be validated as a tool for examiningmeningitis and other broad categories of disease itcould prove very useful. This question is being approachedin the Gambia and in Egypt. It is worth noting,however, that in England 26 out of 94 fatal cases ofmeningitis were undiagnosed until autopsy (17).

Establishment of the disease burden imposed bymeningitis will be essential for a consideration ofvaccine usage. It would also be essential to anyestimate of the size needed to conduct a trial aimed atestablishing vaccine efficacy in a developing country.Obviously such a trial should attempt to documentother systemic Hib, meningococcal and pneumococcaldisease at the same time, particularly through the useof blood cultures. The establishment of bacterialetiology will be more difficult with pneumonia thanwith sepsis and meningitis.

(4) Assessment of vaccine costs and stability

Before further exploration of the vaccine its true costwould have to be established and assessed in terms ofthe results available from the above three investiga-tions. The scale ofdemand might make it an affordablevaccine after recouping the initial development costs inthe industrialized countries.

(5) Efficacy trial

An efficacy trial with the optimal vaccine preparationwill have to be carried out in a developing country todetermine if antibody can be generated in time toprevent the very early onset of disease in this setting.One approach would be to use the conjugated Hibvaccine as a test group in a pneumococcal vaccinestudy. In addition to efficacy against meningitis, the

Hib vaccine might lead to fewer pneumonia cases,approximately 10% of which may be caused by Hib.As the two vaccines would potentially decrease bothtotal meningitis and respiratory illnesses, specificetiologies would have to be very carefully identified.This is the approach originally used in Finland in themeningococcus A and Hib vaccines study. It appearsthat any investigation to assess the impact of encapsu-lated bacteria, even if aimed primarily at acute respira-tory disease, should incorporate a careful examinationof systemic disease into the protocol because of theimpact of the disease and the unequivocal nature oftheendpoint.

The scope of such a trial would be large. InFinland 60 000 children were enrolled and followed foran average of nine months to establish efficacy. Theirrate of illness is about one-tenth of that anticipated ina developing country, where the surveillance wouldalmost certainly be less efficient.

(6) Justification for the approach

The above approach to determine the role of a particu-lar vaccine in immunization programmes in develop-ing countries includes a progression of investigationsthat must be done-some quite simple before aninformed decision can be made on its use, for which thecurrent epidemiological and clinical justifications areinadequate.

AcknowledgementThe author thanks Brian Greenwood, Richard Moxon,Heikki Petola and Joel Ward for their thoughfful commentsduring the preparation of this manuscript.

Resume

Prevention de la meningite bacterlenne algue

dans les pays en developpementLa meningite bacterienne aigue est une infectionpyogenique des meninges resultant de la colonisa-tion du rhinopharynx et de l'envahissement de lamuqueuse nasale, suivie du passage de la bacteriedans le sang, le liquide cephalo-rachidien et lesmeninges. Les principaux microorganismes res-ponsables sont Haemophilus influenzae type b,Streptococcus pneumoniae et Neisseria meningi-tidis. Le diagnostic de la meningite est fonde sur

l'identification de la bacterie en laboratoire apresponction lombaire. 11 est rendu plus difficile par uneantibiotherapie prealable. Le veritable impact de la

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Approaches to prevent acute bacterial meningitis In developing countries

meningite ne peut Otre d6termin6 que si tous les cassurvenus dans une population donnee sont detectes.

Le present article porte principalement sur lameningite a Haemophilus, car il est possible deproteger les nourrissons a l'aide d'un vaccin danslequel le polysaccharide bact6rien est conjuguea une proteine. Le tableau epid6miologique de cetteforme de m6ningite differe d'un pays a I'autre: enEurope, son incidence est moindre et elle survienta un Age plus avance qu'aux Etats-Unis oiu, danscertaines populations (notamment les Esquimaux),la maladie est particulierement frequente dans les6 a 12 premiers mois de la vie. Les rares donneesrecueillies dans les pays en developpement donnenta penser que la situation est comparable a celle quel'on observe chez les Esquimaux.

Un essai mene en Finlande a etabli l'efficacited'un vaccin conjugue anti-Haemophilus dans cepays. Un essai analogue en Alaska a ete moinsconvaincant. II est cependant possible que lesvaccins actuels soient plus antigeniques que ceuxqui ont 6te utilises dans ces essais. II est proposed'entreprendre une serie d'etudes pour evaluerl'importance de la m6ningite dans les pays end6veloppement et etablir les bases d'une strategied'intervention. Ces 6tudes consisteraient &: 1)d6finir les taux d'anticorps maternels diriges contreles Haemophilus et les mecanismes de degradationet d'acquisition des anticorps au cours des deuxpremieres annees de la vie, 2) comparer l'innocuit6et l'immunog6nicite des vaccins dans les pays endeveloppement, 3) definir le taux d'atteinte de lam6ningite en fonction de l'age, 4) evaluer le cout etla stabilite d'un vaccin potentiel, et 5) mettre au pointun essai d'efficacit6 des vaccins bacteriens dont lescrit6res seraient le nombre de cas de m6ningite etd'infection bacterienne ainsi que l'impact du vaccinsur les maladies respiratoires aigues.

References1. Lapeyssonnle, L. La meningite cerebrospinale en

Afrique. Bulletin of the World Health Organization, 28:3-114 (1963).

2. Grenwood, B.M. et al. Factors influencing susceptibil-ity to meningococcal disease during an epidemic inthe Gambia, West Africa. Journal of infection, 14:167-184 (1987).

3. Greenwood, B.M. Selective primary health care: strate-gies for control of disease in the developing world. Xil.Acute bacterial meningitis. Reviews of infectious dis-eases, 6: 374-389 (1984).

4. Taunay, A.E. at al. [Assessment of the protectionconferred by anti-group C meningococcal polysaccha-ride vaccine to 6-36-month-old children.] Revista doInstituto Adolfo Lutz, 38: 77-82 (1978) (in Portuguese).

5. Mohammed, I. et al. Control of epidemic meningococcalmeningitis by mass vaccination. Journal of infection, 9:190-196 (1984).

6. Vlmont-Vicary, P. & Rogerle, F. Epidemie de meningitecdrdbrospinale 4 Neisseria meningitidis dans la rdgionsanitaire de Ruhengeri (Rwanda). Medicine tropicale,43: 155-161 (1983).

7. Benard-Bonln, A.C. & Ekoe, T. Les meningites purulentesde l'enfant a Yaounde: aspects epidemiologiques et prog-nostiques. Annales de la Socidt6 belge de Medecinetropicale, 65: 59-68 (1985).

8. Graotn, M. et al. The aetiology of purulent meningitis inhighland children: a bacteriologic study. Papua NewGuinea medical joumal, 28: 233-240 (1984).

9. Pola, H. & Virtanen, M. Systemic Haemophilus influenzaeinfection in Finland. Clinical pediatrics, 23: 275-278 (1984).

10. Shann, F. et al. Aetiology of pneumonia in children inGoroka hospital, Papua New Guinea. Lancet 2: 537-541(1984).

11. Santoham, M. tal. Prevention of Haemophilusinfluenzaetype b infections in high-risk infants treated with bacterialpolysaccharide immune globulin. New England joumal ofmedicine, 317: 923-29 (1987).

12. Riley, l.D. et al. Pneumococcal vaccine prevents death fromacute lower-respiratory-tract infections in Papua NewGuinean children. Lancet 2: 877-881 (1986).

13. PdbIa, H. etal. Prevention of Haemophilusinfluenzaetypeb bacteremic infectfons with the capsular polysaccharidevaccine. New Englandjournal of medicine, 310:1561-1566(1984).

14. Immunizaton Practices Advsory Commilee. Update: Pre-vention of Haemophilus influezaetype B disease. Morbidityand mortality weekly report, 36: 529 (1987).

15. Eskola, J. et al. Efficacy of Haemophilus influenzaetype b polysaccharide-diphtheria toxoid conjugatevaccine in infancy. New England journal of medicine,317: 717-722 (1987).

16. Habte-Gabr, E. et al. Rapid etiologic diagnosis ofpyogenic meningitis by coagglutination, latex aggluti-nation and immuno-osmophoresis of cerebrospinalfluid, serum and urine. Tropical and geographicalmedicine, 39: 137-143 (1987).

17. Goldacre, M.J. Acute bacterial meningitis in child-hood. Lancet, 1: 28-31 (1976).

18. Olivares, R. & Vacarle, M. Meningites bacteriennes del'enfant 4 Paris de 1982 4 1986 epidemiologie etpronostic. Bulletin dpiddmiologique hebdomadaire(France), 47: 185-186 (1987).

19. Fraser, D.W. et al. Bacterial meningitis in Bernalillocounty, New Mexico: a comparison with three otherAmerican populations. American journal of epidemio-logy, 100: 29-34 (1974).

20. Nottidge, V.A. Haemophilus influenzae meningitis:a 5-year study in Ibadan, Nigeria. Journal of infection,11: 109-117 (1985).

21. Guirguls, N. et al. Bacterial meningitis in Egypt:analysis of CSF isolates from hospital patients inCairo, 1977-78. Bulletin of the World Health Organiza-tion, 61: 517-524 (1983).

22. Hallemeskel, H. & Tafarl, N. Bacterial meningitis inchildhood in an African city. Acta paediatrica scandina-vica, 67: 725-730 (1978).

485

P.F. Wright

23. Juliet, C. et al. [Bacterial meningitis in children:experience with 441 cases.] Revista medica de Chile,111: 690-698 (1983) (in Spanish).

24. Valmarl, P. et al. Invasive Haemophilus influenzaeandmeningococcal infections in Finland. Scandinavianjournal of infectious diseases, 19: 19-27 (1987).

25. Claesson, B. et al. Incidence and prognosis of Haemo-philus influenzae meningitis in children in a Swedish

region. Pediatric infectious disease, 3: 35-39 (1984).26. Ward, J.l. et al. Invasive Haemophilus influenzae type

b disease in Alaska: background epidemiology fora vaccine efficacy trial. Journal of infectious diseases,153: 17-25 (1986).

27. Coulehan, J.L. et al. Bacterial meningitis in NavajoIndians. Public health reports, 91: 464-468 (1976).

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