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Public Health

INFLUENCE OF MEASLES VACCINATION ONSURVIVAL PATTERN OF 7-35-MONTH-OLD

CHILDREN IN KASONGO, ZAIRE

THE KASONGO PROJECT TEAM*

Summary In a zone with a high measles case-fatalityrate the risk of dying between the ages of 7

and 35 months for a vaccinated population was compared withthat for an unvaccinated control-group. Life-table analysis forboth groups showed that measles vaccination reduced the risk

of dying at the age of maximum exposure to measles. The gainin survival probability, however, tended to diminish after-wards, to approach that of the unvaccinated group.

INTRODUCTION

MEASLES is one of the main causes of death in developingcountries amongst the under-fives. Although most publishedinformation is based on hospital data, and little is knownabout the role of measles in mortality among the under-fivesin the community, the general picture is impressive. Morleylattributes 15 - 5% of deaths amongst the under-fives to

measles; Cantrelle2 found that among children aged 1 to 5

years measles was responsible for 15-54% of deaths inSenegal, 31 .6% in Upper-Volta, and 8 8% in Dahomey.The development of measles vaccine held out hopes of a

substantial reduction in mortality. Despite many studies onthe effect of measles vaccine on immune status and

morbidity,3-8 there is a lack of data on the impact of measlesvaccination on the mortality of the under-fives. Measles killsthe weakest children, particularly those with protein-energymalnutrition,9 but little consideration has been given to thepossibility of "natural selection" by measles: it is not clearwhether the children dying of measles would not have diedfrom other causes had they not caught measles.10 The answerto this question is an important consideration in cost-benefitanalysis of measles-vaccination.Exposure to measles could have three possible effects

(hypothetical situations Hl-3) on a population of under-fives :

H1.—Some die and the survivors have an overall risk of dyingequal to that which this population would have had if measles hacnot been introduced.H2.-Some die, and the survivors consist of weakened childrer

(through the detrimental effect of measles on the state of nutrition)the survivors would then have a risk of dying greater than thtpopulation would have had if it had not been exposed to measles.H3.-The weakest die, and the survivors consist of stronge:

children having a smaller overall risk of dying than the populatioiwould have had if it had not been exposed to measles.

If measles vaccination does protect against measles, it!effect on mortality and survival patterns would be as shown itfig. 1. In H 1 a vaccinated population would have a survivarate during exposure to measles which is higher than that of:non-vaccinated population, but after the measles exposure

*Under the direction of the Unit for Research and Training in Public Healthof the Prince Leopold Institute for Tropical Medicine (directors, Dr H. vanBalen and Dr P. Mercenier). Field work and data processing were done by DrP. Daveloose, Dr M. De Bruycker, Mr J. Grosdene, Dr F. Kanamugire, Dr R.Meloni, Dr F. Monet, Dr P. Pangu, Dr B. Storme, Dr W. Van Den Bulcke, DrW. Van Lerberghe. This paper was prepared by Dr W. Van Lerberghe.

Fig. 1-Schematic representation of cumulative survival in an

unvaccinated group (unbroken line) and vaccinated group (brokenline) according to three hypotheses.

both groups have similar survival rates. In H2 the survival

graph of the vaccinated group would show an initial gain dueto a reduction in measles deaths, then it would diverge fromthat of the unvaccinated group because the deleterious effectof measles on the nutritional status of the group as a wholewould also be prevented. The net survival benefit would thusbe greater than that in H1.

In H3, however, the initial gain would diminish: sinceselection would not have taken place, the survivors as a wholewould be at greater risk of dying than the unvaccinated(selected) group.This study aims to clarify what actually happens by

comparing survival in a vaccinated with that in an

unvaccinated population of under-fives in a zone with highmortality from measles.

SUBJECTS AND METHODS

Kasongo, a rural town on the east of Zaire and bordering on forestand savanna, has a tropical climate. It has about 30 000 inhabitantsand is the main town in a "zone" having about 180 000 inhabitants.The economy is mainly agricultural (rice, cotton, groundnuts), andthe annual income per head is about$200 (U.S.).

Since 1971 the public health unit of the Institute for TropicalMedicine, Antwerp, has been conducting a pilot programme ofpreventive and curative medicine in Kasongo, under an agreementwith the government of Zaire. The programme includes a survey ofhealth status, morbidity, mortality, and the influence of measlesvaccination on mortality among the under-fives. This survey wasdone between May, 1974, and December, 1977, inclusive, in twoadjacent areas in Kasongo. Each area has about 10 000 inhabitants.There are no gross social differences between the two areas, andboth areas have the same health services.

All children aged under 5 years in the two areas were visited everythree months. At each visit morbidity and mortality data werecollected to provide survival curves in vaccinated and unvaccinatedgroups of children. The case-fatality rates for measles at differentages were also calculated. A child was said to have measles if themother told the investigator that the child had measles since theprevious visit (investigators were blind as to vaccination status ofchildren). The disease is well recognised by the population and ithas a local name. In about 75% of cases the mother had brought thechild to the health centre or hospital, and in 98% of these diagnosiswas confirmed by a health worker (usually a nurse). Serological testswere not done.A case-fatality was defined as a death from any cause in the month

after onset of measles. There were no significant differencesbetween the case-fatality rates of the two areas before measlesvaccination was introduced. Measurements of weight, height, andarm-circumference were also made at each visit-these data wereused to indicate whether the populations being compared weresimilar in as many respects as possible.

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SubjectsBetween the start of the survey and April, 1977, 7092 children

were entered into the study and were visited, and by the end of thestudy in December, 1977, the average number of visits per child was5.5.Each health centre has a file on each family in the area it serves. At

the start of the survey all children born after June 1, 1969, andregistered in the family files were entered into the study. Up to April,1977, children aged under 5 years continued to be recruited, eitherwhen they were identified by the investigator during visits or whenthey were registered at the health centre. Children were droppedfrom the survey when they reached their 5th birthday, or when theydied or emigrated. After collection of baseline data for 15 months,vaccination was introduced in area 1 for children born in or after

September, 1974.Group 1.-These were children in area 1 who were born between

September, 1974, and October, 1975, inclusive. These children wereoffered vaccination when they were 8 months old. However, duringthe early months of the campaign, children born in September,October, and November, 1974, were also invited even if they were9-12 months old. 306 were formally invited to be vaccinated. Ofthese, 255 (83%) accepted and were vaccinated. The average age atvaccination was 8 .8 months. A separate life-table was constructedfor a subgroup (group I v), made up of those who were vaccinated.Excluded from this subgroup were group 1 children whose parentsdid not resond to (repeated) offers of vaccination; those who hadmeasles before vaccination was due; those who entered the surveyafter vaccination age; or, in a few cases, those whose informationabout vaccination did not get on the survey forms during dataprocessing. -

Group 2. -These were children in area 2 who were born duringthe same period as those in group 1. Group 2 children were notvaccinated.

Groups 3 and 4. -To avoid any bias caused by groups 1 and 2

coming from areas with different mortality patterns, life-tables were

constructed for two other groups from the two areas. Group 3children were those from area 1 born between June, 1973, andAugust, 1974, inclusive, and group 4 consisted of children in area 2who were born in the same period. Groups 3 and 4 children werealso not vaccinated.

Vaccine

Live attenuated measles vaccine (’Atenuvax’, Merck, Sharp andDohme) was used. Vaccines were titrated before they were sent, bymessenger, from Belgium to Kasongo. Unused vaccines broughtback after their expiry dates were also titrated. Titrations were doneat the virology laboratory of the Institute for Tropical Medicine ofAntwerp and the University of Ghent. All samples were found tohave a satisfactory tissue-culture infective dose >1000, indicatingthat the vaccine had not deteriorated during transport or storage.

Construction of Life-tablesThe risk of dying during the i-th month of life (éh) was calculated

from:

qi- c4 diqi=

li-l I + -½ (ii-ei) ni

where d, is the number of children dying at age i months; Ii and ei thenumber immigrating into and emigrating out of the study-area atage i months; and 11-1 the number alive at the i-lth month. Thedenominator (ni) thus represents the number of child-months underobservation at age i. This age-specific risk of dying was used toconstruct life-tables according to standard actuarial methods. Forthe 7 to 35 months of age period the numbers of child-months underobservation used for construction of the life-tables in the different

groups were: for group 1, 7217; for group lv, 4185; for group 2,8795; for group 3, 7616; for group 4, 5323-5. Data used forconstruction of life-tables are given in table i. d was 0 or 1 in mostcases, and at worst was 4.

TABLE I-LIFE-TABLES

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Fig. 2-Survival, by age, of the different groups.

Evaluation of Differences in Survival PatternsTo evaluate the differences in survival pattern of the different

groups shown in fig. 2, the survival probabilities Pk (i.e., the prob-ability of surviving from age 0 to age k) were calculated for eachgroup for the age-intervals 7 to 21 months, 22 to 35 months, and 7 to35 months, from:

Pk=(1-qo) (1-q1) ... (1-qk-1)

Their variance can be estimated from*’:

Var(Pk)=P2k∑1=0k-1P-2

Standard deviations are the positive square roots of the correspond-ing variance. The survival probabilities and their standard deviationfor each group during these different periods are shown in table 11.

RESULTS

Of 1069 children with measles who were followed up for atleast 2 months, 65 5 (6 - .1 %) died within a month of onset ofmeasles. The case-fatality rate was highest in the 13-24months age-group (36/366, 9 - 8%). The rates for the otherage-groups were: 1-6 months, 0/31 (0%); 7-12 months,12/194 (6-2%), 25-36 months, 10/232 (4.3%), and 37-60months, 7/246 (2 - 8%). There were no significant differencesbetween the case-fatality rates of the two areas. The

anthropometric data were also similar for the two areas.

TABLE II-SURVIVAL PROBABILITIES (±SD) OF THE DIFFERENTGROUPS FOR DIFFERENT AGE-INTERVALS

The cumulative survival curves of groups 3 and 4 (fig. 2)were also similar. Groups 1 (and Iv) and 2, however, hadcurves that diverged from each other up to the age of 22months. The curves began to converge after that (fig. 2). Thesurvival probabilities of all four groups are shown in table!!.

DISCUSSION

The circumstances under which the vaccination pro-gramme was carried out gave it a good chance of success.Firstly, the personal invitation and high coverage reduced thebias introduced by vaccinating only health services users, aselected population. Secondly, the vaccine did not deteriorateduring transport or storage. This is reflected in the findingthat after the start of the vaccination programme an eruptionwas noted in 36% of the children in group 2 (unvaccinated)during the period they were under observation; this was so foronly 16% of group 1 children (x2 = 18.8, p<0. 00 I) and 11 Toof group lv children.

, Valid conclusions from comparison studies dependcompletely on the similarity of the groups compared. Thetwo groups compared in this study were very similar: theycame from adjacent areas which had no gross differences insocial composition; their anthropometric data were identical;and they came from areas that had the same standardisedhealth programme. Moreover, their survival patterns areidentical (fig. 2, groups 3 and 4).

In Kasongo, 55% of reported cases of measles occur beforethe age of 24 months. Real-life circumstances are not the ideal

depicted in fig. 1, where exposure to measles is limited to acertain age, but the period 7 to 21 months corresponds moreor less to the highest infection risk period; exposure tomeasles does, however, occur after this age and will continueto affect survival patterns, albeit to a lesser degree.The survival probability during the age-interval 7 to 35

months is higher (p = 0’ 07) for groups 1 and lv children thanfor group 2. The observation that there are no differenciesbetween groups 2, 3, and 4 strengthens the conclusion thatvaccination has a beneficial effect on survival probability.This conclusion does not contradict any of the three

hypotheses&mdash;H1 and H2 predict a benefit; so does H3, butone that tends to decrease with increasing age on exposure tomeasles.

The data can be looked at in another way. The cumulativesurvival graphs of groups 2, 3, and 4 tend to become less steepafter 22 months. This is confirmed by the survival

probabilities for the different age intervals. The P22-35

(probability survival for age interval 22-35 months) is

significantly larger (P<0.01) than the P7-21 for groups 2, 3,and 4. It is not, however, for groups 1 and lv. This differenceprovides an indirect argument against H2, which predictsbetter survival probability with increasing age.According to the three hypotheses survival should be better

in the vaccinated group than in the unvaccinated one duringduring the period of maximum exposure to measles. Survivalprobability for group 1 for age-interval 7 to 21 months isindeed significantly (p<0. 025) larger than that for group 2,but there is no such significant difference between groups 3and 4, nor between group 2 and groups 3 and 4.For the period after 22 months H I predicts equal survival

probabilities in groups 1 and 2; H2 predicts that group 1

should have better survival than group 2; and H3 predictsthat group 2 should have better survival than group 1. Thedata in table II are consistent with H3 in that the survival

probabilities for groups 1 and lv are lower than that for

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groups 2 for the 22 to 35 months age-interval, although thedifferences are not significant. The probabilities of error inrejecting the 0-hypothesis of survival probability equal togroup 2 are 0’ 17 and 0 18, respectively, for groups 1 and 1 v.Our findings thus show that there is a gain in survival

probability for vaccinated children between 7 and 21 months.This again is still present at age 35 months, although there is atendency towards a diminishing survival probability after theage of 22 months. In unvaccinated children, however, thesurvival probability does not diminish after 22 months. Ifthese results do not prove hypothesis 3, they certainly do notprovide evidence against it, nor do they confirm hypothesis 2.A measles vaccination programme has several serious

drawbacks. It is costly when compared with the budgetavailable for health care. Since the cost of the vaccine atsource represents only about one fifth of the actual cost ofdelivering it to the patient,10 even reduction of dosage orlower vaccine prices are not likely to make it much more easilyaccessible for developing countries. Experience fromdeveloped countries indicates that measles incidence is verydifficult to control in the long term;5 maintenance of asufficiently high vaccination rate is difficult,1O especially indeveloping countries. Furthermore, although more stablevaccines are being developed, the potency of many of thevaccines being given is doubtful, because measles vaccinevirus is readily inactivated if not handled and stored properly.The need for expert supervision and surveillance of vaccinequality by testing for vaccine potency and seroconversionrates to avoid administration of inactive vaccine"," is oftendifficult to realise.

Despite these problems, measles vaccination remains

generally unchallenged as a priority. Morley13 called it the"most significant public health measure ... available to thedeveloping world". The reason for this is two-fold: (1)measles has an important role in under-fives mortality, and itis widely accepted that vaccination will reduce mortality;2,14(2) there is considerable evidence that measles plays animportant role in causing malnutrition,1,15 and measlesvaccination is thought to reduce not only the number ofdeaths from measles but also the incidence of severe malnu-trition.lO The implication is that in this way vaccination

brings a supplementary benefit in survival, which is in factthe situation described by hypothesis 2. There is on the otherhand the well-documented fact that measles deaths occur

mostly amongst malnourished children.9,10,12,15Hendrickse10 has already remarked that freedom frommeasles will not guarantee the survival of these children. Onecould easily imagine that the mortality from other causesamongst malnourished children will, at least partly, compen-sate for the benefit obtained by freeing them from measles.We will then have a survival pattern somewhere in betweenthose predicted by H and H3.The benefit that can be expected from measles vaccination

may thus be lower than is generally thought, especiallywhen the children that are most at risk are the ones to whom itis most difficult to extend the vaccination coverage. In view ofthe costs and operational difficulties involved in a measlesvaccination programme, it may be useful to think twicebefore allocating already scarce resources to such a

programme.

Requests for reprints should be addressed to H. van B., Institut de MedicineTroplcale Prince Leopold, Kronenburgstraat 25, B-2000, Antwerp, Belgium.

THE KASONGO PROJECT TEAM: REFERENCES

1. Morley D, Woodland M, Martin WJ. Measles in Nigerian children J Hyg Camb 1963;61: 115-34.

2. Cantrelle P. Mortalit&eacute; et morbidit&eacute; par rougeole dans les pays francophones de l’OuestAfricain. Arch f d ges Virus-forsh 1965; 16: 35-45.

3. Stanfield JP, Bracken PM. Measles vaccination: studies in methods and cost reductionin developing countries. Trans Roy Soc Trop Med Hyg 1971; 65: 620-28.

4. Wallace RB, Landrigan PJ, Smith EA, Pifer J, Teller B, Foster SO. Trial of a reduceddose of measles vaccine in Nigerian children. Bull WHO 1976; 53: 361-64.

5. Sutherland I, Fayers PM. Effect of measles vaccination on incidence of measles in thecommunity. Br Med J 1971; i: 698-702.

6. Ministry of Health of Kenya and World Health Organisation. Measles immunity in thefirst year after birth and the optimum age for vaccination in Kenyan children. BullWHO 1977; 55: 21-30

7. Dick B, Smith T, Kipps A. A minimum age for measles vaccine administration tocoloured children. S Afr Med J 1975; 49: 1951-54.

8. Coffi E, Bomba-Ire RK, Foster SO, Herrmann KL. Evaluation of a measles-smallpoxvaccination campaign by a sero-epidemiologic method. J Epidemiol 1975; 102:554-71.

9. O’Donovan C. Measles in Kenyan children. East Afr Med J 1971; 48: 526-32.10. Hendrickse RG. Problems of future measles vaccinations in developing countries.

Trans Roy Soc Trop Med Hyg 1975; 69: 31-34.11. Elandt-Johnson RC. Various estimators of conditional probabilities of death in follow-

up studies: summary of results. J Chron Dis 1977; 30: 247-56.12. Eghafona NO, Obineche NE, Odoma LE, et al. Importance of measles and potency of

imported live measles vaccine. In: Andr&eacute; FE, ed. Proceedings of the conference onnew developments in vaccines, Rixensart (Belgium), Smith Kline-RIT, Kairo,1977: 239-54.

13. Morley D. Overview of the present situation as to measles in the developing world.Trans Roy Soc Trap Med Hyg 1975; 69: 22-23.

14. Morley DC, Martin WJ, Allen I. Measles in East and Central Africa. East Afr Med J1967; 44: 497-508.

15. Rey M. Place de la rougeole et sa prevention parmi les priorit&eacute;s de la sant&eacute; publique enAfrique Tropicale. L’enfant Milieu Trop 1976; 104: 3-10.

Man in Orbit

This month the American Space Shuttle is due to make its much-delayed maiden flight. If it goes well we can look forward to a sharp dropin the cost of research in space. Here Mr Goode, a principal investigatorin life sciences with the National Aeronautics and SpaceAdministration, discusses some of the ways in which life scientists cantake advantage of "low-cost" microgravity.

MICROGRAVITY RESEARCH: A NEWDIMENSION IN MEDICAL SCIENCE

ANTHONY GOODE

Professorial Department of Surgery, Charing Cross Hospital,London W6

MUCH of our understanding of the functioning of livingorganisms is based on experiments in which physicalconditions are varied in a controlled manner. Nearly alwaysthis is done against the background of gravity. Yet gravity isan all pervasive force and certainly influences design; Galileorecognised that large animals have relatively thicker weight-bearing bones than smaller species.

HAZARDS OF SPACE FLIGHT

In the past two decades man has lived and worked in spacefor up to six months and there is a mass of information on the

physiological changes and potential risks. An immediate

response to the weightless state is the redistribution of abouttwo litres of blood and interstitial fluid from the legs to thehead and thorax, so that the neck veins are distended, the facebecomes puffy, and the legs shrink.l-3 This redistributionreflexly influences cardiac activity, control of the circulation,and the pattern of salt and water excretion by the kidney.