Immune correlate study on human Schistosoma japonicum in a well-defined population in Leyte, Philippines: I. Assessment of ‘resistance’ versus ‘susceptibility’ to S. japonicum

Immune correlate study on human Schistosoma japonicum in awell-defined population in Leyte, Philippines: I. Assessment of

‘resistance’ versus ‘susceptibility’ to S. japonicum infection

Luz P. Acosta a,*, Gemiliano D.L. Aligui a, Wilfred U. Tiu b, DonaldP. McManus c, Remigio M. Olveda a

a Research Institute for Tropical Medicine, FICC Compound, Alabang, Muntinlupa City, Philippinesb Department of Parasitology, College of Public Health, University of the Philippines Manila, Ermita, Manila, Philippines

c Molecular Parasitology Unit, Australian Centre for International and Tropical Health and Nutrition, The Queensland Institute of

Medical Research and the University of Queensland, 300 Herston Road, Brisbane 4029, Queensland, Australia

Received 15 February 2001; received in revised form 17 June 2002; accepted 5 July 2002

Abstract

This study describes the categorical classification of 155 individuals living in an endemic village in Macanip, Leyte,

Philippines as ‘resistant’ or ‘susceptible’ to Schistosoma japonicum infection using available exposure, infection and

reinfection data collected from a 3-year water contact (WC) study. Epidemiological parameters including age, sex, and

infection intensities in relation to observed reinfection patterns are also described. This classification was used in

subsequent immunological studies described in two accompanying papers to identify protective immune mechanisms

among resistant individuals induced by defined candidate vaccine molecules for S. japonicum . The study suggests that

individuals who were most vulnerable to rapid reinfection were children belonging to the 5�/14 age group. A drop in

incidence at age group 15�/19 and decreased intensity of infection starting at this age group and older (15�/) suggests

development of immunity. Controlling for the effect of the other variables, a multivariate analysis showed significant

association for sex, in that females were more likely to be resistant. This implies that other than acquired immunity to

infection, some age-dependent host factors may also play an important role in the overall changes of reinfection

patterns seen in schistosomiasis japonica in this population.

Crown Copyright # 2002 Published by Elsevier Science B.V. All rights reserved.

Keywords: Schistosomiasis; Schistosoma japonicum ; Reinfection; Age-dependent host factors; Resistance; Susceptibility

1. Introduction

Interpretation of age-prevalence or age-infection

intensity patterns observed in schistosomiasis

japonicum-endemic communities has generally

attributed the declining levels of infection in adults

to development of acquired immunity (Ross et al.,

* Corresponding author. Tel.: �/632-807-26-28; fax: �/632-

842-22-45

E-mail address: [email protected] (L.P. Acosta).

Acta Tropica 84 (2002) 127�/136

www.parasitology-online.com

0001-706X/02/$ - see front matter. Crown Copyright # 2002 Published by Elsevier Science B.V. All rights reserved.

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2000; Olveda et al., 1996). Earlier studies onSchistosoma. mansoni (Kloetzel and Da Silva,

1967) have shown that among adult immigrants,

the same convex shape of age-prevalence and

intensity curves persisted, implying that levels of

infection were attributed to duration of exposure

and thus the development of immunity. These

studies, however, were limited because of lack of

field data to back up the observations. It wasargued that the decline in infection levels may well

be because of lack or reduced exposure in adults

and/or partly as a result of spontaneous death of

adult schistosome worms from a primary infection

(Dalton and Pole, 1978).

Until recently, longitudinal studies have been

designed to accurately measure intensity of infec-

tion and reinfection after treatment over a periodof time and at the same time monitor actual levels

of exposure estimated by direct observations of

water contact (WC) at potential transmission sites.

Parallel studies have been conducted for both S.

mansoni in Kenya (Sturrock et al., 1983; Butter-

worth et al., 1985; Dunne et al., 1992) and for

Schistosoma haematobium in the Gambia (Wilkins

et al., 1987). These studies provided evidence foran age-dependent acquired resistance to reinfec-

tion, where younger children were re-infected

faster, with high infection intensities, than adults,

a feature that could not be attributed to changes in

exposure. An 8-year longitudinal study of Schis-

tosoma japonicum in the Philippines also showed

that the time of re-infection in children between

the ages 7 and 13 was significantly more rapid,while a significant decrease in the risk of reinfec-

tion was observed among individuals aged 14�/35

with a history of prior infection (Olveda et al.,

1996).

In this study, we describe the exposure and

reinfection pattern of a sub-group of individuals

who volunteered for blood extraction and whose

blood samples were examined in subsequent im-munological assays described elsewhere (Acosta et

al., 2002a,b). These individuals belonged to a

larger cohort of a WC study undertaken in

1993�/1995.

This study used data from the 3-year field

observation of water exposure and infection pat-

tern to classify two extreme groups of ‘resistant’

and ‘susceptible’ individuals. Those classified as‘resistant’ were those who had high exposure but

showed less reinfection or consistent low infection

intensities. While those classified as ‘susceptible’

were individuals having showed more reinfection

or consistent high intensity infection. Epidemiolo-

gical parameters such as age, sex, exposure and

infection intensities that contributed to the ob-

served reinfection patterns (comparing ‘resistant’and ‘susceptible’) are also described. The classifi-

cation of these individuals into these two groups

who had their blood examined in several immu-

nological assays was the basis in identifying any

indication of protective immune mechanism

among the ‘resistant’ individuals induced by po-

tential candidate vaccine molecules for S. japoni-

cum . Two separate papers describe theimmunological basis of cellular and humoral

immune responses of these individuals to the

defined vaccine molecules and native antigens

(Acosta et al., 2002a,b).

The data presented here are limited to the

estimated exposure and infection patterns for the

subgroup of individuals described in this study,

who agreed to provide blood samples, and not forthe larger WC population. A detailed description

of the 3-year WC follow-up, results and validation

of a mathematical model of potential exposure

index and reinfection patterns for the entire WC

cohort will be published elsewhere (see also Aligui

et al., 1997; Aligui, 1997; thesis).

2. Materials and methods

2.1. Study population

A total of 155 individuals (67 females and 88

males) aged from 5 to 76 years were enrolled in this

study. These individuals were part of a larger study

(n�/412) whose exposures were characterized by

observing WC activities on potential exposure sitesover a 10-month period from 1993 to 1995. From

this larger population, 155 volunteered for blood

extraction in 1995 for the immunological studies,

which comprised the study population described in

this paper. To estimate a yearly incidence of

infection, all received yearly treatment regardless

L.P. Acosta et al. / Acta Tropica 84 (2002) 127�/136128

of parasitology results and, therefore, were assuredof yearly zero infection baseline, since the efficacy

of Praziquantel given at 50 mg/kg body weight was

found to be �/98% (Olveda et al., 1996).

Parasitologic diagnosis used duplicate slides of a

five stool sample Kato�/Katz examination (50 mg

per smear). Egg output intensities remained very

low throughout the duration of the WC follow-up.

Average EPG or egg output were, therefore,categorized as Low (1�/19 EPG); Moderate (20�/

99 EPG) and High (100�/EPG) infection intensi-

ties.

The study was thoroughly reviewed and ap-

proved by the RITM Institutional and Ethical

Review Board.

2.2. Water contact exposure measures

The WC study site located in Macanip, Leyte

(described in earlier studies as Village C by Olveda

et al., 1983, 1996) was approximately 216 hectares

of land area. Thirty water observation sites were

selected from a pilot ocular survey that identified

potential human exposure sites. Local field work-

ers residents of the same village were hired as

observers for the WC activities and snail collectionfor the 3-year duration of the study. Two teams of

observers (four observers per team) were assigned

for an 80-day period of water observation sche-

dules per cycle. Each cycle consisted of ten

observation schedules of 6 days observations and

snail collections, and 2 days rest. A field team

leader was assigned to monitor all field activities

and data collection. Each time a study participantwas observed at one of the sites, WC data were

collected which included: duration (frequency) of

contact in minutes, degree of contact to approx-

imate percent skin surface exposure, activity types

(such as crossing, drawing water, walking in water,

gathering vegetables, washing dishes, washing

clothes, bathing, washing body parts, playing in

water, swimming, ploughing, planting and weed-ing) and time of day. Snails were collected on days

alternating with WC observations. Snail infection

rates for each observation site on a certain date

were then recorded and used as a surrogate marker

for cercarial burden at the WC site and, therefore,

‘potential’ exposure was assumed. This assump-

tion was based on actual data by Pesigan et al.1958, on S. japonicum mouse exposure experi-

ments and cercarial shedding and density measures

at different times of days.

After the baseline parasitology diagnosis and

mass treatment with Praziquantel, three cycles of

WC observations (80 days per cycle) were started

within a 10-month duration followed by two more

rounds of parasitology screening, mass treatmentand 10-month WC observations. For the whole

duration of the 3-year study, WC data from a total

of ten observation cycles (this included the initial

ocular WC observation) were collected.

In deriving an exposure index for S. japonicum

infection, WC measures were tested by modeling

relationships among different WC variables, snail

infection and intensity of infection in humans.Four predictors of infection were found namely:

snail infection, time of day, degree and duration of

contact. A functional additive formula of exposure

risk model called the weighted index of potential

exposure (WIPE) was proposed and computed as

the sum of snail infection and degree of WC in

percent divided by the duration of contact in

minutes, weighted by time of day of activity.WIPE was computed for each contact episode

and aggregated into a summative exposure value

per individual. The assumptions for this proposed

index were validated by explorative correlation

and multivariate analysis using post treatment WC

data and infection intensity at the end of the

observation period (as well as with other indepen-

dent variables to assess multicollinearity) andcompared with the ‘classical’ multiplicative index

(termed as Index 1) used in S. mansoni and S.

haematobium . Infection intensity was regressed for

each index (WIPE and index 1) separately, with

past infection, age and gender as covariates.

Results showed that WIPE was a better predictor

of intensity of infection (P�/0.001) than the

comparison index (P�/0.896), explaining 23% ofthe variation in intensity of infection with past

infection, age, and gender as covariates. A receiver

operator curve (ROC) plot for WIPE index also

showed that it is possible to determine a cut-off

value for the index (50th percentile) and classify

exposure scores into ‘high’ and ‘low’ exposure

index.

L.P. Acosta et al. / Acta Tropica 84 (2002) 127�/136 129

2.3. Assessment of ‘resistant’ versus ‘susceptible’

individuals

‘Resistance’ was assumed for individuals with

any of the following criteria.

1) Individuals, who were initially with moderate

or high EPG and subsequently became unin-

fected or remained with low EPG at least twice

on follow-up despite having a ‘high’ exposure

index.

2) Individuals, who were initially uninfected orwith low EPG and remained uninfected or

with low EPG on follow-up despite having a

‘high’ exposure index.

3) Individuals, who were initially with low EPG

and on follow-up became uninfected despite

having ‘high’ exposure index.

‘Susceptibility’ was assumed for individuals with

any of the following criteria.

1) Individuals, who were initially with moderate

or high EPG and remained with moderate orhigh EPG at least twice on follow-up.

2) Individuals, who were initially uninfected and/

or with low infection and became moderately

to highly infected at least twice on follow-up.

3) Individuals, who became infected at least

twice regardless of intensity of infection dur-

ing the 3-year follow-up having minimal or

‘low’ exposure index.

2.4. Statistical analysis

STATATM/Statistical software version 4.0 (Texas,

USA) was used for all data analysis. Distributions

of infection, reinfection and ‘immune’ profiles

across the different age groups, sex and exposure

categories were either plotted or tabulated. Rela-

tionships between different epidemiological para-

meters such as age, sex, exposure and infectionintensities were initially examined by Spearman’s

rank correlation coefficient test and the Pearson’s

x2-test on log transformed data. Differences be-

tween means used the Student’s t -test and analysis

of variance (ANOVA). Linear trends were eval-

uated by logistic regression analysis to predict a

dichotomous classification of ‘resistant’ and ‘sus-ceptible’ individuals.

3. Results

3.1. Population description

Table 1 shows the average exposure estimatesdistributed across the different age groups and

gender. The age structure of the population of

both the study population and the WC population

as well as for the whole Village of Macanip (parent

population) were typical of a rural endemic area in

the Philippines wherein around 40�/50% were 19

years of age or younger. Comparing exposure

patterns, both the study population and the largerWC population (source population) had a right

skewed exposure and were almost identical (Fig.

1). However, the study population had a signifi-

cant higher mean exposure than the source popu-

lation (Student’s t -test; (P B/0.000). This is of an

advantage for this study, since highly exposed

individuals could provide a clearer distinction

between those who were reinfected more oftenthan those who were not, hence limiting the

number of indiscriminate individuals, who can

not be classified into ‘resistant’ or ‘susceptible’.

Spearman’s rank correlation computed for age

and exposure showed a significant positive corre-

lation coefficient (Spearman’s coefficient r�/

0.3161, P B/0.0001). No significant difference in

terms of mean exposure scores was shown betweenmales and females using the Student’s t-test.

3.2. Incidence, infection and reinfection patterns

Fig. 2 shows the age-specific incidence of infec-

tion computed yearly after every treatment and

follow-up from 1993 to 1995 parasitology survey.

Yearly incidence rates were computed as the

number of new infection in the study populationwithin 1 year after treating all individuals, assum-

ing that all have negative egg counts at the start of

each year. In 1993, incidence rate in age group 5�/9

was generally low, increased in the 10�/14 age

group and reached a peak between the age groups

15 and 29, remaining generally high from ages


30�/. In 1994, incidence gradually increased start-

ing at age 15�/19, but declined at age 50�/ and

over. After 3 years of annual treatment and

follow-up, a significant increase in incidence rates

were seen at age groups 5�/9 and 10�/14, signifi-

cantly decreased at age group 15�/19 and increased

again from age 20�/.

Due to increased sensitivity of the diagnosis

with five-stool samples, high incidence rates were

computed during the WC follow-up. However,

intensities of infections were greatly reduced to

very low levels as a result of intensive community-

based chemotherapy control in this village (Olveda

et al., 1983, 1996) since 1981. Egg intensities were

compared with the 1993 survey done at the start of

the WC study, and at the end of the study in 1995

Table 1

Mean exposure estimates (WIPE) by age and gender

Age N Mean S.E. 95% Confidence interval (CI)

5�/9 16 605.65 163.56 257.03�/954.27

10�/14 35 1046.12 158.50 724.01�/1368.23

15�/19 13 1133.61 260.16 566.76�/1200.45

20�/29 16 748.18 135.59 459.17�/1037.20

30�/39 26 1561.76 268.95 1007.86�/2115.67

40�/49 20 1447.16 260.59 901.74�/1992.58

50�/ 20 1876.16 293.39 1264.19�/2488.13

Males 84 1275.88 115.84 1045.47�/1506.28

Females 61 1180.17 153.30 873.52�/1486.83

Fig. 1. Exposure score of the study population and the WC population (source population, Aligui, 1997).

Fig. 2. Incidence rates after yearly treatment and follow-up

from 1993 to 1995 survey.


(Fig. 3). The graph shows similarity in mean egg

output across the different age groups, except for

age group 10�/14, where it appears to increase and

between age group 20 and 29, where it shows a

decrease in mean EPG after the 3-year treatment

follow-up. These results suggest that there is highannual reinfection occurring at the different age

groups across time, with highest reinfection in

adults 30 years and older. However, children in the

5�/14 years of age appear to have the greatest

change in reinfection rates from 1993 to 1995, with

the age group 10�/14 having the greatest increase

in mean EPG, while there is less reinfection among

age group 15�/19 from 1994 to 1995. Although,incidence of infection tends to increase with age,

majority of adults starting at age 20 and older have

Low (B/20 EPG) egg output intensities.

Infection intensity was also evaluated in relation

to exposure. An increasing trend in average EPG

as exposure increases were shown for the para-

sitology survey in 1993 and 1995 (data not shown).

Using the Spearman rank correlation analysis, asignificant association was computed between

exposure and EPG in 1995 (r�/0.2698, n�/144,

P�/0.0011). These data suggest that exposure

somehow determines infection intensity.

3.3. Immune classification of ‘resistance’ versus

‘susceptibility’

‘Resistance’ versus ‘susceptibility’ to reinfection

in this study was assumed for individuals based on

their exposure (computed WIPE value) and infec-

tion criteria as described in Section 2. Of the 155

individuals enrolled in this study, 13 individualswere not classified into either of the two groups,

and thus were classified as ‘indeterminate’ and

were not included in the analysis. These included

those who had: (a) no parasitology results and/or

no exposure records for the past 3 years and those;

(b) who were egg negative or had Low egg counts

(EPG) with minimal or no exposure.

There were 89 (62%) individuals classified as‘resistant’ and 55 (38%) classified as ‘susceptible’

based on these criteria. Table 2 shows the average

exposure values of individuals classified either as

‘resistant’ or ‘susceptible’ across the different age

groups and gender. Generally, exposure of indivi-

duals classified as ‘susceptible’ included those with

moderate and or high exposure while most in the

‘resistant’ group have high exposure values. Aver-age infection intensities across the different age

groups and gender belonging in the ‘susceptible’

and ‘resistant’ groups are shown in Tables 3�/5.

Mean EPG is relatively higher among ‘susceptible’

individuals than in the resistant group on the 2nd

year (1994) (Table 4) and on the 3rd year (1995)

(Table 5) of follow-up. Fig. 4 shows the overall

mean infection intensities in the ‘resistant’ and‘susceptible’ individuals during the 3 years follow-

up. The graph shows a marked increase in the

overall mean egg output in the susceptible group

from year 1 to 3 of follow up. Significant

differences between means in the ‘susceptible’

and ‘resistant’ groups were shown using the

ANOVA test (F�/1.98, df�/93, P B/0.05) com-

bining both the effect of immune classification andyear of follow-up.

Distribution of observed percentages between

these categories by age and sex are shown in Figs.

5 and 6. There were significantly more individuals

in the 15�/19 age group and in the 40�/ age group

who were classified as ‘resistant’. More females

were likewise classified as ‘resistant’ (Fig. 6) (x2�/

6.84, P B/0009). Logistic regression analysis usedto predict the dichotomous classification of in-

dividuals into either ‘resistant’ or ‘susceptible’

(susceptible�/0/resistant�/1) controlling for the

effect of both age and sex (females�/0/males�/1),

indicated that females were likely to be more

‘resistant’ than males (OR�/0.38, n�/142, P B/

0.01).

Fig. 3. Mean EPG by age in 1993 and 1995.


4. Discussion

Here, we describe a population in the Philip-

pines whose exposure and infection or yearly

reinfection patterns after every treatment for S.

japonicum were monitored closely for a span of 3

years. The unknown life-span of adult worms and

difficulties in determining when new infections

were acquired were overcome by treating all

individuals at the commencement of the study

and monitoring reinfection in this cohort.

The majority of individuals in the study popula-

tion had high exposure with 63% belonging to the

upper 50th percentile of exposure scores. Exposure

patterns by age confirmed that those in the

youngest (5�/9) age group had the lowest exposure

and that exposure significantly increased with age.

In contrast with other studies, where there was

significant reduction in exposure in adults (Dalton

and Pole, 1978), our study population generally

showed high exposure even among older indivi-

duals starting at around age 40 and above.

Although more males appeared to have higher

exposures than females, this was not significant

and thus it can be assumed that males and females

were equally exposed.This study suggests that reinfection appears to

increase with age and exposure. However, children

5�/14 years of age have the greatest change in

reinfection rates across time (Fig. 2) with the 10�/

14 age group having the highest mean EPG after 2

years follow-up in 1995 (Fig. 3). The highest

Table 2

Estimated mean exposure values (WIPE) in the ‘susceptible’ and ‘resistant’ group by age group and gender

Age group Susceptible Resistant

N Mean S.E. 95% CI N Mean S.E. 95% CI

5�/9 6 350.37 149.21 33.18�/733.92 8 913.33 272.57 268.81�/1557.85

10�/14 14 847.00 239.22 330.19�/1363.81 21 1178.87 210.18 740.44�/1617.30

15�/19 2 439.57 121.00 1097.81�/1976.94 10 1333.51 312.57 626.43�/2040.60

20�/29 7 496.33 112.72 220.50�/772.15 8 1002.11 225.48 468.95�/1535.28

30�/39 13 1445.68 495.97 365.05�/2526.32 13 1677.84 230.53 1175.56�/2180.13

40�/49 7 1670.53 664.27 45.11�/3295.94 13 1326.89 207.77 874.19�/1779.58

50�/ 5 708.27 334.87 221.49�/1638.03 15 2265.45 317.36 1584.79�/2946.11

Males 39 1083.58 187.88 703.24�/1463.91 44 1470.41 139.88 1188.31�/1752.51

Females 15 672.22 365.28 111.23�/1455.66 43 1414.88 165.71 1080.47�/1749.30

Overall 54 969.31 169.44 629.46�/1309.15 88 1437.02 106.57 1225.21�/1648.84

Table 3

Mean egg output intensities (EPG) in the ‘susceptible’ and ‘resistant’ groups in 1993 survey



5�/9 4 4.38 4.38 9.55�/18.30 7 1.61 1.05 0.95�/4.18

10�/14 11 17.77 12.61 10.32�/45.85 19 5.41 3.61 2.18�/12.99

15�/19 2 6.88 5.62 64.60�/78.35 9 14.86 9.15 6.22�/35.95

20�/29 5 9.89 6.17 7.26�/27.03 5 26.00 14.20 13.42�/65.42

30�/39 11 18.98 7.03 3.32�/34.63 12 6.75 1.61 3.21�/10.29

40�/49 4 3.25 2.36 4.26�/10.76 9 8.61 3.19 1.26�/15.97

50�/ 5 1.75 0.622 0.022�/3.48 14 4.33 1.09 1.99�/6.68

Males 29 13.71 5.48 2.49�/24.93 38 10.71 3.02 4.58�/16.83

Females 13 8.38 3.04 1.75�/15.02 37 5.14 1.95 1.17�/9.10

Overall 42 12.06 3.89 4.20�/19.92 75 7.96 1.83 4.32�/11.60


reinfection rates in adults from 20 years and older

were presumably due to high exposures in these

age groups, while the big change in reinfection

rates in the youngest age group (5�/9) was pre-

sumably that their exposure increased over time

during these years, before the ‘putative’ immunity

developed. The drop in the estimated incidence in

the 15�/19 age group and the decreased mean egg

output intensities starting at age 15 and older

suggest the appearance of this ‘putative’ immunity

to reinfection. The approach of categorizing

‘resistant’ and ‘susceptible’ individuals also coin-

cided with the infection profile where there were

significantly more resistant individuals classified in

the 15�/19 age group and in those who were 40

years and older (see Fig. 5). In terms of reinfection

Table 4




5�/9 5 4.25 3.95 6.70�/15.20 8 1.64 0.72 0.07�/3.34

10�/14 13 1.64 1.33 1.26�/4.54 21 1.86 0.085 0.091�/3.62

15�/19 1 26.67 0 �/ 9 2.56 1.92 1.86�/6.98

20�/29 5 8.47 3.99 2.60�/19.53 7 1.00 0.72 0.77�/2.77

30�/39 11 18.15 11.04 6.45�/42.75 13 1.70 0.55 0.50�/2.89

40�/49 6 7.71 4.45 3.72�/19.14 12 1.67 0.51 0.54�/2.80

50�/ 5 4.40 2.71 3.13�/11.93 14 1.62 0.75 0.01�/3.22

Males 32 5.65 1.69 2.21�/9.09 41 1.81 0.49 0.83�/2.79

Females 14 14.19 8.67 4.53�/32.91 43 1.69 0.48 0.71�/2.67

Overall 46 8.25 2.88 2.44�/14.05 84 1.75 0.34 1.07�/2.43

Table 5




5�/9 6 5.91 3.14 2.17�/13.99 8 4.14 1.73 0.04�/8.24

10�/14 13 36.62 12.58 9.21�/64.03 21 3.61 1.15 1.20�/6.02

15�/19 2 32.00 32.00 37.46�/43.86 10 3.30 1.92 1.05�/7.64

20�/29 7 17.71 7.58 0.83�/36.26 8 3.03 1.33 0.12�/6.17

30�/39 13 26.95 7.19 11.27�/42.62 13 7.95 2.43 2.66�/13.24

40�/49 6 14.39 4.51 2.80�/25.96 12 7.29 2.67 1.41�/13.16

50�/ 5 7.42 3.24 1.57�/16.42 15 4.76 1.75 1.00�/8.51

Males 37 19.62 4.36 10.77�/28.46 44 5.92 1.18 3.54�/8.30

Females 15 29.83 9.33 9.83�/49.83 43 3.90 0.83 2.24�/5.57

Overall 52 22.56 4.11 14.32�/30.81 87 4.92 0.73 3.48�/6.37

Fig. 4. Mean EPG in the ‘Resistant’ and ‘Susceptible’ group in

1993 and 1995.


pattern between males and females, more females

were significantly categorized as ‘resistant’ (see

Fig. 6).

These results are consistent with the results of an

8-year longitudinal study from 1982 to 1990 done

on the parent population (n�/1241; Olveda et al.,

1996). The use of failure time analysis in the 8-year

study showed that those aged 7�/13 were reinfected

more rapidly, while those in the 14�/35 age group,

who had prior infection, were infected more

slowly. The ‘infection’ requirement, which was

also observed in the present study with a signifi-

cant association with exposure, is suggestive of

acquired immunity. Stratifying by sex, the 8-year

data also show that in this age group (14�/35), boys

were infected more rapidly than females. This

again is consistent with our findings, where more

females were likely to be classified as ‘resistant’.

Despite differences in methodologies used, our

results and the result of the 8-year study in S.

japonicum are generally compatible with other

reinfection studies on S. japonicum in China

(Ross et al., 2000), on S. mansoni (Butterworth

et al., 1985) and on S. haematobium (Wilkins et al.,

1987). Our study showed that intensities of re-

infection were highest among children, but there

was a sharp decline in individuals aged 14 and

above, resistance being associated with previous

experience of infection. Of note, our study showed

significant association for sex in predicting resis-

tance after controlling for the other variables in a

multivariate analysis. As it appears that females

are more likely to be resistant, the marked change

in reinfection and intensity pattern at puberty and

the significant differences seen between males and

females has opened up new opportunities for

future investigation. This study has reinforced

recent views that some age-dependent host factors

such as hormonal changes may override changes

seen in reinfection patterns in certain age groups

(Gryseels, 1994; Fulford et al., 1998).

Nevertheless, this study has again provided

evidence for an acquired resistance to schistosome

Fig. 5. Percent distribution by age of putative ‘susceptible’ and ‘resistant’ subjects in the study population.

Fig. 6. Percentages of putative ‘resistant’ and ‘susceptible’

among males and females.


reinfection indicating slow development of immu-nity not attributable to changes in exposure. The

same individuals in this study were bled and their

blood examined for antigen-specific cellular and

humoral responses described in the two separate

papers (Acosta et al., 2002a,b). These two papers

attempt to verify whether potential anti-S. japoni-

cum vaccine candidates show any indication of

protective immune effector function among indi-viduals who were classified as ‘resistant’ versus

‘susceptible’ in this study.

Acknowledgements

We would like to thank Dr Lilia Portillo (head

of the Schistosomiasis Research and TrainingDivision (SRTD) in Palo, Leyte), Roger Hambre

and Bienvenido Arbas for coordinating the field

activities in Macanip, Leyte for the 3-year WC

study. We also wish to thank Fe Pagado for

helping us in the community organization and

Dr Li Yuesheng for his expert comments on drafts

of the manuscript. This study received financial

support from the UNDP/World Bank/WHO Spe-cial Programme for Research and Training in

Tropical Diseases and the National Health and

Medical Research Council of Australia.

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Immune correlate study on human Schistosoma japonicum in a well-defined population in Leyte, Philippines: I. Assessment of ‘resistance’ versus ‘susceptibility’ to S. japonicum

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