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Malaria and malnutrition remain primary causes of morbidity and mortality among children younger than 5 years in Africa. Studies investigating the association between malnutrition and subsequent malaria outcomes are inconsistent. We studied the effects of malnutrition on incidence and prevalence of malaria parasitemia in data from a cohort studied in the 1990s. Data came from the Asembo Bay cohort study, which collected malaria and health information on children from 1992 to 1996 in western Kenya. Infants were enrolled at birth and followed up until loss to follow-up, death, end of study, or 5 years old. Anthropometric measures and blood specimens were obtained monthly. Nutritional exposures included categorized Z -scores for height-for-age, weight-for-age, and weight-for-height. Febrile parasitemia and afebrile parasitemia were assessed with thick and thin blood films. Multiply imputed and weighted multinomial generalized estimating equation models estimated odds ratios (OR) for the association between exposures and outcomes. The sample included 1,182 children aged 0-30 months who contributed 18,028 follow-up visits. There was no significant association between malnutrition and either incident febrile parasitemia or prevalent febrile parasitemia. Prevalence ORs for afebrile parasitemia increased from 1.07 (95% CI: 0.89, 1.29) to 1.35 (1.03, 1.76) as stunting severity increased from mild to severe, and from 1.16 (1.02, 1.33) to 1.35 (1.09, 1.66) as underweight increased from mild to moderate. Stunting and underweight did not show a significant association with subsequent febrile parasitemia infections, but they did show a modest association with subsequent afebrile parasitemia. Consideration should be given to testing malnourished children for malaria, even if they present without fever.

Background/objectives: Iron deficiency anemia is a major public health problem in developing countries and may affect school performance and physical work capacity in nonpregnant adolescents, and may increase the risk of anemia during subsequent teenage pregnancies. We assessed the effect of weekly iron (120 mg elemental iron) and vitamin A (25 000 IU) supplementation on hemoglobin, iron status and malaria and nonmalaria morbidity in adolescent schoolgirls., Subjects/methods: A total of 279 schoolgirls aged 12-18 years from public primary schools in Kisumu, western Kenya. Double-blind randomized placebo-controlled trial using a factorial design., Results: Five months of iron supplementation was associated with a 0.52 g dl(-1) (0.21, 0.82) greater increase in hemoglobin relative to iron placebo. The effect was only observed in girls with iron deficiency on enrollment (1.34 g dl(-1) (0.79, 1.88)), but not in iron-replete girls (-0.20 g dl(-1) (-0.59, 0.18)). Similar differences in treatment effect were seen between menstruating and nonmenstruating girls. The effect of iron was independent of vitamin A. The baseline prevalence of vitamin A deficiency was low (6.7%) and no sustained increase in hemoglobin was seen with weekly vitamin A (-0.07 g dl(-1) (-0.38, 0.25)). Incidence of malaria parasitemia was higher in the iron than iron-placebo groups (Rate ratio 1.33 (0.94, 1.88))., Conclusions: Weekly iron supplementation results in substantial increases in hemoglobin concentration in adolescent schoolgirls in western Kenya, which may outweigh possible risks caused by malaria, but only in iron-deficient or menstruating girls and not in iron-replete and nonmenstruating girls.

Malaria-associated anaemia is a major public-health problem. Although the treatment of uncomplicated, Plasmodium falciparum malaria aims to clear the parasites, relieve the symptoms and permit haematological recovery, data on the impact of antimalarial treatment on haematological recovery are few. Haematological recovery and the prevalence of anaemia were therefore evaluated in 600 Kenyan children with uncomplicated malaria who were randomly assigned to one of three treatment groups. The children were given sulfadoxine-pyrimethamine (SP) on day 0, SP plus artesunate on day 0 (AS1), or SP on day 0 and artesunate on each of days 0-2 (AS3). Haemoglobin (Hb) concentrations were measured on days 0, 7, 14, 21 and 28, with haematological recovery defined as a day-28 Hb concentration of at least 11 g/dl. Only 96 (18%) of the 543 children who were anaemic (i.e. with <11.0 g Hb/dl) at enrolment achieved haematological recovery. The prevalence of anaemia fell from 91% on day 0 to 74% (252/340) by day 28 (P=0.065). Compared with SP alone, neither artesunate regimen resulted in higher Hb concentrations on day 28 (with means of 10.2, 9.9 and 10.2 g/dl for AS3, AS1 and SP, respectively; P=0.254), a higher frequency of haematological recovery (19%, 14% and 20% for AS3, AS1 and SP, respectively; P=0.301) or a greater reduction in the prevalence of anaemia (prevalences in the AS3, AS1 and SP arms falling from 90%, 89% and 93%, respectively, on day 0, to corresponding values of 71%, 82% and 69% on day 28; P=0.40). In fact, between days 0 and 7, the children in the AS3 arm showed a larger drop in mean Hb than the children in the other two treatment arms. In general, haematological recovery was most likely in older children who had mild anaemia at presentation and were parasitologically cured. Overall, the frequencies of haematological recovery were modest and not influenced by the artesunate treatments. Other factors contributing to anaemia need to be explored more fully.

Objective: Nutritional status is an important marker of overall health and linear growth retardation has serious long-term physiological and economic consequences. Approximately 35 and 29% of preschool children in sub-Saharan Africa are stunted and underweight, respectively. There is relatively little information available about the nutritional status in adolescents, the age group with the highest growth velocity after infancy. We conducted a series of cross-sectional surveys to determine the prevalence and main risk groups for malnutrition and to describe the associations between age, sexual maturation and nutritional status in adolescent schoolgirls in western Kenya., Design: Three cross-sectional surveys; one in Mumias, using random sampling in all schools, and two surveys in Asembo, using a multi-stage random sample design., Setting: Public primary schools in two different rural malaria endemic areas in western Kenya with high levels of malnutrition in preschool children., Subjects: In all, 928 randomly selected adolescent schoolgirls aged 12-18 y., Results: Overall prevalence of stunting and thinness was 12.1 and 15.6%, respectively. Of the total, 2% were severely stunted. Menarche and start of puberty were delayed by approximately 1.5-2 y compared to a US reference population. The prevalence of stunting and thinness decreased with age and mean height for age z-scores converged towards the median of the US reference curve. Girls who had not yet started menstruating were more likely to be stunted than the girls of the same age who were post-menarche., Conclusions: Stunting and thinness are common in young adolescent schoolgirls in these poor rural settings in western Kenya, but the prevalence decreases with age, providing observational support that children catch up on incomplete growth attained earlier in life due to a maturational delay of 1.5-2 y allowing prolonged growth.

Objective: Anemia is a major public health concern in preschool children and pregnant women in the developing world. While many studies have examined these two at-risk groups, there is a paucity of data on anemia in adolescents living in developing countries in the complex ecologic context of poverty, parasitism, and malnutrition. We evaluated the prevalence, severity, and risk factors of anemia in adolescent schoolgirls in an area with intense malaria transmission in western Kenya., Design: Two cross-sectional surveys were conducted, using a multistage random sample design., Setting: Public primary schools in an area with intense malaria transmission in western Kenya., Subjects: A total of 648 randomly selected adolescent schoolgirls aged 12-18 y., Results: The prevalence of anemia (Hb <120 g/l) was 21.1%; only one girl had an Hb less than 70 g/l. Ferritin levels were available from a subsample of 206 girls. The prevalence of iron deficiency (ferritin <12 microg/l) was 19.8, and 30.4% of anemic girls were iron deficient. Malaria and schistosomiasis were the main risk factors for anemia in younger girls (12-13 y), while menstruation was the principal risk factor in older girls (14-18 y)., Conclusions: Iron deficiency and anemia in school-attending girls in western Kenya were more prevalent than in developed countries, but considerably less prevalent than in preschool children and pregnant women from the same study area. Our findings are consistent with other recent school-based surveys from western Kenya, but not with recent community- and school-based cross-sectional surveys from other parts of sub-Saharan Africa. It deserves further study to determine if adolescent girls not attending school are at higher risk of anemia.

Between 1993 and 1999, we monitored the efficacy of sulfadoxine-pyrimethamine in 1175 children aged <24 months receiving 2789 treatments for falciparum malaria in western Kenya using a widely deployed age-based dose regimen: infants, 125 plus 6.25 mg (sulfadoxine plus pyrimethamine); children aged 12 to 23 months; 250 plus 12.5 mg. Cumulative treatment failure by day 7, defined as early clinical failure by day 3 or presence of parasitemia on day 7, increased from 18% in 1993 to 1994 to 22% in 1997 to 1998 (P-trend test = 0.20). Based on body weight, the median dose received was 20 plus 1.00 mg/kg, and 73% of the treatments were given at lower than the recommended target dose of 25 plus 1.25 mg/kg. Underdosing accounted for 26% of cumulative treatment failures. After the dose was increased in 1998 (median, 36 plus 1.8 mg/kg), only 4.2% of patients received less than 25 plus 1.25 mg/kg and there was no association with treatment failure. However, the proportion of cumulative treatment failure continued to increase to 27% by 1999 (P-trend test = 0.03). These results raise concern about the longevity of sulfadoxine-pyrimethamine in these settings. Underdosing may have contributed to the rate at which sulfadoxine-pyrimethamine resistance developed in this area. Treatment guidelines should ensure that adequate doses are given from the initial deployment of antimalarials onward.

Plasmodium falciparum has developed resistance to almost all routinely used antimalarial drugs. Sulfadoxine-pyrimethamine (SP) has replaced chloroquine as first-line treatment of uncomplicated malaria infection in Kenya but resistance to SP is already reported. The addition of artemisinin derivatives to SP may delay the development of drug resistance, improve cure rates, and reduce transmission. The efficacy and safety of artesunate plus SP in the treatment of uncomplicated P. falciparum malaria was evaluated in a randomized trial of 600 children at Siaya District Hospital, western Kenya between October 1999 and March 2000. Children aged < 5 years were randomly assigned to receive SP alone (1.25 mg/kg based on pyrimethamine), or in combination with artesunate (4 mg/kg/d) for either 1 or 3 d. Parasitological failure by days 14 and 28 (polymerase chain reaction [PCR]-corrected for new infections) were the primary endpoints. Treatment failure rates by day 14 were 25.5% in the SP alone group, 16.2% (risk difference [delta]-9.3%, 95% CI -17.3 to -1.2%, P= 0.027) in the 1-dose artesunate group, and 9.4% (delta-16.2%, 95% CI -23.6 to -8.7%, P< 0.001) in the 3-dose artesunate group. Corresponding rates by day 28 were 46.0% in the SP alone group, 38.2% (delta-7.8%, 95% CI -17.7 to 2.1%, P= 0.16) in the 1-dose artesunate group, and 26.0% (delta-20.0%, 95% CI -29.4 to -10.6%, P < 0.001) in the 3-dose artesunate group. The artesunate and SP combination was well tolerated. There were no serious drug-related adverse events. Parasite clearance and gametocyte carriage were reduced significantly in both combination groups compared with SP alone. Three days of artesunate were required to reduce significantly the risk of treatment failure by day 28. However, the high background rate of parasitological failure with SP may make this combination unsuitable for widespread use in Kenya.

In areas where Plasmodium falciparum malaria is endemic, parasite density, morbidity, and mortality decrease with increasing age, which supports the view that years of cumulative exposure are necessary for the expression of maximal protective immunity. Developmental changes in the host also have been implicated in the expression of maximal resistance. To further evaluate the contribution of host developmental factors in malaria resistance, we examined the relationship between P. falciparum parasitemia and pubertal development in a cross-sectional sample of 12-18-year-old schoolgirls from an area of intense transmission in western Kenya. Among pubertal girls, dehydroepiandrosterone sulfate (DHEAS) levels were significantly associated with decreased parasite density, even after adjustment for age. DHEAS levels also were related to increased hemoglobin levels, even after accounting for age and other determinants of hemoglobin level. These findings support the hypothesis that host pubertal development, independent of age and, by proxy, cumulative exposure, is necessary for maximal expression of resistance to malarial infection and morbidity, as assessed by hemoglobin level.

The impact of insecticide (permethrin)-treated bed nets (ITNs) on the health of adolescent schoolgirls was investigated during a community-based, randomized, controlled trial of ITNs in western Kenya. Two school-based cross-sectional surveys were conducted to determine the prevalence of malaria and anemia in 644 schoolgirls 12-18 years old in a rural area with intense perennial malaria transmission. In 12- and 13-year-old schoolgirls, ITNs were associated with a reduced prevalence of all cause anemia (hemoglobin level <12 g/dL, 16.9% versus 31.4%, adjusted odds ratio [OR] = 0.38, 95% confidence interval [CI] = 0.21, 0.69%) and a 0.34 g/dL (95% CI = 0.02, 0.66) increase in mean hemoglobin concentrations. No beneficial effect on all-cause anemia (adjusted OR = 0.79, 95% CI = 0.43, 1.45) or hemoglobin concentrations (difference in mean = 0.14 g/dL, 95% CI = -0.24, 0.53) was evident in older girls. In all age groups, no effect was found on malaria parasite prevalence or density, clinical malaria, all-cause morbidity, standard measures of nutritional status and growth, or the use of antimalarials and other medications. ITNs approximately halved the prevalence of mild anemia in young, school-attending, non-pregnant, adolescent girls, but had no impact in older girls or on other malaria-associated morbidity or nutritional status.

Adherence with permethrin-treated bed net (ITN) use and their proper deployment was directly observed in 2,178 individuals (784 households) participating in a large-scale trial of ITNs on child mortality in western Kenya. The ITNs were distributed free of charge to ensure high coverage, resulting in a ratio of 1.46 persons per ITN. Approximately 30% of ITNs present were unused. The overall percentage adherence was 72.3%. The probability of adherence by individuals depended strongly on age (relative risk [RR] = 0.86, 95% confidence limit [CL] = 0.78-0.94), in which children less than five years of age were less likely to use ITNs than older individuals, and temperature, in which ITNs were more likely to be used in periods of cooler weather. A marginally significant diminution in adherence during the second year of the project was also observed (RR = 0.83, 95% CL = 0.68-1.01). Mosquito numbers, relative wealth, number of house occupants, and the educational level of the head of the household had no effect on adherence. In unstructured questioning of house residents, excessive heat was often cited as a reason for not deploying the child's ITN. The most important reason for non-adherence was disruption of sleeping arrangements, indicating that ITNs were not readily redeployed in the face of shifting sleeping patterns due to visitors, funerals, house construction, and other events. Challenges faced by health education programs to maximize adherence with ITN use are discussed.

Randomized controlled trials in sub-Saharan Africa have shown that permethrin-treated bed nets and curtains reduce all-cause child mortality by 15-33% in areas with low or high but seasonal malaria transmission. This report describes the study site for a community-based, group-randomized, controlled trial in an area of high and year-round malaria transmission in western Kenya. We outline the development of the human and physical infrastructure required to conduct this trial and discuss some of the difficulties encountered and lessons learned in conducting it.

A group-randomized controlled trial of insecticide (permethrin)-treated bed nets (ITNs) was conducted in an area of high perennial malaria transmission in western Kenya to test the effect of ITNs on all-cause mortality in children 1-59 months of age. Child deaths were monitored over a two-year period by biannual household census in Asembo (1997-1998) and in Gem (1998-1999). Overall, 1,722 deaths occurred in children 1-59 months followed for 35,932 child-years. Crude mortality rates/1,000 child-years were 51.9 versus 43.9 in control and ITN villages in children 1-59 months old. The protective efficacy (PE) (95% confidence interval) adjusted for age, study year, study site, and season was 16% (6-25%). Corresponding figures in 1-11- and 12-59-month-old children in control and ITN villages were 133.3 versus 102.3, PE = 23% (11-34%) and 31.1 versus 28.7, PE = 7% (-6-19%). The numbers of lives saved/1,000 child-years were 8, 31, and 2 for the groups 1-59, 1-11, and 12-59 months old, respectively. Stratified analysis by time to insecticide re-treatment showed that the PE of ITNs re-treated per study protocol (every six months) was 20% (10-29%), overall and 26% (12-37%) and 14% (-1-26%) in 1-11- and 12-59-month-old children, respectively. ITNs prevent approximately one in four infant deaths in areas of intense perennial malaria transmission, but their efficacy is compromised if re-treatment is delayed beyond six months.

This study retrospectively studied amendable determinants of sulfadoxine-pyrimethamine (SP) efficacy involving 2869 treatments among 1072 Kenyan children <5 years old who had uncomplicated malaria. The dose was based on age: one-quarter tablet was given to infants <1 year old, one-half tablet was given to 1-3-year-old children, and a full tablet was given to 4-year-old children. Only 23.5% received the internationally recommended target dose of 25/1.25 mg of SP per kg of body weight. SP intake in the previous 15-35 days (adjusted relative risk, 1.67; 95% confidence interval, 1.35-2.07) and low SP dose (<27.5/1.375 mg/kg) (adjusted relative risk, 1.58; 95% confidence interval, 1.17-2.13) explained 38% of parasitological treatment failures by day 7. Patients with recent SP intake are likely to have recrudescent infections and may need close follow-up if treated with SP or alternative treatment. Applying our weight-for-age data to 31 existing age-based SP dose recommendations predicted that 22 of them would result in underdosing of >25% of children <5 years. Many age-based dose recommendations need urgent revision, because SP is increasingly used as first-line treatment in sub-Saharan Africa.

The role of the sickle cell hemoglobin type as a determinant of treatment outcome with sulfadoxine-pyrimethamine was retrospectively studied in young children with uncomplicated falciparum malaria who lived in an area with intense perennial malaria transmission. Between 1993 and 1997, 2795 treatments involving 813 children were monitored. Sickle cell trait (HbAS) was present in 17.7% of the children. Two-and-a-half percent of the children experienced early clinical treatment failure by day 2-3, and 17.3% of the children were parasitemic on day 7. Treatments in HbAS children were less likely than those in HbAA children to result in persistence of parasitemia by day 3 (relative risk [RR], 0.66; 95% confidence interval [CI], 0.47-0.93; P=.02) or in parasitologic treatment failure on day 7 (RR, 0.51; 95% CI, 0.36-0.71; P<.0001). These results suggest that the HbAS phenotype should be included among factors that determine sulfadoxine-pyrimethamine treatment outcome.

We tested tafenoquine (WR 238605), a new long-acting 8-aminoquinoline, for its ability to prevent malaria in an area that is holoendemic for Plasmodium falciparum. In a double-blinded, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of 250 mg halofantrine per day for 3 days, to effect clearance of preexisting parasites. The volunteers were then assigned to 1 of 4 drug regimens: placebo throughout; 3 days of 400 mg (base) of tafenoquine per day, followed by placebo weekly; 3 days of 200 mg of tafenoquine per day, followed by 200 mg per week; and 3 days of 400 mg of tafenoquine per day, followed by 400 mg per week. Prophylaxis was continued for up to 13 weeks. Of the evaluable subjects (223 of 249 randomized subjects), volunteers who received 400 mg tafenoquine for only 3 days had a protective efficacy of 68% (95% confidence interval [CI], 53%-79%), as compared with placebo recipients; those who received 200 mg per day for 3 days followed by 200 mg per week had a protective efficacy of 86% (95% CI, 73%-93%); and those who received 400 mg for 3 days followed by 400 mg per week had a protective efficacy of 89% (95% CI, 77%-95%). A similar number of volunteers in the 4 treatment groups reported adverse events. Prophylactic regimens of 200 mg or 400 mg of tafenoquine, taken weekly for < or =13 weeks, are highly efficacious in preventing falciparum malaria and are well tolerated.

We investigated the development and maintenance of proliferative and antibody responses to apical membrane antigen-1 (AMA-1) epitopes in a holoendemic area of western Kenya. Young children (< 10 years), older children (10-17 years), and adults (> or = 18 years) were followed longitudinally for antibody and T-cell responses at 3 time points with an interval of 3-4 months. The proliferative responses against the AMA-1 T epitopes (PL171, PL172, PL173, PL186, PL191, and PL192) were not stable during follow-up; however, response to mycobacterial antigen PPD was highly stable. The responder frequencies were similar in all 3 time points except for epitope PL192. The younger and older children responded more frequently to T-cell epitopes, but the differences were not significant. A positive proliferative response to PL191 was associated with a significantly lower risk of parasitemia at subsequent follow-up (relative risk, 0.5; P = 0.03). The presence of antibody response to B epitopes PL169, PL170, PL173, PL187, and PL192 in one time point was associated with a subsequent response (P = 0.0001-0.008) suggesting a stable response. Younger (P = 0.046) and older children (P = 0.017) more frequently responded to epitope PL169 than did adults, and adults responded more frequently to PL187 than did younger children (P = 0.009). Responses to AMA-1 T-cell epitopes were short lived, and antibody responses were relatively stable.

Although all-cause mortality has been used as an indicator of the health status of childhood populations, such data are sparse for most rural areas of sub-Saharan Africa, particularly community-based estimates of infant mortality rates. The longitudinal follow-up of more than 1,500 children enrolled at birth into the Asembo Bay Cohort Project (ABCP) in western Kenya between 1992 and 1996 has provided a fixed birth cohort for estimating all-cause mortality over the first 5 yr of life. We surveyed mothers and guardians of cohort children in early 1999 to determine survival status. A total of 1,260 households were surveyed to determine the survival status of 1,556 live births (99.2% of original cohort, n = 1,570). Most mothers (66%) still resided but 27.5% had migrated, and 5.5% had died. In early 1999, the overall cumulative incidence of all-cause mortality for the entire 1992-1996 birth cohort was 26.5% (95% confidence interval, 24.1-28.9%). Neonatal and infant mortality were 32 and 176 per 1,000 live births, respectively. These community-based estimates of mortality in the ABCP area are substantially higher than for Kenya overall (nationally, infant mortality is 75 per 1,000 live births). The results provide a baseline description of all-cause mortality among children in an area with intense Plasmodium falciparum transmission and will be useful in future efforts to monitor changes in death rates attributable to control programs for specific diseases (e.g., malaria and HIV/AIDS) in Africa.

The anti-merozoite surface protein-1 19-kDa IgG (anti-MSP119KD) IgG responses of 33 parasitemic infants, aged 6-14 months, were compared with those of their mothers at the time of the infant's delivery and at the time the infants were sampled; the antimalaria protection associated with these responses was also compared. IgG1 and IgG3 were the predominant subclasses. Infants <300 days old and pregnant mothers had the lowest cytophilic-to-noncytophilic IgG ratio. By 300 days of age, the infants had IgG subclass compositions and levels similar to those of their mothers at the same date. Among infants, older infants with only 1 or 2 detected asexual parasitemias had the highest cytophilic-to-noncytophilic IgG ratio and IgG1 levels. IgG1 level was negatively correlated with protection. The findings suggest that the MSP119KD antibody response develops with age, not with multiple experiences with parasitemia, and, thus, that an antimalaria vaccine strategy for pregnant mothers could delay infants' first parasitemias until they are more capable of mounting a favorable anti-MSP119KD response.

The relative importance of acute high-density versus persistent low-density Plasmodium falciparum parasitemia in contributing to the public health problem of malarial anemia remains unclear. The Asembo Bay Cohort Project in western Kenya collected monthly hemoglobin (Hb) and parasitologic measurements and biweekly assessments of antimalarial drug use among 942 singleton live births between 1992 and 1996. A mixed-model analysis appropriate for repeated measures data was used to study how time-varying parasitemia and antimalarial drug exposures influenced mean Hb profiles. Incidence of World Health Organization-defined severe malarial anemia was 28.1 per 1,000 person-years. Among children aged less than 24 months, concurrent parasitemia was significantly associated with lower mean Hb, especially when compared to children with no concurrent parasitemia. Increased densities of the 90-day history of parasitemia preceding Hb measurement was more strongly associated with mean Hb levels than concurrent parasitemia density. While the highest quartile of 90-day parasitemia history was associated with lowest mean Hb levels, children in the lowest 90-day exposure quartile still experienced significantly lower Hb levels when compared to children who remained parasitemia-free for the same 90-day period. The results highlight the importance of collecting and analyzing longitudinal Hb and parasitologic data when studying the natural history of malarial anemia.

Anemia is an important public health problem. During very early childhood numerous factors affect hemoglobin (Hb) concentration over time, making single cross-sectional measurements difficult to interpret when studying the natural history of anemia or evaluating anemia control strategies. We analyzed repeated Hb measures contributed by 942 Kenyan children between birth and 48 months of life using a mixed effects model, with a regression spline used to describe the population mean Hb profile, and random intercepts and slopes and first-order autoregressive correlation structure to accommodate the within-individual correlation among the repeated Hb measures. The approach facilitates the study of time-stationary and time-varying covariates that influence Hb in early life. The fitted mean Hb profile obtained from the analytic model is consistent with the observed mean Hb of the study population. Village of residence was associated with greatest difference in mean Hb at time of birth (16 versus 19 g/dL; P < 0.0001). Monthly weight-for-age was also associated with mean Hb after 3 months of age. This is the first description of an analysis strategy specifically for repeated Hb measures collected in a longitudinal field study in Africa. The strategy will facilitate improved study of time-varying covariates thought to influence pediatric anemia.

In large experimental trials throughout Africa, insecticide-treated bednets and curtains have reduced child mortality in malaria-endemic communities by 15%-30%. While few questions remain about the efficacy of this intervention, operational issues around how to implement and sustain insecticide-treated materials (ITM) projects need attention. We revisited the site of a small-scale ITM intervention trial, 3 years after the project ended, to assess how local attitudes and practices had changed. Qualitative and quantitative methods, including 16 focus group discussions and a household survey (n = 60), were employed to assess use, maintenance, retreatment and perceptions of ITM and the insecticide in former study communities. Families that had been issued bednets were more likely to have kept and maintained them and valued bednets more highly than those who had been issued curtains. While most households retained their original bednets, none had treated them with insecticide since the intervention trial was completed 3 years earlier. Most of those who had been issued bednets repaired them, but none acquired new or replacement nets. In contrast, households that had been issued insecticide-treated curtains often removed them. Three (15%) of the households issued curtains had purchased one or more bednets since the study ended. In households where bednets had been issued, children 10 years of age and younger were a third as likely to sleep under a net as were adults (relative risk (RR) = 0. 32; 95% confidence interval (95%CI) = 0.19, 0.53). Understanding how and why optimal ITM use declined following this small-scale intervention trial can suggest measures that may improve the sustainability of current and future ITM efforts.

A large-scale longitudinal cohort project was initiated in western Kenya in June 1992. The primary purpose of the project was to study Plasmodium falciparum malaria in a highly endemic area using a comprehensive and multidisciplinary approach, which included epidemiology, entomology, and immunology. Between June 1992 and July 1994, pregnant women living in 15 rural villages were identified during a monthly census and 1,164 were enrolled. The women were followed-up throughout their pregnancy and they, along with their newborn infants and direct siblings of the infants' less than 15 years of age, were monitored over time. As of May 1995, 1,017 infants had been born to these women. This paper presents the design and general methodology used in this study and describes the initial experience with intense monitoring of a large population over a prolonged period.

A large-scale longitudinal cohort project was initiated in western Kenya in June 1992. Between June 1992 and July 1994, 1,848 children less than 15 years of age were monitored prospectively for a mean of 236 days. During this period, 12,035 blood smears were examined for malaria and only 34% were found to be negative. Parasite prevalence (all species) decreased with age (from a high of 83% among children 1-4 years old to 60% among children 10-14 years old). Even more dramatic decreases were noted in the prevalence of high density falciparum infection (from 37% among children 12-23 months old to < 1% among 10-14-year-old children) and in clinical malaria (20% to 0.3% in the same age groups). Children < 1 year of age accounted for 55% of all cases of anemia detected. Anemia was consistently associated with high density infection in children < 10 years of age (20% to 210% increased risk relative to aparasitemic children). These results demonstrate the relationship between high-density malaria infection and two clinical manifestations of malarial illness.

Using a flow cytometry-based parasite growth inhibition assay (GIA) and an antibody-dependent cellular inhibition (ADCI) assay, we have assessed the differential effect and interaction of monocytes, immune sera, and purified immunoglobulins from Kenyan adults on the growth of Plasmodium falciparum parasites in vitro. We found that monocytes from 14 different normal, healthy, non-malaria-exposed donors had varying effects on parasite growth, i.e., inhibition or enhancement of parasitemia, suggesting heterogeneity in anti-parasitic activities of monocytes from individual donors. Twenty-two serum samples collected from clinically immune adults from western Kenya inhibited growth of P. falciparum after 48 hr in culture. In contrast, all IgG preparations, except one, purified from the same serum samples enhanced parasite growth. In ADCI experiments, of the 22 purified IgG samples used, 11 showed ADCI activities with specific growth inhibition (SGI) of more than 10%, with the highest at 27.6%, and the remaining 11 IgG samples had an SGI of less than 10%. Our results also showed that the ratio of IgG1 to IgG3 antibodies, as determined by an indirect immunofluorescence assay, was higher in the high ADCI response group than in the low response group, suggesting that a higher concentration of IgG1 antibodies with a higher IgG1/IgG3 ratio might be associated with ADCI activities. The present study has resulted in the development of simple, reproducible flow cytometry-based GIA and ADCI assays, and also provides baseline information for further investigation of the role of ADCI activity in naturally acquired immune protection against malaria.

A fever case management (CM) approach using sulfadoxine-pyrimethamine (SP) was compared with two presumptive intertmittent SP treatment regimens in the second and third trimesters in pregnant primigravidae and secundigravidae in an area of intense Plasmodium falciparum malaria transmission in western Kenya. The investigation evaluated efficacy of the antimalarial regimens for prevention of placental malaria and examined the effect of human immunodeficiency virus (HIV) infection on antimalarial drug efficacy and adverse drug reactions. Twenty-seven percent (93 of 343) of pregnant women in the CM group had placental malaria compared with 12% (38 of 330; P < 0.001) of women who received two doses of SP and compared with 9% (28 of 316; P < 0.001) of women who received monthly SP. Fourteen percent (49 of 341) of women in the CM group delivered low birth weight (LBW) infants compared with 8% (27 of 325; P=0.118) of women who received two doses of SP and compared with 8% (26 of 331; P=0.078) of women who received monthly SP. Seven percent (7 of 99) of the HIV-negative women on the two-dose SP regimen had placental malaria compared with 25% (10 of 39; P=0.007) of HIV-positive women on the same regimen; the rate of placental malaria in HIV-positive women was reduced to 7% (2 of 28; P=-0.051) for women on the monthly SP regimen. Less than 2% of women reported adverse drug reactions, with no statistically significant differences between HIV-positive and HIV-negative women. Intermittent treatment with SP is safe and efficacious for the prevention of placental malaria in pregnant primigravidae and secundigravidae in sub-Saharan Africa. While a two-dose SP regimen may be effective in areas with low HIV seroprevalence, administration of SP monthly during the second and third trimesters of pregnancy should be considered in areas of high HIV seroprevalence to prevent the effects of maternal malaria on the newborn.

Severe childhood malarial anemia is commonly treated using blood transfusion. Although transfusion may decrease short-term mortality, the risk of human immunodeficiency virus (HIV) transmission is considerable in Africa. We constructed a decision tree to weigh the short-term mortality benefit of transfusion against HIV infection risk. Probability estimates were derived from published studies. The base-case was a two-year-old child with a 13.5% mortality risk to be transfused with screened or unscreened blood (1% or 13% HIV contamination risk, respectively), with reduction of mortality to 5.5% by transfusion (odds ratio=2.7), and a 2.4% risk of fatal transfusion complications. A sensitivity analysis was performed to assess the influence of variation in these estimates. If a child developed acquired immunodeficiency syndrome, survival was weighed as one-tenth of normal survival. For the base-case, we found that transfusion with screened blood provided a survival benefit of 5%. In contrast, transfusion with unscreened blood decreased survival by 2%. Patients with a mortality risk < 5% derived no benefit from a transfusion with screened blood. Other important factors for the benefit of transfusion were the effectiveness of transfusion in reducing mortality and the risk of blood contamination. A blood transfusion was clearly beneficial if the mortality risk was high and the risk of contamination was low. Our findings can be used as a basis for a clinical transfusion policy that limits transfusions to situations in which they are likely to be beneficial. This will in turn optimize child survival and prevent unnecessary exposure of low risk children to the transfusion risks.

Currently recommended prophylactic regimens for Plasmodium falciparum malaria are associated with a high incidence of adverse events and/or suboptimal efficacy. In a double-blind, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of atovaquone/proguanil hydrochloride (250 mg/100 mg per tablet) to eliminate preexisting infection. Immediately thereafter, subjects were randomized to one of the three prophylactic regimens to receive one atovaquone/proguanil tablet daily (n = 68), two atovaquone/proguanil tablets daily (n = 65), or placebo (n = 65) for 10 weeks. The study endpoint for any subject was the development of parasitemia, evident on blood smear, during prophylaxis. Of the evaluable subjects, all in the low-dose (54 of 54) and high-dose (54 of 54) atovaquone/proguanil groups remained malaria-free during the 10-week prophylaxis period, in contrast to only 48% (26 of 54) in the placebo group (P < .001). Both atovaquone/proguanil prophylactic regimens were as well tolerated as placebo. Thus, atovaquone/proguanil appears to be highly efficacious and safe as prophylaxis for P. falciparum malaria.

Chloroquine-resistant malaria is a major public health threat in sub-Saharan Africa. While a few countries have already replaced chloroquine as the first-line therapy for uncomplicated malaria or are in the process of doing so, other countries are faced with the complicated task of assessing the current status of drug resistance, making national policy-level decisions about whether to replace chloroquine or not, and initiating a monitoring system to track changes in the efficacy of malaria therapy. There is currently no standardized approach for collecting and interpreting data on therapy efficacy. There is also no agreement as to how much chloroquine resistance or treatment failure is acceptable and how much warrants a change in treatment policy. Using data collected in 10 sites in eastern and southern Africa between 1990 and 1996, we have assessed the therapeutic response to chloroquine and investigated predictors of clinical success or failure. Based on these experiences and analyses, a standardized protocol for in vivo studies of the efficacy of malaria therapy and for approaches to designing monitoring systems are proposed. The process of making policy-level decisions based on data collected by these systems is also discussed.

This paper describes use of the global positioning system (GPS) in differential mode (DGPS) to obtain highly accurate longitudes, latitudes, and altitudes of 1,169 houses, 15 schools, 40 churches, four health care centers, 48 major mosquito breeding sites, 10 borehole wells, seven shopping areas, major roads, streams, the shore of Lake Victoria, and other geographic features of interest associated with a longitudinal study of malaria in 15 villages in western Kenya. The area mapped encompassed approximately 70 km2 and included 42.0 km of roads, 54.3 km of streams, and 15.0 km of lake shore. Location data were entered into a geographic information system for map production and linkage with various databases for spatial analyses. Spatial analyses using parasitologic and entomologic data are presented as examples. Background information on DGPS is presented along with estimates of effort and expense to produce the map information.

This study was aimed at delineating characteristics of naturally acquired immunity against the merozoite surface antigen-1 (MSP-1) of Plasmodium falciparum, a candidate malaria vaccine antigen. A case/control study was performed on 75 case/control pairs of infants with febrile illness at the time of the first detected infection indicating a clinical case. The presence and level of antibodies at one month prior to the first infection and at the time of the first infection in the afebrile group was significantly higher than in the febrile group. Decreased parasite density and decreased infection-related loss of hemoglobin was seen in infants with anti-MSP-1(19kD) IgG antibodies. In addition, mothers who were positive for the presence of these antibodies conferred protection against placental infection and infection in their infants. In this study, development of anti-MSP-1(19kD) antibody responses in 24 infants were studied longitudinally using monthly serum samples collected from birth until approximately one year of age. In addition, umbilical cord blood sera and respective mothers' sera were analyzed. Longitudinal studies of antibody responses revealed several short-lived IgG and IgM peaks throughout an infant's first year that correlated with detection of parasitemia. The protection against parasitemia and febrile illness was observed in infants when anti-MSP-1(19kD) antibodies were present; when infants were negative for IgG, they had a 10-times greater risk of becoming parasitemic. These data from a longitudinal and prospective study of malaria suggest a protective role for anti-MSP-1(19kD) antibodies in infants and pregnant women.

Azithromycin prevents malaria in animal models and early clinical trials. We determined the prophylactic efficacy of three antibiotic regimens given for 10 weeks (azithromycin, 250 mg daily; azithromycin, 1,000 mg weekly; and doxycycline, 100 mg daily) relative to that of placebo for 232 adult volunteers residing in an area of intense malaria transmission. Any confirmed parasitemia during the study was considered a prophylactic failure. Two hundred thirteen volunteers (92%) completed the study. The prophylactic efficacies were as follows: daily azithromycin, 82.7% (95% confidence interval [CI], 68.5%-91.1%); weekly azithromycin, 64.2% (95% CI, 47.1%-77.1%); and daily doxycycline, 92.6% (95% CI, 79.9%-97.5%). All regimens were well tolerated. We concluded that both 100 mg of doxycycline and 250 mg of azithromycin, given daily, were effective as prophylaxis for malaria in this setting. If studies with nonimmune volunteers confirm these results for semi-immune volunteers, a daily azithromycin regimen may have special utility for individuals with contraindications to treatment with doxycycline or other antimalarial agents.

In this study, we have investigated the extent of natural polymorphism in the CD8+ cytotoxic T lymphocyte (CTL) determinant (amino acids 368-390) of circumsporozoite (CS) protein of Plasmodium falciparum field isolates from a holoendemic region of Kenya, and determined how this variation affects the CTL reactivities in clinically immune adults and binding specificities to human histocompatibility leukocyte antigen (HLA)-B35. Among the eight variant sequences that were found in this region, four were new and not seen in parasites from other geographical regions. When synthetic peptides corresponding to the eight variants were used to test the presence of CTL response in different donors, a different spectrum of CTL reactivity to these variants was noticed. While CTL from some donors recognized the P1 sequence (the most prevalent type of sequence) but not P8 (another major variant), other donors showed a reverse pattern of reactivity. Although none of the donors was able to recognize all the variants, CTL responses to all the eight variant sequences were found in this population. An octamer peptide with P1 sequence KPKDELDY in this polymorphic determinant was known to bind HLA-B35. When we tested the effect of natural variation in this octamer sequence on HLA-B35 binding, it became evident that SP13 with D --> N substitution retained its binding specificity to HLA-B35. On the other hand, the SP12 octamer sequence which had two substitutions did not bind HLA-B35. The most interesting finding was the observation that a D --> G substitution at position 374 rescued the binding ability of SP14, which otherwise could not bind to this HLA molecule due to E --> Q amino acid substitution at position 372. To our knowledge, this is the first demonstration showing that a natural polymorphism can rescue the binding specificity to an HLA-class I molecule that was lost due to another natural amino acid substitution. Altogether, these results demonstrate that natural polymorphism in the CS protein affects both the CTL reactivity and the ability to bind to HLA-B35.

Blood-stage level Plasmodium falciparum infection (parasitemia density) is generally elevated prior to, or at the time of, clinical presentation of severe pediatric malaria episodes. Intensity of exposure to infective Anopheles mosquito bites is a suspected determinant of higher density parasitemia. Analyses of entomologic and parasitologic data collected in 1986-1987 were conducted to investigate whether the dose of infective bites predicted the incidence or degree of P. falciparum parasitemia in Kenyan children < 6 years old. At 21 consecutive 30-day intervals, a new cohort (n approximately 50 each) was enrolled, cured of malaria parasites, and monitored over 84 days for recurrent parasitemia. Outcomes included time to parasitemia, time to parasitemia > or = 5,000/microliter, and parasitemia density. Ecologic and individual-level analyses were conducted. The mean infective bite exposure experienced by each cohort was significantly associated with the incidence of parasitemia (age-adjusted r2 = 0.38, p = 0.022) and more strongly associated with the incidence of parasitemia > or = 5,000/microliter (age-adjusted r2 = 0.72, p < 0.001). The infective bite dose, analyzed as a time-dependent covariate, was associated with a 2.8 times higher rate of parasitemia > or = 5,000/microliter among children exposed to > or = 1 infective bite per day as compared with the referent (rate ratio (RR) = 2.82, 95% confidence interval (CI) 2.24-3.56). Cumulative infective bite exposure, exposure duration, and age were significant predictors of recurrent parasitemia density in multiple linear regression analyses. The results support the contention that reductions in P. falciparum transmission intensity, in the absence of complete elimination, will reduce higher level parasitemia among African children.

Recently, an association was described between the density of Plasmodium falciparum asexual parasitemia in Kenyan children and the entomologic inoculation rate (EIR) measured prior to measurement of asexual parasitemia. This study examined whether transmission pressure, as represented by the EIR, was associated with the prevalence or density of gametocytemia in Kenyan children. Each month for 19 months, a cohort of approximately 50 children was given a radical cure and enrolled in the study. Blood films were taken on days 0, 7, and 14. The EIR was calculated for the 28-day period ending 14 days prior to enrollment: the relationship between blood film data from day 7 and exposure variables was explored. We found that younger children were more likely to be gametocytemic than older children and, if gametocytemic, were more likely to have a dense gametocytemia. There was an inverse relationship between the number of infective bites per night received and prevalence but not density of gametocytemia, even after age adjustment. Concordance of gametocytemia prevalence on days 0 (64%), 7 (66%), and 14 (52%) was poor; 84% of the children were positive on at least one day. This indicates that in many subjects the detectable gametocytemia varied over the 14 days. Under these holoendemic transmission conditions, the EIR is inversely correlated with prevalence of gametocytemia, and point measurements of gametocytemia by conventional microscopy underestimate the number of infective donor hosts.

Potential indicators were assessed for the two classifications of protein-energy malnutrition in the guidelines for integrated management of childhood illness: severe malnutrition, which requires immediate referral to hospital, and very low weight, which calls for feeding assessment, nutritional counselling and follow-up. Children aged < 2 years require feeding assessment and counselling as a preventive intervention. For severe malnutrition, we examined 1202 children admitted to a Kenyan hospital for any association of the indicators with mortality within one month. Bipedal oedema indicating kwashiorkor, and two marasmus indicators (visible severe wasting and weight-for-height (WFH) Z-score of < -3) were associated with a significantly increased mortality risk (odds ratios, 3.1-3.9). Very low weight-for-age (WFA) (Z-score of < -4.4) was not associated with an increased risk of mortality. Because first-level health facilities generally lack length-boards, bipedal oedema and visible severe wasting were chosen as indicators of severe malnutrition. To assess potential WFA thresholds for the very low weight classification, our primary source of data came from 1785 Kenyan outpatient children, but we also examined data from surveys in Nepal, Bolivia, and Togo. We examined the performance of WFA at various thresholds to identify children with low WFH and, for children aged < or = 2 years, low height-for-age (HFA). Use of a WFA threshold Z-score of < -2 identified a considerable proportion of children (from 13% in Bolivia to 68% in Nepal) which, in most settings, would pose an enormous burden on the health facility. Among ill children in Kenya, a threshold WFA Z-score of < -3 had a sensitivity of 89-100% to detect children with WFH Z-scores of < -3, and, with an identification rate of 9%, would avoid overburdening the clinics. Potential modifications include use of a more restrictive cut-off in countries with high rates of stunting, or the elimination of the WFA screen in order to concentrate efforts on intervention for all children below the 2-year age cut-off. Key issues in every country include the capacity to provide counselling for many children and linkage to nutritional improvement programmes in the community.

In 1993, the World Health Organization completed the development of a draft algorithm for the integrated management of childhood illness (IMCI), which deals with acute respiratory infections, diarrhoea, malaria, measles, ear infections, malnutrition, and immunization status. The present study compares the performance of a minimally trained health worker to make a correct diagnosis using the draft IMCI algorithm with that of a fully trained paediatrician who had laboratory and radiological support. During the 14-month study period, 1795 children aged between 2 months and 5 years were enrolled from the outpatient paediatric clinic of Siaya District Hospital in western Kenya; 48% were female and the median age was 13 months. Fever, cough and diarrhoea were the most common chief complaints presented by 907 (51%), 395 (22%), and 199 (11%) of the children, respectively; 86% of the chief complaints were directly addressed by the IMCI algorithm. A total of 1210 children (67%) had Plasmodium falciparum infection and 1432 (80%) met the WHO definition for anaemia (haemoglobin < 11 g/dl). The sensitivities and specificities for classification of illness by the health worker using the IMCI algorithm compared to diagnosis by the physician were: pneumonia (97% sensitivity, 49% specificity); dehydration in children with diarrhoea (51%, 98%); malaria (100%, 0%); ear problem (98%, 2%); nutritional status (96%, 66%); and need for referral (42%, 94%). Detection of fever by laying a hand on the forehead was both sensitive and specific (91%, 77%). There was substantial clinical overlap between pneumonia and malaria (n = 895), and between malaria and malnutrition (n = 811). Based on the initial analysis of these data, some changes were made in the IMCI algorithm. This study provides important technical validation of the IMCI algorithm, but the performance of health workers should be monitored during the early part of their IMCI training.

We have characterized the natural immune responses to the 19-kDa domain of merozoite surface protein 1 in individuals from an area of western Kenya in which malaria is holoendemic. We used the three known natural variant forms of the yeast-expressed recombinant 19-kDa fragment that are referred to as the E-KNG, Q-KNG, and E-TSR antigens. T-cell proliferative responses in individuals older than 15 years and the profile of immunoglobulin G (IgG) antibody isotypes in individuals from 2 to 74 years old were determined. Positive proliferative responses to the Q-KNG antigen were observed for 54% of the individuals, and 37 and 35% of the individuals responded to the E-KNG and E-TSR constructs, respectively. Considerable heterogeneity in the T-cell proliferative responses to these three variant antigens was observed in different individuals, suggesting that the 19-kDa antigen may contain variant-specific T epitopes. Among responses of the different isotypes of the IgG antibody, IgG1 and IgG3 isotype responses were predominant, and the prevalence and levels of the responses increased with age. We also found that a higher level of IgG1 antibody response correlated with lower parasite density among young age groups, suggesting that IgG1 antibody response may play a role in protection against malaria. However, there was no correlation between the IgG3 antibody level and protection. Furthermore, we observed that although the natural antibodies cross-reacted with all three variant 19-kDa antigens, IgG3 antibodies in 12 plasma samples recognized only the E-KNG and Q-KNG constructs and not the E-TSR antigen. This result suggests that the fine specificity of IgG3 antibodies differentiates among variant-specific natural B-cell determinants in the second epidermal growth factor domain (KNG and TSR) of the antigen.

It has been hypothesized that antibody induced by Plasmodium falciparum circumsporozoite protein vaccine would be effective against endemic human malaria. In a malaria endemic region of Kenya, 76 volunteers, in 38 pairs sleeping adjacently, were immunized with subunit circumsporozoite protein Asn-Ala-Asn-Pro tetrapeptide repeat-pseudomonas toxin A, or hepatitis B vaccine. After quinine and doxcycycline, volunteers were followed for illness daily, parasitemia weekly, antibody, T-lymphocyte responses, and treated if indicated. Anopheles mosquitoes resting in houses were collected, and tested for P. falciparum antigen, or dissected for sporozoites and tested for blood meal ABO type and P. falciparum antigen. Vaccine was safe, with side-effects similar in both groups, and immunogenic, engendering IgG antibody as high as 600 micrograms ml-1, but did not increase the proportion of volunteers with T-lymphocyte responses. Estimation of P. falciparum challenge averaged 0.194 potentially infective Anopheles bites/volunteer/ day. Mosquito blood meals showed no difference in biting intensity between vaccine and control groups. Both groups had similar malaria-free survival curves, cumulative positive blood slides, cumulative parasites mm-3, and numbers of parasites mm-3 on first positive blood slide, during three post-vaccination observation periods. Every volunteer had P. falciparum parastemia at least once. Vaccinees had 82% and controls 89% incidences of symptomatic parasitemia (P = 0.514, efficacy 9%, statistical power 95% probability of efficacy < 50%). Vaccine-induced anti-sporozoite antibody was not protective in this study. Within designed statistical precisions the present study is in agreement with efficacy studies in Colombia, Venezuela and Tanzania.

In a blind field evaluation of a nonisotopic liquid hybridization assay for detection of malaria parasites, 100 blood samples were tested from an area in which malaria is endemic; light microscopy was used as the reference test. Sensitivity, specificity, and positive and negative predictive values of the hybridization assay were 100%. One sample that was microscopy-negative and hybridization-positive was positive when reexamined. Another sample that was microscopy-positive and hybridization-negative was negative at reexamination. The detection limit of the test was > or = 0.0005% parasitemia. Four samples with mixed infections were misdiagnosed by microscopy as single-species infections. Four samples diagnosed as mixed infections by microscopy and single infection by the hybridization test had no evidence of a second Plasmodium species upon reexamination. The polymerase chain-reaction-based nonisotopic liquid hybridization assay was better than conventional light microscopy in detecting low-grade parasite infection and offers an exceptional advantage for detecting mixed infections.

AMA-1 of Plasmodium falciparum is a promising candidate antigen in malaria vaccine development. In this study, we have mapped the immunodominant T-cell determinants in this antigen by using synthetic peptides. From the amphipathic scores, 17 putative T-cell determinants were identified. Nine of the 17 peptides complementary to the putative T-cell determinants induced proliferation of peripheral blood mononuclear cells (PBMC) from Kenyan residents who had lifelong exposure to malaria; none of these peptides induced proliferation of PBMC from donors who were not previously exposed to malaria. This indicates that AMA-1 peptides were stimulating T cells that were previously primed by prior exposure to P. falciparum. Many positive responders showed reactivity to more than one peptide, and some of the potent proliferative T epitopes were found to be localized in the highly conserved regions of AMA-1, suggesting that it may be possible to induce T-cell memory that can recognize different variant forms of the parasite. This information on the natural immune responses against the AMA-1 vaccine antigen in clinically immune adults will be helpful in the development of an AMA-1 antigen-based malaria vaccine and may also guide testing of AMA-1-based vaccine formulations.

Malaria in Kenya has been characterised by marked variability in its epidemiology, partly reflecting the obstacles and progress made in the control strategies. The impact of anti-vector activities in the 1970s and before have been observed for variable lengths of time afterwards. Malaria has re-emerged in areas previously with little or no transmission. The recovery of infective Anopheles gambiae vector in higher altitudes affirms the potential for transmission in areas where epidemics have been known to occur. Morbidity and mortality patterns in the otherwise endemic lowlands have become increasingly severe, an observation which would be attributed to the increasing inefficacy of chloroquine. Efforts to promote personal protection suffer substantial setbacks in sustainability inspite of apparent acceptability. There are indications that the mosquito vector susceptibility to permethrin and other insecticides will now require continual monitoring in order to detect development of significant resistance. In this communication, we review some emergent issues in malaria transmission in Kenya and the potential for control as adduced from historical and contemporary perspectives.

In the last decade, Plasmodium falciparum resistance to a number of commonly used anti-malarials especially chloroquine, has increased considerably. Newer anti-malarial drugs are therefore being aggressively evaluated as alternatives. A randomized double-blind controlled trial was therefore undertaken, to compare the efficacy of halofantrine to that of metakelfin, in the treatment of moderately severe infections of Plasmodium falciparum in an endemic malaria area in Kenya. Three hundred and thirty five subjects with laboratory confirmed malaria were recruited and randomized to receive treatment with either halofantrine (171 subjects) or metakelfin (164 subjects). Two thirds (66%) of the study subjects were under the age of five years, and were therefore considered to have minimal immunity. All study subjects were initially admitted to hospital for three days and then followed up as out-patients on days 7, 14, 21, and 28. The level of parasitaemia, the presence of fever and the occurrence of adverse effects were evaluated. Halofantrine was found to be comparable to metakelfin in terms of resolution of fever (mean time 45 and 51 hours respectively). No major adverse side effects were observed. Halofantrine is a viable drug in the treatment of uncomplicated P. falciparum malaria.

To facilitate design of vaccine trials, malaria was studied in 6-month- to 6-year-old Kenyans during high (HI) and low intensity transmission seasons. During 84 days after cure, exposure to infected mosquitoes was 9-fold greater in the HI group, yet incidence of P. falciparum infection was increased only 2-fold, with no age effect. The density of recurrent P. falciparum was 14-fold greater in the HI group, and there was a striking association between age and parasitemia > or = 5000/microL. Fever was the only clinical manifestation attributable to parasitemia and only when the parasite density was > or = 5000/microL. Sixty-four percent of children with > or = 20,000 parasites/microL versus 10% with 1-4999/microL were febrile when parasitemic. Recurrent P. falciparum infection as a vaccine trial end point can be studied year-round among children < or = 6 years [corrected] in western Kenya. However, high-grade parasitemia (> or = 5000 or 20,000/microL) with or without elevated temperature will be optimally studied in the high transmission season among children < 2 years.