Rolling back malaria in pregnancy.
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Disease Susceptibility↗
Biomedical subjects
B L Nahlen
Publications and source records attributed to B L Nahlen.
Immunity to placental malaria. II. Placental antigen-specific cytokine responses are impaired in human immunodeficiency virus-infected women.
An association was demonstrated recently between elevated in vitro production of interferon (IFN)-gamma by intervillous blood mononuclear cells (IVBMCs) and protection against placental malaria (PM). Because human immunodeficiency virus (HIV)-infected pregnant women have increased susceptibility to PM, loss of the IFN-gamma response in these women may impair their ability to control PM. Measurement of cytokines in culture supernatants by ELISA revealed that IFN-gamma responses by HIV-positive IVBMCs were impaired, especially after malarial antigen stimulation. Interleukin (IL)-4 and IL-10 responses also were reduced in HIV-positive persons, the latter more so in HIV-positive, PM-positive persons. In contrast, tumor necrosis factor-alpha production generally was enhanced in PM-positive and HIV-positive persons. Overall, cytokine production was reduced in HIV-positive persons with CD4 T cell counts <500/microL, particularly in response to malarial antigen. Thus, HIV-mediated cytokine dysregulation and impairment of the protective IFN-gamma response may contribute to the increased susceptibility of HIV-positive pregnant women to malaria.
Adult↗
Anti-merozoite surface protein-1 19-kDa IgG in mother-infant pairs naturally exposed to Plasmodium falciparum: subclass analysis with age, exposure to asexual parasitemia, and protection against malaria. V. The Asembo Bay Cohort Project.
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.
Aging↗
Immunologic memory in the placenta: a lymphocyte recirculation hypothesis.
The placenta is an immunologically unique organ where a balance between maternal immunity and fetoplacental well-being must be maintained for successful pregnancy to occur. The intervillous blood is important in this context, yet little is known about local immunologic processes, particularly how placenta-specific memory immune responses are maintained. Using malaria as an illustrative case, we describe an hypothetical model in which recirculation of memory T lymphocytes from the intervillous blood to local lymphoid tissue facilitates maintenance of local memory immunity. This explains how memory cells might be retained when the placenta is expelled at parturition and thus remain available for rapid recall from the local lymphoid tissue to the intervillous space when exposure to the same antigenic stimulus occurs in subsequent pregnancies. Study of cell-mediated immunity to infections like malaria in the intervillous blood and the use of animal models will be necessary to provide proof for this hypothesis.
Female↗
Cytokine responses to Plasmodium falciparum liver-stage antigen 1 vary in rainy and dry seasons in highland Kenya.
Seasonal epidemics of malaria occur in highland areas of western Kenya where transmission intensity varies according to rainfall. This study describes the seasonal changes in cytokine responses to Plasmodium falciparum liver-stage antigen 1 (LSA-1) by children (< or =17 years old) and adults (> or =18 years old) living in such a highland area. Fourteen- to 24-mer peptides corresponding to the N- and C-terminal nonrepeat regions of LSA-1 stimulated production of interleukin-5 (IL-5), interleukin-10 (IL-10), gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMC) from 17 to 73% of individuals in both age groups in both seasons. IL-10 and TNF-alpha responses were more frequent during the high-transmission, rainy season than during the low-transmission, dry season (73 and 67% versus 17 and 25% response rates, respectively). In contrast, there was no seasonal change in the proportion of LSA-1-driven IFN-gamma and IL-5 responses. Children produced less IFN-gamma than adults, but IL-5, IL-10, and TNF-alpha levels were similar for both age groups. Depletion of CD8(+) cells from PBMC decreased IFN-gamma but increased IL-10 production. Individuals with LSA-1-stimulated IL-10 responses in the dry season were less likely to become reinfected in the subsequent rainy season than those without IL-10 responses (25% versus 49%; P = 0.083). These data support the notion that maintenance of LSA-1-driven IL-10 and TNF-alpha responses requires repeated and sustained exposure to liver-stage P. falciparum. In contrast, IFN-gamma responses increase slowly with age but persist once acquired. CD8(+) T cells are the major source of IFN-gamma but may suppress production or secretion of IL-10.
Adolescent↗
Risk factors for HIV infection among asymptomatic pregnant women attending an antenatal clinic in western Kenya.
Our objective was to evaluate HIV prevalence and identify risk factors for HIV infection among women attending the antenatal clinic (ANC) at a large public hospital in Kisumu town, western Kenya. Between June 1996 and November 1997, in the context of a study to determine the effect of placental malaria on mother-to-child transmission of HIV in western Kenya, HIV-1 antibody testing was offered to women with a singleton uncomplicated pregnancy of > or =32 weeks' gestation attending the ANC. Women were interviewed using a structured questionnaire and had a fingerstick blood sample collected for haemoglobin (Hb), malaria smears, and HIV antibody testing. Overall HIV seroprevalence was 26.1% (743/2844) (95% confidence interval (CI): 24.5-27.7) and in bivariate evaluation was significantly associated with anaemia (Hb <11 g/dl) (risk ratio (RR) 1.8), malarial parasitaemia (RR 1.6), fever (axillary temperature > or =37.5 degrees C at screening) (RR 1.6), a history of being treated for either vaginal discharge (RR 1.5) or tuberculosis (RR 1.6), reported alcohol consumption (RR 1.6), being an unmarried multigravida (RR 2.2) or a history of the most recent child having died (RR 2.0). Poisson regression analysis for all women identified 5 significant factors independently associated with HIV seropositivity: anaemia (adjusted RR 1.7; 95% CI 1.3-2.0), malarial parasitaemia (adjusted RR 1.7; 95% CI 1.4-2.0), a history of being treated for vaginal discharge (adjusted RR 1.5; 95% CI 1.1-2.0), fever (adjusted RR 2.0; 95% CI 1.3-3.2) and reported alcohol consumption (adjusted RR 1.6; 95% CI 1.1-2.5). Multigravidae women whose most recent child had died were also more likely to be HIV seropositive (adjusted RR 1.9; 95% CI 1.7-2.8). Only 5.5% (156/2844) of the women had none of these risk factors, of whom 12% (18/156) were HIV(+). Even though the model containing the 5 identified factors fitted the data well (goodness-of-fit chi2=18.41, P=0.10), its collective capacity to predict HIV infection was poor; while 74% of the truly positive women were correctly predicted positive by the model, 52% of the truly negative women were misclassified. Among pregnant women attending the ANC in western Kenya, we were unable to identify a subgroup at risk of HIV infection using non-serological information, indicating that wherever possible universal access to voluntary HIV counselling and testing would be preferable to targeted screening.
Adolescent↗
Maintenance and sustained use of insecticide-treated bednets and curtains three years after a controlled trial in western Kenya.
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.
Bedding and Linens↗
Immunity to placental malaria. I. Elevated production of interferon-gamma by placental blood mononuclear cells is associated with protection in an area with high transmission of malaria.
In areas in which malaria is holoendemic, primigravidae and secundigravidae, compared with multigravidae, are highly susceptible to placental malaria (PM). The nature of gravidity-dependent immune protection against PM was investigated by measuring in vitro production of cytokines by placental intervillous blood mononuclear cells (IVBMC). The results demonstrated that interferon (IFN)-gamma may be a critical factor in protection against PM: production of this cytokine by PM-negative multigravid IVBMC was elevated compared with PM-negative primigravid and secundigravid and PM-positive multigravid cells. Low IFN-gamma responsiveness to malarial antigen stimulation, most evident in the latter group, was balanced by increased interleukin (IL)-4 production, suggesting that counter-regulation of these two cytokines may be a crucial determinant in susceptibility to PM. A counter-regulatory relationship between IL-10 and tumor necrosis factor-alpha was also observed in response to malarial antigen stimulation. These data suggest that elevated production of IFN-gamma, as part of a carefully regulated cytokine network, is important in the control of PM.
Adult↗
Differential effect and interaction of monocytes, hyperimmune sera, and immunoglobulin G on the growth of asexual stage Plasmodium falciparum parasites.
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.
Adult↗
Transmission of epidemic Vibrio cholerae O1 in rural western Kenya associated with drinking water from Lake Victoria: an environmental reservoir for cholera?
Sub-Saharan Africa has the highest reported cholera incidence and mortality rates in the world. In 1997, a cholera epidemic occurred in western Kenya. Between June 1997 and March 1998, 14,275 cholera admissions to hospitals in Nyanza Province in western Kenya were reported. There were 547 deaths (case fatality rate = 4%). Of 31 Vibrio cholerae O1 isolates tested, all but one were sensitive to tetracycline. We performed a case-control study among 61 cholera patients and age-, sex-, and clinic-matched controls. Multivariate analysis showed that risk factors for cholera were drinking water from Lake Victoria or from a stream, sharing food with a person with watery diarrhea, and attending funeral feasts. Compared with other diarrheal pathogens, cholera was more common among persons living in a village bordering Lake Victoria. Cholera has become an important public health concern in western Kenya, and may become an endemic pathogen in the region.
Adolescent↗
Analysis of repeated hemoglobin measures in full-term, normal birth weight Kenyan children between birth and four years of age. III. The Asemobo Bay Cohort Project.
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.
Adolescent↗
Predicted and observed alleles of Plasmodium falciparum merozoite surface protein-1 (MSP-1), a potential malaria vaccine antigen.
The 19-kDa antigenic domain of Plasmodium falciparum merozoite surface protein (MSP)-1 is a potential malaria vaccine candidate. Based on the amino acid substitution, four known alleles, E-TSR (PNG-MAD20 type), E-KNG (Uganda-PA type), Q-KNG (Wellcome type), and Q-TSR (Indo type) of this domain have been identified. Using single or double crossover recombinational events, we predicted the existence of additional alleles of this antigen. The presence of the predicted alleles was determined in parasite isolates from western Kenya, by undertaking a cross-sectional and a longitudinal study. Of the ten predicted alleles, we have revealed the presence of three new alleles: E-KSG-L (Kenya-1 type); E-KSR-L (Kenya-2 type); and E-KNG-F (Kenya-3 type). The results of this study suggest that it may be possible to predict the complexity of the genetic makeup of natural parasite populations.
Alleles↗
A longitudinal investigation of IgG and IgM antibody responses to the merozoite surface protein-1 19-kiloDalton domain of Plasmodium falciparum in pregnant women and infants: associations with febrile illness, parasitemia, and anemia.
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.
Anemia↗
A geographic information system applied to a malaria field study in western Kenya.
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.
Altitude↗
Studies on schistosomiasis in western Kenya: II. Efficacy of praziquantel for treatment of schistosomiasis in persons coinfected with human immunodeficiency virus-1.
Praziquantel is the drug of choice for schistosomiasis chemotherapy. Although the exact mechanism of how praziquantel kills schistosomes remains poorly understood, the immune response of the host is an important factor in drug efficacy. It is thus possible that disease states of humans that lead to immunodeficiencies, such as infection with human immunodeficiency virus-1 (HIV-1), may render praziquantel less effective in treating schistosomiasis. To test this hypothesis, persons with high levels of Schistosoma mansoni infection who were or were not also infected with HIV-1 were treated with a standard regimen of praziquantel and monitored by quantitative fecal examination and plasma circulating cathodic antigen. Both groups responded to praziquantel therapy equally and individuals with low percentages (< 20%) of CD4+ T cells did not differ from individuals with higher CD4 cell percentages. These data demonstrate that persons with HIV-1 infection can be treated effectively for schistosomiasis with praziquantel.
Animals↗
Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection.
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.
Adolescent↗
Cytotoxic T cell reactivity and HLA-B35 binding of the variant Plasmodium falciparum circumsporozoite protein CD8+ CTL epitope in naturally exposed Kenyan adults.
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.
Adult↗