Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine.

BACKGROUND: The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS: We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS: In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS: These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

Stabilization of HIV incidence in women of reproductive age in southern Mozambique.

INTRODUCTION: The collection of incidence data on HIV infection is necessary to evaluate the status and dynamics of the epidemic and the effectiveness of intervention strategies. However, this is usually difficult in low-income countries. METHODS: Five yearly point HIV prevalence estimations (in 1999, 2003, 2004, 2005 and 2008) were obtained for women between 15 and 45 years of age participating in three studies carried out for other purposes at the Antenatal Clinic (ANC) in Manhiça, Mozambique. HIV incidence was estimated between prevalence points using a previously validated methodology. Two methods were used, one based on mortality rates for three HIV epidemic scenarios, and the other based on survival information after infection. The pattern over time was captured by fitting a log-regression model. RESULTS: The prevalence of HIV infection ranged from 12% in 1999 to 49% in 2008. The HIV incidence increased from approximately 3.5 cases per 100 person-years in 2001 to 14 per 100 person-years in 2004, with stabilization thereafter to levels of around 12 cases per 100 person-years. The incidence estimates were comparable for the two methods used. CONCLUSION: These findings indicate an increase in the prevalence and incidence of HIV infection among women of reproductive age over the 9 years of the analysis, with a plateau in the incidence of infection since 2005. However, the very high figures for both prevalence and incidence highlight the importance of the continuation of the prevention and treatment programmes that already exist, and suggest that implementation of preventive measures is needed in this area.

Safety and immunogenicity of the RTS,S/AS02A candidate malaria vaccine in children aged 1-4 in Mozambique.

BACKGROUND: The development of a malaria vaccine remains a public health priority for sub-Saharan Africa. RTS,S/AS02A candidate malaria vaccine has been shown to be safe and immunogenic in previous studies in adults and staggered dose-escalation studies in children in The Gambia. However, genetic features and the intensity of malaria transmission may modify the safety and immune response of a vaccine. OBJECTIVE: We carried out a phase I, double-blind randomized controlled trial in 60 children aged 1-4 in Mozambique to evaluate the safety, reactogenicity and immunogenicity of the paediatric vaccine dose (fixed 25 microg RTS,S in 0.25 ml) of RTS,S/AS02A, prior to undertaking a planned larger phase IIb proof-of-concept of efficacy study in the same population. METHOD: Children were randomized to receive either RTS,S/AS02A or Engerix-B vaccine. Monitoring of safety and reactogenicity included detailed clinical and laboratory analyses and assessment of adverse events (AEs). RESULTS: The RTS,S/AS02A was found to be safe and well tolerated. Serious adverse events were balanced between both groups and none was related to vaccination. The frequency of adverse events reported with RTS, S/AS02A was comparable to previous studies in children. Grade 3 AEs were infrequent (one case of pain, one of fever in each group and some swelling greater than 20 mm in diameter), transient and resolved without sequelae. RTS,S/AS02A was highly immunogenic for anti-circumsporozoite protein antibody response and induced a strong anti-hepatitis-B surface antigen response.

Community incidences of respiratory infections in an actively followed cohort of children <1 year of age in Manhiça, a rural area of southern Mozambique.

OBJECTIVE: To estimate the community incidence-rates of respiratory infections among infants in Manhiça, southern Mozambique, and to determine risk factors associated with these infections. METHODS: A cohort of children <1 year of age were visited at home every week until they turned one. During the visits, field workers recorded signs/symptoms of respiratory infections and tested the children for malaria parasites when they had fever. RESULTS: Between 1 July 1998 and 30 June 1999, 1,044 children contributed with 23,726 weeks at risk. Children met the criteria for acute respiratory infection in 19.2% of the visits, for lower respiratory infection in 0.9% and for severe lower respiratory infection in 0.2%. The crude incidence rate measured for acute respiratory infections was 23.0, that for lower respiratory infection was 0.9 and that for severe lower respiratory infection was 0.2 per 100-person-week-at-risk. The risk of acute and lower respiratory infection was inversely related to age. Females were at significantly lower risk for all three conditions than males. A trend of increased risk of severe lower respiratory infection was noted among children born during the rainy season (adjusted rate ratio = 1.95, P = 0.122 in only 47 episodes). Malaria was strongly associated with an increased risk of all three respiratory infections [rate ratio of 2.35, 10.90 and 13.82 (P < 0.001) in the adjusted analysis, respectively]. Thirty-five children died during the follow-up period; 20% of them from lower respiratory infection. Conclusions Respiratory infections are a major cause of morbidity and mortality among infants in rural Mozambique. Our study provides a better understanding of the associated determinants.

Entomological characteristics of malaria transmission in Manhiça, a rural area in southern Mozambique.

From October 1997 to September 1998, an entomological survey was carried out in Manhiça, Mozambique, to describe the anopheline population and intensity of malaria transmission. Ten different huts were randomly selected for entomological surveillance throughout the year. CDC light trap collections were conducted during three nights each month. Additional knockdown spraying catches were carried out in the morning, after the last catch. A total of 17,245 Culicinae and 1,251 Anophelinae were collected during the study. There was substantial house to house variation and seasonality in the distribution of Anophelinae population, with a peak in April towards the end of the warm and rainy season. Four species of genus Anopheles (Diptera: Culicidae) were described: Anopheles funestus Giles, Anopheles tenebrosus Dönitz, Anopheles arabiensis Patton, and Anopheles merus Dönitz. An. funestus constitutes 72.3% of the anopheline population. The estimated sporozoite rate was 1.2% and the average entomological inoculation rate for the area was 15 infective bites per person per year.

Efficacy of chloroquine, amodiaquine, sulphadoxine-pyrimethamine and combination therapy with artesunate in Mozambican children with non-complicated malaria.

This paper reports a two-phase study in Manhiça district, Mozambique: first we assessed the clinical efficacy and parasitological response of Plasmodium falciparum to chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ), then we tested the safety and efficacy in the treatment of uncomplicated malaria, of three combinations: AQ + SP, artesunate (AR) + SP and AQ + AR. Based on the WHO (1996, WHO/MAL/96.1077) in vivo protocol, we conducted two open, randomized, clinical trials. Children aged 6-59 months with axillary body temperature > or = 37.5 degrees C and non-complicated malaria were randomly allocated to treatment groups and followed up for 21 days (first and second trial) and 28 days (first trial). The therapeutic efficacy of AQ (91.6%) was better than that of SP (82.7%) and CQ (47.1%). After 14 days, 69% of the strains were parasitologically resistant to CQ, 21.4% to SP and 26% to AQ. Co-administration of AQ + SP, AR + SP and AQ + AR was safe and had 100% clinical efficacy at 14-day follow-up. The combination therapies affected rapid fever clearance time and reduced the incidence of gametocytaemia during follow-up.

The incidence of clinical malaria detected by active case detection in children in Ifakara, southern Tanzania.

Between July 2000 and June 2001, we used weekly active case detection (ACD) of clinical malaria episodes in 618 children aged < 5 years to describe the epidemiology of malaria in Ifakara, southern Tanzania. Plasmodium falciparum-positive blood slides prepared from children with axillary temperature 37.5 degrees C were used to define clinical malaria and a rolling cross-sectional survey documented the prevalences of parasitaemia and anaemia. A random subsample of children was visited daily for 1 month at the end of the study to assess the effect of more frequent visits on estimated incidence rates. Only 50 (8%) children had 1 or more episodes of clinical malaria during the year, an overall incidence of 0.275 episodes/100 child-weeks-at-risk, with no age dependence. The maximum parasite prevalence of 25% was reached in children aged 4 years. The incidence of illness was significantly lower in children visited daily than in those visited weekly, suggesting a marked effect of frequent visits on estimated incidence rates. We conclude that the age pattern of malaria detected through ACD is a more robust epidemiological indicator than absolute incidence rate estimates and that, in contrast to the surrounding area, Ifakara town is subject to only moderate perennial malaria transmission.

Inter-observer variation in the assessment of clinical signs in sick Tanzanian children.

We assessed the inter-observer agreement in identification of a range of 24 clinical signs associated with disease presentation in 327 children aged < 5 years admitted to hospital in January-June 1999 in Ifakara, southern Tanzania. Children with diagnoses of malaria, pneumonia, diarrhoea, anaemia and malnutrition were examined independently by 2 clinical officers. Findings were recorded on a standard proforma. The Kappa-statistic was used to assess inter-observer agreement for each sign. Physical signs were more likely to be agreed upon by clinicians if they involved inspection than if they involved auscultation. The signs included in the Integrated Management of Childhood Illness (IMCI) algorithm were found to be largely appropriate (Kappa-scores > 0.41) although there was only fair agreement (Kappa-score 0.21-0.40) in the detection of neck stiffness and chest indrawing and slight agreement in the detection of dehydration (Kappa-score 0.199). All objective neurological signs were less reliably assessed in infants than in older children. The difficulties surrounding the diagnosis of impaired consciousness in young children should increase vigilance in the diagnosis and management of neurological complications of illnesses in infancy.

Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation.

BACKGROUND: Survival after liver transplantation for early hepatocellular carcinoma (HCC) is worsened by the increasing dropout rate while waiting for a donor. AIMS: To assess the cost effectiveness of adjuvant therapy while waiting for liver transplantation in HCC patients. METHOD: Using a Markov model, a hypothetical cohort of cirrhotic patients with early HCC was considered for: (1) adjuvant treatment-resection was limited to Child-Pugh's A patients with single tumours, and percutaneous treatment was considered for Child-Pugh's A and B patients with single tumours unsuitable for resection or with up to three nodules < 3 cm; and (2) standard management. Length of waiting time ranged from six to 24 months. RESULTS: Surgical resection increased the transplantation rate (>10%) and provided gains in life expectancy of 4.8-6.1 months with an acceptable cost ($40,000/ year of life gained) for waiting lists > or = 1 year whereas it was not cost effective ($74,000/life of year gained) for shorter waiting times or high dropout rate scenarios. Percutaneous treatment increased life expectancy by 5.2-6.7 months with a marginal cost of approximately $20,000/year of life gained in all cases, remaining cost effective for all waiting times. CONCLUSIONS: Adjuvant therapies for HCC while waiting for liver transplantation provide moderate gains in life expectancy and are cost effective for waiting lists of one year or more. For shorter waiting times, only percutaneous treatment confers a relevant survival advantage.

Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis.

OBJECTIVES: The significance of small intestinal bacterial overgrowth in patients with cirrhosis is not fully understood and its diagnostic criteria are not uniform. We examined the association of small intestinal bacterial overgrowth with spontaneous bacterial peritonitis and compared various microbiological criteria. METHODS: Jejunal secretions from 70 patients with cirrhosis were cultivated quantitatively and classified according to various definitions. Clinical characteristics of patients were evaluated and the incidence of spontaneous bacterial peritonitis was monitored during a 1-yr follow-up. RESULTS: Small intestinal bacterial overgrowth, defined as > or = 10(5) total colony-forming units/ml jejunal secretions, was present in 61% of patients. Small intestinal bacterial overgrowth was associated with acid-suppressive therapy (p = 0.01) and hypochlorhydria (p < 0.001). Twenty-nine patients with persistent ascites were observed. Six episodes of spontaneous bacterial peritonitis occurred after an average 12.8 wk. Occurence of spontaneous bacterial peritonitis correlated with ascitic fluid protein concentration (p = 0.01) and serum bilirubin (p = 0.04) but not with small intestinal bacterial overgrowth (p = 0.39). Its association with acid-suppressive therapy was of borderline significance (hazard ratio = 7.0, p = 0.08). CONCLUSIONS: Small intestinal bacterial overgrowth in cirrhotic patients is associated with acid-suppressive therapy and hypochlorhydria, but not with spontaneous bacterial peritonitis. The potential role of acid-suppressive therapy in the pathogenesis of spontaneous bacterial peritonitis merits further studies.

Effect of malaria on soluble transferrin receptor levels in Tanzanian infants.

The diagnosis of iron deficiency anemia in malaria endemic areas is complicated by the influence of the infection on the laboratory tests conventionally used to assess iron status. Determination of soluble transferrin receptor (sTfR) levels has been shown to be a sensitive indicator of iron deficiency in adults and is not affected by a range of infectious and inflammatory conditions. The utility of sTfR levels in the diagnosis of iron deficiency in malaria endemic areas remains unresolved. Three hundred and fourteen infants in a rural area of southern Tanzania living under conditions of intense and perennial malaria transmission were studied to determine the utility of sTfR plasma levels in the assessment of iron deficiency anemia. Independent of the presence of anemia, malaria parasitemia was associated with a significant increase in sTfR plasma levels that were even higher than those found in iron deficiency anemia. We conclude that the measurement of sTfR levels does not have a role in the diagnosis of iron deficiency anemia in young children exposed to malaria infection.

Prevalence of the K76T mutation in the putative Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene and its relation to chloroquine resistance in Mozambique.

K76T, a mutation in the Plasmodium falciparum chloroquine (CQ) resistance transporter protein, has been implicated in resistance to CQ. A modified 14-day in vivo test to estimate the CQ resistance level was done in southern Mozambique: 21 (42%) of 50 subjects who completed the follow-up were CQ susceptible. Use of msa2-restriction fragment length polymorphism (RFLP) genotyping to differentiate new from recrudescent infections made little difference in the estimated prevalence of resistance. The K76T mutation prevalence was estimated by RFLP-polymerase chain reaction and sequencing, and its relation to parasitological CQ resistance was explored on day 0 samples: 51 of 56 pretreatment samples presented the T76 codon, and it was present in 100% of children with parasitological resistance. T76 also was present in 18 of 23 subjects in whom the infection resolved after CQ treatment. These findings show a high prevalence of the K76T mutation among wild isolates but also suggest additional factors responsible for CQ resistance.

Prenatal risk factors of wheezing at the age of four years in Tanzania.

BACKGROUND: A study was undertaken to assess the interactions between prenatal exposures, early life infections, atopic predisposition, and allergen exposures in the development of wheezing up to the age of 4 years in a tropical region of Africa. METHODS: The study subjects comprised children born at the district hospital in Ifakara, Tanzania during a 1 year period who were participating in a trial of iron supplementation and malaria chemoprophylaxis during the first year of life and followed for up to 4 years. From this group of subjects, 658 (79%) participated in the interview at 18 months and 528 (64%) in a second interview at 4 years. Wheezing was measured with the ISAAC questionnaire. A hospital based inpatient and outpatient surveillance system was set up to document all attendance by study children for any cause, including episodes of clinical malaria and lower respiratory tract infections. Total IgE levels and malaria parasites were measured in maternal and cord blood. Total IgE was also measured at 18 months of age. Indoor environmental levels of Der p I and Fel d I were determined using an enzyme linked immunosorbent assay at the same time as the interview at the age of 18 months. RESULTS: The prevalence of wheezing at 4 years is common in Ifakara (14%, range 13-15%). The presence of malaria parasites in cord blood (odds ratio, OR = 6.84, 95% CI 1.84 to 24.0) and maternal asthma (OR = 8.47, 95% CI 2.72 to 26.2) were positively associated with wheezing at the age of 4 years, and cord blood total IgE was negatively associated (OR = 0.24, 95% CI 0.07 to 0.85) (all p<0.05). Parasitaemia at birth was not related to total IgE levels in cord blood (p=0.6). Clinical episodes of malaria during infancy were not associated with wheezing, and nor were levels of indoor aeroallergens. CONCLUSION: These findings suggest that events occurring during pregnancy may play a role in the future appearance of wheezing, although the results must be interpreted with caution because of the small numbers studied.

Derivation and validation of guidelines for stool cultures for enteropathogenic bacteria other than Clostridium difficile in hospitalized adults.

CONTEXT: The yield of in-hospital stool cultures performed more than 72 hours after admission is low, and a commonly used policy dictates that laboratories reject these cultures to save costs. However, enteropathogenic bacteria other than Clostridium difficile (EPB) may cause nosocomial illness that would be missed by use of such a "3-day rule." OBJECTIVE: To develop guidelines for hospital use of stool cultures that are sensitive to clinically relevant cases of sporadic and epidemic nosocomial diarrhea. DESIGN: Five-part study that incorporated a derivation sample based on retrospective chart review and a prospective cohort study (including cost savings analysis), and a validation sample based on retrospective chart review. SETTING: Four European academic health care centers. PATIENTS: Derivation sample: 1735 adult inpatients from whom 3416 stool cultures were obtained during a 19-month period (1995-1997) and 68 adult inpatients for whom EPB were grown from stool cultures during a 10-year period (1988-1998); validation sample: 65 patients with sporadic isolation of EPB (1993-1998), 56 patients involved in 2 nosocomial Salmonella outbreaks (1992 and 1997), and 330 patients who had stool cultures performed (1998). MAIN OUTCOME MEASURE: Performance of derived criteria in detecting pathogenic bacteria and outbreaks and reducing total number of stool cultures performed. RESULTS: Stool cultures grew EPB in 3.3% of samples obtained 72 hours after admission was not associated with clinical symptoms or signs but was associated with community-acquired diarrhea (24%), age 65 years or older with preexisting comorbid disease (25%), neutropenia (13%), HIV infection (10%), and nondiarrheal manifestations of enteric infections (16%). Twelve percent were asymptomatic carriers. These characteristics were used to create criteria for selecting patients for whom stool cultures would be indicated. These criteria were applied post hoc to a series of 1025 stool cultures; the number of stool cultures would have been reduced by 52% and no clinically significant cases would have been missed. Annual savings to a 355-bed institution would be approximately $7800 for reagent costs and 75 hours of technician time. In the validation samples, only 2 patients of 65 who had EPB would not have been identified, and neither required treatment. If the 3-day rule had been applied, 52 cases would not have been identified, 28 of which required antibiotic treatment. CONCLUSION: Our modified 3-day rule for use in selecting cases for stool culture is sensitive to sporadic and epidemic cases of nosocomial diarrhea in hospitalized adults.

Diarrhea in children under 5 years of age from Ifakara, Tanzania: a case-control study.

A matched case-control study was conducted in the Maternal and Child Health Clinic (MCH) in Ifakara, Tanzania, during the rainy season in order to elucidate the risk factors for and etiology of diarrheal diseases in children under 5 years of age. Cases (103) and controls (206) were matched for sex and age group. Precoded questionnaires with demographic details, clinical history, and physical signs were completed. Stools samples were collected for bacterial, parasitological, and viral studies. A high number of siblings (odds ratio [OR], 0.86; P = 0.027), the number of siblings surviving (OR, 0.82; P = 0.007), the birth order (OR, 0.85; P = 0.018) and the distance from the house to the water source (OR, 0.33; P = 0.011) were associated with the risk of diarrhea. There were high rates of enteropathogen isolates in stool samples from children without diarrhea (52.23%). Shigella species were the only enteropathogen statistically related with diarrhea (OR, 2.90; P < 0.029). Enterotoxigenic, enteropathogenic, and enteroaggregative strains of Escherichia coli were not related with diarrhea, and neither were Giardia lamblia or Salmonella species.

Humoral immune responses during a malaria vaccine trial in Tanzanian infants.

The development of a malaria vaccine is a priority for improved and sustained malaria control. Optimal use of a vaccine in Africa will only be achieved if it can be delivered through the Expanded Programme of Immunization (EPI). We have completed a trial of the peptide vaccine SPf66 in Tanzanian infants, given alongside the EPI vaccines. This paper describes the humoral responses to SPf66 and the EPI vaccines. A total of 1207 infants were recruited into a two-arm, double-blind, individually randomized placebo-controlled trial of SPf66. The objectives of the trial were to determine the safety, immunogenicity and efficacy of SPf66 and to assess interactions with EPI vaccines when three doses of SPf66 were delivered alongside the EPI vaccines. Cross-sectional surveys were carried out to asses seroconversion rates to the EPI vaccines and the antibody response to SPf66 (NANP)50 and Plasmodium falciparum lysates. Seroconversion rates to EPI vaccines were high and no statistically significant differences in prevalence or titres were found between SPf66 and placebo recipients. IgG antibodies against SPf66 (NANP)50 and whole P. falciparum lysate were present in high titres in mothers of recruited children at the time of birth. Vaccination with SPf66 stimulated a good anti-SPf66 IgG response which declined to preimmunization levels by 2 years of age and which was not associated with protection against clinical malaria. The vaccine induced no IgG antibodies against (NANP)50 or P. falciparum lysates. SPf66 stimulated a humoral immune response when given to very young infants and did not interfere with seroconversion to EPI vaccines. The response to SPf66 was qualitatively different from that seen in older children, in whom SPf66 has been shown to be moderately efficacious. This difference raises concerns about the difficulties of immunizing very young infants who need to be targeted by antimalarial vaccination programs.

The impact of placental malaria on gestational age and birth weight.

Maternal malaria is associated with reduced birth weight, which is thought to be effected through placental insufficiency, which leads to intrauterine growth retardation (IUGR). The impact of malaria on preterm delivery is unclear. The effects of placental malaria-related changes on birth weight and gestational age were studied in 1177 mothers (and their newborns) from Tanzania. Evidence of malaria infection was found in 75.5% of placental samples. Only massive mononuclear intervillous inflammatory infiltration (MMI) was associated with increased risk of low birth weight (odds ratio ¿OR, 4.0). Maternal parasitized red blood cells and perivillous fibrin deposition both were associated independently with increased risk of premature delivery (OR, 3.2; OR, 2.1, respectively). MMI is an important mechanism in the pathogenesis of IUGR in malaria-infected placentas. This study also shows that placental malaria causes prematurity even in high-transmission areas. The impact of maternal malaria on infant mortality may be greater than was thought previously.

Placental pathology in malaria: a histological, immunohistochemical, and quantitative study.

To characterize the histological changes in malarial placentas and their relationship with parity and maternal and cord parasitemias, we conducted a histological study on 1,179 placentas from Ifakara, Tanzania, an area with intense and perennial malaria transmission. Immunohistochemical and quantitative studies for CD45, fibrin, and villous area were performed in 60 cases. Four hundred fifteen placentas (35.2%) showed parasites (active infections); in 303 of them, parasites co-existed with pigment covered by fibrin (chronic infections), and in 112 only parasites were detected (acute infections). Four hundred seventy-five cases (40.3%) showed hemozoin deposition without parasites (past infections). Of women with parasitized placentas, 46.3% did not show parasites in the peripheral blood. Basal membrane thickening (P = .002), fibrinoid necrosis (P = .004), and prominence of syncytial knots (P = .031) were associated with active malarial infection. No quantitative differences for perivillous fibrin deposition or villous area were found. The most significant association with active malarial infection was intervillous infiltration by mononuclear inflammatory cells (P < .001). Chronic infections were associated with the most severe changes, particularly intervillous mononuclear inflammation (OR, 28.7; 95% CI = 16.0 to 51.5, P< .001). Past infections showed only minimal differences with noninfected placentas. Primiparas showed chronic infections more frequently than multiparas (52% v 15%, P < .001). They also showed significantly higher placental parasitemias and intervillous inflammatory infiltrate. In conclusion, placental histology is more sensitive than peripheral blood examination in detecting malarial infection during pregnancy. Most malarial infections recover during pregnancy, leaving few residual changes in the placenta. Intervillous inflammation is the most frequent finding associated with malaria and is especially severe in primiparas, suggesting that mechanisms other than immunosuppression are responsible for the high susceptibility in this group.

African children with malaria in an area of intense Plasmodium falciparum transmission: features on admission to the hospital and risk factors for death.

Malaria remains the most important parasitic cause of mortality in humans. Its presentation is thought to vary according to the intensity of Plasmodium falciparum transmission. However, detailed descriptions of presenting features and risk factors for death are only available from moderate transmission settings. Such descriptions help to improve case management and identify priority research areas. Standardized systematic procedures were used to collect clinical and laboratory data on 6,624 children admitted to hospital over a 1-year period in an intensely malarious part of Tanzania. Frequencies of signs and symptoms were calculated and their association with a fatal outcome was assessed using multivariate logistic regression. There were 72 deaths among 2,432 malaria cases (case fatality rate [CFR] = 3.0%); 44% of the cases and 54% of the deaths were in individuals less than 1 year of age. There was no association between level of parasitemia and CFR. Increased risk of dying was independently found in all children with hypoglycemia (odds ratio [OR] = 6.7, 95% confidence interval [CI] = 3.9-11.7), in children 1-7 months of age with tachypnea (OR = 8.8, 95% CI = 2.6-30.5) and dehydration (OR = 5.0, 95% CI = 1.9-14.2), and in children 8 months to 4 years of age with chest indrawing (OR = 4.7, 95% CI = 2.0-11.2) and inability to localize a painful stimulus (OR = 6.9, 95% CI = 2.9-16.5). Children in the bottom quartile of weight-for-age were more likely to die (OR = 2.1, 95% CI = 1.3-3.5). Eight percent of the malaria cases had severe anemia (packed cell volume < 15%) but 24% received a blood transfusion. The epidemiology of malaria disease may be more complex than previously thought. Improved case management in a wide variety of health facilities may result from adequate identification and treatment of dehydration and hypoglycemia. Transfusion-requiring anemia is a major problem and sustainable, effective preventive measures are urgently needed.

Evaluation of the SPf66 vaccine for malaria control when delivered through the EPI scheme in Tanzania.

BACKGROUND: Malaria control programmes need to protect young children, who bear the brunt of malaria disease and death in Africa. The development of a vaccine is a priority if improved and sustained malaria control is to be achieved. The best use of a vaccine in Africa will be achieved if it can be delivered through the expanded programme of immunization (EPI). We conducted a trial designed to evaluate the efficacy of SPf66 vaccine for malaria control when delivered through the EPI scheme in Tanzania. METHODS: The study was a two-arm, double blind, individually randomized placebo controlled trial involving 1207 infants. The primary objective of the trial was to estimate the efficacy of three doses of SPf66 given at 1, 2 and 7 months of age in preventing clinical episodes of malaria. These were documented through a health facility-based passive case detection system. RESULTS: Among 1207 randomized children, overall compliance for third dose was 91%. SPf66 was safe, immunogenic and did not interfere with the humoral immune responses to EPI vaccines. There were 294 children among SPf66 recipients and 288 among placebo recipients with at least one malaria episode, yielding a vaccine efficacy estimate of 2% (95% CI: -16, 16; P = 0.84). CONCLUSION: This has been the first trial of a malaria vaccine among very young infants. It provides information on the safety of peptide vaccines administered at this early age as well as their capacity to induce immune responses without negatively interacting with EPI vaccines. Given the modest protection previously documented in older age groups and the lack of efficacy in younger infants, this vaccine in its current alum-based formulation does not appear to have a role in malaria control in sub-Saharan Africa. The lack of efficacy found in this trial also raises concerns about potential difficulties of inducing protective immune responses against malaria through immunization in infants.