Assessing seasonal variations and age patterns in mortality during the first year of life in Tanzania.

Lack of birth and death registries in most of developing countries, particularly those in sub-Saharan Africa led to the establishment of Demographic Surveillance Systems (DSS) sites which monitor large population cohorts within defined geographical areas. DSS collects longitudinal data on migration, births, deaths and their causes via verbal autopsies. DSS data provide an opportunity to monitor many health indicators including mortality trends. Mortality rates in Sub-Sahara Africa show seasonal patterns due to high infant and child malaria-related mortality which is influenced by seasonal features present in environmental and climatic factors. However, it is unclear whether seasonal patterns differ by age in the first few months of life. This study provides an overview of approaches to assess, capture and detect seasonality peaks and patterns in mortality using the infant mortality data from the Rufiji DSS, Tanzania. Seasonality was best captured using Bayesian negative binomial models with time and cycle dependent seasonal parameters and autoregressive temporal error terms. Seasonal patterns are similar among different age groups during infancy and timing of their mortality peaks do not differ. Seasonality in mortality rates with two peaks per year is pronounced which corresponds to rainy seasons. Understanding of these trends is important for public health preparedness.

Optic neuropathy endemic in secondary school children in Dar es Salaam, Tanzania.

AIM: To investigate the prevalence and causes of optic neuropathy, reported as epidemic in 1997, among secondary school students in Dar es Salaam, Tanzania. PATIENTS AND METHODS: First year students (n = 10,892) from 63 secondary schools located within 30 km from the base hospital were interviewed and had a visual acuity (VA) screening test. Students failing the 6/12-line in either eye were defined as having "poor eyesight" and referred to the base hospital where an optometrist re-tested VA and refracted them. An ophthalmologist examined students with VA of 6/12 or worse in either eye and visual impairment was defined as VA of worse than 6/12 with best correction. Associations between optic neuropathy, socioeconomic status and educational results were investigated. RESULTS: Students' ages ranged from 12 to 22 (mean 15.2) years; 50.6% were male. The prevalence of optic neuropathy was 0.3 (SD 0.051)%. The condition affected older students and was associated with the family having fewer economic possessions (car, computer, television). Optic neuropathy accounted for 19/33 (58%) of bilateral visual impairment cases. No effect of the disease on educational performance was identified. CONCLUSION: Optic neuropathy remains a significant problem in this population and can now be termed endemic rather than epidemic. Further research into its causes is required.

Two strategies for correcting refractive errors in school students in Tanzania: randomised comparison, with implications for screening programmes.

PURPOSE: To compare whether free spectacles or only a prescription for spectacles influences wearing rates among Tanzanian students with un/undercorrected refractive error (RE). DESIGN: Cluster randomised trial. SETTING: 37 secondary schools in Dar es Salaam, Tanzania. PARTICIPANTS: Distance visual acuity was measured in 6,904 year-1 students (90.2% response rate; median age 14 years; range 11-25 years) using a Snellen E-chart. 135 had RE requiring correction. INTERVENTIONS: Schools were randomly allocated to free spectacles (arm A) or prescription only (arm B). PRIMARY OUTCOME: Spectacle use at 3 months. RESULTS: The prevalence of un/undercorrected RE was 1.8% (95% CI: 1.5 to 2.2%). At 3 months, 27/58 (47%) students in arm A were wearing spectacles or had them at school compared with 13/50 (26%) in arm B (adjusted OR 2.4, 95% CI 1.0 to 6.7). Free spectacles and myopia were independently associated with spectacle use. CONCLUSIONS: The low prevalence of un/undercorrected RE and poor uptake of spectacles, even when provided free, raises doubts about the value of vision-screening programmes in Tanzanian secondary schools. Policy decisions on school vision screening in middle- and low-income countries should take account of the cost-effectiveness as well as competing demands for scarce resources.

Effect of insecticide-treated bed nets on haemoglobin values, prevalence and multiplicity of infection with Plasmodium falciparum in a randomized controlled trial in Tanzania.

A randomized controlled trial of insecticide-treated bed nets (ITNs) was conducted in an area of high malaria transmission in Tanzania in order to assess the effects of ITNs on infection and anaemia. One hundred and twenty-two children, aged 5 to 24 months, were randomly allocated to 2 groups, one of which received ITNs. Outcome measures were assessed in 6 consecutive months with monthly cross-sectional surveys. These measures were haemoglobin values, Plasmodium falciparum prevalence and density, and multiplicity of infection determined by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) of the msp2 locus. There was a significant increase in mean heamoglobin values and a significant decrease of 16.4% in microscopically determined P. falciparum prevalence in children in the ITN group six months after the start of the trial. Both effects were more pronounced in younger children. However, no significant difference was observed in parasite density or multiplicity of infection among infected children. Comparison with PCR results indicated that microscopically subpatent parasitaemia was more frequently found in children in the ITN group. This, together with the observed similar multiplicity in the 2 groups, suggests that infections are maintained despite ITN use, owing to the chronicity of infections. This study shows that ITNs reduce the risk of anaemia in highly exposed young children. The virtually unchanged multiplicity of infection indicates that the potentially protective concomitant immunity is not compromised.

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.

Safety in infants of SPf66, a synthetic malaria vaccine, delivered alongside the EPI.

The most likely mechanism to deliver a malaria vaccine in African countries is through the Expanded Program of Immunization (EPI). So far only SPf66, a multistage synthetic peptide, has shown any evidence of protection in Phase III field trials. In Tanzania, SPf66 reduced the risk of clinical malaria by 31% in children aged 1-5 years. In order to progress in the critical path of vaccine development and testing towards the implementation of a new vaccine in malaria control programs, we carried out a randomized double-blind placebo controlled efficacy trial of SPf66 when given alongside the EPI scheme. Monitoring of safety and reactogenicity during this trial included detailed clinical and laboratory assessments on 98 infants and assessment of adverse effects within 1 h of vaccination for all 1207 children vaccinated. Surveillance systems monitored attendances as outpatients, admissions to hospital and fatal events in the community. No serious adverse effects were detected more frequently amongst SPf66 recipients compared to placebo. This first assessment in very young infants of a synthetic vaccine provides evidence of a good safety profile.

The use of morbidity questionnaires to identify communities with high prevalences of schistosome or geohelminth infections in Tanzania.

Parasitic infections were investigated in Morogoro Rural District, Tanzania, between October 1992 and June 1993. A total of 4589 schoolchildren (aged 7-17 years) from 30 primary schools was screened for infection with Ascaris lumbricoides, Trichuris trichiura, hookworms (3456 children only), Schistosoma mansoni and S. haematobium. The children were also asked about their recent experiences of the following: diarrhoea, abdominal pain, blood in stool, perception of suffering from schistosomiasis, and worm infection and examined for spleen and liver enlargement. Among schools, there were correlations between the prevalence of S. mansoni infection and bloody stools, spleen enlargement and liver enlargement, and between S. haematobium infection and the presence of blood in urine. To exclude ecological explanations for the correlations, logistic regression was used to estimate the adjusted odds ratio (OR) for each infection and each sign or symptom. No sign or symptom was significantly associated with any geohelminth infection. Reported blood in stool was significantly associated with S. mansoni infection (OR = 1.62, P = 0.045). Reported blood in urine was significantly associated with S. haematobium infection (OR = 7.71, P < 0.001), as was reported blood in stool (OR = 11.52, P < 0.001), indicating that presence of blood in either form of excreta was related to the local term for schistosomiasis. These results support the possibility of using reported blood in stool as a means of rapid assessment for identifying communities with a high prevalence of S. mansoni infection.

Incidence of Plasmodium falciparum infection in infants in relation to exposure to sporozoite-infected anophelines.

The relationship of the incidence of Plasmodium falciparum infection to entomologic inoculation rates (EIRs) was studied in 163 children less than one year of age in a Tanzanian village to determine likely effects of transmission-reducing interventions on infection incidence. A total of 66,727 Anopheles gambiae s.l. and 17,620 An. funestus mosquitoes were caught in 1,056 light trap collections from 139 houses over a period of more than two years. Time period-specific human biting rates were estimated for 11 village neighborhoods. Sporozoites were detected by ELISA in 4.4% of the An. funestus and 2.5% of the An. gambiae s.l. Eight hundred seventeen pairs of blood slides with approximately two-week intervals between slides were used to estimate incidence of parasitemia by fitting reversible catalytic models to parasite positivity data. Estimated EIRs during the four weeks preceding each intersurvey interval averaged 1.6 (SD = 2.1) per adult per night. Parasites were present at the end of 31% of the 443 intervals that commenced with a parasite-negative slide. Attack rates were comparable with those in western Kenya, and the proportion of bites resulting in human infections was strongly dependent on mosquito density. Incidence of infection increased with the EIR up to approximately one bite from a sporozoite-carrying mosquito per adult per night. However, higher levels of transmission observed locally in the wet season did not result in a correspondingly higher incidence. These data suggest that transmission-reducing measures cannot be expected to reduce incidence of infection at the highest levels of EIR.

Relationships of malaria morbidity with exposure to Plasmodium falciparum in young children in a highly endemic area.

To study incidence of clinical Plasmodium falciparum malaria in relation to exposure to parasites, attendance of children less than eighteen months old at a village dispensary in a highly endemic area of Tanzania was recorded. Entomologic inoculation rates (EIRs), estimated as a function of time period and place of residence, exceeded one sporozoite positive bite per adult per night in some village neighborhoods during the wet season. Incidence of clinical P. falciparum malaria, defined either as fever with parasitemia or as fever with hyperparasitemia, increased with the EIR over the whole range of exposures. Each 10-fold increase in the EIR corresponded to a 1.6-fold increase in incidence of fever plus parasitemia (95% confidence interval = 1.4-2.0). Therefore reduction of human-vector contacts will probably reduce morbidity incidence even at very high exposures. Incidence showed little relationship to estimated cumulative numbers of inoculations since birth, but decreased steeply with estimated cumulative time infected with trophozoites. This suggests that clinical immunity depends mainly on the extent of exposure to blood-stage antigens, not on the diversity of inocula seen, and thus temporary reductions in human-vector contacts are unlikely to result in subsequent increases in morbidity.

Immune responses to Plasmodium falciparum antigens during a malaria vaccine trial in Tanzanian children.

Among Tanzanian children living in an area of intense and perennial malaria transmission, prevalence of naturally acquired IgG antibodies that recognize SPf66, NANP, p190 and a 19 kDa fragment of the merozoite surface protein-1 (MSP-1) is high and increases with age. This possibly reflects the high level of natural exposure of the children to P. falciparum. The prevalences of IgG antibodies that recognize the three putative merozoite derived sequences contained in the malaria vaccine SPf66 (83.1, 55.1 and 35.1) is low but also show some age dependence. Three doses of the SPf66 vaccine induce a strong IgG antibody response against both the SPf66 construct, NANP and the three individual peptides. Vaccination with SPf66 did not result in an increase of anti19 kDa fragment antibodies. This reflects the specificity of the humoral immune response induced by the SPf66 construct. Among vaccinated children, antibody titres against SPf66 decreased over time following the third dose. However, 18 months after the third dose, SPf66 recipients still had significantly higher IgG titres and stimulation indices of peripheral blood mononuclear cells (PBMC) than placebo recipients. Within the vaccine group, there is a trend for increasing anti-SPf66 IgG titre to be associated with decreasing risk of clinical malaria but this was not statistically significant. Results also show the difficulties of establishing whether antibody responses are related to protection in field trials in endemic areas.

The role of low level Plasmodium falciparum parasitaemia in anaemia among infants living in an area of intense and perennial transmission.

Children under one year of age in an area of intense and perennial Plasmodium falciparum transmission were followed up for one year to establish to what extent chronic, low parasitaemia was associated with severe anaemia. There was a significant increase in the prevalence of anaemia (PCV < or = 25%) with increase in parasite density. PCV levels were related not only to concurrent parasite density but also decreased with densities measured one month previously. At any point in time, the mean PCV level in infants with low parasitaemia (< 1000 parasites/microliter) was higher than that of infants with intermediate (1000-9999/microliter) and high parasite densities (> or 10000/microliter). After the age of 7 months, infants with low parasite densities tend to recover, probably as a result of developing immunity. At the age of 12 months, they have similar PCV levels to infants with no detectable parasitaemia by microscopy. The maintenance of low parasite density appears crucial to the survival of infants in malaria endemic areas. The findings suggest that interventions which lower parasite densities in areas of intense transmission reduce the development of severe malarial anaemia and thus malaria-related mortality and morbidity in infants.

Plasmodium falciparum malaria in the first year of life in an area of intense and perennial transmission.

A longitudinal study of Plasmodium falciparum malaria in infants in Idete village, south-eastern Tanzania, was conducted over a period of 14 months in order to determine the incidence of P. falciparum infection and clinical malaria in the first year of life. Of 1356 blood slides from cross-sectional surveys, 52.1% were positive for asexual stages of P. falciparum. There were marked increases in P. falciparum prevalence, parasite densities, overall fever incidence and the incidence of malaria fevers with age for the first 6 months of life. The average attack rate, estimated from a reversible catalytic model, was 0.029 per day with a slight increase with age but there was no initial period of protection against infection in neonates. Estimated average duration of infections was 64 days, with infections in older infants lasting much longer than those contracted during the first 2 months of life. These results support the hypotheses that the main effect of passively transferred maternal immunity to malaria is in the control of asexual stage parasites, and that the level of clinical immunity depends upon the extent of recent exposure to parasites. Infants as young as 4 months of age are at high risk of clinical attacks. Intervention programmes against malaria in areas of the highest transmission should therefore be designed to include this group.

Duration of protection and age-dependence of the effects of the SPf66 malaria vaccine in African children exposed to intense transmission of Plasmodium falciparum.

The SPf66 synthetic vaccine is safe and partly efficacious against Plasmodium falciparum malaria among children 1-5 years old. The estimated vaccine efficacy [VE] for all clinical episodes over a period of 18 months after the third dose is 25% (95% confidence interval [CI], 1%-44%; P = .044). The observed temporal variations in efficacy could have been due to chance (likelihood ratio chi 2 = 13.8, 8 df; P = .086). Efficacy against clinical malaria did not vary significantly with age (chi 2 = 1.07, 4 df; P = .90). Overall parasite density was 21% lower in vaccine recipients than in the placebo group (95% CI, 0%-38%; P = .044). Further development of SPf66 may require trials to evaluate safety, immunogenicity, and efficacy when administered in the first year of life, together with other vaccines contained in the Expanded Programme of Immunization schedule.

Randomised trial of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania.

Malaria, especially that due to Plasmodium falciparum, is one of the most important parasitic disease in man. It causes more than 400 million cases per year and between 1 to 3 million deaths, mainly among young children and pregnant women in sub-Saharan Africa. The current malaria control strategies using rapid diagnosis and treatment as well as methods to reduce the man-vector contact have had limited success. In Kilombero district (Southern Tanzania), malaria transmission is perennial (parasite prevalence > or = 80% all year) and intense (approximatively 300 infectious bites per year). At the household level, each under-5 child suffers on average 3 clinical fever episodes per year. Minimum estimated community rates for serious malaria (cerebral malaria or malaria and anaemia) affect approximatively 5% of all children. Under conditions of a field experiment, the annual incidence of a febrile illness (axillary temperature > or = 37.5 degrees C) reported to the curative primary health services in each child was 0.86 of which 0,35 can be attributed to Plasmodium falciparum malaria. The best estimate of the SPf66 vaccine protective efficacy in the Kilombero was 31% (95% CI : 0.52).

Randomised trial of efficacy of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania.

Effective, safe antimalarial vaccines have proved elusive. The synthetic polypeptide SPf66 vaccine is based on preerythrocytic and asexual blood-stage proteins of Plasmodium falciparum. We report here a randomised double-blind placebo-controlled trial of the efficacy of the SPf66 vaccine against clinical P falciparum malaria in idete, southern Tanzania, an area of intense perennial malaria transmission. 586 children aged 1-5 years received three doses of vaccine (n = 274) or placebo (n = 312). The incidence and density of parasitaemia were assessed through repeated cross-sectional surveys on subgroups of children. Morbidity was monitored over a 1 year period through passive case detection in all children plus active case detection in a subgroup of 191. An episode of clinical malaria was defined as measured fever (> or = 37.5 degrees C) and parasite density > 20,000/microL. No severe side-effects were seen and the frequency of mild side-effects after the third dose was less than 6%. The vaccine was highly immunogenic and after three doses all vaccine recipients had detectable anti-SPf66 antibodies: the geometric mean index of response was 8.3 in the vaccine group and 0.7 in the placebo group. The incidence of parasitaemia was similar in both groups. 123 children had at least one episode of clinical malaria during the follow-up period after the third dose and annual incidence rates were 0.25 in the vaccine group and 0.35 in the placebo group. Estimated vaccine efficacy was 31% (95% confidence interval 0-52%; p = 0.046). After the third dose there were 6 deaths among the study cohort (1 vaccine, 5 placebo). This study confirms that SPf66 is safe, immunogenic and reduces the risk of clinical malaria among children exposed to intense P falciparum transmission.

SPf66, a chemically synthesized subunit malaria vaccine, is safe and immunogenic in Tanzanians exposed to intense malaria transmission.

As part of the first trial of the SPf66 malaria vaccine in Africa, three randomized double-blind placebo-controlled studies of SPf66 have been conducted in a highly endemic area of Tanzania. The objectives were to confirm that the product is immunogenic and safe in highly exposed individuals. Results from ten male adult expatriates indicated that the product used in Tanzania is at least as immunogenic as that used in Colombia. No major side-effects were observed in indigenous SPf66 recipients (18 adults, and 25 children aged 1-4 years). Anti-SPf66 antibody titres in all groups showed clear responses to three doses of the vaccine.