Ethical perspective on malaria research for Africa.

Malaria is a leading cause of death and illness in Africa, afflicting mainly young children, infants and young pregnant women, especially in rural areas where access to health services is often limited. Resistance to the safest and most affordable antimalarials, the threat of insecticide resistance, demand for research and development of new malaria treatment, prevention and control tools in the form of new antimalarials, vaccines, diagnostics, insecticides and devices. New antimalarial tools must be tested on the most afflicted groups (young children, infants and pregnant women) whose autonomy especially in tradition African rural settings is severely impaired or diminished. They, therefore, deserve special protection by the researcher; thorough ethical review ensuring genuine informed consent is therefore crucial. The testing of new products, particularly with novel vaccine formulations and new adjuvants in the vulnerable groups, age de-escalation, trial of transmission blocking vaccines, the initial testing (Phases Ia and IIa) of vaccines and drugs in non-endemic populations all pose ethical dilemmas, as do bioprospecting (biopiracy) and the standard of care during and after the research. Besides these concerns, ethical issues relating to epidemiological research are also addressed.

Malaria vaccines in Africa.

Besides being a leading cause of morbidity and mortality, malaria is also a cause and consequence of rampant poverty in Africa, where current control efforts are mainly frustrated by antimalaria drug and insecticide resistance. The development of malaria vaccines is therefore a priority for Africa. The paper examines the still limited role played by African institutions in trials of malaria vaccines. The process of antigen discovery and validation is mainly restricted to universities and public research institutions in the north, and relies on public funding. Industry is generally uninterested in malaria vaccine development; travellers' vaccines are attracting limited industrial interest. Public funding of neglected phases (asexual and transmission blocking) of malaria vaccine candidates is very recent. Malaria vaccine trials in Africa favour sites with historical affiliations to Europe (UK and France); recently the USA entered the race. Trials at neutral or African led, or African owned sites are rare, although they are essential for multi-centre Phase III trials. The selection of new trial sites should consider epidemiological, ownership and leadership criteria. Establishment of new sites should be guided by needs assessment, followed by capacity strengthening to fill the gaps in personnel, equipment, transport and infrastructure. All systems (e.g. financial, management, ethics and regulatory review) should be strengthened. Given the enormity of the challenges involved public-private partnerships are essential.

Scaling-up coverage with insecticide-treated nets against malaria in Africa: who should pay?

Insecticide-treated nets (ITNs) have been shown to reduce the burden of malaria in African villages by providing personal protection and, if coverage of a community is comprehensive, by reducing the infective mosquito population. We do not accept the view that scaling-up this method should be by making villagers pay for nets and insecticide, with subsidies limited so as not to discourage the private sector. We consider that ITNs should be viewed as a public good, like vaccines, and should be provided via the public sector with generous assistance from donors. Our experience is that teams distributing free ITNs, replacing them after about 4 years when they are torn and retreating them annually, have high productivity and provide more comprehensive and equitable coverage than has been reported for marketing systems. Very few of the free nets are misused or sold. The estimated cost would be an annual expenditure of about US$295 million to provide for all of rural tropical Africa where most of the world's malaria exists. This expenditure is affordable by the world community as a whole, but not by its poorest members. Recently, funding of this order of magnitude has been committed by donor agencies for malaria control.

Bancroftian filariasis on Pemba Island, Zanzibar, Tanzania: an update on the status in urban and semi-urban communities.

Cross-sectional clinical, parasitological and entomological surveys for bancroftian filariasis were conducted in Konde, Chake Chake and Kengeja, three urban and semiurban communities on Pemba Island, and the results were compared with similar surveys done 15 years earlier. The overall prevalences of clinical manifestations among males aged 15 years or more (n = 614) was remarkably similar to those recorded 15 years earlier: elephantiasis 1.4% in 1975 and 1.1% in 1990; hydrocele, 22.4% and 21.8%, respectively. However, when the communities were compared individually, there was a reduction in the hydrocele prevalence in Konde from 22.4% to 11.5% and an increase in Kengeja from 27.0% to 35.5%. The overall microfilarial prevalence found during night blood surveys of all individuals aged 1 year or more (n = 2687) was 9.7%, compared to 14.2% recorded in 1975. The reduction was most pronounced in Konde. Of 1052 female mosquitoes caught with CDC light traps, 95% were Culex quinquefasciatus and 5% Anopheles gambiae s.l. Infective larvae of Wuchereria bancrofti were found only in the former. The filariasis situation in urban and semiurban communities on Pemba Island appears not to have changed considerably over the last 15 years.

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.

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.

Morbidity markers for Schistosoma haematobium infection.

A description is given of a field study design, including pretreatment and short and long-term posttreatment measurements, which is conducted as a case-control study among school children in Kaloleni District, Kenya, and Kilosa District, Tanzania, including 500 school children from each endemic setting. The aim of the study is to evaluate eosinophil cationic protein (ECP) in urine as a marker for Schistosoma haematobium morbidity by comparing levels of ECP in urine with S. haematobium egg counts in urine, level of excreted S. haematobium egg antigen in urine, microhaematuria and urinary tract pathology assessed by ultrasonography. Initial results have been promising and are now subject to an extensive evaluation. Strong training components and transfer of technology are included in the project, thus contributing to the strengthening of the research capacity of the collaborating African institutions. Simple non-invasive assays for ECP and excreted S. haematobium egg antigen could provide new tools for evaluation of chemotherapy effects and morbidity in urinary schistosomiasis, helping to understand the dynamic process of posttreatment resolution and reappearance of pathological changes.

Application of a biochemical key to study transmission of malaria and Bancroftian filariasis in sibling species of the Anopheles gambiae complex in north-eastern Tanzania.

A biochemical key was applied in order to study transmission of malaria and Bancroftian filariasis in Anopheles gambiae sensu stricto, An. arabiensis and An. merus in different localities in north-eastern Tanzania. The technique was found to be a useful additional taxonomic tool for field entomologists. Significant differences between species in the rate of infection with Bancroftian filariasis were obtained between An. gambiae s.s. and An. funestus (P less than 0.005) and between An. funestus and An. arabiensis (P less than 0.0001). There were also significant differences between most of the investigated localities in the rate of filarial infection. However, there were no significant differences between the three species or between localities with respect to malaria sporozoite rates. Possible reasons for the observed variation between species and localities with respect to vectorial activity for Bancroftian filariasis are discussed.

Low resistance of Plasmodium falciparum to mefloquine in Tanga region, Tanzania.

Studies were undertaken in the towns of Muheza, Korogwe and Tanga in Tanga region, north-eastern Tanzania in 1986 to assess the sensitivity of Plasmodium falciparum to mefloquine using an in vitro microtechnique. Successful tests were achieved on 29, 40 and 118 isolates from Korogwe, Muheza and Tanga respectively. The mean minimum inhibitory concentrations (logometric) were 0.52, 0.50 and 0.59 mumol per litre of blood for Korogwe, Muheza and Tanga respectively. Six isolates, 2 from Muheza and 4 from Tanga, showed resistance to mefloquine, having minimum inhibitory concentrations greater than 3.2 mumol per litre of blood. The chloroquine and mefloquine sensitivities of the isolates which showed mefloquine resistance were determined.

Observations on the distribution of the Anopheles gambiae complex in Tanzania.

Adult male and female mosquitoes of the Anopheles gambiae group of species from fourteen localities in Tanzania were studied using either chromosomal inversions, enzyme electrophoresis or both techniques. The 6481 specimens analyzed consisted of 64.4% An. gambiae, 33.6% An. arabiensis, and 2.0% An. merus, but no An. quadriannulatus. An. gambiae and An. merus are reported from Zanzibar for the first time. An. merus was recorded at Buiko, 167 km inland. An. arabiensis is the predominant or exclusive species in dry and semi-arid areas. An. gambiae predominates or is the only species in humid coastal and humid lacustrine areas.