Malaria vaccine research and development: the role of the WHO MALVAC committee.

The WHO Malaria Vaccine Advisory Committee (MALVAC) provides advice to WHO on strategic priorities, activities and technical issues related to global efforts to develop vaccines against malaria. MALVAC convened a series of meetings to obtain expert, impartial consensus views on the priorities and best practice for vaccine-related research and development strategies. The technical areas covered during these consultations included: guidance on clinical trial design for candidate sporozoite and asexual blood stage vaccines; measures of efficacy of malaria vaccines in Phase IIb and Phase III trials; standardization of immunoassays; the challenges of developing assays and designing trials for interventions against malaria transmission; modelling impact of anti-malarial interventions; whole organism malaria vaccines, and Plasmodium vivax vaccine-related research and evaluation.

Human immune responses that reduce the transmission of Plasmodium falciparum in African populations.

Malaria-infected individuals can develop antibodies which reduce the infectiousness of Plasmodium gametocytes to biting Anopheles mosquitoes. When ingested in a bloodmeal together with gametocytes, these antibodies reduce or prevent subsequent parasite maturation in the insect host. This transmission-blocking immunity is usually measured in human sera by testing its effect on the infectivity of gametocytes grown in vitro.

Malaria vaccines and their potential role in the elimination of malaria.

Research on malaria vaccines is currently directed primarily towards the development of vaccines that prevent clinical malaria. Malaria elimination, now being considered seriously in some epidemiological situations, requires a different vaccine strategy, since success will depend on killing all parasites in the community in order to stop transmission completely. The feature of the life-cycles of human malarias that presents the greatest challenge to an elimination programme is the persistence of parasites as asymptomatic infections.

Data safety and monitoring boards for African clinical trials.

The recent increase in funding for diseases endemic in resource-poor countries has led to a progressive rise in the number of trials conducted in Africa for product development purposes or to answer important questions on reduction of disease burden. This causes an increasing demand for data safety monitoring boards (DSMBs) within Africa, where there is currently a shortage of appropriately skilled people. To address this, and in line with capacity-building efforts directed at improved quality research, AMANET invited the authors to create a curriculum and to train selected Africans with the skills required for members of DSMBs.

Plasmodium falciparum antigens on the surface of the gametocyte-infected erythrocyte.

Background: The asexual blood stages of the human malaria parasite Plasmodium falciparum produce highly immunogenic polymorphic antigens that are expressed on the surface of the host cell. In contrast, few studies have examined the surface of the gametocyte-infected erythrocyte.

Methodology/principal Findings: We used flow cytometry to detect antibodies recognising the surface of live cultured erythrocytes infected with gametocytes of P.

Randomised trial of chloroquine/sulphadoxine-pyrimethamine in Gambian children with malaria: impact against multidrug-resistant P. falciparum.

Objectives: In the Gambia, the combination of chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) has replaced CQ monotherapy for treatment of malaria caused by Plasmodium falciparum. We measured the efficacy of the combination CQ/SP, and the prevalence of parasites carrying alleles associated with resistance to CQ or SP.

Design: We conducted a single-blind, randomised, controlled trial to compare the efficacy of CQ/SP to that of SP or CQ alone.

Chloroquine/sulphadoxine-pyrimethamine for gambian children with malaria: transmission to mosquitoes of multidrug-resistant Plasmodium falciparum.

Objectives: In the Gambia, chloroquine (CQ) plus sulphadoxine-pyrimethamine (SP) is the first-line antimalarial treatment. Plasmodium falciparum parasites carrying mutations associated with resistance to each of these drugs were present in 2001 but did not cause a significant loss of therapeutic efficacy among children receiving the combination CQ/SP. We measured their effect on parasite transmission to Anopheles gambiae mosquitoes.

The epidemiology of Plasmodium falciparum gametocytes: weapons of mass dispersion.

Much of the epidemiology of Plasmodium falciparum in Sub-Saharan Africa focuses on the prevalence patterns of asexual parasites in people of different ages, whereas the gametocytes that propagate the disease are often neglected. One expected benefit of the widespread introduction of artemisinin-based combination therapy for malaria is a reduction in gametocyte carriage. However, the factors that affect the transmission of parasites from humans to mosquitoes show complex dynamics in relation to the intensity and seasonality of malaria transmission, and thus such benefits might not be automatic.

Capacity strengthening in malaria research: the Gates Malaria Partnership.

The Gates Malaria Partnership (GMP) includes five African and four European partner institutions. Its research programme has five priority areas involving an extensive range of field-based studies. GMP research has contributed significantly to the development of new research consortia investigating strategies for improving means of malaria control, and has already had an impact on policy and practice.

Malaria vaccines 1985-2005: a full circle?

Few who were actively engaged in malaria vaccine research 20 years ago (including myself) would have imagined that, in 2005, there would still be a prediction of a 10-20-year horizon before vaccines become part of malaria-control strategies. Why is it still proving so challenging to produce effective vaccines?

Malaria.

Malaria is the most important parasitic infection in people, accounting for more than 1 million deaths a year. Malaria has become a priority for the international health community and is now the focus of several new initiatives. Prevention and treatment of malaria could be greatly improved with existing methods if increased financial and labour resources were available.

Reduction of malaria transmission to Anopheles mosquitoes with a six-dose regimen of co-artemether.

Background: Resistance of malaria parasites to chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) is increasing in prevalence in Africa. Combination therapy can both improve treatment and provide important public health benefits if it curbs the spread of parasites harbouring resistance genes. Thus, drug combinations must be identified which minimise gametocyte emergence in treated cases, and so prevent selective transmission of parasites resistant to any of the partner drugs.

Combination therapy counteracts the enhanced transmission of drug-resistant malaria parasites to mosquitoes.

Malaria parasites carrying genes conferring resistance to antimalarials are thought to have a selective advantage which leads to higher rates of transmissibility from the drug-treated host. This is a likely mechanism for the increasing prevalence of parasites with resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine in sub-Saharan Africa. Combination therapy is the key strategy being implemented to reduce the impact of resistance, but its effect on the transmission of genetically resistant parasites from treated patients to mosquito vectors has not been measured directly.

Addition of artesunate to chloroquine for treatment of Plasmodium falciparum malaria in Gambian children causes a significant but short-lived reduction in infectiousness for mosquitoes.

Objectives: Combination therapy using existing anti-malarials together with artesunate (AS) has been advocated as a method to slow the spread of drug resistance. We assessed the effect on Plasmodium falciparum transmissibility of the addition of AS to chloroquine (CQ) in an area of The Gambia where resistance to CQ is increasing.

Methods: Gambian children with acute uncomplicated P.

The addition of artesunate to chloroquine for treatment of Plasmodium falciparum malaria in Gambian children delays, but does not prevent treatment failure.

In a randomized controlled trial, chloroquine monotherapy was compared with the combination of artesunate and chloroquine for treating uncomplicated Plasmodium falciparum malaria in 536 Gambian children. Chloroquine-treated children exhibited a 28-day clinical failure rate of 15% (95% confidence interval [CI] = 9.2-22%) compared with 11% (7.

Sympatric Plasmodium falciparum isolates from Venezuela have structured var gene repertoires.

Background: The human malaria parasite Plasmodium falciparum expresses adhesins belonging to the erythrocyte membrane protein 1 (PfEMP1) family on the surface of the infected host erythrocyte. These antigens elicit a strain-specific antibody response that is associated with protection from disease. During clonal expansion of blood-stage parasites, the surface phenotype of the infected erythrocyte changes because of transcriptional switching among the 40 to 50 members of the highly polymorphic var multi-gene family which encode PfEMP1 variants.

Gambian children successfully treated with chloroquine can harbor and transmit Plasmodium falciparum gametocytes carrying resistance genes.

Polymorphisms in two genes of Plasmodium falciparum (P. falciparum multidrug resistance 1 [pfmdr1] and P. falciparum chloroquine [CQ] resistance transporter [pfcrt]) are associated with CQ treatment failure.

Genetic complexity of Plasmodium falciparum gametocytes isolated from the peripheral blood of treated Gambian children.

The genetic complexity of Plasmodium falciparum gametocytes isolated from Gambian children participating in a controlled trial of anti-malarial therapy was investigated. RNA and DNA were prepared from gametocyte-positive blood, which was also used in transmission experiments with Anopheles gambiae mosquitoes. Amplification by a reverse transcriptase-polymerase chain reaction (RT-PCR) of transcripts from the genes for the ring-infected erythrocyte surface antigen and the 16-kD antigen, which exhibit asexual and sexual stage-specific expression, was used to identify 30 post-treatment gametocyte isolates in which trophozoites persisted below the threshold of detection by microscopy.