Immune responses to defined antigens may differ between individuals in a population as the reflection of differences in genetic regulation. In experimental animals, variation in responsiveness to a given epitope may be due to major histocompatibility complex (HLA, in hans) class II restrictions, implying serious limitations for the development of subunit vaccines. For human populations, knowledge of the relative importance of genetic as opposed to environmental factors affecting the immune response is scarce. We have compared antibody levels after immunization through repeated infections to a major malarial antigen (Pf155/RESA) in monozygotic twins with those in dizygotic twins, siblings, or unrelated controls. Antibody responses to the intact antigen and to some of its immunodominant epitopes were found to be more concordant within monozygotic twin pairs than in dizygotic pairs or age-and sex-matched siblings living under similar environmental conditions. The results support the conclusion that the antibody responses were genetically regulated. When the responses were assessed for possible associations with different HLA class II DRB, DQA, and DQB alleles and haplotypes, no associations were found. This suggests that the regulation of the Pf155/RESA antibody responses seen in this study reflects the impact of factors encoded by genes outside the HLA class II region.The occurrence and degree of an immune response to a given antigen following infection or vaccination are governed by both genetic and environmental factors. The effects of different genetic factors such as major histocompatibility complex (MHC) restriction or macrophage function (1) have to a large extent been clarified by studies of inbred animals (2). However, in human populations, immune responses to an infectious agent are strongly biased by environmental factors, including intensity of exposure to the pathogen and immune or health status or socioeconomic conditions of the hosts. Therefore, it may be difficult to decide whether different levels of responsiveness in individual human responders represent an intrinsic genetic regulation of the response or external factors.In this work, we have attempted to approach these questions for the humoral response in Plasmodium falciparum malaria, one of the most significant infectious diseases worldwide. The major antigen studied here was Pfl55/RESA (3-6), a polypeptide that the P. falciparum merozoite deposits in the membrane of erythrocytes at invasion. Of clinically immune adults living in villages of northern Liberia where malaria is holoendemic and perennial, -75% have antiPf155/RESA antibodies, as detected by a modified erythrocyte membrane immunofluorescence (EMIF) assay (3), although all have elevated antibodies to intracellular P. falciparum antigens. When assayed in ELISA with short synthetic peptides, concentrations of antibodies to different immunodominant epitopes of Pf155/RESA vary in different donors, resulting in individual antibody profiles that are characteristic for each donor, r...

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The central region of Madagascar is a vast area of highlands (altitude 700-2000 m). Malaria transmission has re-established itself here since the last epidemic of 1985-90 and has caused the deaths of 40,000 persons according to the Minister of Health. To combat the main malaria vector in the region, Anopheles funestus, annual programmes of indoor house spraying of DDT were carried out between December 1993 and January 1998 in most rural areas at altitude 1000-1500 m. A parasitological and serological study was then conducted in the highland schools to evaluate the impact of the programme and set up a database on the region. Using a cluster-sampling method 2 independent selections were conducted (one of 130 sites, the other of 40 sites). During the study, 13,462 schoolchildren were examined, 71% living in sprayed villages. Parasite prevalence among schoolchildren declined as altitude increases, from 11% at 700-900 m to 0.4% at > 1500 m. Below 1500 m, the impact of the spraying on the prevalence of the parasite was very clear (an average decrease of from 20% to 2.7% below 1000 m and of from 4.5% without spraying to 0.8% at 1000-1500 m). Geographical analysis of the data showed that the marginal regions remained the most affected by malaria (especially outside spraying zones), and persistence of 'pockets of transmission' at 1000-1500 m, essentially in areas where spraying has never been used. In 9 schools, anti-Plasmodium antibodies were sought by indirect immunofluorescence on thick smears of parasitized red blood cells. The seroprevalence ranged from 22% to 63%, which suggests that the parasite is still circulating in the region. Even though our data show that vector control continues to be very successful in the Madagascan highlands, rapid reinfection could occur and must be monitored following spraying. To this end, the Minister for Health, with the support of the Italian Co-operation, has placed the region under epidemiological surveillance since 1997. An alert system for the timely detection of the sources of epidemics and the targeting of the antivectoral campaign is also in operation. Our study suggests that this strategy should be reinforced by the spraying of DDT in the marginal zones in order to consolidate the results obtained at higher altitudes.

Abstract. To establish a simple definition of a malaria attack based on blood parasite density and other explanatory covariates, a cohort study was conducted from 1993 to 1996 in the Madagascar highlands undergoing a low seasonal transmission of falciparum malaria. Using logistic regression, the explanatory variables found to be significantly related to the risk of fever are parasite density, age, season, and year. However, and in contrast with other studies, we found no evidence of a clear cutoff in parasite density values consistent with the concept of "pyrogenic threshold" despite a gradual increase of the risk of fever with increasing parasite density. Furthermore, the model evidenced an individualdependent relationship at a given age. This point was in accordance with the immunological data recorded from the participants. The investigators conclude that the parasite density to distinguish malaria attacks from other causes of fever is not reliable in a context of low falciparum transmission.

Background: In order to improve the monitoring of the antimalarial drug resistance in Madagascar, a new national network based on eight sentinel sites was set up. In 2006/2007, a multisite randomized clinical trial was designed to assess the therapeutic efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP), amodiaquine (AQ) and artesunate plus amodiaquine combination (ASAQ), the antimalarial therapies recommended by the National Malaria Control Programme (NMCP).