Malaria Immunology
Objectives:
Test the safety and efficacy of experimental malaria vaccines in holoendemic
populations.
Determine the nature of protective immune responses
that develop after frequent malaria infection, identify the target antigens and
apply this knowledge to the development of an effective malaria vaccine. Identify factors in children with severe malaria that increase susceptibility of erythrocytes to undergo destruction. Immunology and Malaria pathogenesis Western Kenya has one of the highest rates of malaria transmission in the world, variously reported between 40 and 300 infective bites per person per year. The burden of intense transmission falls on young children, who, if they survive, progressively develop immunity. In the vicinity of Kisumu, where our operations are centred, severe anaemia is the most common cause of morbidity and death in children 6 - 24 months old suffering from Plasmodium falciparum malaria. In these children, the level of parasitemia cannot account for the RBC loss and hence, alternative mechanisms of destruction of uninfected RBCs must be active. In areas where the annual inoculation rate is less than 50, cerebral malaria in 3 - 5 year olds is the most important complication of infection. It is not known how P. falciparum induces two distinct, age related immune responses. Infants born of immune mothers benefit from maternal antibodies for the first few months of life and therefore have lower parasite burdens or fewer episodes of malaria compared to slightly older children. This protection is lost as the maternal antibodies wane, and it is regained following repeated exposure. We have focused attention on the study of RBC complement regulatory proteins (CR1, CD55 and CD59). These proteins control the complement activation cascade, remove immune complexes (IC) from circulation and protect RBCs from complement mediated damage. In addition, CR1 has been shown to be involved in rosette formation between infected and uninfected RBCs (Rowe et al. Nature. 338, 292-295, 1997), a phenomenon linked to the occurrence of cerebral malaria. An efficacious malaria vaccine
that either confers sterile immunity or prevents the most of lethal
complications described above has been a goal of tropical disease research for
more than 70 years. Modern technology, which allows unprecedented
exploration of parasite genetics and biochemistry, bring the goal closer.
USAMRU-Kenya has been involved in developing or testing candidate vaccines since
1986. Most recently it tested a promising antigen construct from
sporozoites (RTS, S) and it is now planning extensive tests of candidate vaccines based
on merozoite surface proteins (MSP-1) or the apical merozoite antigen 1 (AMA-1).
Phase I field trials will begin in October, 2001 at the recently expanded site
at Kombewa, the site of our new clinic. Findings
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