Scand. J. Immunol. 39, 409-417, 1994 The Multifactorial and Multistage Character of Protective Immunity to Plasmodium falciparum. Naturally Acquired by an Indigenous Population in Burkina Faso C. BOUDIN*t, I. SHEICK*, B. CHUMPITAZI*, L, PAZARTf, B. HOGHJ, F. PEYRON*, P. DELORON§, S. PICOT* & P. AMBROISE-THOMAS* *ERS 15 CNRS, Grenoble, France f Centre Muraz, Bobo-Dioulasso, Burkina Faso XStatens Seruminstitut, Copenhagen, Denmark ^Unite 13 INSERM, Paris, France Boudin C, Sheick I, Chumpitazi B, Pazart L, Hogh B, Peyron F, Deloron P, Picot S, Ambroise-Thomas P, The Multifactorial and Multistage Character of Protective Immunity to Plasmodium falciparum. Naturally Acquired by an Indigenous Population in Burkina Faso. Scand J Immunol 1994;39:409-417 In malaria-endemic areas, protective immunity is acquired gradually. Some authors have proposed that different stages can be distinguished during development. To test this hypothesis, several in vitro assays of the host immune response to P. falciparum were performed in three groups of individuals: 'unprotected' children with clinical attacks, 'semi-immune' children, without clinical attacks but with transient high parasitaemias during the transmission period, and 'protected' adults with low residual parasitaemias. By comparison of immune responses in these groups and multifactorial analyses, discriminant factors and potential protective mechanisms were identified. Anti-RESA antibody levels were lower in 'unprotected' than in 'semi-immune' children, while specific cellular responses, TNF levels and percentage of activated T lymphocytes were higher. Low humoral immunity and high cellular activation in children were followed by high humoral immunity and low cellular activation in adults. Therefore, protective immunity seems to pass through different stages and to result from the association of different immune mechanisms according to the level and duration of the individual experience of malaria, Christian Boudin, OCEAC, BP 288, Yaounde, Cameroun INTRODUCTION In malaria-endemic areas with stable transmission, young children experience clinical symptoms from malaria and are considered as 'unprotected' subjects. Older children develop gradually a state of functional immunity and become pro- tected from malaria attacks. However, they can present transient high and asymptomatic parasitaemias. Adults de- velop gradually another state of non-sterilizing immunity, which protects them from high parasitaemias. They are considered as 'protected' subjects. The exact timing of these Abbreviations: MA, malaria attack; RESA, ring-infected erythrocyte surface antigen; CST, one of the T epitopes of the P. falciparum circumsporozoite protein; GLURP, glutamate-rich protein; SI, stimulation index; IF, indirect immunofluorescent assay; I, inhibition index; ^ixa, beta2 microglobulin; CD (3,4,8), identification marks for T, T helper, and cytotoxic/suppressive T lymphocytes; B, identification mark for B lymphocytes, Ta, identification mark for activated T lymphocytes. events varies with the level and duration of transmission, McGregor [1] has proposed that individuals living in endemic areas pass through five stages before protective immunity is acquired. Playfair and associates [2] have proposed two stages of protective immunity: a period of 'clinical' immunity in children, and a period of 'antiparasite' immunity in adults. Effector mechanisms in these different stages of malaria immunity are poorly understood. Only a few studies, which investigated the relationships between specific immune re- sponses and protection, have been conducted in humans. Most were performed using a single antigen [3-6], Marsh et al. [7] reported the pattern of antibody responses to different P. falciparum antigens and their relationships to the development of'clinical' or 'antiparasite' immunity. However, immunity to malaria involves both humoral and cellular components. In the study described here, three groups of individuals ('unprotected', 'semi-immune' and 'protected') were com- pared. Relationships between cellular or humoral immune 409