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Breadth and Magnitude of Antibody Responses to Multiple Plasmodium falciparum Merozoite Antigens Are Associated with Protection from Clinical Malaria ^,

KEMRI Centre for Geographic Medicine Research, Coast, P.O. Box 230-80108, Kilifi, Kenya,¹ London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom,² Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom,³ Dipartimento di Scienze di Sanita' Pubblica, Sezione di Parassitologia, University of Rome "La Sapienza," 00185 Rome, Italy,⁴ BPRC, Department of Parasitology, P.O. Box 3306, 2280, GH Rijswijk, The Netherlands,⁵ Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, EH9 3JT Edinburgh, United Kingdom,⁶ Department of Immunology, Walter Reed Army Institute of Research, Forest Glen Annex, Silver Spring, Maryland 20910,⁷ Medical Research Council Laboratories, Fajara, P.O. Box 273, Banjul, The Gambia⁸

Received 1 December 2007/ Returned for modification 9 February 2008/ Accepted 23 February 2008

Individuals living in areas where malaria is endemic are repeatedly exposed to many different malaria parasite antigens. Studies on naturally acquired antibody-mediated immunity to clinical malaria have largely focused on the presence of responses to individual antigens and their associations with decreased morbidity. We hypothesized that the breadth (number of important targets to which antibodies were made) and magnitude (antibody level measured in a random serum sample) of the antibody response were important predictors of protection from clinical malaria. We analyzed naturally acquired antibodies to five leading Plasmodium falciparum merozoite-stage vaccine candidate antigens, and schizont extract, in Kenyan children monitored for uncomplicated malaria for 6 months (n = 119). Serum antibody levels to apical membrane antigen 1 (AMA1) and merozoite surface protein antigens (MSP-1 block 2, MSP-2, and MSP-3) were inversely related to the probability of developing malaria, but levels to MSP-1₁₉ and erythrocyte binding antigen (EBA-175) were not. The risk of malaria was also inversely associated with increasing breadth of antibody specificities, with none of the children who simultaneously had high antibody levels to five or more antigens experiencing a clinical episode (17/119; 15%; P = 0.0006). Particular combinations of antibodies (AMA1, MSP-2, and MSP-3) were more strongly predictive of protection than others. The results were validated in a larger, separate case-control study whose end point was malaria severe enough to warrant hospital admission (n = 387). These findings suggest that under natural exposure, immunity to malaria may result from high titers antibodies to multiple antigenic targets and support the idea of testing combination blood-stage vaccines optimized to induce similar antibody profiles.

Published ahead of print on 3 March 2008.

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Editor: J. L. Flynn