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Infection and Immunity, May 2006, p. 2867-2875, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2867-2875.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Levels of Plasma Immunoglobulin G with Specificity against the Cysteine-Rich Interdomain Regions of a Semiconserved Plasmodium falciparum Erythrocyte Membrane Protein 1, VAR4, Predict Protection against Malarial Anemia and Febrile Episodes

John P. A. Lusingu,^1,2* Anja T. R. Jensen,¹ Lasse S. Vestergaard,^1,3 Daniel T. Minja,² Michael B. Dalgaard,¹ Samwel Gesase,² Bruno P. Mmbando,² Andrew Y. Kitua,² Martha M. Lemnge,² David Cavanagh,⁴ Lars Hviid,¹ and Thor G. Theander¹

Centre for Medical Parasitology, Institute for Medical Microbiology and Immunology and Copenhagen University Hospital (Rigshospitalet), University of Copenhagen,¹ Department of Bacteriology, Mycology and Parasitology, Serum Statens Institute, Copenhagen, Denmark,³ National Institute for Medical Research, Tanga Centre and Headquarters, Dar es Salaam, Tanzania,² Institute of Cell, Animal, and Population Biology, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom⁴

Received 24 November 2005/ Returned for modification 6 January 2006/ Accepted 25 February 2006

Antibodies to variant surface antigen have been implicated as mediators of malaria immunity in studies measuring immunoglobulin G (IgG) binding to infected erythrocytes. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is an important target for these antibodies, but no study has directly linked the presence of PfEMP1 antibodies in children to protection. We measured plasma IgG levels to the cysteine-rich interdomain region 1 (CIDR1) of VAR4 (VAR4-CIDR1), a member of a semiconserved PfEMP1 subfamily, by enzyme-linked immunosorbent assay in 561 Tanzanian individuals, who were monitored clinically for 7 months. The participants resided in Mkokola (a high-transmission village where malaria is holoendemic) or Kwamasimba (a moderate-transmission village). For comparison, plasma IgG levels to two merozoite surface protein 1 (MSP1) constructs, MSP1-19 and MSP1 block 2, and a control CIDR1 domain were measured. VAR4-CIDR1 antibodies were acquired at an earlier age in Mkokola than in Kwamasimba, but after the age of 10 years the levels were comparable in the two villages. After controlling for age and other covariates, the risk of having anemia at enrollment was reduced in VAR4-CIDR1 responders for Mkokola (adjusted odds ratio [AOR], 0.49; 95% confidence interval [CI], 0.29 to 0.88; P = 0.016) and Kwamasimba (AOR, 0.33; 95% CI, 0.16 to 0.68; P = 0.003) villages. The risk of developing malaria fever was reduced among individuals with a measurable VAR4-CIDR1 response from Mkokola village (AOR, 0.51; 95% CI, 0.29 to 0.89; P = 0.018) but not in Kwamasimba. Antibody levels to the MSP1 constructs and the control CIDR1 domain were not associated with morbidity protection. These data strengthen the concept of developing vaccines based on PfEMP1.

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* Corresponding author. Mailing address: Centre for Medical Parasitology, Institute for Medical Microbiology and Immunology, Panum Institute 24.2, Blegdamsvej 3, 2200 Copenhagen N, Denmark. Phone: 45-35-32-76-84. Fax: 45-35-32-78-51. E-mail: jpalusingu{at}yahoo.co.uk.

Editor: W. A. Petri, Jr.

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Infection and Immunity, May 2006, p. 2867-2875, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2867-2875.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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