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Infection and Immunity, March 2009, p. 1165-1174, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.01129-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Immunoglobulin G Subclass-Specific Responses against Plasmodium falciparum Merozoite Antigens Are Associated with Control of Parasitemia and Protection from Symptomatic Illness ^,

Danielle I. Stanisic,^1,2 Jack S. Richards,^1,6 Fiona J. McCallum,^1,6 Pascal Michon,² Christopher L. King,³ Sonja Schoepflin,⁴ Paul R. Gilson,¹ Vincent J. Murphy,⁵ Robin F. Anders,⁵ Ivo Mueller,² and James G. Beeson^1*

Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Australia,¹ Papua New Guinea Institute of Medical Research, Madang MP511, Papua New Guinea,² Centre for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio,³ Swiss Tropical Institute, Basel, Switzerland,⁴ Department of Biochemistry, LaTrobe University, Bundoora, Australia,⁵ Department of Medical Biology, University of Melbourne, Victoria, Australia⁶

Received 10 September 2008/ Returned for modification 3 November 2008/ Accepted 1 January 2009

Substantial evidence indicates that antibodies to Plasmodium falciparum merozoite antigens play a role in protection from malaria, although the precise targets and mechanisms mediating immunity remain unclear. Different malaria antigens induce distinct immunoglobulin G (IgG) subclass responses, but the importance of different responses in protective immunity from malaria is not known and the factors determining subclass responses in vivo are poorly understood. We examined IgG and IgG subclass responses to the merozoite antigens MSP1-19 (the 19-kDa C-terminal region of merozoite surface protein 1), MSP2 (merozoite surface protein 2), and AMA-1 (apical membrane antigen 1), including different polymorphic variants of these antigens, in a longitudinal cohort of children in Papua New Guinea. IgG1 and IgG3 were the predominant subclasses of antibodies to each antigen, and all antibody responses increased in association with age and exposure without evidence of increasing polarization toward one subclass. The profiles of IgG subclasses differed somewhat for different alleles of MSP2 but not for different variants of AMA-1. Individuals did not appear to have a propensity to make a specific subclass response irrespective of the antigen. Instead, data suggest that subclass responses to each antigen are generated independently among individuals and that antigen properties, rather than host factors, are the major determinants of IgG subclass responses. High levels of AMA-1-specific IgG3 and MSP1-19-specific IgG1 were strongly predictive of a reduced risk of symptomatic malaria and high-density P. falciparum infections. However, no antibody response was significantly associated with protection from parasitization per se. Our findings have major implications for understanding human immunity and for malaria vaccine development and evaluation.

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* Corresponding author. Mailing address: Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Phone: 61-3-93452555. Fax: 61-3-93470852. E-mail: beeson{at}wehi.edu.au

Published ahead of print on 12 January 2009.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: J. F. Urban, Jr.

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Infection and Immunity, March 2009, p. 1165-1174, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.01129-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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