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Clinical and Vaccine Immunology, March 2009, p. 293-302, Vol. 16, No. 3
1071-412X/09/$08.00+0     doi:10.1128/CVI.00230-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Prediction of Merozoite Surface Protein 1 and Apical Membrane Antigen 1 Vaccine Efficacies against Plasmodium chabaudi Malaria Based on Prechallenge Antibody Responses{triangledown}

Michelle M. Lynch,1 Amy Cernetich-Ott,1 William P. Weidanz,1,2 and James M. Burns Jr.1*

Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129,1 Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 537062

Received 20 June 2008/ Returned for modification 4 August 2008/ Accepted 21 December 2008

For the development of blood-stage malaria vaccines, there is a clear need to establish in vitro measures of the antibody-mediated and the cell-mediated immune responses that correlate with protection. In this study, we focused on establishing correlates of antibody-mediated immunity induced by immunization with apical membrane antigen 1 (AMA1) and merozoite surface protein 142 (MSP142) subunit vaccines. To do so, we exploited the Plasmodium chabaudi rodent model, with which we can immunize animals with both protective and nonprotective vaccine formulations and allow the parasitemia in the challenged animals to peak. Vaccine formulations were varied with regard to the antigen dose, the antigen conformation, and the adjuvant used. Prechallenge antibody responses were evaluated by enzyme-linked immunosorbent assay and were tested for a correlation with protection against nonlethal P. chabaudi malaria, as measured by a reduction in the peak level of parasitemia. The analysis showed that neither the isotype profile nor the avidity of vaccine-induced antibodies correlated with protective efficacy. However, high titers of antibodies directed against conformation-independent epitopes were associated with poor vaccine performance and may limit the effectiveness of protective antibodies that recognize conformation-dependent epitopes. We were able to predict the efficacies of the P. chabaudi AMA1 (PcAMA1) and P. chabaudi MSP142 (PcMSP142) vaccines only when the prechallenge antibody titers to both refolded and reduced/alkylated antigens were considered in combination. The relative importance of these two measures of vaccine-induced responses as predictors of protection differed somewhat for the PcAMA1 and the PcMSP142 vaccines, a finding confirmed in our final immunization and challenge study. A similar approach to the evaluation of vaccine-induced antibody responses may be useful during clinical trials of Plasmodium falciparum AMA1 and MSP142 vaccines.

* Corresponding author. Mailing address: Drexel University College of Medicine, Department of Microbiology and Immunology, 2900 Queen Lane, Philadelphia, PA 19129. Phone: (215) 991-8490. Fax: (215) 848-2271. E-mail: jburns{at}drexelmed.edu

{triangledown} Published ahead of print on 30 December 2008.

Clinical and Vaccine Immunology, March 2009, p. 293-302, Vol. 16, No. 3
1071-412X/09/$08.00+0     doi:10.1128/CVI.00230-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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