Protection againstPlasmodium chabaudiMalaria Induced by Immunization with Apical Membrane Antigen 1 and Merozoite Surface Protein 1 in the Absence of Gamma Interferon or Interleukin-4

Abstract

Strategies to optimize formulations of multisubunit malaria vaccines require a basic knowledge of underlying protective immune mechanisms induced by each vaccine component. In the present study, we evaluated the contribution of antibody-mediated and cell-mediated immune mechanisms to the protection induced by immunization with two blood-stage malaria vaccine candidate antigens, apical membrane antigen 1 (AMA-1) and merozoite surface protein 1 (MSP-1). Immunologically intact or selected immunologic knockout mice were immunized with purified recombinantPlasmodium chabaudiAMA-1 (PcAMA-1) and/or the 42-kDa C-terminal processing fragment ofP. chabaudiMSP-1 (MSP-1₄₂). The efficacy of immunization in each animal model was measured as protection against blood-stageP. chabaudimalaria. Immunization of B-cell-deficient J_H^−/−mice indicated that PcAMA-1 vaccine-induced immunity is largely antibody dependent. In contrast, J_H^−/−mice immunized with PcMSP-1₄₂were partially protected againstP. chabaudimalaria, indicating a role for protective antibody-dependent and antibody-independent mechanisms of immunity. The involvement of γδ T cells in vaccine-induced PcAMA-1 and/or PcMSP-1₄₂protection was minor. Analysis of the isotypic profile of antigen-specific antibodies induced by immunization of immunologically intact mice revealed a dominant IgG1 response. However, neither interleukin-4 and the production of IgG1 antibodies nor gamma interferon and the production of IgG2a/c antibodies were essential for PcAMA-1 and/or PcMSP-1₄₂vaccine-induced protection. Therefore, for protective antibody-mediated immunity, vaccine adjuvants and delivery systems for AMA-1- and MSP-1-based vaccines can be selected for their ability to maximize responses irrespective of IgG isotype or any Th1 versus Th2 bias in the CD4⁺-T-cell response.