title: Immunization with a functional protein complex required for erythrocyte invasion protects against lethal malaria.
abstract: An essential step in the invasion of red blood cells (RBCs) by Plasmodium falciparum (Pf) merozoites is the binding of rhoptry neck protein 2 (RON2) to the hydrophobic groove of apical membrane antigen 1 (AMA1), triggering junction formation between the apical end of the merozoite and the RBC surface to initiate invasion. Vaccination with AMA1 provided protection against homologous parasites in one of two phase 2 clinical trials; however, despite its ability to induce high-titer invasion-blocking antibodies in a controlled human challenge trial, the vaccine conferred little protection even against the homologous parasite. Here we provide evidence that immunization with an AMA1-RON2 peptide complex, but not with AMA1 alone, provided complete protection against a lethal Plasmodium yoelii challenge in mice. Significantly, IgG from mice immunized with the complex transferred protection. Furthermore, IgG from PfAMA1-RON2-immunized animals showed enhanced invasion inhibition compared with IgG elicited by AMA1 alone. Interestingly, this qualitative increase in inhibitory activity appears to be related, at least in part, to a switch in the proportion of IgG specific for certain loop regions in AMA1 surrounding the binding site of RON2. Antibodies induced by the complex were not sufficient to block the FVO strain heterologous parasite, however, reinforcing the need to include multiallele AMA1 to cover polymorphisms. Our results suggest that AMA1 subunit vaccines may be highly effective when presented to the immune system as an invasion complex with RON2.
authors: Laboratory of Malaria and Vector Research and srinivasanp@niaid.nih.gov lmiller@niaid.nih.gov.
authors: Prakash
authors: P
authors: Srinivasan
authors: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and.
authors: Emmanuel
authors: E
authors: Ekanem
authors: Laboratory of Malaria and Vector Research and.
authors: Ababacar
authors: A
authors: Diouf
authors: Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada V8W 3P6.
authors: Michelle L
authors: ML
authors: Tonkin
authors: Laboratory of Malaria and Vector Research and.
authors: Kazutoyo
authors: K
authors: Miura
authors: Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada V8W 3P6.
authors: Martin J
authors: MJ
authors: Boulanger
authors: Laboratory of Malaria and Vector Research and.
authors: Carole A
authors: CA
authors: Long
authors: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and.
authors: David L
authors: DL
authors: Narum
authors: Laboratory of Malaria and Vector Research and srinivasanp@niaid.nih.gov lmiller@niaid.nih.gov.
authors: Louis H
authors: LH
authors: Miller
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D004912:Erythrocytes / Q000276:immunology* / Q000469:parasitology; D006801:Humans; D007114:Immunization; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D010967:Plasmodium yoelii / Q000235:genetics / Q000276:immunology; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium