Aspects of immunity for the AMA-1 family of molecules in humans and non-human primates malarias

Thomas, Aline; Narum, David L.; Waters, Andrew P.; Trape, Jean‐François; Rogier, C.; Gonçalves, Antônio José; Rosário, Virgílio Estólio do; Druilhe, Pierre; Mitchell, G. H.; Dennis, David T.

doi:10.1590/s0074-02761994000600016

Cited by 16 publications

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“…This interpretation is supported by, first, the finding in vitro for P. knowlesi that antibodies inhibit RBC invasion by free merozoites (35) and that these antibodies do not mediate inhibition by merozoite agglutination (32). Second, it has been suggested that PfAMA-1-derived peptides inhibit merozoite interaction with RBC (38), and third, it has been suggested that there is a broadening of the range of species of target RBC which can be invaded by parasites whose AMA-1 gene has been complemented by a heterospecific AMA-1 (36).…”

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Apical Membrane Antigen 1, a Major Malaria Vaccine Candidate, Mediates the Close Attachment of Invasive Merozoites to Host Red Blood Cells

et al. 2004

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Apical membrane antigen 1 (AMA-1) of Plasmodium merozoites is established as a candidate molecule for inclusion in a human malaria vaccine and is strongly conserved in the genus. We have investigated its function in merozoite invasion by incubating Plasmodium knowlesi merozoites with red cells in the presence of a previously described rat monoclonal antibody (MAb R31C2) raised against an invasion-inhibitory epitope of P. knowlesi AMA-1 and then fixing the material for ultrastructural analysis. We have found that the random, initial, long-range (12 nm) contact between merozoites and red cells occurs normally in the presence of the antibody, showing that AMA-1 plays no part in this stage of attachment. Instead, inhibited merozoites fail to reorientate, so they do not bring their apices to bear on the red cell surface and do not make close junctional apical contact. We conclude that AMA-1 may be directly responsible for reorientation or that the molecule may initiate the junctional contact, which is then presumably dependent on Duffy binding proteins for its completion.

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Apical Membrane Antigen 1, a Major Malaria Vaccine Candidate, Mediates the Close Attachment of Invasive Merozoites to Host Red Blood Cells

et al. 2004

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“…It is possible that the recombinant DIII used for these analyses was not folded correctly into the native conformation. Most AMA1 epitopes recognized by antibodies in human sera are discontinuous (56,57), and the formation of correct disulfide bonds in the protein is required for the induction of significant levels of inhibitory antibody following immunization (1). The solution structure of E. coli-expressed and refolded DII and DIII has been determined by nuclear magnetic resonance methods (14,42).…”

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confidence: 99%

“…Alkaline phosphatase-conjugated secondary antibodies (anti-rabbit, antirat, and anti-mouse, antibodies as appropriate) were used to detect the primary antibodies using bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium as the substrate. Antigenicity of a full-length ectodomain protein (P. falciparum 4mH) was further evaluated by enzyme-linked immunosorbent assay (ELISA) using PfAMA1-specific MAbs 4G2, 58F8, and 28G2 and human serum from Guinea-Bissau, an area where malaria is endemic (56).…”

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confidence: 99%

Malaria Vaccine-Related Benefits of a Single Protein ComprisingPlasmodium falciparumApical Membrane Antigen 1 Domains I and II Fused to a Modified Form of the 19-Kilodalton C-Terminal Fragment of Merozoite Surface Protein 1

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et al. 2007

Infect Immun

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We show that the smallest module of Plasmodium falciparum AMA1 (PfAMA1) that can be expressed in the yeast Pichia pastoris while retaining the capacity to induce high levels of parasite-inhibitory antibodies comprises domains I and II. Based on this, two fusion proteins, differing in the order of the modules, were The annual malaria burden of 300 to 500 million clinical cases results in an estimated mortality for up to 2 million people, predominantly sub-Saharan African children under 5 years of age (52). A malaria vaccine would make a significant contribution to reducing the enormous socioeconomic burden caused by this disease. A number of vaccine approaches, targeting various stages of the complex parasite life cycle, are being investigated (21). Apical membrane antigen 1 (AMA1) and merozoite surface protein 1 (MSP1) are potential vaccine components, and a number of vaccines using elements of these molecules are currently in early clinical evaluation. Previous research has indicated that a combination of MSP1 and AMA1 has vaccine-related advantages over either antigen alone (3, 55). Both molecules are essential components of the asexual blood-stage merozoite (50, 60), the developmental stage of the parasite stage responsible for invasion of erythrocytes. They are also both present on merozoites that emerge from infected liver cells, and AMA1 has also been identified as a sporozoite protein (51). Plasmodium falciparum AMA1 (PfAMA1) is a polymorphic protein; over 10% of its amino acid residues can change without obvious effects on its function in invasion. With few exceptions, polymorphic residues are bi-or trimorphic, and all are located on the outside of the molecule, predominantly on one face (47). One strategy to tackle any potential negative effect of polymorphism in vaccine development is to combine PfAMA1 with other targets that are not, or are less, polymorphic, such as MSP1 19 (59). A single-protein vaccine has cost, speed, and potential functionality benefits compared with vaccines prepared from mixtures of proteins. We have therefore investigated how minimal elements of AMA1 and MSP1, each retaining the ability to induce growth-inhibitory antibodies, can be incorporated into fusion proteins that allow the development of single-protein, multitarget malaria vaccines.Micronemes are organelles of the merozoite apical complex, a structure intimately associated with the invasion of erythrocytes. AMA1 is initially trafficked to micronemes as an 83-kDa type 1 integral membrane protein; subsequently, the N-terminal prodomain is proteolytically cleaved prior to relocalization to the merozoite outer membrane (43). Further cleavage, proximal to the transmembrane region, then releases the ectodomain from the parasite surface (26). AMA1 contains 16 conserved cysteine residues that form eight intramolecular disulfide bonds (20). The recently elucidated three-dimensional structure of AMA1 (47) confirms that after cleavage of the prodomain, the ectodomain essentially comprises three interacting domains (DI, DII, and D...

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“…Gene disruption and substitution studies suggest that AMA1 is a critical component necessary for successful invasion of red blood cells (RBCs) by merozoites (36,47). Vaccination with recombinant AMA1 has been shown to elicit antibody responses that provide protection against homologous parasite challenges in a number of rodent and primate models (2,11,24,26,35,44,45). Additional support for the importance of AMA1-specific antibodies was provided by adoptive-transfer experiments where monoclonal antibodies or purified hyperimmune rabbit immunoglobin protected mice against Plasmodium yoelii or Plasmodium chabaudi challenge (12).…”

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Posttranslational Modification of RecombinantPlasmodium falciparumApical Membrane Antigen 1: Impact on Functional Immune Responses to a Malaria Vaccine Candidate

et al. 2005

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Recombinant apical membrane antigen 1 (AMA1) is a leading vaccine candidate for Plasmodium falciparum malaria, as antibodies against recombinant P. falciparum AMA1 (PfAMA1) interrupt merozoite invasion into erythrocytes. In order to investigate the role of posttranslational modification in modulating the functional immune response to recombinant AMA1, two separate alleles of PfAMA1 (FVO and 3D7), in which native N-glycosylation sites have been mutated, were produced using Escherichia coli and a Pichia pastoris expression system. Recombinant Pichia pastoris AMA1-FVO (PpAMA1-FVO) and PpAMA1-3D7 are O-linked glycosylated, and 45% of PpAMA1-3D7 is nicked, though all four recombinant molecules react with conformation-specific monoclonal antibodies. To address the immunological effect of O-linked glycosylation, we compared the immunogenicity of E. coli AMA1-FVO (EcAMA1-FVO) and PpAMA1-FVO antigens, since both molecules are intact. The effect of antigen nicking was then investigated by comparing the immunogenicity of EcAMA1-3D7 and PpAMA1-3D7. Our data demonstrate that there is no significant difference in the rabbit antibody titer elicited towards EcAMA1-FVO and PpAMA1-FVO or to EcAMA1-3D7 and PpAMA1-3D7. Furthermore, we have demonstrated that recombinant AMA1 (FVO or 3D7), whether expressed and refolded from E. coli or produced from the Pichia expression system, is equivalent and mimics the functionality of the native protein in in vitro growth inhibition assay experiments. We conclude that in the case of recombinant AMA1, the E. coliand P. pastoris-derived antigens are immunologically and functionally equivalent and are unaffected by the posttranslational modification resulting from expression in these two systems.

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Aspects of immunity for the AMA-1 family of molecules in humans and non-human primates malarias

Cited by 16 publications

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Apical Membrane Antigen 1, a Major Malaria Vaccine Candidate, Mediates the Close Attachment of Invasive Merozoites to Host Red Blood Cells

Apical Membrane Antigen 1, a Major Malaria Vaccine Candidate, Mediates the Close Attachment of Invasive Merozoites to Host Red Blood Cells

Malaria Vaccine-Related Benefits of a Single Protein ComprisingPlasmodium falciparumApical Membrane Antigen 1 Domains I and II Fused to a Modified Form of the 19-Kilodalton C-Terminal Fragment of Merozoite Surface Protein 1

Posttranslational Modification of RecombinantPlasmodium falciparumApical Membrane Antigen 1: Impact on Functional Immune Responses to a Malaria Vaccine Candidate

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