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John H Adams - One of the best experts on this subject based on the ideXlab platform.
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Identification of an Immunogenic Broadly Inhibitory Surface Epitope of the Plasmodium vivax Duffy Binding Protein Ligand Domain.
mSphere, 2019Co-Authors: Miriam T. George, Francis B. Ntumngia, Jesse Schloegel, Samantha J. Barnes, Joanne L. Casey, Christopher L King, Michael Foley, John H AdamsAbstract:ABSTRACT The Plasmodium vivax Duffy Binding Protein region II (DBPII) is a vital ligand for the parasite’s invasion of reticulocytes, thereby making this molecule an attractive vaccine candidate against vivax malaria. However, strain-specific immunity due to DBPII allelic variation in Bc epitopes may complicate vaccine efficacy, suggesting that an effective DBPII vaccine needs to target conserved epitopes that are potential targets of strain-transcending neutralizing immunity. The minimal epitopes reactive with functionally inhibitory anti-DBPII monoclonal antibody (MAb) 3C9 and noninhibitory anti-DBPII MAb 3D10 were mapped using phage display expression libraries, since previous attempts to deduce the 3C9 epitope by cocrystallographic methods failed. Inhibitory MAb 3C9 binds to a conserved conformation-dependent epitope in subdomain 3, while noninhibitory MAb 3D10 binds to a linear epitope in subdomain 1 of DBPII, consistent with previous studies. Immunogenicity studies using synthetic linear peptides of the minimal epitopes determined that the 3C9 epitope, but not the 3D10 epitope, could induce functionally inhibitory anti-DBPII antibodies. Therefore, the highly conserved Binding-inhibitory 3C9 epitope offers the potential as a component in a broadly inhibitory, strain-transcending DBP subunit vaccine. IMPORTANCE Vivax malaria is the second leading cause of malaria worldwide and the major cause of non-African malaria. Unfortunately, efforts to develop antimalarial vaccines specifically targeting Plasmodium vivax have been largely neglected, and few candidates have progressed into clinical trials. The Duffy Binding Protein is considered a leading blood-stage vaccine candidate because this ligand’s recognition of the Duffy blood group reticulocyte surface receptor is considered essential for infection. This study identifies a new target epitope on the ligand’s surface that may serve as the target of vaccine-induced Binding-inhibitory antibody (BIAb). Understanding the potential targets of vaccine protection will be important for development of an effective vaccine.
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persistence of long lived memory b cells specific to Duffy Binding Protein in individuals exposed to plasmodium vivax
Scientific Reports, 2018Co-Authors: Siriruk Changrob, John H Adams, Amy M Mchenry, Jetsumon Sattabongkot, Myat Htut Nyunt, Patchanee ChootongAbstract:The major challenge in designing a protective Duffy Binding Protein region II (DBPII)-based vaccine against blood-stage vivax malaria is the high number of polymorphisms in critical residues targeted by Binding-inhibitory antibodies. Here, longevity of antibody and memory B cell response (MBCs) to DBL-TH variants, DBL-TH2, -TH4, -TH5, -TH6 and -TH9 were analyzed in P. vivax-exposed individuals living in a low malaria transmission area of southern Thailand. Antibody to DBL-TH variants were significantly detected during P. vivax infection and it was persisted for up to 9 months post-infection. However, DBL-TH-specific MBC responses were stably maintained longer than antibody response, at least 3 years post-infection in the absence of re-infection. Phenotyping of B cell subsets showed the expansion of activated and atypical MBCs during acute and recovery phase of infection. While the persistence of DBL-TH-specific MBCs was found in individuals who had activated and atypical MBC expansion, anti-DBL-TH antibody responses was rapidly declined in plasma. The data suggested that these two MBCs were triggered by P. vivax infection, its expansion and stability may have impact on antibody responses. Our results provided evidence for ability of DBPII variant antigens in induction of long-lasting MBCs among individuals who were living in low malaria endemicity.
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the presence persistence and functional properties of plasmodium vivax Duffy Binding Protein ii antibodies are influenced by hla class ii allelic variants
PLOS Neglected Tropical Diseases, 2016Co-Authors: Flora S Kano, Flavia A Souzasilva, Leticia M Torres, Bruno A M Sanchez, Tais Nobrega De Sousa, Cor Jesus Fernandes Fontes, R S Rocha, Barbara A S Lima, Jessica R S Alves, John H AdamsAbstract:Background: The human malaria parasite Plasmodium vivax infects red blood cells through a key pathway that requires interaction between Duffy Binding Protein II (DBPII) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). A high proportion of P. vivax-exposed individuals fail to develop antibodies that inhibit DBPII-DARC interaction, and genetic factors that modulate this humoral immune response are poorly characterized. Here, we investigate if DBPII responsiveness could be HLA class II-linked. Methodology/Principal Findings: A community-based open cohort study was carried out in an agricultural settlement of the Brazilian Amazon, in which 336 unrelated volunteers were genotyped for HLA class II (DRB1, DQA1 and DQB1 loci), and their DBPII immune responses were monitored over time (baseline, 6 and 12 months) by conventional serology (DBPII IgG ELISA-detected) and functional assays (inhibition of DBPII–erythrocyte Binding). The results demonstrated an increased susceptibility of the DRB1*13:01 carriers to develop and sustain an anti-DBPII IgG response, while individuals with the haplotype DRB1*14:02-DQA1*05:03-DQB1*03:01 were persistent non-responders. HLA class II gene polymorphisms also influenced the functional properties of DBPII antibodies (BIAbs, Binding inhibitory antibodies), with three alleles (DRB1*07:01, DQA1*02:01 and DQB1*02:02) comprising a single haplotype linked with the presence and persistence of the BIAbs response. Modelling the structural effects of the HLA-DRB1 variants revealed a number of differences in the peptide-Binding groove, which is likely to lead to altered antigen Binding and presentation profiles, and hence may explain the differences in subject responses. Conclusions/Significance:The current study confirms the heritability of the DBPII antibody response, with genetic variation in HLA class II genes influencing both the development and persistence of IgG antibody responses. Cellular studies to increase knowledge of the Binding affinities of DBPII peptides for class II molecules linked with good or poor antibody responses might lead to the development of strategies for controlling the type of helper T cells activated in response to DBPII.
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broadly neutralizing epitopes in the plasmodium vivax vaccine candidate Duffy Binding Protein
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Edwin Chen, Francis B. Ntumngia, John H Adams, Nichole D Salinas, Yining Huang, Manolo D Plasencia, Michael L Gross, Niraj H ToliaAbstract:Plasmodium vivax Duffy Binding Protein (PvDBP) is the most promising vaccine candidate for P. vivax malaria. The polymorphic nature of PvDBP induces strain-specific immune responses, however, and the epitopes of broadly neutralizing antibodies are unknown. These features hamper the rational design of potent DBP-based vaccines and necessitate the identification of globally conserved epitopes. Using X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange mass spectrometry, and mutational mapping, we have defined epitopes for three inhibitory mAbs (mAbs 2D10, 2H2, and 2C6) and one noninhibitory mAb (3D10) that engage DBP. These studies expand the currently known inhibitory epitope repertoire by establishing protective motifs in subdomain three outside the receptor-Binding and dimerization residues of DBP, and introduce globally conserved protective targets. All of the epitopes are highly conserved among DBP alleles. The identification of broadly conserved epitopes of inhibitory antibodies provides critical motifs that should be retained in the next generation of potent vaccines for P. vivax malaria.
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strain transcending inhibitory antibodies against homologous and heterologous strains of Duffy Binding Protein region ii
PLOS ONE, 2016Co-Authors: Sudarat Wongkidakarn, Amy M Mchenry, John H Adams, Jetsumon Sattabongkot, Patchanee ChootongAbstract:Duffy Binding Protein region II (DBPII) is a promising vaccine candidate against vivax malaria. However, polymorphisms of DBPII are the major obstacle to designing a successful vaccine. Here, we examined whether anti-DBPII antibodies from individual P. vivax exposures provide strain-transcending immunity and whether their presence is associated with DBPII haplotypes found in patients with acute P. vivax. The ability of antibodies to inhibit DBL-TH-erythrocyte Binding was tested by COS7 erythrocyte Binding inhibition assay. Seven samples of high responders (HR) were identified from screening anti-DBPII levels. HR no.3 and HR no.6 highly inhibited all DBL-TH Binding to erythrocytes, by >80%. Antibodies from these two patients’ plasma had the potential to be broadly inhibitory against DBL-TH1, -TH2, -TH6, -TH7, -TH8 and -TH9 haplotypes when plasma was serially diluted from 1:500 to 1:2000. To further examine the association of DBPII haplotypes and the ability of antibodies to broadly inhibit DBL-TH variants, the individual samples underwent sequencing analysis and the inhibitory function of the anti-DBPII antibodies was tested. The patterns of DBPII polymorphisms in acute patients were classified into two groups, DBPII Sal I (55%) and DBL-TH variants (45%). Plasma from Sal I and DBPII-TH patients who had the highest inhibition against Sal I or DBL-TH4 and -TH5 was serially diluted from 1:500 to 1:2000 and their inhibitory capacity was tested against a panel of DBL-TH haplotypes. Results provided evidence of both strain-transcending inhibition as well as strain-specific inhibition by antibodies that blocked erythrocyte Binding against some DBL-TH variants and against homologous alleles. This study demonstrated broad inhibition by anti-DBPII antibodies against DBL-TH haplotypes in natural P. vivax exposed individuals. The identification of conserved epitopes among DBL-TH may have implications for vaccine development of a DBPII-based vaccine against diverse P. vivax infections.
Francis B. Ntumngia - One of the best experts on this subject based on the ideXlab platform.
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Identification of an Immunogenic Broadly Inhibitory Surface Epitope of the Plasmodium vivax Duffy Binding Protein Ligand Domain.
mSphere, 2019Co-Authors: Miriam T. George, Francis B. Ntumngia, Jesse Schloegel, Samantha J. Barnes, Joanne L. Casey, Christopher L King, Michael Foley, John H AdamsAbstract:ABSTRACT The Plasmodium vivax Duffy Binding Protein region II (DBPII) is a vital ligand for the parasite’s invasion of reticulocytes, thereby making this molecule an attractive vaccine candidate against vivax malaria. However, strain-specific immunity due to DBPII allelic variation in Bc epitopes may complicate vaccine efficacy, suggesting that an effective DBPII vaccine needs to target conserved epitopes that are potential targets of strain-transcending neutralizing immunity. The minimal epitopes reactive with functionally inhibitory anti-DBPII monoclonal antibody (MAb) 3C9 and noninhibitory anti-DBPII MAb 3D10 were mapped using phage display expression libraries, since previous attempts to deduce the 3C9 epitope by cocrystallographic methods failed. Inhibitory MAb 3C9 binds to a conserved conformation-dependent epitope in subdomain 3, while noninhibitory MAb 3D10 binds to a linear epitope in subdomain 1 of DBPII, consistent with previous studies. Immunogenicity studies using synthetic linear peptides of the minimal epitopes determined that the 3C9 epitope, but not the 3D10 epitope, could induce functionally inhibitory anti-DBPII antibodies. Therefore, the highly conserved Binding-inhibitory 3C9 epitope offers the potential as a component in a broadly inhibitory, strain-transcending DBP subunit vaccine. IMPORTANCE Vivax malaria is the second leading cause of malaria worldwide and the major cause of non-African malaria. Unfortunately, efforts to develop antimalarial vaccines specifically targeting Plasmodium vivax have been largely neglected, and few candidates have progressed into clinical trials. The Duffy Binding Protein is considered a leading blood-stage vaccine candidate because this ligand’s recognition of the Duffy blood group reticulocyte surface receptor is considered essential for infection. This study identifies a new target epitope on the ligand’s surface that may serve as the target of vaccine-induced Binding-inhibitory antibody (BIAb). Understanding the potential targets of vaccine protection will be important for development of an effective vaccine.
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broadly neutralizing epitopes in the plasmodium vivax vaccine candidate Duffy Binding Protein
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Edwin Chen, Francis B. Ntumngia, John H Adams, Nichole D Salinas, Yining Huang, Manolo D Plasencia, Michael L Gross, Niraj H ToliaAbstract:Plasmodium vivax Duffy Binding Protein (PvDBP) is the most promising vaccine candidate for P. vivax malaria. The polymorphic nature of PvDBP induces strain-specific immune responses, however, and the epitopes of broadly neutralizing antibodies are unknown. These features hamper the rational design of potent DBP-based vaccines and necessitate the identification of globally conserved epitopes. Using X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange mass spectrometry, and mutational mapping, we have defined epitopes for three inhibitory mAbs (mAbs 2D10, 2H2, and 2C6) and one noninhibitory mAb (3D10) that engage DBP. These studies expand the currently known inhibitory epitope repertoire by establishing protective motifs in subdomain three outside the receptor-Binding and dimerization residues of DBP, and introduce globally conserved protective targets. All of the epitopes are highly conserved among DBP alleles. The identification of broadly conserved epitopes of inhibitory antibodies provides critical motifs that should be retained in the next generation of potent vaccines for P. vivax malaria.
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structural analysis of the synthetic Duffy Binding Protein dbp antigen deknull relevant for plasmodium vivax malaria vaccine design
PLOS Neglected Tropical Diseases, 2015Co-Authors: Edwin Chen, Francis B. Ntumngia, John H Adams, Nichole D Salinas, Niraj H ToliaAbstract:The Plasmodium vivax vaccine candidate Duffy Binding Protein (DBP) is a Protein necessary for P. vivax invasion of reticulocytes. The polymorphic nature of DBP induces strain-specific immune responses that pose unique challenges for vaccine development. DEKnull is a synthetic DBP based antigen that has been engineered through mutation to enhance induction of blocking inhibitory antibodies. We determined the x-ray crystal structure of DEKnull to identify if any conformational changes had occurred upon mutation. Computational and experimental analyses assessed immunogenicity differences between DBP and DEKnull epitopes. Functional Binding assays with monoclonal antibodies were used to interrogate the available epitopes in DEKnull. We demonstrate that DEKnull is structurally similar to the parental Sal1 DBP. The DEKnull mutations do not cause peptide backbone shifts within the polymorphic loop, or at either the DBP dimerization interface or DARC receptor Binding pockets, two important structurally conserved protective epitope motifs. All B-cell epitopes, except for the mutated DEK motif, are conserved between DEKnull and DBP. The DEKnull Protein retains Binding to conformationally dependent inhibitory antibodies. DEKnull is an iterative improvement of DBP as a vaccine candidate. DEKnull has reduced immunogenicity to polymorphic regions responsible for strain-specific immunity while retaining conserved Protein folds necessary for induction of strain-transcending blocking inhibitory antibodies.
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the association of Duffy Binding Protein region ii polymorphisms and its antigenicity in plasmodium vivax isolates from thailand
Parasitology International, 2014Co-Authors: Patchanee Chootong, Francis B. Ntumngia, Amy M Mchenry, Jetsumon Sattabongkot, John H AdamsAbstract:Plasmodium vivax Duffy Binding Protein II (DBPII) plays an important role in reticulocyte invasion and is a potential vaccine candidate against vivax malaria. However, polymorphisms in DBPII are a challenge for the successful design of a broadly protective vaccine. In this study, the genetic diversity of DBPII among Thai isolates was analyzed from Plasmodium vivax-infected blood samples and polymorphism characters were defined with the MEGA4 program. Sequence analysis identified 12 variant residues that are common among Thai DBPII haplotypes with variant residues L333F, L424I, W437R and I503K having the highest frequency. Variant residue D384K occurs in combination with either E385K or K386N/Q. Additionally, variant residue L424I occurs in conjunction with W437R in most Thai DBPII alleles and these variants frequently occur in combination with the I503K variant. The polymorphic patterns of Thai isolates were defined into 9 haplotypes (Thai DBL-1, -2, -3, etc.…). Thai DBL-2, -5, -6 haplotypes are the most common DBPII variants in Thai residents. To study the association of these Thai DBPII polymorphisms with antigenic character, the functional inhibition of anti-DBPII monoclonal antibodies against a panel of Thai DBL variants was characterized by an in vitro erythrocyte Binding inhibition assay. The functional inhibition of anti-DBPII monoclonal antibodies 3C9, 2D10 and 2C6 against Thai variants was significantly different, suggesting that polymorphisms of Thai DBPII variants alter the antigenic character of the target epitopes. In contrast, anti-DBPII monoclonal antibody 2H2 inhibited all Thai DBPII variants equally well. Our results suggest that the immune efficacy of a DBPII vaccine will depend on the specificity of the anti-DBPII antibodies induced and that it is preferable to optimize responses to conserved epitopes for broadly neutralizing protection against P. vivax.
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plasmodium vivax Duffy Binding Protein understanding targets of protective immunity
Malaria Journal, 2014Co-Authors: John H Adams, Francis B. Ntumngia, Miriam T. George, Jesse Schloegel, Samantha J. Barnes, Amy M MchenryAbstract:Plasmodium vivax merozoite invasion of reticulocytes is a rapid process that involves a series of specific, sequential interactions. These interactions are crucial for invasion and continued blood-stage infection, thus representing attractive targets for vaccine development. The Duffy Binding Protein (DBP) is a vital microneme Protein associated with the decisive, irreversible step of junction formation during the later stages of the invasion process. The ligand domain of DBP, known as region II (DBPII), binds the Duffy Antigen Receptor for Chemokines (DARC) by dimerization of two DBP and two DARC molecules forming a heterotetrameric structure. Naturally acquired antibodies to DBPII are prevalent in residents of areas where vivax malaria is endemic. These antibodies can inhibit DBPII Binding and merozoite invasion of human reticulocytes; however, they tend to be poorly inhibitory, strain-specific, and short-lived. Remarkably, strain-specific serologic activity can be altered by even single amino acid substitutions found in allelic variants of DBPII. While strain-transcending, broadly neutralizing antibodies are less prevalent, there is a significant correlation of their antibody reactivity to certain epitopes and inhibition of DBPII-receptor function. Our data indicate epitopes at or near the dimer interface of DBPII represent the primary targets of naturally occurring protective anti-DBPII antibodies that can inhibit merozoite invasion of host erythrocytes. However, these epitopes also contain most of the prevalent variable residues resulting from DBP allelic diversity. These data are consistent with the hypothesis that DBP variation is an immune evasion mechanism responsible for strain-specific immunity and stable, broadly neutralizing immunity is achieved when antibodies target functionally-conserved epitopes, thereby blocking DBP dimerization and inhibiting invasion. To overcome the natural tendency for eliciting a strain-specific response, synthetic DBPII alleles were evaluated for their ability to broaden efficacy of strain-transcending inhibition against diverse DBPII alleles. In an effort to identify potential conserved, protective epitopes we have prepared and evaluated a panel of anti-DBPII murine monoclonal antibodies. Inhibitory activities of these monoclonal antibodies were characterized with in vitro functional assays for DBPII and their respective minimal epitopes were mapped using phage display. These targets of putative strain-transcending inhibition identify epitopes that may be targeted for vaccine-induced anti-DBPII inhibitory antibodies.
Christopher L King - One of the best experts on this subject based on the ideXlab platform.
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amplification of Duffy Binding Protein encoding gene allows plasmodium vivax to evade host anti dbp humoral immunity
Nature Communications, 2020Co-Authors: Jean Popovici, Chetan E Chitnis, Camille Roesch, Lenore L Carias, Nimol Khim, Amelie Vantaux, Ivo Mueller, Christopher L KingAbstract:Antigenic variation, the capacity to produce a range of variable antigens, is a well-described strategy of Plasmodium and other parasites to evade host immunity. Here, we show that gene amplification is an additional evasion mechanism used by Plasmodium vivax to escape humoral immunity targeting PvDBP, the key ligand involved in reticulocyte invasion. PvDBP gene amplification leads to increased mRNA levels and protects P. vivax in vitro against invasion inhibitory human monoclonal antibodies targeting a conserved Binding domain of DBP. Patient samples suggest that parasites with increased pvdbp copy number are able to infect individuals with naturally acquired antibodies highly blocking the Binding of PvDBP to the Duffy receptor. These results show that gene copy number variation affect the parasite’s ability to evade anti-PvDBP humoral immunity. Duffy Binding Protein (DBP) of Plasmodium vivax is important for invasion and is a potential vaccine candidate. Here, the authors show that PvDBP gene amplification protects P vivax in vitro against invasion inhibitory human monoclonal antibodies and is associated to infection of patients with PvDBP Binding inhibitory antibodies.
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Identification of an Immunogenic Broadly Inhibitory Surface Epitope of the Plasmodium vivax Duffy Binding Protein Ligand Domain.
mSphere, 2019Co-Authors: Miriam T. George, Francis B. Ntumngia, Jesse Schloegel, Samantha J. Barnes, Joanne L. Casey, Christopher L King, Michael Foley, John H AdamsAbstract:ABSTRACT The Plasmodium vivax Duffy Binding Protein region II (DBPII) is a vital ligand for the parasite’s invasion of reticulocytes, thereby making this molecule an attractive vaccine candidate against vivax malaria. However, strain-specific immunity due to DBPII allelic variation in Bc epitopes may complicate vaccine efficacy, suggesting that an effective DBPII vaccine needs to target conserved epitopes that are potential targets of strain-transcending neutralizing immunity. The minimal epitopes reactive with functionally inhibitory anti-DBPII monoclonal antibody (MAb) 3C9 and noninhibitory anti-DBPII MAb 3D10 were mapped using phage display expression libraries, since previous attempts to deduce the 3C9 epitope by cocrystallographic methods failed. Inhibitory MAb 3C9 binds to a conserved conformation-dependent epitope in subdomain 3, while noninhibitory MAb 3D10 binds to a linear epitope in subdomain 1 of DBPII, consistent with previous studies. Immunogenicity studies using synthetic linear peptides of the minimal epitopes determined that the 3C9 epitope, but not the 3D10 epitope, could induce functionally inhibitory anti-DBPII antibodies. Therefore, the highly conserved Binding-inhibitory 3C9 epitope offers the potential as a component in a broadly inhibitory, strain-transcending DBP subunit vaccine. IMPORTANCE Vivax malaria is the second leading cause of malaria worldwide and the major cause of non-African malaria. Unfortunately, efforts to develop antimalarial vaccines specifically targeting Plasmodium vivax have been largely neglected, and few candidates have progressed into clinical trials. The Duffy Binding Protein is considered a leading blood-stage vaccine candidate because this ligand’s recognition of the Duffy blood group reticulocyte surface receptor is considered essential for infection. This study identifies a new target epitope on the ligand’s surface that may serve as the target of vaccine-induced Binding-inhibitory antibody (BIAb). Understanding the potential targets of vaccine protection will be important for development of an effective vaccine.
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naturally acquired Binding inhibitory antibodies to plasmodium vivax Duffy Binding Protein and clinical immunity to malaria in rural amazonians
The Journal of Infectious Diseases, 2016Co-Authors: Christopher L King, Vanessa C Nicolete, Sarah Frischmann, Susana Barbosa, Marcelo U FerreiraAbstract:BACKGROUND: Antibodies to the cysteine-rich domain II of Plasmodium vivax Duffy Binding Protein (PvDBP) can inhibit Binding of this parasite ligand to its receptor on red blood cells, the Duffy antigen/receptor for chemokines. These Binding-inhibitory antibodies (BIAbs) also inhibit P. vivax invasion of reticulocytes in vitro. METHODS: To investigate whether naturally acquired anti-PvDBP antibodies are associated with reduced risk of clinical malaria in a population exposed to low levels of P. vivax transmission, we measured total levels of immunoglobulin G antibodies to 5 PvDBP variants and used a functional in vitro assay to quantify their Binding-inhibitory activity in a cohort of 466 rural Amazonians followed up for up to 37 months. RESULTS: No association between total immunoglobulin G antibody responses to any PvDBP variant and risk of symptomatic, laboratory-confirmed vivax malaria was observed in this cohort. However, a Cox proportional hazards model, adjusted for age, sex, and genotype for the Duffy antigen/receptor for chemokines, showed a >40% decrease in the prospective risk of clinical vivax malaria in subjects with the strongest BIAb responses (upper and middle terciles). High BIAb responses were mostly PvDBP variant transcending and stable over time. CONCLUSIONS: Strong naturally acquired BIAb responses are associated with a reduced risk of clinical P. vivax malaria in rural Amazonians.
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finding the sweet spots of inhibition understanding the targets of a functional antibody against plasmodium vivax Duffy Binding Protein
International Journal for Parasitology, 2012Co-Authors: Francis B. Ntumngia, Christopher L King, John H AdamsAbstract:Abstract Plasmodium vivax Duffy Binding Protein region II (DBPII) is an essential ligand for reticulocyte invasion, thereby making this molecule an attractive vaccine candidate against asexual blood-stage P. vivax . Similar to other Plasmodium blood-stage vaccine candidates, strain-specific immunity due to DBPII allelic variation may complicate vaccine efficacy. Targeting immune responses to more conserved epitopes that are potential targets of strain-transcending neutralising immunity is necessary to avoid induction of strain-specific responses to dominant variant epitopes. In this article, we focus on different approaches to optimise the design of DBP immunogenicity to target conserved epitopes, which is important for developing a broadly effective vaccine against P. vivax.
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fine specificity of plasmodium vivax Duffy Binding Protein Binding engagement of the Duffy antigen on human erythrocytes
Infection and Immunity, 2012Co-Authors: Asim A Siddiqui, Francis B. Ntumngia, Jia Xainli, Jesse Schloegel, Joanne L. Casey, John H Adams, Michael Foley, Lenore L Carias, Menachem Shoham, Christopher L KingAbstract:Plasmodium vivax invasion of human erythrocytes requires interaction of the P. vivax Duffy Binding Protein (PvDBP) with its host receptor, the Duffy antigen (Fy) on the erythrocyte surface. Consequently, PvDBP is a leading vaccine candidate. The Binding domain of PvDBP lies in a cysteine-rich portion of the molecule called region II (PvDBPII). PvDBPII contains three distinct subdomains based upon intramolecular disulfide bonding patterns. Subdomain 2 (SD2) is highly polymorphic and is thought to contain many key residues for Binding to Fy, while SD1 and SD3 are comparatively conserved and their role in Fy Binding is not well understood. To examine the relative contributions of the different subdomains to Binding to Fy and their abilities to elicit strain-transcending Binding-inhibitory antibodies, we evaluated recombinant Proteins from SD1+2, SD2, SD3, and SD3+, which includes 24 residues of SD2. All of the recombinant subdomains, except for SD2, bound variably to human erythrocytes, with constructs containing SD3 showing the best Binding. Antisera raised in laboratory animals against SD3, SD3+, and SD2+3 inhibited the Binding of full-length PvDBPII, which is strain transcending, whereas antisera generated to SD1+2 and SD2 failed to generate blocking antibodies. All of the murine monoclonal antibodies generated to full-length PvDBPII that had significant Binding-inhibitory activity recognized only SD3. Thus, SD3 binds Fy and elicits blocking antibodies, indicating that it contains residues critical to Fy Binding that could be the basis of a strain-transcending candidate vaccine against P. vivax.
Amy M Mchenry - One of the best experts on this subject based on the ideXlab platform.
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persistence of long lived memory b cells specific to Duffy Binding Protein in individuals exposed to plasmodium vivax
Scientific Reports, 2018Co-Authors: Siriruk Changrob, John H Adams, Amy M Mchenry, Jetsumon Sattabongkot, Myat Htut Nyunt, Patchanee ChootongAbstract:The major challenge in designing a protective Duffy Binding Protein region II (DBPII)-based vaccine against blood-stage vivax malaria is the high number of polymorphisms in critical residues targeted by Binding-inhibitory antibodies. Here, longevity of antibody and memory B cell response (MBCs) to DBL-TH variants, DBL-TH2, -TH4, -TH5, -TH6 and -TH9 were analyzed in P. vivax-exposed individuals living in a low malaria transmission area of southern Thailand. Antibody to DBL-TH variants were significantly detected during P. vivax infection and it was persisted for up to 9 months post-infection. However, DBL-TH-specific MBC responses were stably maintained longer than antibody response, at least 3 years post-infection in the absence of re-infection. Phenotyping of B cell subsets showed the expansion of activated and atypical MBCs during acute and recovery phase of infection. While the persistence of DBL-TH-specific MBCs was found in individuals who had activated and atypical MBC expansion, anti-DBL-TH antibody responses was rapidly declined in plasma. The data suggested that these two MBCs were triggered by P. vivax infection, its expansion and stability may have impact on antibody responses. Our results provided evidence for ability of DBPII variant antigens in induction of long-lasting MBCs among individuals who were living in low malaria endemicity.
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strain transcending inhibitory antibodies against homologous and heterologous strains of Duffy Binding Protein region ii
PLOS ONE, 2016Co-Authors: Sudarat Wongkidakarn, Amy M Mchenry, John H Adams, Jetsumon Sattabongkot, Patchanee ChootongAbstract:Duffy Binding Protein region II (DBPII) is a promising vaccine candidate against vivax malaria. However, polymorphisms of DBPII are the major obstacle to designing a successful vaccine. Here, we examined whether anti-DBPII antibodies from individual P. vivax exposures provide strain-transcending immunity and whether their presence is associated with DBPII haplotypes found in patients with acute P. vivax. The ability of antibodies to inhibit DBL-TH-erythrocyte Binding was tested by COS7 erythrocyte Binding inhibition assay. Seven samples of high responders (HR) were identified from screening anti-DBPII levels. HR no.3 and HR no.6 highly inhibited all DBL-TH Binding to erythrocytes, by >80%. Antibodies from these two patients’ plasma had the potential to be broadly inhibitory against DBL-TH1, -TH2, -TH6, -TH7, -TH8 and -TH9 haplotypes when plasma was serially diluted from 1:500 to 1:2000. To further examine the association of DBPII haplotypes and the ability of antibodies to broadly inhibit DBL-TH variants, the individual samples underwent sequencing analysis and the inhibitory function of the anti-DBPII antibodies was tested. The patterns of DBPII polymorphisms in acute patients were classified into two groups, DBPII Sal I (55%) and DBL-TH variants (45%). Plasma from Sal I and DBPII-TH patients who had the highest inhibition against Sal I or DBL-TH4 and -TH5 was serially diluted from 1:500 to 1:2000 and their inhibitory capacity was tested against a panel of DBL-TH haplotypes. Results provided evidence of both strain-transcending inhibition as well as strain-specific inhibition by antibodies that blocked erythrocyte Binding against some DBL-TH variants and against homologous alleles. This study demonstrated broad inhibition by anti-DBPII antibodies against DBL-TH haplotypes in natural P. vivax exposed individuals. The identification of conserved epitopes among DBL-TH may have implications for vaccine development of a DBPII-based vaccine against diverse P. vivax infections.
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the association of Duffy Binding Protein region ii polymorphisms and its antigenicity in plasmodium vivax isolates from thailand
Parasitology International, 2014Co-Authors: Patchanee Chootong, Francis B. Ntumngia, Amy M Mchenry, Jetsumon Sattabongkot, John H AdamsAbstract:Plasmodium vivax Duffy Binding Protein II (DBPII) plays an important role in reticulocyte invasion and is a potential vaccine candidate against vivax malaria. However, polymorphisms in DBPII are a challenge for the successful design of a broadly protective vaccine. In this study, the genetic diversity of DBPII among Thai isolates was analyzed from Plasmodium vivax-infected blood samples and polymorphism characters were defined with the MEGA4 program. Sequence analysis identified 12 variant residues that are common among Thai DBPII haplotypes with variant residues L333F, L424I, W437R and I503K having the highest frequency. Variant residue D384K occurs in combination with either E385K or K386N/Q. Additionally, variant residue L424I occurs in conjunction with W437R in most Thai DBPII alleles and these variants frequently occur in combination with the I503K variant. The polymorphic patterns of Thai isolates were defined into 9 haplotypes (Thai DBL-1, -2, -3, etc.…). Thai DBL-2, -5, -6 haplotypes are the most common DBPII variants in Thai residents. To study the association of these Thai DBPII polymorphisms with antigenic character, the functional inhibition of anti-DBPII monoclonal antibodies against a panel of Thai DBL variants was characterized by an in vitro erythrocyte Binding inhibition assay. The functional inhibition of anti-DBPII monoclonal antibodies 3C9, 2D10 and 2C6 against Thai variants was significantly different, suggesting that polymorphisms of Thai DBPII variants alter the antigenic character of the target epitopes. In contrast, anti-DBPII monoclonal antibody 2H2 inhibited all Thai DBPII variants equally well. Our results suggest that the immune efficacy of a DBPII vaccine will depend on the specificity of the anti-DBPII antibodies induced and that it is preferable to optimize responses to conserved epitopes for broadly neutralizing protection against P. vivax.
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plasmodium vivax Duffy Binding Protein understanding targets of protective immunity
Malaria Journal, 2014Co-Authors: John H Adams, Francis B. Ntumngia, Miriam T. George, Jesse Schloegel, Samantha J. Barnes, Amy M MchenryAbstract:Plasmodium vivax merozoite invasion of reticulocytes is a rapid process that involves a series of specific, sequential interactions. These interactions are crucial for invasion and continued blood-stage infection, thus representing attractive targets for vaccine development. The Duffy Binding Protein (DBP) is a vital microneme Protein associated with the decisive, irreversible step of junction formation during the later stages of the invasion process. The ligand domain of DBP, known as region II (DBPII), binds the Duffy Antigen Receptor for Chemokines (DARC) by dimerization of two DBP and two DARC molecules forming a heterotetrameric structure. Naturally acquired antibodies to DBPII are prevalent in residents of areas where vivax malaria is endemic. These antibodies can inhibit DBPII Binding and merozoite invasion of human reticulocytes; however, they tend to be poorly inhibitory, strain-specific, and short-lived. Remarkably, strain-specific serologic activity can be altered by even single amino acid substitutions found in allelic variants of DBPII. While strain-transcending, broadly neutralizing antibodies are less prevalent, there is a significant correlation of their antibody reactivity to certain epitopes and inhibition of DBPII-receptor function. Our data indicate epitopes at or near the dimer interface of DBPII represent the primary targets of naturally occurring protective anti-DBPII antibodies that can inhibit merozoite invasion of host erythrocytes. However, these epitopes also contain most of the prevalent variable residues resulting from DBP allelic diversity. These data are consistent with the hypothesis that DBP variation is an immune evasion mechanism responsible for strain-specific immunity and stable, broadly neutralizing immunity is achieved when antibodies target functionally-conserved epitopes, thereby blocking DBP dimerization and inhibiting invasion. To overcome the natural tendency for eliciting a strain-specific response, synthetic DBPII alleles were evaluated for their ability to broaden efficacy of strain-transcending inhibition against diverse DBPII alleles. In an effort to identify potential conserved, protective epitopes we have prepared and evaluated a panel of anti-DBPII murine monoclonal antibodies. Inhibitory activities of these monoclonal antibodies were characterized with in vitro functional assays for DBPII and their respective minimal epitopes were mapped using phage display. These targets of putative strain-transcending inhibition identify epitopes that may be targeted for vaccine-induced anti-DBPII inhibitory antibodies.
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immunogenicity of a synthetic vaccine based on plasmodium vivax Duffy Binding Protein region ii
Clinical and Vaccine Immunology, 2014Co-Authors: Francis B. Ntumngia, Miriam T. George, Jesse Schloegel, Samantha J. Barnes, Amy M Mchenry, John H AdamsAbstract:Molecules that play a role in Plasmodium merozoite invasion of host red blood cells represent attractive targets for blood-stage vaccine development against malaria. In Plasmodium vivax, merozoite invasion of reticulocytes is mediated by the Duffy Binding Protein (DBP), which interacts with its cognate receptor, the Duffy antigen receptor for chemokines, on the surface of reticulocytes. The DBP ligand domain, known as region II (DBPII), contains the critical residues for receptor recognition, making it a prime target for vaccine development against blood-stage vivax malaria. In natural infections, DBP is weakly immunogenic and DBPII allelic variation is associated with strain-specific immunity, which may compromise vaccine efficacy. In a previous study, a synthetic vaccine termed DEKnull that lacked an immunodominant variant epitope in DBPII induced functional antibodies to shared neutralizing epitopes on the native Sal1 allele. Anti-DEKnull antibody titers were lower than anti-Sal1 titers but produced more consistent, strain-transcending anti-DBPII inhibitory responses. In this study, we further characterized the immunogenicity of DEKnull, finding that immunization with recombinant DEKnull produced an immune response comparable to that obtained with native recombinant DBP alleles. Further investigation of DEKnull is necessary to enhance its immunogenicity and broaden its specificity.
Luzia H Carvalho - One of the best experts on this subject based on the ideXlab platform.
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plasmodium simium a plasmodium vivax related malaria parasite genetic variability of Duffy Binding Protein ii and the Duffy antigen receptor for chemokines
PLOS ONE, 2015Co-Authors: Daniela Camargos Costa, Tais Nobrega De Sousa, Luzia H Carvalho, Flora S Kano, Gabriela Maira Pereira De Assis, Flavia Alessandra De Souza Silva, Flavia Carolina Faustino De Araujo, Julio Cesar De Souza, Zelinda Maria Braga Hirano, Cristiana Ferreira Alves De BritoAbstract:Plasmodium simium is a parasite from New World monkeys that is most closely related to the human malaria parasite Plasmodium vivax; it also naturally infects humans. The blood-stage infection of P. vivax depends on Duffy Binding Protein II (PvDBPII) and its cognate receptor on erythrocytes, the Duffy antigen receptor for chemokines (hDARC), but there is no information on the P. simium erythrocytic invasion pathway. The genes encoding P. simium DBP (PsDBPII) and simian DARC (sDARC) were sequenced from Southern brown howler monkeys (Alouatta guariba clamitans) naturally infected with P. simium because P. simium may also depend on the DBPII/DARC interaction. The sequences of DBP Binding domains from P. vivax and P. simium were highly similar. However, the genetic variability of PsDBPII was lower than that of PvDBPII. Phylogenetic analyses demonstrated that these genes were strictly related and clustered in the same clade of the evolutionary tree. DARC from A. clamitans was also sequenced and contained three new non-synonymous substitutions. None of these substitutions were located in the N-terminal domain of DARC, which interacts directly with DBPII. The interaction between sDARC and PvDBPII was evaluated using a cytoadherence assay of COS7 cells expressing PvDBPII on their surfaces. Inhibitory Binding assays in vitro demonstrated that antibodies from monkey sera blocked the interaction between COS-7 cells expressing PvDBPII and hDARC-positive erythrocytes. Taken together, phylogenetic analyses reinforced the hypothesis that the host switch from humans to monkeys may have occurred very recently in evolution, which sheds light on the evolutionary history of new world plasmodia. Further invasion studies would confirm whether P. simium depends on DBP/DARC to trigger internalization into red blood cells.
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distinct hla class ii alleles influence antibody response to the plasmodium vivax Duffy Binding Protein
Malaria Journal, 2014Co-Authors: Flora S Kano, Flavia A Souzasilva, Michaelis L Tang, Tais Nobrega De Sousa, R S Rocha, C F A Brito, Jessica R S Alves, Ana Maria Sell, Luzia H CarvalhoAbstract:Plasmodium vivax infects human reticulocytes through a major pathway that requires interaction between an apical parasite Protein, the Duffy Binding Protein (region II, DBPII) and its cognate receptor on reticulocytes, the Duffy antigen receptor for chemokines (DARC). Although most people naturally exposed to P. vivax fail to develop antibodies that inhibit the DBPII-DARC interaction, the genetic factors that modulate humoral responsiveness are poorly characterized. Aiming to investigate if DBPII non-responsiveness could be HLA class II-linked (DRB1, DQB1 and DQA1), we carried-out an open cohort study among 340 non-related volunteers in an agricultural settlement of the Brazilian Amazon; three cross-sectional surveys were conducted at 6-month intervals, and 240 out of 340 (71%) subjects had consecutive samples. At enrolment, 40.9% of the study population had DBPII IgG antibodies, as measured by conventional serology (ELISA); two alleles at HLA-DR locus (DRB1*10:01 and DRB1*14:02) were negatively associated with the antibody response, while two alleles at HLA-DQ locus (DQB1*02:02 and DQA1*01:03) were positively associated with antibody response. The 12-month follow-up study confirmed that those alleles associated with positive antibody response were also associated with the persistence of this specific antibody response. Further, we investigated whether HLA class II polymorphisms would influence the functional proprieties of DBPII antibodies (BIAbs, Binding inhibitory antibodies), as assessed by the COS-7 cytoadherence assay. The results demonstrated that four alleles were associated with the presence (DRB1*07:01; DQB1*02:02, DQA1*02:01) or absence (DRB1*16:02) of DBPII BIAbs response. Taken together, this is the first demonstration that HLA class II polymorphisms might influence the frequency and stability of the DBPII immune response. Due to the relevance of these findings for vaccines now in development, it would be pertinent to investigate whether such an association exists in other P. vivax malaria endemic areas.
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the Duffy Binding Protein as a key target for a plasmodium vivax vaccine lessons from the brazilian amazon
Memorias Do Instituto Oswaldo Cruz, 2014Co-Authors: Tais Nobrega De Sousa, Cristiana Ferreira Alves De Brito, Flora S Kano, Luzia H CarvalhoAbstract:Plasmodium vivax infects human erythrocytes through a major pathway that requires interaction between an apical parasite Protein, the Duffy Binding Protein (PvDBP) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). The importance of the interaction between PvDBP (region II, DBPII) and DARC to P. vivax infection has motivated our malaria research group at Oswaldo Cruz Foundation (state of Minas Gerais, Brazil) to conduct a number of immunoepidemiological studies to characterise the naturally acquired immunity to PvDBP in populations living in the Amazon rainforest. In this review, we provide an update on the immunology and molecular epidemiology of PvDBP in the Brazilian Amazon - an area of markedly unstable malaria transmission - and compare it with data from other parts of Latin America, as well as Asia and Oceania.
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worldwide genetic variability of the Duffy Binding Protein insights into plasmodium vivax vaccine development
PLOS ONE, 2011Co-Authors: Tais Nobrega De Sousa, Luzia H Carvalho, Cristiana Ferreira Alves De BritoAbstract:The dependence of Plasmodium vivax on invasion mediated by Duffy Binding Protein (DBP) makes this Protein a prime candidate for development of a vaccine. However, the development of a DBP-based vaccine might be hampered by the high variability of the Protein ligand (DBPII), known to bias the immune response toward a specific DBP variant. Here, the hypothesis being investigated is that the analysis of the worldwide DBPII sequences will allow us to determine the minimum number of haplotypes (MNH) to be included in a DBP-based vaccine of broad coverage. For that, all DBPII sequences available were compiled and MNH was based on the most frequent nonsynonymous single nucleotide polymorphisms, the majority mapped on B and T cell epitopes. A preliminary analysis of DBPII genetic diversity from eight malaria-endemic countries estimated that a number between two to six DBP haplotypes (17 in total) would target at least 50% of parasite population circulating in each endemic region. Aiming to avoid region-specific haplotypes, we next analyzed the MNH that broadly cover worldwide parasite population. The results demonstrated that seven haplotypes would be required to cover around 60% of DBPII sequences available. Trying to validate these selected haplotypes per country, we found that five out of the eight countries will be covered by the MNH (67% of parasite populations, range 48–84%). In addition, to identify related subgroups of DBPII sequences we used a Bayesian clustering algorithm. The algorithm grouped all DBPII sequences in six populations that were independent of geographic origin, with ancestral populations present in different proportions in each country. In conclusion, in this first attempt to undertake a global analysis about DBPII variability, the results suggest that the development of DBP-based vaccine should consider multi-haplotype strategies; otherwise a putative P. vivax vaccine may not target some parasite populations.
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genetic variability and natural selection at the ligand domain of the Duffy Binding Protein in brazilian plasmodium vivax populations
Malaria Journal, 2010Co-Authors: Tais Nobrega De Sousa, Cor Jesus Fernandes Fontes, Marcelo U Ferreira, Luzia H Carvalho, Eduardo Tarazonasantos, Daniel J Wilson, Ana Paula Madureira, Paula R K Falcao, Cristiana Ferreira Alves De BritoAbstract:Background: Plasmodium vivax malaria is a major public health challenge in Latin America, Asia and Oceania, with 130-435 million clinical cases per year worldwide. Invasion of host blood cells by P. vivax mainly depends on a type I membrane Protein called Duffy Binding Protein (PvDBP). The erythrocyte-Binding motif of PvDBP is a 170 aminoacid stretch located in its cysteine-rich region II (PvDBPII), which is the most variable segment of the Protein. Methods: To test whether diversifying natural selection has shaped the nucleotide diversity of PvDBPII in Brazilian populations, this region was sequenced in 122 isolates from six different geographic areas. A Bayesian method was applied to test for the action of natural selection under a population genetic model that incorporates recombination. The analysis was integrated with a structural model of PvDBPII, and T- and B-cell epitopes were localized on the 3-D structure. Results: The results suggest that: (i) recombination plays an important role in determining the haplotype structure of PvDBPII, and (ii) PvDBPII appears to contain neutrally evolving codons as well as codons evolving under natural selection. Diversifying selection preferentially acts on sites identified as epitopes, particularly on amino acid residues 417, 419, and 424, which show strong linkage disequilibrium. Conclusions: This study shows that some polymorphisms of PvDBPII are present near the erythrocyte-Binding domain and might serve to elude antibodies that inhibit cell invasion. Therefore, these polymorphisms should be taken into account when designing vaccines aimed at eliciting antibodies to inhibit erythrocyte invasion.
