Conserved and Variant Epitopes of Plasmodium vivax Duffy Binding Protein as Targets of Inhibitory Monoclonal Antibodies

Ntumngia, Francis B.; Schloegel, Jesse; Barnes, Samantha J.; McHenry, Amy M.; Singh, Sanjay; King, Christopher L.; Adams, John

doi:10.1128/iai.05924-11

Cited by 58 publications

(108 citation statements)

References 38 publications

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“…4D). 3D10 is noninhibitory, with an IC 50 several orders of magnitude weaker than that of 2D10 and 2H2 (32). The decreased potency can be attributed to the fact that this motif is not implicated in primary DARC receptor binding or DBP-II dimerization (19).…”

Section: Mutational Screens Identify Critical Binding Residues For Mamentioning

confidence: 94%

“…Anti-DBP-II Abs can inhibit DBP-DARC receptor binding and parasite invasion (7,9,18,19,32); however, high d N /d S ratios in DBP-II, a pattern seen when selective pressure drives allelic diversity as a mechanism for immune invasion (47)(48)(49), result in diverse polymorphic populations within endemic regions that manifest as mixed infections with multiple strains. These polymorphisms result in strain-specific immune responses that render individuals susceptible to future infections by alternate strains and require vaccine efforts to preemptively account for this vulnerability (50).…”

Section: Discussionmentioning

confidence: 99%

“…Three monoclonal antibodies (mAbs), 2D10, 2H2, and 2C6, block DBP from binding to erythrocytes (32). Here we present a crystal structure of DBP-II bound to a single-chain variable fragment (scFv) derived from a potent inhibitory mAb 2D10 that identifies a specific inhibitory epitope within SD3.…”

Section: Significancementioning

confidence: 99%

“…In addition, antibodies that engage the dimer interface and/or receptor binding residues of DBL domains are potently neutralizing (9,18,19,31). Polymorphisms in DBP and the presence of multiple strains in endemic regions present unique challenges (32)(33)(34). Analysis of 676 bp within DBP-II revealed 127 polymorphic sites with nucleotide diversity varying between 0.006 and 0.0109, resulting in 193 haplotypes (35).…”

mentioning

confidence: 99%

“…Analysis of 676 bp within DBP-II revealed 127 polymorphic sites with nucleotide diversity varying between 0.006 and 0.0109, resulting in 193 haplotypes (35). These factors induce strain-specific protection rather than strain-transcending immunity, which leaves individuals susceptible to continued infection and disease (6,9,17,32,33,36).…”

mentioning

confidence: 99%

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Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

Chen

Salinas

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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129

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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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Section: Mutational Screens Identify Critical Binding Residues For Mamentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

Chen

Salinas

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

129

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Inhibition of a malaria host–pathogen interaction by a computationally designed inhibitor

et al. 2022

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Malaria is a substantial global health burden with 229 million cases in 2019 and 450,000 deaths annually. Plasmodium vivax is the most widespread malariacausing parasite putting 2.5 billion people at risk of infection. P. vivax has a dormant liver stage and therefore can exist for long periods undetected. Its bloodstage can cause severe reactions and hospitalization. Few treatment and detection options are available for this pathogen. A unique characteristic of P. vivax is that it depends on the Duffy antigen/receptor for chemokines (DARC) on the surface of host red blood cells for invasion. P. vivax employs the Duffy binding protein (DBP) to bind to DARC. We first de novo designed a three helical bundle scaffolding database which was screened via protease digestions for stability. Protease-resistant scaffolds highlighted thresholds for stability, which we utilized for selecting DARC mimetics that we subsequentially designed through grafting and redesign of these scaffolds. The optimized design small helical protein disrupts the DBP:DARC interaction. The inhibitor blocks the receptor binding site on DBP and thus forms a strong foundation for a therapeutic that will inhibit reticulocyte infection and prevent the pathogenesis of P. vivax malaria.

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Structure‐based design of a Plasmodium vivax Duffy‐binding protein immunogen focuses the antibody response to functional epitopes

Dickey,

McAleese,

Salinas

et al. 2024

Protein Science

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The Duffy‐binding protein (DBP) is a promising antigen for a malaria vaccine that would protect against clinical symptoms caused by Plasmodium vivax infection. Region II of DBP (DBP‐II) contains the receptor‐binding domain that engages host red blood cells, but DBP‐II vaccines elicit many non‐neutralizing antibodies that bind distal to the receptor‐binding surface. Here, we engineered a truncated DBP‐II immunogen that focuses the immune response to the receptor‐binding surface. This immunogen contains the receptor‐binding subdomain S1S2 and lacks the immunodominant subdomain S3. Structure‐based computational design of S1S2 identified combinatorial amino acid changes that stabilized the isolated S1S2 without perturbing neutralizing epitopes. This immunogen elicited DBP‐II‐specific antibodies in immunized mice that were significantly enriched for blocking activity compared to the native DBP‐II antigen. This generalizable design process successfully stabilized an integral core fragment of a protein and focused the immune response to desired epitopes to create a promising new antigen for malaria vaccine development.

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Conserved and Variant Epitopes of Plasmodium vivax Duffy Binding Protein as Targets of Inhibitory Monoclonal Antibodies

Cited by 58 publications

References 38 publications

Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

Inhibition of a malaria host–pathogen interaction by a computationally designed inhibitor

Structure‐based design of a Plasmodium vivax Duffy‐binding protein immunogen focuses the antibody response to functional epitopes

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