Epitope-Specific Humoral Immunity to Plasmodium vivax Duffy Binding Protein

ABSTRACT Erythrocyte invasion by Plasmodium vivax is completely dependent on binding to the Duffy blood group antigen by the parasite Duffy binding protein (DBP). The receptor-binding domain of this protein lies within a cysteine-rich region referred to as region II (DBPII). To examine whether antibody responses to DBP correlate with age-acquired immunity to P. vivax, antibodies to recombinant DBP (rDBP) were measured in 551 individuals residing in a village endemic for P. vivax in Papua New Guinea, and linear epitopes mapped in the critical binding region of DBPII. Antibody levels to rDBPII increased with age. Four dominant linear epitopes were identified, and the number of linear epitopes recognized by semiimmune individuals increased with age, suggesting greater recognition with repeated infection. Some individuals had antibodies to rDBPII but not to the linear epitopes, indicating the presence of conformational epitopes. This occurred in younger individuals or subjects acutely infected for the first time with P. vivax, indicating that repeated infection is required for recognition of linear epitopes. All four dominant B-cell epitopes contained polymorphic residues, three of which showed variant-specific serologic responses in over 10% of subjects examined. In conclusion, these results demonstrate age-dependent and variant-specific antibody responses to DBPII and implicate this molecule in partial acquired immunity to P. vivax in populations in endemic areas.

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Antibody Responses and Avidity of Naturally Acquired Anti-Plasmodium vivax Duffy Binding Protein (PvDBP) Antibodies in Individuals from an Area with Unstable Malaria Transmission

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.2011.11-0001 ◽

2011 ◽

Vol 84 (6) ◽

pp. 944-950 ◽

Cited By ~ 17

Author(s):

Sedigheh Zakeri ◽

Akram Abouie Mehrizi ◽

Navid Dinparast Djadid ◽

Laleh Babaeekhou ◽

Maryam Abbasi

Keyword(s):

Plasmodium Vivax ◽

Malaria Transmission ◽

Binding Protein ◽

Antibody Responses ◽

Duffy Binding Protein

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Mapping Epitopes of the Plasmodium vivax Duffy Binding Protein with Naturally Acquired Inhibitory Antibodies

Infection and Immunity ◽

10.1128/iai.01036-09 ◽

2009 ◽

Vol 78 (3) ◽

pp. 1089-1095 ◽

Cited By ~ 64

Author(s):

Patchanee Chootong ◽

Francis B. Ntumngia ◽

Kelley M. VanBuskirk ◽

Jia Xainli ◽

Jennifer L. Cole-Tobian ◽

...

Keyword(s):

Plasmodium Vivax ◽

Binding Protein ◽

High Titer ◽

Blood Stage ◽

Duffy Binding Protein ◽

Linear Peptide ◽

Binding Function ◽

Blood Stage Infection ◽

Erythrocyte Binding ◽

Linear Epitopes

ABSTRACT Plasmodium vivax Duffy binding protein (DBP) is a merozoite microneme ligand vital for blood-stage infection, which makes it an important candidate vaccine for antibody-mediated immunity against vivax malaria. A differential screen with a linear peptide array compared the reactivities of noninhibitory and inhibitory high-titer human immune sera to identify target epitopes associated with protective immunity. Naturally acquired anti-DBP-specific serologic responses observed in the residents of a region of Papua New Guinea where P. vivax is highly endemic exhibited significant changes in DBP-specific titers over time. The anti-DBP functional inhibition for each serum ranged from complete inhibition to no inhibition even for high-titer responders to the DBP, indicating that epitope specificity is important. Inhibitory immune human antibodies identified specific B-cell linear epitopes on the DBP (SalI) ligand domain that showed significant correlations with inhibitory responses. Affinity-purified naturally acquired antibodies on these epitopes inhibited the DBP erythrocyte binding function greatly, confirming the protective value of specific epitopes. These results represent an important advance in our understanding of part of blood-stage immunity to P. vivax and some of the specific targets for vaccine-elicited antibody protection.

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Strain-Specific Duffy Binding Protein Antibodies Correlate with Protection against Infection with Homologous Compared to Heterologous Plasmodium vivax Strains in Papua New Guinean Children

Infection and Immunity ◽

10.1128/iai.00158-09 ◽

2009 ◽

Vol 77 (9) ◽

pp. 4009-4017 ◽

Cited By ~ 56

Author(s):

Jennifer L. Cole-Tobian ◽

Pascal Michon ◽

Moses Biasor ◽

Jack S. Richards ◽

James G. Beeson ◽

...

Keyword(s):

Plasmodium Vivax ◽

Cox Regression ◽

Binding Protein ◽

Blood Stage ◽

Incidence Density ◽

High Antibody ◽

Duffy Binding Protein ◽

Specific Immunity ◽

Antibody Levels ◽

Papua New Guinean

ABSTRACT Individuals repeatedly infected with malaria acquire protection from infection and disease; immunity is thought to be primarily antibody-mediated and directed to blood-stage infection. Merozoite surface proteins involved in the invasion of host erythrocytes are likely targets of protective antibodies. We hypothesized that Papua New Guinean children (n = 206) who acquire high antibody levels to two Plasmodium vivax merozoite proteins, Duffy binding protein region II (PvDBPII) and the 19-kDa C-terminal region of P. vivax merozoite surface protein 1 (PvMSP119), would have a delay in the time to reinfection following treatment to clear all blood-stage malaria infections. Ninety-four percent of the children were reinfected with P. vivax during biweekly follow-ups for 6 months. Since PvDBPII is polymorphic, we examined whether individuals acquired strain-specific immunity to PvDBPII. Children with high antibody levels to a prevalent PvDBPII allele (O) were associated with a delay in the time to reinfection with the same variant of P. vivax by 25% compared to parasites expressing other PvDBPII alleles (age-adjusted hazard ratio, 0.75 [95% confidence interval, 0.56 to 1.00 by Cox regression]) and 39% lower incidence density parasitemia (P = 0.01). Two other prevalent alleles (AH and P) showed a similar trend of 16% and 18% protection, respectively, against parasites with the same PvDBPII allele and reduced incidence density parasitemia. Antibodies directed to PvDBPII PNG-P and -O were both associated with a 21 to 26% reduction in the risk of P. vivax infections with higher levels of parasitemia (>150 parasites/μl), respectively. There was no association with high antibody levels to PvMSP119 and a delay in the time to P. vivax reinfection. Thus, anti-PvDBPII antibodies are associated with strain-specific immunity to P. vivax and support the use of PvDBPII for a vaccine against P. vivax.

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Non-allele specific antibody responses to genetically distinct variant forms of Plasmodium vivax Duffy binding protein (PvDBP-II) in Iranians exposed to seasonal malaria transmission

Acta Tropica ◽

10.1016/j.actatropica.2014.03.019 ◽

2014 ◽

Vol 136 ◽

pp. 89-100 ◽

Cited By ~ 6

Author(s):

Vahideh Valizadeh ◽

Sedigheh Zakeri ◽

Akram Abouei Mehrizi ◽

Navid Dinparast Djadid

Keyword(s):

Plasmodium Vivax ◽

Malaria Transmission ◽

Specific Antibody ◽

Binding Protein ◽

Antibody Responses ◽

Duffy Binding Protein ◽

Allele Specific

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Plasmodium vivax Duffy binding protein: baseline antibody responses and parasite polymorphisms in a well-consolidated settlement of the Amazon Region

Tropical Medicine & International Health ◽

10.1111/j.1365-3156.2012.03016.x ◽

2012 ◽

Vol 17 (8) ◽

pp. 989-1000 ◽

Cited By ~ 20

Author(s):

Flora S. Kano ◽

Bruno A. M. Sanchez ◽

Tais N. Sousa ◽

Michaelis L. Tang ◽

Jéssica Saliba ◽

...

Keyword(s):

Plasmodium Vivax ◽

Binding Protein ◽

Amazon Region ◽

Antibody Responses ◽

Duffy Binding Protein

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Evaluation of immune responses elicited in mice against a recombinant malaria vaccine based on Plasmodium vivax Duffy binding protein

Vaccine ◽

10.1016/j.vaccine.2004.03.030 ◽

2004 ◽

Vol 22 (27-28) ◽

pp. 3727-3737 ◽

Cited By ~ 40

Author(s):

Syed Shams Yazdani ◽

Ahmad Rushdi Shakri ◽

Paushali Mukherjee ◽

Sanjeev Kumar Baniwal ◽

Chetan E. Chitnis

Keyword(s):

Immune Responses ◽

Plasmodium Vivax ◽

Malaria Vaccine ◽

Binding Protein ◽

Duffy Binding Protein

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Production of recombinant PvDBPII, receptor binding domain of Plasmodium vivax Duffy binding protein, and evaluation of immunogenicity to identify an adjuvant formulation for vaccine development

Protein Expression and Purification ◽

10.1016/j.pep.2015.06.011 ◽

2017 ◽

Vol 136 ◽

pp. 52-57 ◽

Cited By ~ 7

Author(s):

Rukmini Bhardwaj ◽

Ahmad Rushdi Shakri ◽

Dhiraj Hans ◽

Pankaj Gupta ◽

Carmen Fernandez-Becerra ◽

...

Keyword(s):

Plasmodium Vivax ◽

Receptor Binding ◽

Vaccine Development ◽

Binding Protein ◽

Binding Domain ◽

Receptor Binding Domain ◽

Duffy Binding Protein

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Identification and evaluation of universal epitopes in Plasmodium vivax Duffy binding protein

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2008.10.153 ◽

2008 ◽

Vol 377 (4) ◽

pp. 1279-1283 ◽

Cited By ~ 9

Author(s):

Carolina Saravia ◽

Paola Martinez ◽

Diana S. Granados ◽

Carolina Lopez ◽

Claudia Reyes ◽

...

Keyword(s):

Plasmodium Vivax ◽

Binding Protein ◽

Duffy Binding Protein

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Single-Chain Antibody Fragment Specific for Plasmodium vivax Duffy Binding Protein

Clinical and Vaccine Immunology ◽

10.1128/cvi.00456-06 ◽

2007 ◽

Vol 14 (6) ◽

pp. 726-731 ◽

Cited By ~ 6

Author(s):

So-Hee Kim ◽

Seung-Young Hwang ◽

Yong-Seok Lee ◽

In-Hak Choi ◽

Sae-Gwang Park ◽

...

Keyword(s):

Phage Display ◽

Plasmodium Vivax ◽

Binding Protein ◽

Antibody Fragment ◽

Neutralizing Antibody ◽

Active Immunization ◽

Single Chain ◽

Single Chain Antibody ◽

Duffy Binding Protein ◽

Erythrocyte Binding

ABSTRACT Phage display of single-chain variable fragment (scFv) antibodies is a powerful tool for selecting important, useful, and specific human antibodies. We constructed a library from three patients infected with Plasmodium vivax. Panning on recombinant PvRII enriched a population of scFvs that recognized region II of the P. vivax Duffy binding protein (DBP). Three clones of scFvs that reacted with PvRII were selected, and their biological functions were analyzed. These scFvs inhibited erythrocyte binding to DBP. Clone SFDBII92 had the greatest affinity (dissociation constant = 3.62 × 10−8 M) and the greatest inhibition activity (50% inhibitory concentration ≈ 2.9 μg/ml) to DBP. Thus, we demonstrated that human neutralizing antibody could be made from malaria patients using phage display and that these neutralizing scFvs should prove valuable for developing both passive and active immunization strategies based on DBP.

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