Plasmodium vivax is responsible for 132-391 million cases of clinical malaria each year causing about 12% of infections in Africa and more than 70% of infections in Asia and the Americas. Vivax malaria is known to incapacitate individuals of all ages resulting in repeated febrile episodes, severe anemia, respiratory distress and poor outcomes in pregnancy. Exclusion of P. vivax from much of Africa is associated with high prevalence of Duffy blood group negativity while the parasite's strong preference for reticulocytes has limited our ability to conduct experimental research in the laboratory. Both of these biological characteristics can be attributed to ligands expressed by invasive blood-stage merozoites. Humoral immunity to P. vivax invasion ligands is believed to play a critical role in controlling the blood-stage infection thereby limiting clinical disease. Therefore, the Duffy binding protein, which binds its cognate receptor the Duffy blood group antigen, has become a leading candidate against vivax malaria with the primary focus on the cysteine-rich ligand domain, or region II (DBPII). The major obstacle for developing this antigen as an effective vaccine is its high degree of polymorphism within the receptor-binding site that makes ineffective the weak strain-specific immunity that typically results from infection. We hypothesize that dominant B-cell epitopes of DBPII are polymorphic as an evasion mechanism that diverts the immune response away from the more conserved, functionally important neutralizing epitopes similar to other microbial ligands. Data generated from our initial funding period supported this underlying hypothesis that guide our project and the methodological approaches pursued.
The specific aims will define the immunological properties of DBPII and identify functionally conserved determinants that are targets of strain-transcending inhibitory antibodies. Our long-term goal is to optimize efficacy of DBPII as a broadly effective vaccine that elicits antibodies to conserved strain-transcending neutralizing epitopes.

Public Health Relevance

Malaria is a significant global health problem and Plasmodium vivax is the major cause of non-African malaria, causing 132-391 million cases of clinical malaria each year at an estimated cost of $1.4 - $4 billion per year. Widespread drug resistance, the relapsing nature of P. vivax, and emerging virulent forms of P. vivax emphasizes the critical need for development of a vaccine against P. vivax. Our goal is to develop a vaccine to eliminate vivax malaria as a major health problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064478-08
Application #
8611893
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
MO, Annie X Y
Project Start
2005-04-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
8
Fiscal Year
2014
Total Cost
$611,586
Indirect Cost
$99,555
Name
University of South Florida
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Roobsoong, Wanlapa; Maher, Steven P; Rachaphaew, Nattawan et al. (2014) A rapid sensitive, flow cytometry-based method for the detection of Plasmodium vivax-infected blood cells. Malar J 13:55
Ntumngia, Francis B; Barnes, Samantha J; McHenry, Amy M et al. (2014) Immunogenicity of a synthetic vaccine based on Plasmodium vivax Duffy binding protein region II. Clin Vaccine Immunol 21:1215-23
Chootong, Patchanee; McHenry, Amy M; Ntumngia, Francis B et al. (2014) The association of Duffy binding protein region II polymorphisms and its antigenicity in Plasmodium vivax isolates from Thailand. Parasitol Int 63:858-64
Ntumngia, Francis B; Schloegel, Jesse; McHenry, Amy M et al. (2013) Immunogenicity of single versus mixed allele vaccines of Plasmodium vivax Duffy binding protein region II. Vaccine 31:4382-8
Handa, Sumit; Ramamoorthy, Divya; Spradling, Tyler J et al. (2013) Production of recombinant 1-deoxy-d-xylulose-5-phosphate synthase from Plasmodium vivax in Escherichia coli. FEBS Open Bio 3:124-9
Ntumngia, Francis B; Schloegel, Jesse; Barnes, Samantha J et al. (2012) Conserved and variant epitopes of Plasmodium vivax Duffy binding protein as targets of inhibitory monoclonal antibodies. Infect Immun 80:1203-8
Ntumngia, Francis B; Adams, John H (2012) Design and immunogenicity of a novel synthetic antigen based on the ligand domain of the Plasmodium vivax duffy binding protein. Clin Vaccine Immunol 19:30-6
McHenry, Amy M; Barnes, Samantha J; Ntumngia, Francis B et al. (2011) Determination of the molecular basis for a limited dimorphism, N417K, in the Plasmodium vivax Duffy-binding protein. PLoS One 6:e20192
King, Christopher L; Adams, John H; Xianli, Jia et al. (2011) Fy(a)/Fy(b) antigen polymorphism in human erythrocyte Duffy antigen affects susceptibility to Plasmodium vivax malaria. Proc Natl Acad Sci U S A 108:20113-8
Russell, Bruce; Suwanarusk, Rossarin; Borlon, Celine et al. (2011) A reliable ex vivo invasion assay of human reticulocytes by Plasmodium vivax. Blood 118:e74-81

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