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2023-01-01
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AN ENGINEERED VACCINE OF THE PLASMODIUM VIVAX DUFFY BINDING PROTEIN ENHANCES INDUCTION OF BROADLY NEUTRALIZING ANTIBODIES
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University of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Department of Global Health. Tampa, FL, USA.
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
University of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Department of Global Health. Tampa, FL, USA.
University of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Department of Global Health. Tampa, FL, USA.
University of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Department of Global Health. Tampa, FL, USA.
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
Washington University School of Medicine. Departments of Molecular Microbiology & Microbial Pathogenesis, and Biochemistry & Molecular Biophysics. Saint Louis, USA.
Centro de Pesquisa em Medicina Tropical de Rondonia. Porto Velho, RO, Brazil.
Washington University School of Medicine. Departments of Molecular Microbiology & Microbial Pathogenesis, and Biochemistry & Molecular Biophysics. Saint Louis, USA.
Center for Global Health and Diseases, Case Western Reserve University, Cleveland, 44106, USA
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
University of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Department of Global Health. Tampa, FL, USA.
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
University of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Department of Global Health. Tampa, FL, USA.
University of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Department of Global Health. Tampa, FL, USA.
University of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Department of Global Health. Tampa, FL, USA.
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
Washington University School of Medicine. Departments of Molecular Microbiology & Microbial Pathogenesis, and Biochemistry & Molecular Biophysics. Saint Louis, USA.
Centro de Pesquisa em Medicina Tropical de Rondonia. Porto Velho, RO, Brazil.
Washington University School of Medicine. Departments of Molecular Microbiology & Microbial Pathogenesis, and Biochemistry & Molecular Biophysics. Saint Louis, USA.
Center for Global Health and Diseases, Case Western Reserve University, Cleveland, 44106, USA
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil.
University of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Department of Global Health. Tampa, FL, USA.
Abstract
Plasmodium vivax invasion into human reticulocytes is a complex process. The Dufy binding protein (DBP) dimerization with its cognate receptor is vital for junction formation in the invasion process. Due to its functional importance, DBP is considered a prime vaccine candidate, but variation in B-cell epitopes at the dimer interface of DBP leads to induction of strain-limited immunity. We believe that the polymorphic residues tend to divert immune responses away from functionally conserved epitopes important for receptor binding or DBP dimerization. As a proof of concept, we engineered the vaccine DEKnull to ablate the dominant Bc epitope to partially overcome strain-specifc immune antibody responses. Additional surface engineering on the next generation immunogen, DEKnull-2, provides an immunogenicity breakthrough to conserved protective epitopes. DEKnull-2 elicits a stronger broadly neutralizing response and reactivity with long-term persistent antibody responses of acquired natural immunity. By using novel engineered DBP immunogens, we validate that the prime targets of protective immunity are conformational epitopes at the dimer interface. These successful results indicate a potential approach that can be used generally to improve efcacy of other malaria vaccine candidates.
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