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Principal Investigator: Dipak Kumar Raj
Organization: UNIVERSITY OF SOUTH FLORIDA
Fiscal Year: 2024
Award: $375,000
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
The overall aim of this application is to advance PfCDPK5 and PfGARP as vaccine candidates for
falciparum malaria. P.falciparum malaria affects almost one-half of the world's population and causes more
than 500,000 deaths annually. Young children in malaria endemic areas of Africa have the highest mortality
rate because of their immature immune systems. Global efforts to control the disease have had limited
success, and no vaccine has yet been approved for clinical use. Therefore, there is an urgent, unmet need to
discover new vaccine candidates. A vaccine against childhood malaria is a priority because children below the
age of 5 years are highly vulnerable to the disease. In recent studies, our laboratory discovered Schizont
Egress Antigen-1 (PfSEA-1), a 244-kDa-parasite antigen that is crucial for parasite egress from an infected red
blood cell (iRBC), which was published as a comprehensive, full-length Research Article in Science.
In a parallel approach, we have screened phage display cDNA libraries constructed from parasites
isolated at our Tanzanian field site with/without culture adaptation using positive selection with antibodies
pooled from resistant two-year-olds and negative selection with antibodies pooled from susceptible children.
We identified several independent cDNA clones encoding plasmodium falciparum glutamic acid reach protein
(PfGARP) and plant-like calcium-dependent protein kinase (PfCDPK5) that were uniquely recognized by
antibodies in resistant, but not susceptible sera. Our preliminary data demonstrate that PfGARP and PfCDPK5
is critical for parasite development in side RBC and egress respectively). PfGARP expresses on the surface of
the trophozoite infected RBC and PfCDPK5 is expressed by merozoites as they rupture from erythrocytes.
Antibodies against PfGARP and PfCDPK5 block parasite growth up to 99% in vitro, and ortholog vaccine of
CDPK5 protect mice from parasitemia, and extend the survival of mice challenged with lethal P. berghei ANKA.
Our vaccine discovery program has also identified several known invasion ligands (MSP-4 and MSP-7
collectively referred to as MSPs) In this application, we will evaluate these vaccine candidates with CDPK5 as
single fusion protein (PfCDPK5-MSP4 & PfCDPK5-MSP7) in combination with PfGARP in in vitro assays and
using multiple adjuvant systems in murine vaccine trials. The lead fusion antigen will be further evaluated for
cell mediated immune response using TFRS depletion method in murine model. The deliverables from this study
will be an adjuvant optimized tri-valent vaccine ready for Aotus/ P. falciparum challenge and Phase-1 clinical
trial in human that targets the entry, intracellular development, and the exit of the parasite cycle in .
Terms: <0-11 years old><2 year old><2 years of age><5 year old><5 years of age><Achievement><Achievement Attainment><Adjuvant><Adjuvant Study><Adjuvant Trials><Affect><Africa><Africa South of the Sahara><Alhydrogel><Animals><Antibodies><Antibody titer measurement><Antigens><Aotus><Aotus primate><Area><Assay><B blood cells><B cell><B cells><B-Cell Development><B-Cells><B-Lymphocytes><B-cell><BALB/cJ Mouse><Bioassay><Biological Assay><Birth><Blocking Antibodies><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood erythrocyte><Cell Body><Cells><Cerebral Malaria><Cessation of life><Child><Child Youth><Childhood><Children (0-21)><Chimera Protein><Chimeric Proteins><Clinical><Complementary DNA><Country><Data><Death><Death Rate><Development><Disease><Disorder><Dose><ELISA><Early-Stage Clinical Trials><Encapsulated><Enzyme-Linked Immunosorbent Assay><Epidemiological data><Epidemiology data><Erythrocytes><Erythrocytic><Evaluation><Falciparum Malaria><Formulation><Fusion Protein><Future><Gene Transcription><Generalized Growth><Generations><Genes><Genetic Transcription><Glutamic Acid><Growth><Growth and Development><Growth and Development function><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hemoglobin concentration result><Human><Immune system><Immunize><Immunodominant Antigenic Determinants><Immunodominant Determinants><Immunodominant Domains><Immunodominant Epitopes><Immunodominant Regions><Immunodominant Sites><In Vitro><Individual><Inducer Cells><Inducer T-Lymphocytes><Infection><Invaded><L-Glutamic Acid><Laboratories><Lead><Legal patent><Length><Libraries><Life Cycle><Life Cycle Stages><Ligands><Lipids><Malaria><Malaria Vaccines><Malarial Vaccines><Marrow erythrocyte><Measures><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Methods><Mice><Mice Mammals><Modeling><Modern Man><Monkeys><Morbidity><Morbidity - disease rate><Murine><Mus><Ortholog><Orthologous Gene><P falciparum><P. falciparum><P.falciparum><Paludism><Parasitemia><Parasites><Parasitic Diseases><Parturition><Patents><Pathway interactions><Pb element><Phage Display><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Planets><Plants><Plasma><Plasma Serum><Plasmodium Infections><Plasmodium falciparum><Plasmodium falciparum Malaria><Population><Predisposition><Primates><Primates Mammals><Process><Proteins><Proteome><Publications><Publishing><RNA Expression><Red Blood Cells><Red Cell><Regulatory T-Lymphocyte><Research><Resistance><Reticuloendothelial System, Serum, Plasma><Rodent><Rodentia><Rodents Mammals><Rupture><Science><Scientific Publication><Side><Site><Sub-Saharan Africa><Subsaharan Africa><Surface><Susceptibility><System><Tanzania><Tissue Growth><Titer Max><TiterMax><Transcription><Treg><Vaccinated><Vaccination><Vaccines><Work><adjuvant protocol><age 2 years><age 5 years><aged 2 years><aged two years><antibody assay><antibody based test><antibody test><antibody titering><asexual><blood corpuscles><cDNA><cDNA Library><calcium-dependent protein kinase><cell mediated immune response><cohort><compare to control><comparison control><design><designing><developmental><discover vaccines><disease control><disorder control><enzyme linked immunoassay><epidemiologic data><evaluate vaccines><five year old><five years of age><heavy metal Pb><heavy metal lead><hemoglobin level><immunogen><in vitro Assay><kids><life course><mRNA><mortality><mortality rate><mortality ratio><mouse model><murine model><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel><novel vaccines><ontogeny><parasaetemia><pathway><pediatric><phase I protocol><polyclonal antibody><primary outcome><programs><regulatory T-cells><resistant><response><screening><screenings><secondary outcome><success><synergism><two year old><two years of age><vaccination study><vaccination trial><vaccine candidate><vaccine discovery><vaccine efficacy><vaccine evaluation><vaccine screening><vaccine study><vaccine testing><vaccine trial><vaccines against malaria><youngster>