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Principal Investigator: Jonathan D. Kurtis
Organization: BROWN UNIVERSITY
Fiscal Year: 2023
Award: $500,144
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
The goal of this R01 application is to discover the targets of naturally acquired protection against severe
Plasmodium falciparum malaria and to develop them as novel blood-stage vaccine candidates. Of the ~100
malaria vaccine candidates currently under investigation, more than 60% are based on only four parasite
antigens and the most advanced vaccine, RTS,S, generates only modest protection 1, 2.
In previous studies, we developed a highly innovative whole proteome differential screening strategy which
identifies the subset of parasite antigens that are recognized by antibodies expressed by resistant individuals
but not susceptible individuals. Using this strategy, we discovered Schizont Egress Antigen-1 (PfSEA-1), a
244-kDa parasite antigen that is the target of antibodies which arrest parasites at the schizont stage and are
associated with significant protection from severe malarial disease in a cohort of n=785 two yr old children.
This is the first demonstration that antibodies that specifically block egress can protect against severe malaria
in humans (Science 4).
In parallel studies, we also identified PfGARP, a previously unrecognized vaccine candidate which localized
to the exofacial surface of the RBC membrane in trophozoite infected RBC. Antibodies to the highly invariant
carboxyl terminal of PfGARP (PfGARP-A, aa 411-673) inhibit parasite growth in vitro by 99% compared to
controls (P < 0.001) by killing trophozoite stage parasites. Numerous mechanistic assays demonstrated that
the binding of anti-PfGARP to the surface of the infected RBC induces parasite programed cell death as
evidenced by pyknotic nuclear morphology, caspase activation, mitochondrial depolarization, DNA
fragmentation, and release of intracellular calcium. In addition, vaccination of non-human primates with
PfGARP formulated as a lipid encapsulated mRNA results in significant protection from P. falciparum challenge
compared to controls (Nature 5).
These preliminary results were based on differential screening using sera from resistant and susceptible
individuals with the definition of resistance based solely on parasitemia. Previous work has demonstrated that
children develop resistance to severe malaria after only one or two episodes, and this protection is distinct from
responses that simply control parasitemia 6. In the current proposal, we will capitalize on this observation to
identify parasite antigens that are targets of antibody responses which are acquired and expressed during the
convalescent phase of an episode of severe malaria and protect against future episodes of severe malaria.
We will: 1) conduct a case-control study at our field site in a holoendemic region of western Kenya to
identify infants and children with severe malaria and matched controls. 2) perform whole proteome differential
screening using sera from this case-control study, and 3) down select candidates for follow-on vaccine studies
using a suite of assays (growth inhibition, human immunoepidemiologic studies, and murine vaccine trials).
Terms: <0-11 years old><Age><Ambulatory Care Facilities><Antibodies><Antibody Response><Antigen Targeting><Antigens><Antisera><Aotus><Aotus primate><Assay><Binding><Bioassay><Biologic Assays><Biological Assay><Blocking Antibodies><Blood><Blood Plasma><Blood Reticuloendothelial System><Calcium><Case-Base Studies><Case-Comparison Studies><Case-Compeer Studies><Case-Referent Studies><Case-Referrent Studies><Case/Control Studies><Caspase><Caspase Gene><Cell Body><Cell Death><Cell-Death Protease><Cells><Cerebral Malaria><Child><Child Youth><Children (0-21)><Complement><Complement Activation><Complement Proteins><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><DNA Fragmentation><Data><Disease><Disorder><Early-Stage Clinical Trials><Encapsulated><Enrollment><Evaluation><Falciparum Malaria><Future><Generalized Growth><Glutamic Acid><Goals><Growth><Hospitals><Human><ICE-like protease><Immune><Immune Sera><Immunes><Immunity><Immunologic Epidemiology><In Vitro><Individual><Infant><Investigation><Kenya><L-Glutamic Acid><Libraries><Lipids><Malaria><Malaria Vaccines><Malarial Vaccines><Measures><Membrane><Messenger RNA><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular Interaction><Morphology><Murine><Mus><Nature><Nuclear><Ortholog><Orthologous Gene><Outpatient Clinics><P falciparum><P. falciparum><P.falciparum><Paludism><Parasitemia><Parasites><Phage Display><Phagocytosis><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Plasma><Plasma Serum><Plasmodium Infections><Plasmodium falciparum><Plasmodium falciparum Malaria><Predisposition><Proteins><Proteome><Resistance><Resistance development><Resistant development><Reticuloendothelial System, Serum, Plasma><Site><Surface><Susceptibility><Tissue Growth><Vaccination><Vaccines><Work><ages><antibody assay><antibody based test><antibody test><candidate selection><case-controlled studies><cohort><compare to control><comparison control><complement pathway regulation><cystein protease><cystein proteinase><cysteine endopeptidase><design><designing><developing resistance><enroll><immune serum><immunoepidemiology><immunogen><innovate><innovation><innovative><kids><mRNA><membrane structure><mitochondrial><necrocytosis><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel><novel vaccines><ontogeny><parasaetemia><phase I protocol><polyclonal antibody><resistant><response><screening><screenings><vaccination study><vaccination trial><vaccine candidate><vaccine study><vaccine trial><vaccines against malaria><youngster>