Document text
Principal Investigator: James Matthew Burns
Organization: DREXEL UNIVERSITY
Fiscal Year: 2024
Award: $738,445
Funding agency: National Institute of Allergy and Infectious Diseases
The heavy burden of Plasmodium falciparum and Plasmodium vivax malaria drove international efforts
to coordinate and integrate tools and programs for mosquito vector control, rapid diagnosis, and drug treatment.
Success has been significant but may be approaching a limiting boundary. The effort to develop a vaccine to
further enhance malaria control has faced many challenges. The advancement of the pre-erythrocytic-stage
RTS,S vaccine is a major accomplishment, providing the foundation for an effort that must continue to improve
efficacy and durability of vaccine-induced protection to further reduce the disease burden. In this regard, the
development of a multivalent vaccine that concurrently targets pre-erythrocytic-stage, blood-stage and sexual
stage parasites is attractive but adds complexity. The immunogenicity of each component must be maintained
while effectively driving both antibody and cell-mediated immune responses. We have utilized a recombinant
antigen plus adjuvant approach to systematically formulate an immunogenic, multi-stage, multivalent malaria
vaccine made feasible through the use of an optimized malaria-specific carrier protein, P. falciparum merozoite
surface protein 8. While successful, there are still challenges and limits to this approach considering the breadth
and nature of immune responses that are needed. Several features of the emerging mRNA vaccine technology
are extremely attractive for malaria vaccine development and may overcome challenges inherent to producing
multiantigen, multistage formulations. At the same time, the technology must be evaluated and optimized to
address issues unique to Plasmodium and malaria. In the proposed studies, we will test the hypothesis that an
mRNA-based vaccine can be optimized to concurrently drive durable, antibody-mediated and cell-mediated
protective immune responses to pre-erythrocytic and blood-stage malaria vaccine candidates. We will optimize
mRNA vaccine-induced, antibody-mediated, and cell-mediated protection to pre-erythrocytic stage parasites
using a novel P. falciparum circumsporozoite protein (PfCSP) vaccine candidate. We will design, produce, and
evaluate an mRNA-based vaccine targeting P. falciparum reticulocyte-binding protein homologue 5 (PfRh5) to
drive high titer antibodies that block merozoite invasion of erythrocytes. We will apply data on a highly protective,
Plasmodium yoelii mRNA blood-stage vaccine to the design and testing of a vaccine targeting the 19 kDa C-
terminal domain of P. falciparum merozoite surface protein 1 (PfMSP119). We will evaluate a multivalent mRNA-
based vaccine that concurrently targets sporozoites and liver-stage parasites (PfCSP) as well as blood-stage
merozoites (PfRh5 and PfMSP119). Success in the effort will determine the potential and the limitations of mRNA-
based technology for delivery of a multicomponent malaria vaccine and provide a foundation to integrate
additional targets and/or modifications to advance development of a true multi-stage malaria vaccine.
Terms: <0-11 years old><Address><Adjuvant><Advanced Development><Antibodies><Antibody titer measurement><Antigenic Determinants><Antigens><Area><Automobile Driving><Binding><Binding Determinants><Binding Proteins><Blocking Antibodies><Blood><Blood Reticuloendothelial System><Blood erythrocyte><Blood reticulocyte><C-terminal><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Carrier Proteins><Cell Body><Cells><Cessation of life><Child><Child Youth><Children (0-21)><Clinical><Data><Death><Development><Diffusely basophilic erythrocyte><Disease><Disorder><Drug Therapy><Epitopes><Erythrocytes><Erythrocytic><Evaluation><Formulation><Foundations><Gametes><Germ Cells><Germ-Line Cells><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Homologous Protein><Immune response><Immunization><Immunological response><Impairment><Individual><International><Invaded><Left><Ligand Binding Protein><Ligand Binding Protein Gene><Liver><Liver Cells><MSA-1><MSA-1 Protein><MSA1><MSA1 Protein><MSP-1><MSP1><Major Merozoite Surface Protein Precursor><Malaria><Malaria Vaccines><Malaria prevention><Malarial Vaccines><Mammalian Cell><Marrow erythrocyte><Marrow reticulocyte><Mediating><Merozoite Surface Antigen 1><Merozoite Surface Protein 1><Messenger RNA><Modification><Molecular Interaction><N-terminal><NH2-terminal><Nature><P Domain><P falciparum><P-Type Domain><P. falciparum><P.falciparum><PFM-PSCP><PMMSA><Paludism><Parasites><Peptide Domain><Pharmacotherapy><Plasmodium><Plasmodium Infections><Plasmodium falciparum><Plasmodium falciparum Merozoite Precursor Surface Coat Protein><Plasmodium vivax Malaria><Plasmodium yoelii><Polychromatophilic Erythrocyte><Polyvalent Vaccine><Population><Predisposition><Production><Protein Binding><Protein Domains><Protein Homolog><ProteinHomolog><RNA vaccine><RNA-based vaccine><Recombinants><Red Blood Cells><Red Cell><Reporting><Reproductive Cells><Research><Reticulocytes><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Safety><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Sex Cell><Sporozoites><Subunit Vaccines><Susceptibility><T cell response><T8 Cells><T8 Lymphocytes><TFF Domain><Technology><Tertiary Protein Structure><Testing><Therapeutic><Time><Transport Protein Gene><Transport Proteins><Transporter Protein><Trefoil Motif><Vaccination acquired immunity><Vaccination induced immunity><Vaccine Antigen><Vaccine Design><Vaccines><Vivax Malaria><Work><antibody titering><blood corpuscles><bound protein><burden of disease><burden of illness><cell mediated immune response><circumsporozoite protein><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cs protein><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><disease burden><driving><drug treatment><experience><hepatic body system><hepatic organ system><host response><human subject><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><improved><initial cell><kids><mRNA><mRNA vaccine><mRNA-based vaccine><merozoite surface protein><neutralizing antibody><novel><pathogenic virus><programs><protein protein interaction><rapid diagnosis><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sexual cell><success><tool><vaccine acquired immunity><vaccine associated immunity><vaccine candidate><vaccine development><vaccine platform><vaccine-induced immunity><vaccine-induced protection><vaccines against malaria><vector control><vector mosquito><viral pathogen><virus pathogen><youngster>