Document text
Principal Investigator: Sean C Murphy
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $829,705
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Our U01 project supports NIAID’s mission to better understand, treat, and prevent infectious diseases by
focusing on pre-erythrocytic malaria vaccine development. Vaccines that efficiently stop the Plasmodium
sporozoite (spz) or liver stage can provide complete protection against malarial disease and will enable
eradication efforts. There are currently no FDA-approved malaria vaccines for use in humans although
repeated dosing with intravenously-administered attenuated spz has shown sterile protection against challenge
in multiple Phase 1-2 clinical trials. Recently, CD8+ T cells that reside in the liver, namely liver resident memory
T cells or TRM cells, have been identified as key cell types in protection against liver stage infection. Vaccine
strategies that increase liver TRM cells and can be readily adapted to clinical use are therefore critically needed.
Such vaccines could bolster CD8+ T cell immunity and may result in T cell-focused vaccines that achieve
durable, high-grade protection for persons in endemic and non-endemic regions. Our laboratory has developed
a two-dose vaccine that uses a DNA prime followed by an attenuated spz boost or ‘trapping dose’ that
increases liver TRM cells and achieves sterile protection. This project aims to improve upon spz-based trapping
by developing an orally-administered nanoparticle-based trapping vaccine. The University of Washington will
collaborate with Johns Hopkins University to develop this more easily manufactured, more easily deliverable,
and less expensive vaccine. In Project 1, we will define a threshold of Pf antigen-specific TRM cells needed to
achieve protection using DNA prime/sporozoite trapping. In Project 2, we will optimize nanoparticles for liver-
specific delivery and expression profile in hepatocytes using a variety of nanoparticle compositions, sizes,
surface characteristics, and formulation strategies. In Project 3, we will evaluate the optimized nanoparticles in
prime-and-trap vaccination in mice and non-human primates for safety, tolerability, immunogenicity, and
efficacy. If successful, this project will deliver an optimized prime-and-oral trap vaccine rationally designed to
elicit complete protection against the Plasmodium liver stage.
Terms: <Acceleration><Adeno-Associated Viruses><Antigen Presentation><Antigens><Attenuated><Bile><Bile Acids><Bile Juice><Bile fluid><Biocompatible Materials><Biolistics><Biology><Biomaterials><Blood erythrocyte><Body Tissues><Brittle Diabetes Mellitus><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cell Body><Cell-Mediated Lympholytic Cells><Cells><Cessation of life><Characteristics><Chemistry><Circulation><Clinical><Clinical Trials><Collaborations><Communicable Diseases><Communities><Coupled><Culicidae><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><DNA><DNA Therapy><DNA delivery><Data><Death><Deoxyribonucleic Acid><Dependoparvovirus><Dependovirus><Development><Diabetes Mellitus><Disease><Disorder><Doctor of Philosophy><Dose><Drug Delivery><Drug Delivery Systems><Engineering><Ensure><Entero-Hepatic Circulation><Enterohepatic Circulation><Erythrocytes><Erythrocytic><FDA approved><Formulation><Frequencies><Gene Combinations><Gene Transfer Clinical><Gene-Gun Technique><Genetic Intervention><Goals><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><Humulin R><IDDM><Immune signaling><Immunity><Immunology><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Injections><Insulin><Insulin-Dependent Diabetes Mellitus><Intravenous><Investigators><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Knowledge><LYT3><Laboratories><Life Cycle><Life Cycle Stages><Lipids><Literature><Liver><Liver Cells><Malaria><Malaria Diagnostic><Malaria Vaccines><Malarial Vaccines><Marrow erythrocyte><Memory><Methods><Mice><Mice Mammals><Mission><Modern Man><Mosquitoes><Murine><Mus><NIAID><National Institute of Allergy and Infectious Disease><Non-Polyadenylated RNA><Novolin R><Nucleic Acids><Oral><Oral Administration><Oral Drug Administration><Paludism><Parasites><Performance><Persons><Ph.D.><PhD><Pharmacology><Phase><Plasmodium><Plasmodium Infections><Plasmodium vaccine><Polymers><Preclinical Testing><RNA><RNA Gene Products><Radiation><Ramp><Red Blood Cells><Red Cell><Regimen><Regular Insulin><Reporting><Research Personnel><Researchers><Rhesus><Ribonucleic Acid><Safety><Salivary Glands><Salivary Glands Head and Neck><Scientist><Shapes><Small Intestines><Sporozoites><Sterility><Sudden-Onset Diabetes Mellitus><Surface><T-Cells><T-Lymphocyte><T1 DM><T1 diabetes><T1D><T1DM><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Tissues><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Universities><Vaccination><Vaccines><Viral><Washington><Work><absorption><adeno associated virus group><attenuate><attenuates><biological material><blood corpuscles><booster dose><booster shot><booster vaccine><cell killing><cell type><deliver DNA><deploy vaccines><develop a vaccine><develop vaccines><development of a vaccine><developmental><diabetes><distribute vaccines><first in man><first-in-human><gene gun><gene repair therapy><gene therapeutics><gene therapy><gene-based therapeutic><gene-based therapeutics><gene-based therapy><genes therapeutic><genes therapeutics><genetic therapy><genomic therapy><hepatic body system><hepatic organ system><immunogen><immunogenicity><improved><insulin dependent diabetes><insulin dependent type 1><intraoral drug delivery><intravenous administration><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><killer T cell><life course><manufacture><materials science><nano particle><nano-sized particle><nanoparticle><nanosized particle><next generation><non-human primate><nonhuman primate><novel><oral vaccine><plasmid DNA><polymer><polymeric><pre-clinical testing><prevent><preventing><rational design><recruit><resident memory T cell><small bowel><sterile><success><therapeutic gene><thymus derived lymphocyte><tissue resident memory T cell><type I diabetes><type one diabetes><vaccine boost><vaccine deployment><vaccine development><vaccine distribution><vaccine roll-out><vaccine rollout><vaccine strategy><vaccines against malaria><vector>