Project #3:Active Vaccination and Immunotherapy Against Coccidioidomycosis

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Principal Investigator: CHIUNG-YU  HUNG
Organization: UNIVERSITY OF TEXAS SAN ANTONIO
Fiscal Year: 2023
Award: $395,776
Funding agency: National Institute of Allergy and Infectious Diseases

Project Summary
An estimated 350,000 people in the United States become infected with Coccidioides annually. There is an
unmet need to develop better chemotherapies and a vaccine for active immunization and/or immunotherapy
against coccidioidomycosis (CM). We have previously created a recombinant chimeric polypeptide antigen
(rCpa1) composed of the most immunogenic fragments of 3 previously identified Coccidioides antigens and 5
human T-cell epitopes. The bacterial-expressed rCpa1 is loaded into yeast glucan-chitin particles (GCPs) to
create GCP-rCpa1 protein vaccine. The latter stimulates a robust Th1 and Th17 response and confers
protection for human MHC II-expressing HLA-DR4 transgenic mice against a lethal pulmonary infection with
both species of Coccidioides. The challenges to advance a protein vaccine to clinical readiness are to produce
high quantity and quality of the rCpa1 antigen and to validate human immune response to the vaccine. In this
project, we propose to create two types of formulation methods using mRNA and vector-based delivery and
adjuvant systems. The vaccine recepients will express the coccidioidal antigen in vivo to prime their own
immune system. Our central hypothesis is that an optimized rCpa-1-based vaccine using an mRNA or vector
delivery/adjuvant platform will stimulate robust Th1 and Th17 immunity against CM. These two delivery
platforms can be easily scaled up to produce safe vaccines for preclinical and clinical testing. The GCP-rCpa1
protein vaccine will be used as a benchmark for comparison. There are 3 specific aims. Aim 1: We will design
DNA constructs for in vitro transcription of mRNAs that encode Coccidioides rCpa1 antigen. IVT-mRNAs will
be loaded into GCPs to create GCP-rCpa1-mRNA vaccines. The second approach will create a vector-based
vaccine using a Francisella novicida mutant (Fn-iglD). Wild typle Fn rarely causes tularemia, while F. tularensis
(Ft) is highly virulent. Fn-iglD is highly attenuated and it protects both rats and macaques againt a lethal
pulmonary Ft infection. Fn-iglD also elictis a mixed Th1/Th17 immunity and it is currently under formulation for
clinical safety trial. We will create a Fn-iglD-rCpa1 vaccine. The antigen expression levels of these platforms
and their capacity to stimulate cytokine production in human monoctyic THP-1 cells and murine macrophages
will be determined. Aim 2: The newly created vaccines that show both good antigen expression and capable of
eliciting cytokine production will be further evaluated for their efficacy, immune correlates and protective
mecahnisms. We will apply the HLA-DR4 murine model of CM and human blood cells to delineate immune
correlates and protective mechanisms using a global immune gene profiling method and confirmed with
immiunlogical methods in our laboratories. Aim3: We will establish a murine immunotherapy model of CM for
evaluating treatment efficacy of the most protective vaccine alone or in combination with an azole or the newly
identified drugs in Project #1 and Project #2.

Terms: <Active Immunization><Active Immunotherapy><Adjuvant><Antifungal Agents><Antifungal Drug><Antigen Presentation><Antigen-Presenting Cells><Antigens><Area><Armed Forces Personnel><Attenuated><Azoles><Benchmarking><Best Practice Analysis><Blood Cells><Blood Sample><Blood specimen><Cell Body><Cells><Chitin><Chronic><Clinical><Clinical Evaluation><Clinical Testing><Clinical Trials><Clinical assessments><Coccidioides><Coccidioidomycosis><Combined Modality Therapy><Common Rat Strains><DNA><Deoxyribonucleic Acid><Domestic Rabbit><Drugs><F tularensis><F tularensis infection><F. tularensis><F. tularensis infection><Fever><Fluconazole resistance><Fluconazole resistant><Formulation><Francisella><Francisella infection><Francisella tularensis><Francisella tularensis infection><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Transcription><Genes><Genetic Transcription><Glucans><Glucose Polymer><HLA-DR4><HLA-DR4 Antigen><Human><Immune><Immune mediated therapy><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapeutic agent><Immunotherapy><In Vitro><Individual><Laboratories><Lung><Lung Respiratory System><Lung infections><Macaca><Macaque><Macrophage><Mediating><Medication><Messenger RNA><Methods><Mice><Mice Mammals><Military><Military Personnel><Modeling><Modern Man><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mφ><Oryctolagus cuniculus><Pasteurella tularensis><Patients><Peripheral Blood Cell><Personal Satisfaction><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Polyglucoses><Population><Preclinical Testing><Process><Production><Proteins><Protocol><Protocols documentation><Pyrexia><RNA Expression><RNA vaccine><RNA-based vaccine><Rabbits><Rabbits Mammals><Rat><Rats Mammals><Rattus><Recombinants><Reporting><Research><Resistance to Fluconazole><Rodent><Rodentia><Rodents Mammals><Safety><Speed><Subunit Vaccines><System><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><Therapeutic Fungicides><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transgenic Mice><Travel><Treatment Efficacy><Tularemia><United States><Vaccination><Vaccine Antigen><Vaccines><Virulent><Yeasts><accessory cell><adaptive immunity><analyze gene expression><anti-fungal><anti-fungal agents><anti-fungal drug><antifungals><attenuate><attenuates><attenuation><benchmark><beta-Glucans><chemotherapy><clinic ready><clinical ready><clinical test><combination therapy><combined modality treatment><combined treatment><commercial scale manufacturing><cytokine><delivery vector><delivery vehicle><design><designing><develop a vaccine><develop vaccines><development of a vaccine><drug/agent><febrile><febris><gene expression analysis><gene expression assay><host response><human disease><immune drugs><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenic><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><improved><in vivo><infected with F tularensis><infected with F. tularensis><infected with Francisella tularensis><intervention efficacy><mRNA><mRNA vaccine><mRNA-based vaccine><manufacturing ramp-up><manufacturing scale-up><military population><mouse model><multi-modal therapy><multi-modal treatment><murine model><mutant><new vaccines><next generation vaccines><novel><novel vaccines><particle><plasmid vaccine><polypeptide><pre-clinical testing><pre-clinical trial><preclinical trial><protective efficacy><pulmonary><pulmonary infections><research clinical testing><resistance strain><resistant strain><resistant to fluconazole><response><scale up><scale up batch><scale up production><therapeutic agent development><therapeutic development><therapeutic efficacy><therapeutic outcome><therapy efficacy><therapy outcome><thymus derived lymphocyte><transcriptional profiling><upscale manufacturing><vaccine candidate><vaccine development><vaccine formulation><vector><vector vaccine><vector-based vaccine><well-being><wellbeing><β-Glucans>