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Principal Investigator: FREDERICK D QUINN
Organization: UNIVERSITY OF GEORGIA
Fiscal Year: 2022
Award: $484,996
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
Bacterial and viral respiratory pathogens interact closely with mucosal surfaces. Specialized innate and adaptive mucosal
immune systems protect these surfaces and are the first line of defense for the body. One of the more important reasons for
the development of mucosal vaccines is the increasing evidence that stimulating and preparing local mucosal immune
responses is important for protection against infectious against diseases, such as tuberculosis. Although the entire immune
response repertoire needed for protection against Mycobacterium tuberculosis (Mtb) infection is not known, recent data in
animal models suggest that vaccine-induced CD4+ cells of the T helper 17 (Th17) cell subtype, which naturally traffic to
the airways, can accelerate the recruitment of protective Th1 cells and production of IFN, IL-17 and other cytokines.
Cytotoxic CD8+ and CD4+ T cells also are important and can be assessed via levels of antigen-specific induction of perforin,
granzyme B, and granulysin. In addition, IgA and IgG mucosal antibodies have been shown to interfere with the progression
towards disease with other respiratory pathogens and may act similarly against Mtb. The respiratory epithelial cell is a
primary target for mucosal vaccines. A major portion of the mucosa is comprised of cells that can provide a barrier function
and serve as sensors to detect dangerous microbial components through pattern-recognition receptors and transmit signals
to underlying mucosal cells to trigger innate and promote adaptive immune responses. Studies involving several Mtb
secreted proteins including HBHA, Rv3351c and ESAT6 have identified links between the initial interaction of the inhaled
pathogen with alveolar epithelial cells and the subsequent dissemination of the microbes from the lung. These Mtb proteins
also have been shown to generate important immune responses in mice given subcutaneous or intranasal doses.
Nanoparticles (NPs) are attractive mucosal vaccine/immunotherapy delivery vehicles due to the enhanced uptake by
antigen-presenting cells, the preferential draining of NPs to lymphatics rather than to the bloodstream, and depending on
size and composition, the ability of NPs to diffuse through mucus and cross mucosal barriers. Delivery of NP-based vaccines
to the respiratory tract may be a means of enhancing innate immune responses and will be the emphasis of this study. By
combining all three of these epithelial cell-targeting Mtb proteins on a NP vehicle combined with VacSIM® immune-
stimulating matrix plus adjuvant, and deploying as a mucosal booster vaccine to the subcutaneous BCG prime, we expect
protective cellular and humoral responses in animal lungs and significantly-elevated protection from Mtb infection
compared to that conferred by BCG vaccination alone. In Aims 1 and 2, we will evaluate the efficacy and immune responses
for multiple vaccine preparations and identify the two most protective which will be assessed in Aim 3 for safety, stability,
and then protective efficacy will be confirmed in guinea pigs. Our hypothesis is that by stimulating humoral and cellular
immune responses with our Mtb multi-antigen mucosal nanoparticle matrix vaccine, subsequent Mtb aerosol exposure will
result in reduced bacterial replication in the lungs and augment systemic immune responses generated by the BCG-priming
vaccine to more-effectively clear residual bacteria and decrease or prevent dissemination. We are confident this approach
will be successful against Mtb in two different animal models, and thus, lay the groundwork for subsequent non-human
primate trials.
Terms: <0-11 years old><519 protein><7S Gamma Globulin><Adjuvant><Aerosols><Airway mucosa><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antigen Targeting><Antigen-Presenting Cells><Antigens><BCG Live><BCG Vaccine><BCG immunization><BCG vaccination><BCG-vaccinated><Bacille Calmette Guerin vaccine><Bacille Calmette-Guerin vaccinated><Bacille Calmette-Guerin vaccination><Bacille Calmette-Guérin><Bacillus><Bacillus Calmette Guerin Vaccine><Bacillus Calmette Guérin><Bacillus Calmette-Guerin vaccination><Bacillus Calmette-Guérin vaccination><Bacillus Calmette-Guérin vaccine><Bacteria><Bacterial Adhesins><Blood Circulation><Blood Screening><Bloodstream><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchopulmonary Lavage><C57BL/6 Mouse><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8B><CD8B1><CD8B1 gene><COVID-19><COVID19><CTLA-8><CTLA8><CV-19><CV19><Cause of Death><Cavia><Cell Body><Cell Communication and Signaling><Cell Membrane Lipid Rafts><Cell Signaling><Cells><Child><Child Youth><Children (0-21)><Chimera Protein><Chimeric Proteins><Circulation><Combination Vaccines><Combined Vaccines><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><D2S69E><Dangerousness><Data><Development><Diffuse><Disease><Disorder><Dose><Epithelial Cells><Fluorescence Light Microscopy><Fluorescence Microscopy><Fusion Protein><Future><GNLY><Genes><Glycolates><Goals><Granzyme><Guinea Pigs><Guinea Pigs Mammals><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Histopathology><Human><IFN><IL-17><IL-17A><IL17 Protein><IL17A><IgA><IgG><Immune><Immune mediated therapy><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunoglobulin A><Immunoglobulin G><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapy><Inducer Cells><Inducer T-Lymphocytes><Infection><Infectious Agent><Inhalation><Inhaling><Innate Immune Response><Interferons><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 Precursor><Interleukin-17><Intracellular Communication and Signaling><LAG-2><LAG2><LYT3><Link><Lung><Lung Alveolar Epithelia><Lung Lavage><Lung Respiratory System><Lymphatic><M tb><M tuberculosis><M tuberculosis antigen><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis antigen><M. tuberculosis infection><M.tb antigen><M.tb infection><M.tuberculosis infection><MTB infection><MTB vaccine><Membrane Microdomains><Mice><Mice Mammals><Microbe><Microscopic><Modern Man><Mtb antigen><Mucosa><Mucosal Immune Responses><Mucosal Immune System><Mucosal Tissue><Mucous Membrane><Mucous body substance><Mucus><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis antigens><Mycobacterium tuberculosis infection><NKG5><Organ><Pathology><Pattern recognition receptor><Phase><Preparation><Production><Proteins><Pulmonary Body System><Pulmonary Organ System><Residual><Residual state><Respiratory Epithelium><Respiratory Mucosa><Respiratory System><Respiratory Tracts><Respiratory tract structure><Route><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Spleen><Spleen Reticuloendothelial System><Structure of respiratory epithelium><Surface><T-lymphocyte activation gene 519><T4 Cells><T4 Lymphocytes><TB infection><TB vaccine><TLA519><Temperature><Testing><Th-1 Cell><Th1 Cells><Toxic effect><Toxicities><Tuberculosis><Tuberculosis Vaccines><Type 1 Helper Cell><VDAC1><VDAC1 gene><Vaccination><Vaccine Adjuvant><Vaccine Antigen><Vaccine for TB><Vaccine for Tuberculosis><Vaccines><Viral><Waxes><accessory cell><adaptive immune response><adhesin><airway epithelium><allergic/immunologic body system><allergic/immunologic organ system><alveolar epithelium><anti-TB vaccine><base><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><booster dose><booster shot><booster vaccine><bronchopulmonary lavage therapy><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytokine><cytotoxic><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><delivery vector><delivery vehicle><developmental><disseminated TB><disseminated tuberculosis><efficacy analysis><efficacy assessment><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><glycolic acid><granulysin><guinea pig model><heparin-binding hemagglutinin><host response><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunoresponse><improved><infection due to Mycobacterium tuberculosis><infectious organism><lipid raft><lymphocyte pore-forming protein><microbial><model of animal><model organism><mtb><mucosa associated lymphoid tissue><mucosa associated lymphoid-tissue><mucosa-associated lymphoid tissue><mucosal vaccine><mucous><mutant><mycobacteria HBHA><mycobacterial><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><non-human primate><nonhuman primate><novel><pathogen><perforin><pore forming protein><porin><prevent><preventing><protective efficacy><protein complex><pulmonary><recruit><respiratory pathogen><response><safety study><screening><sensor><subcutaneous><subdermal><trafficking><tuberculosis infection><tuberculous spondyloarthropathy><uptake><vaccine safety><youngster>