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Principal Investigator: ASHOK K CHOPRA
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2024
Award: $757,093
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
The increasing number of bubonic/pneumonic plague cases globally (2010-2018), including the U.S., with a
~18% case fatality rate may reflect climate changes and a rodent carrier range shift. The 2017-18 plague
outbreak in Madagascar with ~2400 cases (>75% pneumonic) and ~9% causalities has led WHO (April 2018) to
intensify the need for developing new generation subunit and live-attenuated plague vaccines. This need is
exemplified by deadly plague cases in China (2019) and Congo (2020 with a 35% fatality rate). Y. pestis’ (Yp)
ability to persist in dead hosts to resurge after years of silence, existence of antibiotic-resistant strains that occur
naturally or have been intentionally developed, and no FDA-approved plague vaccine, is fearsome. Two-
component subunit vaccines composed of capsular antigen F1 and a T3SS component and effector LcrV (low
calcium response V antigen), which only generate a humoral immune response, provide variable protection in
African green monkeys (AGM) and generate poor T cell responses in humans. Such vaccines will not be effective
against Yp strains lacking F1 or possessing LcrV variants. Since the cellular immunity is also critical for
protection, we focused first on identifying new virulence genes of Yp and then to delete them in combination to
develop novel live-attenuated vaccine (LAV) strains. Two such LAVs were 100% attenuated in inducing
bubonic/pneumonic plague in mice/rats and generated long-term humoral and cellular immune responses to
provide 100% protection to rodents against developing plague. No clinical symptoms of the disease or
histopathological lesions were noted either during immunization or when the vaccinated animals were
subsequently exposed to Yp CO92 in a more stringent pneumonic plague model. Therefore, further
immunological characterization of these mutants and their testing in higher animals, such as cynomolgus
macaques (CM) and AGM, will provide a rationale for future clinical studies. There is a precedent for using a
LAV against plague (EV76 strain) in humans. However, this vaccine is reactogenic, represents a spontaneous
mutant, and causes disease in patients with over iron load. In Aim 1, we will demonstrate efficacy and immune
responses of two vaccine candidates generated from Yp CO92 (biovar Orientalis) against other Yp biovars
(Antiqua and Medievalis), the F1-minus mutant of CO92, and Yp CO92 with LcrV variants, in bubonic and
pneumonic mouse models. Our data with the mutants indicated a role of IL-17 (a Th17 cytokine), Th1-IFN-γ, and
antibodies, in protection. In Aim 2, we will study the mechanistic basis of this protection (one chosen mutant) by
using RORt-/- mice, which lack Th17 cells, as well as IFN-γ and IgA k/o mice, to discern their links to neutrophil
recruitment and mucosal immunity, to combat Yp infection in bubonic/pneumonic plague models. In Aim 3, CM
and AGM will be used with one mutant to demonstrate its short- and long-term efficacy in causing bubonic and/or
pneumonic plague as well as reactogenicity. The correlates of protective immunity will then be established.
These innovative mechanistic/translational approaches will result in effective new generation plague vaccines.
Terms: <7S Gamma Globulin><Ab response><Acyltransferase><African Green Monkey><Animals><Antibiotic Resistance><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antibody titer measurement><Antigens><Aphaniptera><Armed Forces Personnel><Attenuated><Attenuated Vaccines><Bacteria><Bacterial Antigens><Belgian Congo><Binding><Bite><Black Plague><Blood Serum><Bubonic Plague><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Calcium><Case Fatality Rates><Categories><Causality><Cell Body><Cell Communication and Signaling><Cell Mediated Immunology><Cell Signaling><Cell-Mediated Immunity><Cells><Cellular Immunity><Cessation of life><China><Chlorocebus aethiops><Chlorocebus sabaeus><Clinical><Clinical Research><Clinical Study><Clinical Trials><CoV emergence><Common Rat Strains><Congo><Coronaviridae><Coronavirus><Country><Crab-Eating Macaque><Crab-Eating Monkey><Cynomolgus Monkey><Cynomolgus macaque><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data><Death><Democratic Republic of the Congo><Disease><Disease Outbreaks><Disorder><Dodecanoic Acids><Dose><EC 2.3><Engineering><Esteroproteases><Etiology><Exclusion><Exposure to><FDA approved><Fatality rate><Fe overload><Fear><Fleas><Fright><Future><Gene Deletion><Generations><Genes><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Goals><Green Monkey><Homolog of Drosophila TOLL><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IgA><IgG><Immune Interferon><Immune response><Immunity><Immunization><Immunize><Immunochemical Immunologic><Immunoglobulin A><Immunoglobulin G><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Infection><Injections><Interferon Gamma><Interferon Type II><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-17><Intracellular Communication and Signaling><Intramuscular><Invaded><Iron Overload><Laboratories><Lauric Acids><Left><Legal patent><Lesion><Licensing><Link><Lipopolysaccharides><Lipoproteins><Live-attenuated Vaccine><M fascicularis><M. fascicularis><Macaca><Macaca fascicularis><Macaque><Madagascar><Mainland China><Malagasy Republic><Mice><Mice Mammals><Military><Military Personnel><Modeling><Modern Man><Molecular Interaction><Mucosal Immunity><Murine><Mus><Nature><Nepal><Neutrophil Infiltration><Neutrophil Recruitment><Neutrophilic Infiltrate><Outbreaks><Pasteurella pestis><Patents><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peptidases><Peptide Hydrolases><Pestis Fulminans><Pestis Major><Plague><Plague Vaccine><Plasminogen Activator><Pneumonic Plague><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Quarantine><Rat><Rats Mammals><Rattus><Recombinant DNA Technology><Reporting><Resistance><Resistance to antibiotics><Resistant to antibiotics><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Siphonaptera><Site><Subunit Vaccines><Symptoms><T cell response><T3SS><TIL4><TLR2><TLR2 gene><TLR2 receptor><TLR4><TLR4 gene><Testing><Th-1 Cell><Th1 Cells><Toll Homologue><Toll-Like Receptor 2><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Toxicology><Type 1 Helper Cell><Type III Secretion System><Type III Secretion System Pathway><Vaccinated><Vaccine Design><Vaccines><Variant><Variation><Virulence><Y pestis><Y. pestis><Yersinia pestis><Yersinia pestis disease><Zaire><Zoonoses><Zoonotic><Zoonotic Infection><access to vaccination><access to vaccines><antibiotic drug resistance><antibiotic resistant><antibody biosynthesis><antibody titering><arm><attenuate><attenuates><biological signal transduction><biological weapon><bioweapon><black death><causation><climate change><climatic changes><co-infection><coinfection><combat><corona virus><corona virus emergence><coronavirus emergence><cytokine><disease causation><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><emerging human pathogen><gene deletion mutation><genetically engineered><global climate change><host response><immune system response><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><innovate><innovation><innovative><isolation/quarantine><lFN-Gamma><live vaccine><live vaccines><military population><mouse model><murine model><mutant><nCoV><new CoV><new corona virus><new coronavirus><non-human primate><nonhuman primate><novel><novel CoV><novel corona virus><novel coronavirus><pandemic><pandemic disease><pathogen><pathogenicity gene><patient oriented outcomes><pre-clinical><preclinical><rational design><resistance strain><resistant><resistant strain><respiratory><response><social role><toll-like receptor 4><translation strategy><translational approach><translational strategy><type 3 secretion system><vaccination access><vaccination availability><vaccine access><vaccine availability><vaccine candidate><vaccine candidate against plague><vaccine efficacy><vaccines against plague><virulence gene><virulent gene>