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Principal Investigator: YUYING LIANG
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $227,848
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Title: Novel multivalent viral vectored tuberculosis vaccines targeting lung immunity
Tuberculosis (TB) persists as the deadliest bacterial infection, with more than 10 million new cases of active TB
diagnosed and 1.5 million deaths attributed to TB worldwide each year, because there is no highly effective
preventative vaccine. Mycobacterium tuberculosis (Mtb) also causes asymptomatic latent infections in ~25% of
the world’s population. Latently infected individuals have a 10% lifetime risk of developing active TB disease.
Vaccines that prevent pulmonary Mtb infection, limit reactivation from latency and/or therapeutically treat active
TB disease are urgently needed. The objective of this R21 proposal is to explore the unique immunological
features of an innovative Pichinde virus (PICV)-based vaccine platform combined with novel Mtb antigens to
develop next generation TB vaccines. PICV is a non-pathogenic arenavirus with a bi-segmented RNA genome.
The proposal exploits a recombinant PICV engineered with three RNA segments, rP18tri, which can encode two
additional open-reading frames (ORFs) to express antigens. The rP18tri platform is safe, versatile and induces
balanced antibody and T cell responses. Moreover, the rP18tri platform is simple to modify to produce a variety
of multivalent antigens, which enables rapid analysis of candidates to identify those antigens that induce the
greatest protection. The proposed research will test the hypothesis that optimized multivalent antigens delivered
intranasally via the rP18tri viral vector platform will induce robust protective immunity against pulmonary Mtb
infection. Preliminary data from proof-of-concept studies establish that rP18tri-based TB vaccines can be
efficiently generated, induce strong antigen-specific T cell immunity and protect against pulmonary Mtb infection
in a mouse aerosol challenge model. In this R21 proposal, we will generate additional rP18tri vector-based
multivalent TB vaccine candidates with novel immunogens (Aim 1), evaluate antibody as well as systemic and
lung tissue-resident T cell responses induced by these vaccines in mice (Aim 2), and assess the efficacy of these
vaccines for prevention of Mtb infection in a mouse model (Aim 3). The study is significant because it is
expected to produce at least one viral vectored multivalent TB vaccine candidate with demonstrated safety and
efficacy in mice to be advanced to the next phases of preclinical and clinical evaluations. The study is also
expected to generate new knowledge on protective immunity induced by novel Mtb antigens, which will guide
the design of next generation TB vaccines, and to advance development of the PICV vector platform, which will
expand the toolbox for fighting infectious diseases.
Terms: <21+ years old><Adult><Adult Human><Advanced Development><Aerosols><Antibodies><Antibody Response><Antigens><Arenaviridae><Arenavirus><Arenavirus group><Attenuated><Bacterial Infections><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><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 Mediated Immunology><Cell surface><Cell-Mediated Immunity><Cellular Immunity><Cessation of life><Childhood><Clinical Evaluation><Clinical Testing><Communicable Diseases><Complex><Data><Death><Development><Diagnosis><Disease><Disorder><Engineering><Exhibits><Genome><Goals><Immune response><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Knowledge><LYT3><Licensing><Lung><Lung Parenchyma><Lung Respiratory System><Lung TB><Lung Tissue><Lung Tuberculosis><M bovis><M tb><M tuberculosis><M tuberculosis antigen><M tuberculosis infection><M. bovis><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><Memory><Mice><Mice Mammals><Modeling><Mtb antigen><Murine><Mus><Mycobacterium bovis><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis antigens><Mycobacterium tuberculosis infection><Mycobacterium tuberculosis var. bovis><Non-Polyadenylated RNA><ORFs><Open Reading Frames><Phase><Pichinde><Pichinde virus><Population><Preventative vaccine><Prevention><Preventive vaccine><Prophylactic vaccine><Protein Coding Region><Proteins><Pulmonary TB><Pulmonary Tuberculosis><RNA><RNA Gene Products><Recombinants><Research><Ribonucleic Acid><Route><Safety><Structure of parenchyma of lung><T cell response><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TB diagnosis><TB immunity><TB infection><TB vaccine><Testing><Therapeutic><Tuberculosis><Tuberculosis Vaccines><Tuberculosis diagnosis><Vaccination><Vaccine Research><Vaccine for TB><Vaccine for Tuberculosis><Vaccines><Viral Vector><Virulent><adaptive immune response><adulthood><anti-TB vaccine><antigen based test><antigen test><antigen-specific T cells><attenuate><attenuates><bacteria infection><bacterial disease><booster dose><booster shot><booster vaccine><clinical test><design><designing><determine efficacy><develop a vaccine><develop vaccines><development of a vaccine><developmental><diagnosed with TB><diagnosed with Tuberculosis><disseminated TB><disseminated tuberculosis><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><fighting><host response><immune system response><immunity against M. tuberculosis><immunity against Mtb><immunity against Mycobacterium tuberculosis><immunity against TB><immunity against tuberculosis><immunity in tuberculosis><immunity to TB><immunity to tuberculosis><immunogen><immunogenicity><immunoresponse><improved><infection due to Mycobacterium tuberculosis><innovate><innovation><innovative><latency/reactivation><latent infection><life-time risk><lifetime risk><long term memory><longterm memory><mouse model><mtb><murine model><next generation><novel><pathogen><pediatric><pre-clinical evaluation><preclinical evaluation><prevent><preventing><protective efficacy><pulmonary><reactivation from latency><recruit><research clinical testing><thymus derived lymphocyte><tuberculosis immunity><tuberculosis infection><tuberculous spondyloarthropathy><vaccine against M. tuberculosis><vaccine against Mtb><vaccine against Mycobacterium tuberculosis><vaccine against TB><vaccine against tuberculosis><vaccine boost><vaccine candidate><vaccine candidates against tuberculosis><vaccine development><vaccine efficacy><vaccine platform><vaccine response><vaccine responsiveness><vaccine-induced response><vaccine-related research><vector>