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Principal Investigator: Julie Magarian Blander
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2019
Award: $419,267
Funding agency: National Institute of Allergy and Infectious Diseases
PROPOSAL SUMMARY
Live attenuated vaccines have proven to be the most efficient human vaccines for many serious infectious
diseases. When compared to their dead counterparts, live vaccines induce superior immune protection and
lasting memory. But despite the efficacy of live vaccines, concerns over their safety have led to vaccine refusal
by some and withholding their administration to the very young, the elderly and immunocompromised.
Preservation and delivery of live vaccines especially to impoverished areas in developing countries is difficult
and expensive. Understanding the molecular basis for the efficacy of live vaccines is significant because it
would enable targeting of the relevant immune pathways that induce optimal and long-lasting protective
immunity. Importantly, it would set the stage for the development of vaccines that are safe and afford the same
protection as live vaccines, alleviating public fears and increasing the segment of the population that is
vaccinated. We began our work eight years ago with the hypothesis that innate immune cells sense microbial
viability as a distinct set of pathogen associated molecular patterns (PAMPs), and we identified bacterial
messenger RNA (mRNA) as a vita-PAMP that signifies bacterial viability and mobilizes a tailored immune
response not warranted for dead microorganisms. The Toll-like receptor (TLR) signaling adaptor TRIF plays a
central role here upstream of inflammatory type I interferon and NLRP3 inflammasome pathways. Adding
bacterial mRNA to dead bacteria recapitulates these innate responses, and supplementing a dead vaccine with
bacterial mRNA (what we call a vita-vaccine) augments its performance in mice. A vita-vaccine performed
similarly to a live vaccine in uniquely eliciting a follicular T helper cell response (that helps B cells), germinal
center formation, and B cell isotype class switching, all in a TRIF-dependent manner. These studies provide
strong evidence that vita-vaccine versions of existing vaccines could represent a significant advance in being
able to combine the efficacy of live vaccines with the safety of dead vaccines. The three overlapping areas we
will investigate in this project are:
1. We will determine how adaptive immunity elicited by the supplementation of a dead bacterial vaccine with
the vita-PAMP bacterial mRNA compares to that elicited by PAMPs such as bacterial lipopeptides and others.
2. We will investigate how bacterial mRNA impacts the performance of subunit vaccines. We will test vita-
vaccine versions of the licensed anthrax subunit vaccine and Influenza A virus monovalent subunit vaccine.
3. We will test a vita-vaccine version of a trivalent inactivated Influenza virus vaccine and compare it to the
live attenuated influenza vaccine.
The completion of these studies should provide sufficient experimental evidence to warrant the use of
bacterial mRNAs as superior vita-adjuvants that restore the signatures of microbial viability to dead vaccines
and improve existing inactivated and subunit vaccines for protection against either bacterial or viral diseases.
Terms: <7S Gamma Globulin><Adjuvant><Advanced Development><Agonist><Aldara><Anthrax><Anthrax Vaccines><Anthrax disease><Antibodies><Antibody Response><Apoptosis-Related Cysteine Protease Caspase 1><Area><Attenuated Live Virus Vaccine><Attenuated Vaccines><B anthracis><B blood cells><B cell><B cells><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><B. anthracis><Bacillus anthracis><Bacteria><Bacterial Infections><Bacterial RNA><Bacterial Vaccines><Bacterin><Beta Proprotein Interleukin 1><Biothrax><Booster Immunization><CASP-1><CASP1><CASP1 gene><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Caspase-1><Caspase-1 Gene><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Signaling><Cells><Chitosan><Class Switching><Class Switchings><Communicable Diseases><DNA><Deoxyribonucleic Acid><Developing Countries><Developing Nations><E coli><E. coli><Elderly><Endogenous Interferon Beta><Escherichia coli><Evaluation><Fear><Fibroblast Interferon><Formulation><Fright><Germinal Center><Grippe><H1N1><H1N1 Virus><Health><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hematopoietic><Human><ICE Protease><IFN-Beta><IFN-regulatory factor 3><IFN-β><IFNb><IL-1 beta><IL-1 beta Convertase><IL-1 beta-Converting Enzyme><IL-1 β><IL-1-b><IL-1BC><IL-1b Converting Enzyme><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1B-Convertase><IL1BC><IL1BCE><IL1F2><IL1β><IRF-3 protein><IRF3><IRF3 gene><IgG><Imiquimod><Immune><Immune response><Immune system><Immunes><Immunity><Immunization><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin G><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><Immunosuppressed Host><Inactivated Vaccines><Inactivated Virus Vaccine><Individual><Inducer Cells><Inducer T-Lymphocytes><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammasome><Inflammatory><Influenza><Influenza A><Influenza A Virus, H1N1 Subtype><Influenza A virus><Influenza Vaccines><Influenza Viruses Type A><Influenzavirus A><Injections><Innate Immune System><Interferon Regulatory Factor 3><Interferon Type I><Interferon-beta><Interferon-β><Interleukin 1-B Converting Enzyme><Interleukin 1-Beta Convertase><Interleukin 1beta><Interleukin-1 Beta Converting Enzyme><Interleukin-1 Converting Enzyme><Interleukin-1 beta><Interleukin-1β><Interleukins><Intracellular Communication and Signaling><Isotype Switching><Isotype Switchings><Killed Vaccines><Knowledge><Less-Developed Countries><Less-Developed Nations><Ligands><Live-attenuated Vaccine><Mediating><Memory><Messenger RNA><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><Natural Interferon Beta><Natural human interferon beta><Nature><Orthomyxovirus Type A><Pathogenicity Factors><Pathway interactions><Pattern><Pattern Recognition><Performance><Play><Poliglusam><Poly I-C><Polyinosinic-Polycytidylic Acid><Population><Preinterleukin 1 Beta><Production><Receptor Protein><Receptor Signaling><Risk><Role><Safety><Secondary Immunization><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Structure of germinal center of lymph node><Subunit Vaccines><Supplementation><T cell response><T8 Cells><T8 Lymphocytes><TLR protein><Testing><Third-World Countries><Third-World Nations><Time><Toll-Like Receptor Family Gene><Toll-like receptors><Type A Influenza><Under-Developed Countries><Under-Developed Nations><Vaccinated><Vaccines><Viral Diseases><Virulence Factors><Virus Diseases><Wild Type Mouse><Work><adaptive immunity><advanced age><allergic/immunologic body system><allergic/immunologic organ system><anthracis><attenuated microorganism><bacteria infection><bacterial disease><biological signal transduction><booster vaccination><cytokine><develop a vaccine><development of a vaccine><elders><flu infection><flu vaccine><flu virus vaccine><geriatric><hemopoietic><host response><immunoresponse><immunosuppressed patient><improved><influenza infection><influenza virus vaccine><insight><late life><later life><live attenuated flu vaccine><live attenuated influenza vaccine><live attenuated influenza virus vaccine><live vaccine><mRNA><microbial><microorganism><novel><older adult><older person><pathogen><pathway><poly IC><preservation><receptor><response><senior citizen><social role><vaccine against flu><vaccine against influenza><vaccine development><vaccine formulation><viral infection><virus infection><virus-induced disease>