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Principal Investigator: Evan Alexander Scott
Organization: NORTHWESTERN UNIVERSITY
Fiscal Year: 2020
Award: $685,339
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Subunit vaccines combine immunodominant protein or peptide antigens from pathogens with select
adjuvants, aiming to provide a more scalable, reproducible, low cost and rapid alternative to attenuated vaccines
that contain live pathogens. Unfortunately, current subunit vaccines lack lipid antigens and rarely achieve the
broad T cell responses required for lasting immunological memory and protection. In contrast, attenuated
vaccines lack customization and scalability, but incorporate the entire pathogen to provide both protein and lipid
antigens during immunization. This combination of lipid and protein antigens activates a broad spectrum of
effector T cells, including conventional MHC-restricted T cells that respond to peptides and display considerable
polymorphism, as well as nonpolymorphic CD1-restricted T cells that are directed against specific lipids. A more
biomimetic strategy that simultaneously activates both lipid- and peptide-specific T cells may therefore show
enhanced efficacy and control compared to subunit vaccines limited to protein antigens.
The neglect of lipid antigens from current subunit vaccines and immunotherapies is primarily due to 1)
difficulties in targeted delivery of lipids, and 2) a lack of suitable mouse models. In humans, the CD1 family
consists of group 1 CD1 molecules (CD1a, CD1b, and CD1c) and the group 2 CD1 molecule CD1d. Mice,
however, only express CD1d. This project, which involves a close collaboration between research groups led by
a bioengineer and a basic immunologist, aims to overcome these obstacles by designing nanobiomaterials for
enhanced dual delivery of both lipid and protein antigens in combination with adjuvants to induce CD1- and
MHC- restricted T cell response in humanized CD1 transgenic (hCD1Tg) mice. To characterize, optimize and
benchmark these novel nanobiomaterials against the most frequently used attenuated vaccine in the world, the
bacillus Calmette-Guérin (BCG) tuberculosis (TB) vaccine, the following aims are proposed: In Aim 1, in vitro
and in vivo approaches will identify the optimal nanobiomaterials and adjuvant combination for eliciting a
combined CD1- and MHC-restricted T cell response. In Aim 2, a lipid/protein multi-antigen approach will be
validated in hCD1Tg mice challenged with virulent Mycobacterium tuberculosis (Mtb). In Aim 3, a novel hydrogel
delivery system will be employed for controlled and sustained release of lipid-antigen-loaded nanobiomaterials
to assess efficacy and safety of chronic CD1-restricted T cell activation. The proposed study will provide a “proof
of concept” that combining Mtb lipids and proteins into a single subunit vaccine formulation that targets both
conventional and unconventional T cell subsets can enhance overall immunity to Mtb infection. The methodology
and antigen/adjuvant delivery systems developed in this study will guide the next generation of multi-subunit
vaccines for TB and other bacterial pathogens to provide scalable routes of rapid vaccine fabrication.
Terms: <1,2-Ethanediol><2-Hydroxyethanol><Adjuvant><Antibody Response><Antigen Presentation><Antigens><Assay><Attenuated><Attenuated Vaccines><BCG Live><Bacille Calmette-Guérin><Bacillus Calmette Guérin><Bacterial Vaccines><Bacterin><Benchmarking><Best Practice Analysis><Bioassay><Biologic Assays><Biological Assay><Biological Mimetics><Biomedical Engineering><Biomimetics><CD1 Antigens><CD1 molecule><Chronic><Collaborations><Combination Vaccines><Combined Vaccines><Custom><Data><Dihydroxyethanes><Engineering><Equilibrium><Ethanediols><Ethylene Glycols><Family><Formulation><Genetic Polymorphism><Glycolates><Human><Hydrogels><Hydrophobicity><Immune mediated therapy><Immune memory><Immune response><Immune system><Immunity><Immunization><Immunochemical Immunologic><Immunologic><Immunologic Memory><Immunologic Sensitization><Immunologic Stimulation><Immunological><Immunological Memory><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunologist><Immunomodulation><Immunostimulation><Immunotherapeutic agent><Immunotherapy><In Vitro><Intranasal Administration><Intranasal Drug Administration><Isoforms><Lipid Trafficking><Lipids><Lung><Lung Respiratory System><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><MTB vaccine><Methodology><Methods><Mice><Mice Mammals><Micelles><Modeling><Modern Man><Monoethylene Glycol><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Mycolic Acid><Nanosphere><Nanostructures><Peptides><Phase><Polymers><Precipitation><Protein Isoforms><Proteins><Reproducibility><Research><Route><Safety><Subunit Vaccines><Sulfides><System><T cell response><T-Cell Activation><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><TB infection><TB vaccine><Techniques><Toxic effect><Toxicities><Transgenic Mice><Transgenic Organisms><Tuberculosis><Tuberculosis Vaccines><Vaccinated><Vaccination><Vaccine for TB><Vaccine for Tuberculosis><Vaccines><Virulent><allergic/immunologic body system><allergic/immunologic organ system><anamnestic reaction><anti-TB vaccine><aqueous><autoreactivity><bacterial pathogen><balance><balance function><base><bio-engineered><bio-engineers><bioengineering><bionanomaterial><cost><design><designing><develop a vaccine><development of a vaccine><disseminated TB><disseminated tuberculosis><effector T cell><ethylene glycol><glycolic acid><host response><humanized mice><humanized mouse><immune drugs><immune modulation><immune regulation><immune regulator><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><immunologic preparation><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapeutics><immunotherapy agent><in vivo><in vivo evaluation><in vivo testing><infection due to Mycobacterium tuberculosis><isopropylidene><lipid transport><live vaccine><mouse model><mtb><murine model><nano><nano particle><nano sphere><nano-sized particle><nano-structures><nanobiomaterial><nanoparticle><nanosized particle><neglect><next generation><novel><pathogen><pathogenic bacteria><polymorphism><propene><propylene><protective efficacy><pulmonary><recruit><secondary immune response><site targeted delivery><targeted delivery><thymus derived lymphocyte><transgenic><tuberculosis infection><tuberculous spondyloarthropathy><vaccination strategy><vaccine delivery><vaccine development><vaccine formulation>