Influenza viruses cause seasonal epidemics and occasional pandemics that inflict significant global morbidity andmortality. The threat of emerging influenza infections has stimulated development of vaccines to induce broadlyprotective and durable immunity. Technology that may boost immunogenicity safely beyond levels afforded bycurrently used adjuvants is critical to advancing vaccine design and development. While research over severaldecades has identified broad peptidoglycan (PGN) immunostimulatory properties with potential application as anadjuvant, technical, regulatory, and development challenges have prevented development of native PGN forvaccine applications. Teichos Laboratories, LLC (Teichos) proprietary technology produces a platform ofmacromolecular immunostimulatory biologics by chemoenzymatic total synthesis of authentic PGN core structure,termed sPGN. Preliminary results with a prototype sPGN, TL-001, support its utility as a vaccine adjuvant. TL-001is a single-strand, uncrosslinked, macromolecular (ca. 20 - 200 kDa) sPGN produced by robust, scalable, andflexible total synthesis from commercially available small molecules, standard reagents, and a single enzyme.Therefore, TL-001, like all sPGN, is produced free of the adventitious, and often potent, contaminant immune reactivematerials that accompany similar macromolecules isolated from microorganisms. In a laboratory vaccinationmodel, low dose TL-001 induces a robust response that is mediated through TLR2 and NOD2 receptors to stimulatecoordinated innate and adaptive immune responses through two synergistic layers of signalling that amplifyantibody production and T cell activation. Neither toxicity nor reactogenicity were observed when high dose sPGNwas administered to laboratory animals. This proposal seeks support to advance TL-001 from discovery(preliminary data) to development phase (application to disease prevention studies) by conducting proof-of-principle experiments to validate development as a human influenza vaccine adjuvant. We will produce a test lot ofTL-001 that will be evaluated to define the role of TLR2 and other cellular mechanisms in mediating theimmunostimulatory responses in human monocytes and macrophages. We will characterize the antibody and Tcell responses to TL-001 using an influenza H1 subunit vaccination model in mice. Anticipated technical successin the proposed studies will help support Phase II assessments of TL-001 safety, protection in lethal influenzachallenge models, alternate routes of administration, and formulation development.
Public Health Relevance Statement: Teichos technology, a macromolecular platform of peptidoglycan biologics (sPGN) produced by proprietary
chemoenzymatic total synthesis, offers improved influenza vaccines through significantly improved adjuvant
performance. TL-001, a stimulatory sPGN, demonstrated adjuvant activity at low doses in standard laboratory
vaccination model. We propose to evaluate TL-001 for its potential utility as an influenza vaccine adjuvant by
confirming its mechanism of action in monocyte and macrophage cultures and its ability to enhance antibody
and T cell responses using an influenza H1 subunit vaccination model in mice.
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