SBIR-STTR Award

There are currently no approved vaccines for most emerging biological pathogens (Ebola, Chikungunya, MERS CoV, SARS, Zika), opportunistic infections (S. aureus, Candidiasis, adenovirus) or potential bioterrorism agents (Y. pestis, B. Pseudomallei, F. tularensis, Bunyaviridae, Flaviviridae), and therapeutic interventions such as antibiotics and antivirals are only effective for a select few pathogens. A promising approach for rapidly neutralizing the risk of pathogen exposure is the use of immunomodulators capable of eliciting a robust innate immune response within hours of administration that would provide protective resistance against a wide range of biological agents. Innate immunity has evolved as a first line of defense against invading pathogens and acts through highly conserved pattern- recognition receptors such as Toll-like receptors (TLR) to coordinate the innate inflammatory response to both endogenous and exogenous stimuli. The objective of this Phase I research proposal is to initiate an investigation of structure-activity relationships within a new class of chemically and metabolically more stable synthetic TLR4 agonists in order to identify the structural requirements for the development of a broad-spectrum immunomodulator that would provide non-specific protective resistance (NSR) against a wide range of biological agents. In addition to potentially providing weeks-long NSR against a wide range of viruses and bacteria, the improved stability profile of these synthetic immunomodulators should improve thermal stability leading to a longer shelf-life and avoidance of cold-chain requirements for distribution. Aim 1 will focus on (i) the synthesis of six new TLR4 agonists in which the labile ester and phosphate groups are replaced with more stable bioisosters, and (ii) evaluation of the stability of these new agonists in aqueous formulations. Aim 2 will evaluate the biological activity of the new compounds in vitro for (i) TLR4 species-specificity and potency in a TLR4 specific reporter assay and (ii) cytokine induction from human peripheral blood mononuclear cells. This phase I research proposal and subsequent phase II have the potential to develop broad- spectrum immunomodulators that would provide non-specific protective resistance (NSR) against a wide range of biological agents, and is primarily targeted for preventing upper respiratory tract infections in individuals or populations at risk for emerging or opportunistic pathogen exposure. Such treatment could help prevent deaths associated with seasonal or pandemic influenza viruses as well as other respiratory pathogens of significant medical concern.

Public Health Relevance Statement:
Project Narrative There are currently no approved vaccines for most emerging biological pathogens (Ebola, Chikungunya, MERS CoV, SARS, Zika), opportunistic infections (S. aureus, Candidiasis, adenovirus) or bioterrorism agents (Y. pestis, B. Pseudomallei, F. tularensis, Bunyaviridae, Flaviviridae), and therapeutic interventions such as antibiotics and antivirals are only effective for a select few pathogens. A promising approach for rapidly neutralizing the risk of pathogen exposure is the use of immunomodulators capable of eliciting a rapid robust innate immune response that would provide protective resistance against a wide range of biological agents. The objective of this Phase I research proposal is to initiate an investigation of structure-activity relationship (SAR) within a new class of chemically and metabolically more stable synthetic Toll- like receptor 4 (TLR4) agonists for the development of a safe self-administered intranasal broad- spectrum immune-therapeutic with effective anti-viral and anti-bacterial activity to prevent upper respiratory tract infections in individuals or populations at risk for emerging or opportunistic pathogen exposure.

Project Terms:
adaptive immune response; Address; Adenoviruses; Adjuvant; Agonist; analog; Anti-Bacterial Agents; Antibiotics; Antiviral Agents; aqueous; Bacteria; Biological; Biological Assay; Biological Products; Bioterrorism; Bunyaviridae; Burkholderia pseudomallei; Candidiasis; Cessation of life; Chemicals; chikungunya; Cold Chains; Complex; cytokine; Development; Ebola virus; Embryo; Enzyme-Linked Immunosorbent Assay; Esters; Evaluation; Fatty Acids; Flavivirus; Formulation; Francisella tularensis; Goals; Hour; Human; Immune; Immunomodulators; Immunotherapeutic agent; improved; In Vitro; Individual; Inflammation; Inflammatory Response; Influenza; influenzavirus; Innate Immune Response; inorganic phosphate; Invaded; Investigation; kidney cell; Life; Link; Lipid A; Listeria; Medical; Metabolic; Middle East Respiratory Syndrome Coronavirus; Modeling; monocyte; Mucosal Immunity; Mus; Natural Immunity; novel; Opportunistic Infections; pandemic influenza; pathogen; pathogen exposure; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Phase; Plague; Populations at Risk; Positioning Attribute; prevent; receptor; Reporter; Research Project Grants; Research Proposals; Resistance; respiratory; Risk; seasonal influenza; Self-Administered; Severe Acute Respiratory Syndrome; Species Specificity; Staphylococcus aureus; Stimulus; Structure; Structure-Activity Relationship; Temperature; Testing; Therapeutic; Therapeutic Intervention; TLR4 gene; Toll-like receptors; Tularemia; Upper Respiratory Infections; Vaccines; Virus; Yersinia pestis; Zika Virus

There are currently no approved vaccines for most emerging biological pathogens (Ebola, Chikungunya, MERS CoV, SARS, Zika), opportunistic infections (S. aureus, Candidiasis, adenovirus) or potential bioterrorism agents (Y. pestis, B. Pseudomallei, F. tularensis, Bunyaviridae, Flaviviridae), and therapeutic interventions such as antibiotics and antivirals are only effective for a select few pathogens. A promising approach for rapidly neutralizing the risk of pathogen exposure is the use of immunomodulators capable of eliciting a robust innate immune response within hours of administration that would provide protective resistance against a wide range of infectious diseases. Proof-of-principle has been established that a new class of chemically and metabolically more stable synthetic TLR4 agonists provide safe and effective protection to mice when administered intranasally two days before a lethal influenza virus challenge. In this Phase II application, we will further optimize these new synthetic TLR4 agonists and formulations for stability, potency and safety, and optimize an administration schedule to provide weeks-long non-specific resistance against influenza virus. We will also assess the potential toxicity of the new TLR4 agonists in mice and develop a scalable cGMP synthesis of the lead candidate. This phase II proposal has the potential to develop a new broad-spectrum immunomodulator that would provide non-specific protective resistance (NSR) against a wide range of biological pathogens, and is primarily targeted for preventing upper respiratory tract infections in individuals or populations at risk for emerging or opportunistic pathogen exposure. Such treatment could reduce morbidity and mortality associated with seasonal or pandemic influenza viruses as well as other respiratory pathogens of significant medical concern. The work proposed herein will comprise the pre-clinical basis for IND-filing and human clinical trials using a safe and effective synthetic TLR4 agonist for individuals or populations with a high risk of exposure to seasonal and pandemic influenza viruses.

Public Health Relevance Statement:
Project Narrative There are currently no approved vaccines for most emerging biological pathogens (Ebola, Chikungunya, MERS CoV, SARS, Zika), opportunistic infections (S. aureus, Candidiasis, adenovirus) or bioterrorism agents (Y. pestis, B. Pseudomallei, F. tularensis, Bunyaviridae, Flaviviridae), and therapeutic interventions such as antibiotics and antivirals are only effective for a select few pathogens. A promising approach for rapidly neutralizing the risk of pathogen exposure is the use of immunomodulators capable of eliciting a rapid robust innate immune response that would provide protective resistance against a wide range of biological pathogens. This proposal seeks to develop a new class of chemically and metabolically more stable synthetic Toll-like receptor 4 (TLR4) agonists for the development of a safe self-administered intranasal broad-spectrum immune-therapeutic with effective anti-viral and anti-bacterial activity to prevent upper respiratory tract infections in individuals or populations at risk for emerging or opportunistic pathogen exposure.

Project Terms:
Adenoviruses; Agonist; analog; Anti-Bacterial Agents; Antibiotics; Antiviral Agents; aqueous; Benchmarking; Biological; Biological Products; Bioterrorism; Bunyaviridae; Burkholderia pseudomallei; Candidiasis; Cells; Chemicals; chikungunya; Clinical Trials; Communicable Diseases; Cyclic GMP; cytokine; cytotoxicity; Development; Dose; Ebola virus; Embryo; Esters; Evaluation; Exposure to; Flaviviridae; Formulation; Francisella tularensis; Glycosides; high risk; Hour; Human; Immune; Immunomodulators; Immunotherapeutic agent; improved; In Vitro; in vivo; Individual; Influenza; influenza virus strain; influenzavirus; Innate Immune Response; inorganic phosphate; Investigation; kidney cell; Lead; lead candidate; lead optimization; Liposomes; Mediating; Medical; Metabolic; Middle East Respiratory Syndrome Coronavirus; Modeling; Modification; Molecular; Morbidity - disease rate; mortality; mouse model; Mus; novel; Opportunistic Infections; pandemic influenza; pathogen; pathogen exposure; Peripheral Blood Mononuclear Cell; Phase; phosphonate; Population; Populations at Risk; pre-clinical; prevent; receptor; Regimen; Reporter; Resistance; respiratory; Risk; Route; Safety; Schedule; seasonal influenza; Self Administration; Severe Acute Respiratory Syndrome; Small Business Innovation Research Grant; Species Specificity; Staphylococcus aureus; Structure-Activity Relationship; Therapeutic; Therapeutic Intervention; Time; TLR4 gene; Toxic effect; Treatment Protocols; Upper Respiratory Infections; Vaccines; Work; Yersinia pestis; Zika Virus