Fast-Track proposals will be accepted. Direct-to-phase II proposals will be accepted. Number of anticipated awards: 1-3 Budget (total costs): Phase I: $300,000/year for up to 2 years; Phase II: $1,000,000/year with appropriate justification by the applicant for up to 3 years. Background The goal of this program is to support the preclinical development of novel vaccine adjuvant candidates against infectious diseases or of tolerogenic adjuvants for immune-mediated diseases. For the purpose of this SBIR, vaccine adjuvants are defined according to the U.S. Food and Drug Administration (FDA) as “agents added to, or used in conjunction with, vaccine antigens to augment or potentiate, and possibly target, the specific immune response to the antigen”. Tolerogenic adjuvants are defined as compounds that promote immunoregulatory or immunosuppressive signals to induce non-responsiveness to self-antigens in autoimmune diseases, or environmental antigens in allergic diseases. Currently, only a few adjuvants other than aluminum salts (“Alum”) have been licensed as components of vaccines in the United States (U.S.): 4’-monophosphoryl lipid A (MPL), adsorbed to alum as an adjuvant for an HPV vaccine; CpG Oligodinucleotide as an adjuvant for a recombinant Hepatitis B vaccine; MPL and QS-21 combined in a liposomal formulation for a varicella vaccine; and the oil-in-water emulsion MF59 as part of an influenza vaccine for people age 65 years and older. Additional efforts are needed to develop promising novel adjuvants, particularly for vulnerable populations such as the young, elderly and immune-compromised. In addition, adjuvants may facilitate the development of immunotherapeutics for immune-mediated diseases (e.g., allergic rhinitis, asthma, food allergy, autoimmunity, transplant rejection). The field of tolerogenic adjuvants is still in its infancy. No compounds have been licensed yet in the U.S. and immune-mediated diseases are treated mostly with broadly immunosuppressive drugs or long-term single- or multi-allergen immunotherapy. In contrast to drugs, tolerogenic or immunomodulatory adjuvants may regulate immune responses to specific antigens through a variety of mechanisms, including induction of regulatory T cells or alterations in the profile of the pathogenic lymphocyte response (e.g., Th1 to Th2 or vice versa). For tolerogenic and immune modifying adjuvants, the antigens may originate from environmental (allergy) or endogenous (autoimmunity) sources and may not need to be supplied exogenously together with the adjuvant. When using this approach, the proposal must describe a compelling mechanism by which the adjuvant would modulate an antigen- specific response, and include studies demonstrating altered or suppressed responses against the allergen or autoantigen. Adjuvanticity may be obtained with a single immunostimulatory (or immunoregulatory/tolerizing) compound or formulation, or with a combination adjuvant. For this solicitation, a combination-adjuvant is defined as a complex exhibiting synergy between individual adjuvants, such as: overall enhancement or tolerization of the immune response depending on the focus and nature of the vaccine antigen; potential for adjuvant-dose sparing to reduce reactogenicity while preserving immunogenicity or tolerizing effects; or broadening of effector responses, such as through target-epitope spreading or enhanced antibody avidity. Project Goal The goal of each project will be to accelerate the pre-clinical development and optimization of a single lead adjuvant candidate or a select combination-adjuvant for prevention of human disease caused by non-HIV infectious pathogens, for the treatment of autoimmune or allergic diseases, or transplantation. The adjuvant products supported by this program must be studied and further developed toward human licensure with currently licensed or new investigational vaccines and may not be developed as stand-alone agents. Phase I Activities: Depending on the developmental stage at which an adjuvant is entered into the program, the offeror may choose to perform one or more of the following: • Optimization of one candidate compound for enhanced safety and efficacy. Studies may include: o Structural alterations of the adjuvant o Formulation modifications (adjuvant alone or in combination with antigen(s)) o Optimization of immunization regimens • Development of novel combinations of previously described individual adjuvants, including the further characterization of an adjuvant combination previously shown to enhance or tolerize immune responses synergistically • Preliminary studies in a suitable animal model to evaluate: immunologic profile of activity; immunotoxicity and safety profile; protective or tolerizing efficacy of a lead adjuvant:antigen/vaccine combination Phase II Activities: Extended pre-clinical studies that may include IND-enabling studies such as: • Additional animal testing of the lead adjuvant:vaccine combination to evaluate immunogenicity or tolerance induction, protective efficacy, and immune mechanisms of protection • Pilot lot or cGMP manufacturing of adjuvant or adjuvant:vaccine • Advanced formulation and stability studies • Toxicology testing • Pharmacokinetics/absorption, distribution, metabolism and excretion studies • Establishment and implementation of quality assurance and quality control protocols Areas of Interest: • Adjuvants to improve the efficacy of vaccines to protect against infectious disease, particularly for vaccines targeted towards vulnerable populations • Novel combination adjuvants • Tolerogenic or immune deviating adjuvants for allergen immunotherapy This SBIR will not support: • The further development of an adjuvant that has been previously licensed for use with any vaccine unless such an adjuvant is use as a component of a novel combination adjuvant as defined above • The conduct of clinical trials (see https://osp.od.nih.gov/wp- content/uploads/2014/11/NIH%20Definition%20of%20Clinical%20Trial%2010-23-2014-UPDATED_0.pdf for the NIH definition of a clinical trial) • The discovery and initial characterization of adjuvant candidates • The development of adjuvants or vaccines to prevent or treat cancer • Development of platforms, such as vehicles, or delivery systems that have no immunostimulatory or tolerogenic activity themselves • The development of the vaccine’s antigen component • The development of immunostimulatory compounds or formulations as stand-alone immunotherapeutics (i.e., without a specific antigen/pathogen-specific vaccine component) unless the adjuvant is used to modulate or suppress the response against an allergen or autoantigen. In this case, the proposal must include assays to demonstrate the effect of the treatment with an adjuvant on specific allergens or autoantigens.