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Induction of Mucosal Immune Response to Parenterally Delivered Vaccines


Fast-Track proposals will be accepted Number of anticipated awards: 2-3 Budget (total costs):
Phase I: $225,000 for up to 1 year
Phase II: $1,500,000 for up to 3 years

For a wide range of pathogens, the first contact between the pathogen and the human host occurs at a mucosal surface, such as the gastrointestinal tract. Ideally, vaccines against enteric infections would elicit protective immunity at both systemic and mucosal compartments. Non-living, subunit, or conjugate vaccines given parenterally may induce systemic responses, but generally elicit less-than-optimal responses, if any, in mucosal tissues. Oral administration of such vaccines is not practical because the acidic stomach environment may degrade the antigen, which then requires increased amounts of vaccine to reach the target, inductive site. One strategy to overcome this limitation is to include components that elicit mucosal immunity when formulating parenteral vaccines. Mucosal adjuvants, such as bacterial toxins or toxin derivatives, induce homing receptor expression on T cells and B cells that leads to their migration to intestinal mucosal compartments and, thus, ultimately elicits protective immunity. Examples of enteric infections for which vaccine candidates are under development include Enterotoxigenic E. coli, Shigella spp., Salmonella spp., Campylobacter jejuni, Clostridium difficile, C. botulinum, and enteric viruses (e.g., norovirus or rotavirus), and the addition of mucosal adjuvants to their formulation may enhance vaccine immunogenicity and efficacy. Thus, the overall goal of this topic is to formulate parenterally delivered enteric vaccines that will elicit mucosal immune responses in addition to systemic immune responses.
Project Goals
 To determine the best vaccine:adjuvant formulation(s) of current enteric vaccine candidate(s) that induce immune
responses at both mucosal and systemic compartments;  To characterize systemic and mucosal immune responses to parenterally-delivered enteric vaccine candidates;  To encourage collaboration between academic institutions and small business entities to determine the optimal
formulation for such vaccines.
Phase I activities may include but are not limited to:
 Identification of enteric vaccine candidate(s) and relevant adjuvant(s) that may be delivered parenterally to mice and that induce systemic and intestinal immune responses;  Performance of preliminary studies in mouse model with various vaccine:adjuvant combinations to determine immunogenicity and optimal dose;  Development of in vitro assays to evaluate immune responses, including functional assays using mucosal and systemic samples;  Selection of at least two vaccine:adjuvant combinations for further studies; each vaccine must target a different enteric disease.
Phase II activities may include but are not limited to:
 Confirmation of preliminary results obtained during Phase I with the selected vaccine:adjuvant combinations;  Additional testing of lead vaccine candidate(s) for progress towards IND-enabling studies, including but not limited
to testing to improve safety, efficacy, and QA/QC;  Pilot lot cGMP manufacturing of the vaccine candidate(s);  Formulation, stability, and toxicology studies, as appropriate, for later stages in the vaccine product development
This SBIR will not support:
 The design and conduct of clinical trials (see for the NIH definition of a clinical trial). For SBIR phase II clinical trial support, see the NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement program announcement.
 Platform development such as vehicle or delivery systems.

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