Safe and effective adjuvants for prophylactic and therapeutic vaccine use are resulting from the identification of small molecules and optimization of their formulations. For a new adjuvant to be widely accepted and used, however, non-clinical safety and efficacy are not the only important aspects to be considered. Also helpful are detailed knowledge of mechanism of action, local and systemic effects on immune activation, magnitude and duration of effects, as well as quality, manufacturability, and stability of the active ingredients and excipients used in the final adjuvant composition. Effectively engaging macrophages and dendritic cells (DC), leading to T cell responses is essential for developing a new generation of T cell vaccines (e.g. tuberculosis, malaria, HIV), as well as for improving the quality and duration of antibody responses (influenza, HPV, HIV, etc.). The most advanced approaches to new adjuvant development consist of using TLR ligands (TLRL), which when properly formulated can be used in minimal amounts to achieve desired effects. The manner in which TLRL are formulated dramatically influences the nature of the immune response they induced. We have developed formulations of synthetic of several TLR4L and have evaluated a variety of these, including oil/water emulsions, micellar, and liposomal, in non-clinical and clinical studies. Formulations have been developed with desirable adjuvant properties, adjustable potency, focused Th1 or balanced Th1/Th2 responses, down-regulation of Th2 responses, induction of CD8 T cells, induction of mucosal immune responses, and effective broadening of specific antibody responses. We have also shown that cells from elderly individuals strongly recognize formulated TLRL, producing cytokines in a manner qualitatively and quantitatively indistinguishable from cells from healthy adults. Thus, selective molecular synthesis and formulation may lead to a new generation of TLR4L- based adjuvants with improved qualities over natural products. Non-clinical and clinical data using these and other novel adjuvants in development will be discussed.
Founder, President and Chief Scientific Officer, Infectious Disease Research Institute (IDRI)No slides available
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