Safe and effective adjuvants for prophylactic and therapeutic vaccine use are resulting from the identification and optimizing formulations of small molecules. For a new adjuvant to be widely accepted and used, important considerations include non-clinical safety and efficacy, understanding of mechanism of action, and 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.). Among the most advanced approaches to new adjuvant development consist of using TLR ligands (TLRL) that, when properly formulated, can be effective when used in minimal amounts. We have developed formulations of our lead TLR4L, GLA, and have evaluated a variety of these, including oil/water emulsions, micellar, and liposomal, in non-clinical and clinical studies. When properly formulated, GLA has the ability to focus toward Th1 responses, induce CD8 T cells, and enhance and broadened specific antibody responses. Clinical trials using formulated GLA have been have completed using seasonal and pandemic influenza, and schistosoma antigens, and ongoing are trials in HIV, tuberculosis, leishmaniasis, malaria, pandemic influenza, and a study to examine innate responses to adjuvant alone. Excellent safety and immunogenicity profiles have been observed in non-clinical and clinical studies.
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