The National Instute of Allergy and Infectous Diseases at NIH supports research projects that explore innate immune mechanisms, their impact on adaptive immunity, and the discovery and development of novel adjuvants triggering these mechanisms. One of them, the Adjuvant Discovery Program, is designed to generate novel compounds capable of safely enhancing the efficacy of vaccines for the general population as well as for special populations. A major challenge for the identification of novel candidates is the lack of robust, validated and widely applicable in vitro assays to predict in vivo adjuvanticity. This is, in part, due to the wide range of cellular and molecular targets of vaccine adjuvants, but also to the lack of understanding what in vitro responses correlate with adjuvanticity and/or reactogenicity in vivo. The NIAID discovery program involves HTS of compounds for adjuvant activity and has yielded valuable insights into the usefulness of different in vitro screening assays for novel adjuvants. A commonly used approach for identifying novel candidates is the use of NF-kB reporter cells. Numerous cellular processes, including engagement of innate immune receptors involve NF-kB signaling. Nevertheless, many “hits” from NF-kB –based screens do not stimulate cytokine production in confirmatory screens. Cytokine-secretion is a more biologically relevant readout, but more expensive and limited by our understanding of what cytokines correlate with in vivo adjuvanticity. A frequently used exclusion criterion for adjuvant candidates is cytotoxicity. However, cell death is associated with the efficacy of many immunostimulatory compounds and, thus, it is advisable to study the extent as well as the type of cell death induced rather than to simply dismiss such compounds. Systematic adjuvant discovery is a multidisciplinary effort and greatly benefits from the close collaboration between medicinal chemists, immunologists and formulation experts.

NIAID Adjuvant Program: Lessons and insights from the frontiers of vaccine adjuvant research

249th National Meeting (2015)

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