Small molecule TLR7 agonists have been used as vaccine adjuvants by enhancing innate immune activation to afford better adaptive response. These vaccine formulations are prepared by co-mixing the antigen and adjuvant, with the hope that the two would stay together in spatial proximity to boost an antigen-specific immune response. Indeed, it has been reported that localized TLR7 agonists without systemic exposure can afford good adjuvanticity, suggesting peripheral innate activation (non-antigen-specific) is not required for immune priming. To enhance co-localization of antigen and adjuvant, benzonaphthyridine TLR7 agonists are chemically modified with phosphonates to allow adsorption onto aluminum hydroxide (alum), a formulation commonly used in vaccines for antigen stabilization and injection site depo. The adsorption process is facilitated by enhancing aqueous solubility of benzonaphthyridine analogs to avoid physical mixture of two insoluble particulates. In vitro, these benzonaphthyridine phosphonates are highly adsorbed onto alum. In vivo, alum-adsorption of TLR7 agonist significantly reduced systemic exposure and increased local retention post injection. This report demonstrates a novel approach in vaccine adjuvant design using phosphonate modification to afford adsorption of SMIP onto alum, thereby enhancing co-delivery with antigen.

Incorporation of phosphonate into benzonaphthyridine TLR7 agonists for adsorption onto aluminum hydroxide

251st National Meeting (2016)

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