The Facility
Detoxified LPS immunomodulatory adjuvants are the most common PAMP compounds, but only one variant (from Salmonella) is currently included in a registered adjuvant product. Neisseria meningitidis contains a very potent hexa-acylated LPS that would be too toxic for therapeutic applications. We have used systematic molecular bioengineering of the meningococcal LPS through deletion of enzymes involved in LPS biosynthesis in combination with induction of LPS modifying enzymes (for example the deacylase PagL) to yield a variety of novel LPS mutant strains with changes in both lipid A acylation and phosphorylation. Altogether these purified LPS derivatives display a broad range of TLR4 activity and differential cytokine inducing properties, which can be exploited for use as an adjuvant in vaccines We will use our panel of genetically-detoxified LPS compounds to optimise their preferred presentation form and delivery vehicle. Their physicochemical states will be assessed, including aggregation behaviour and dynamics, and abilities to influence in vitro innate immune responses (antigen presenting cell (APC) activation, cytokine induction) quantified. The purified LPS will then be formulated in well-characterised particles, e.g. liposomes. The design space will be determined using parameters such as lipid composition, particle size, and LPS loading.
