Mechanisms of liposomal and squalene emulsion adjuvants

Thesis

Adjuvanted protein vaccines can provide a high level of protection against many pathogens. Yet the mechanisms underlying their function are not well understood, a fact that is complicated by the proprietary nature of most potent adjuvants. In this context, the Vaccine Formulation Institute develops liposomal (LQ and LMQ) and squalene emulsion (SQ and SMQ) adjuvants for open-access usage. This thesis addresses the challenge of understanding the mechanisms of action of these adjuvants towards the aim of enabling rational mechanistically informed vaccine design.

In this thesis, adjuvants are mapped across cells and tissues in terms of adjuvant tropism, drainage and transcriptomic modulation. Fluorescently labelled liposomal and squalene emulsion adjuvants were used to identify the cellular targets and drainage patterns of these adjuvants in the muscle spleen and lymph node. Through a comprehensive screening of cell types by flow cytometry it was found that adjuvant drainage was restricted primarily to the muscle and draining lymph nodes with little systemic spread to the spleen. In addition, liposomal adjuvants displayed a higher level of uptake across cell types, particularly with an increased capacity for uptake in resident non-hematopoietic cells in the lymph node in comparison to squalene emulsion adjuvants. Whole transcriptome sequencing approaches were used to generate a map of the transcriptomic inflammatory response to LMQ and SQ in the muscle and draining lymph nodes. It was identified that while both adjuvants induce a core innate immune response, LMQ was characterised by a transcriptomic Type II interferon response driven by ILC1s and NK cells that was not found after immunisation with SQ.

Authors: Nee, E

• DOI: 10.5287/ora-wxzgeoye6
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English