Assessing immunological responses to next-generation vaccine candidate delivery systems – linking Physico-chemical characteristics to biological response

Description

Complex medicines, such as nanotherapeutics, have significantly transformed treatment in biomedicine. Liposomes and lipidic nanoparticles (LNP) have been utilised in clinical settings for over 40 years, initially for the administration of chemotherapeutics like Doxorubicin (in its PEGylated liposomal form as Doxil) to improve their circulation time in the bloodstream and lessen the occurrence of side effects. Recently, they have played a crucial role in the global vaccination effort, delivering SARS-CoV-2 antigens through mRNA technology. The introduction of mRNA-based, liposomal vaccines to fight the COVID-19 pandemic has highlighted their clinical value as adaptable delivery systems that swiftly react to new and emerging pathogens. While liposomes are generally considered non-toxic but not immunologically neutral, a thorough evaluation of immune responses is essential from a safety standpoint. This also uncovers new properties that could be advantageous in vaccine applications.

LNPs and the Immune system

With decades of research into their development and use in the clinic, liposomes are generally considered non-toxic but are increasingly shown not to be immunologically inert [1]. In the case of vaccine applications, it is suggested that this adjuvanticity may be beneficial through activation of the innate immune system inflammasomes. However, applying liposomal technology to deliver other nucleic acids in disease areas outside of infection and gene therapies more broadly may be undesirable as it may elicit unwanted immunological responses that lead to adverse reactions. Several hypotheses have been put forward, suggesting what it is about the physical and chemical characteristics (PCC) of liposomes that may generate this inflammation, including, but not limited to, the inclusion of cationic ionisable lipids in their formulation, such as SM-102 used in the Moderna SARS-CoV-2 vaccine [2, 3]. However, work at the University of Liverpool has shown that even without cationic ionisable lipids, immune stimulation is still possible through the activation of inflammasomes [4], key components of the innate immune response. It is, therefore, vital to understand which PCC is linked to an immunological response to complex medicines to understand their Immunocompatibility profiles fully, to be assured of safety and efficacy [5].

The overarching aim of the current project is to define and implement an integrated approach to the immunocompatibility assessment of nanotherapeutics, using liposomes as a clinically relevant paradigm. Throughout the project, we will identify the physical and chemical characteristics of liposomes associated with immunotoxicological events through a harmonised assay cascade in human systems, employ metabolomic and bioenergetic approaches to ascertain whether there are profiles that predispose to immune activation by liposomes, and further enhance our 3D model of the subcutaneous space, a key route of administration for nucleic acid therapeutics. This project is well-positioned in integrated toxicology, cultivating students' expertise in immunocompatibility, metabolomics and bioenergetics, nano-metrology, physicochemical characterisation, and developing complex medicines.

The University of Liverpool is a global leader in developing advanced therapeutics and complex medicines, particularly nanotherapeutics, to combat infectious diseases. The supervisory team spearheads several national and international initiatives and infrastructures to advance these therapeutics and enhance our understanding of their interactions with biological systems. As in this studentship, the research environment is ideal for training candidates in complex medicines, immunocompatibility, and clinical translation. The student will collaborate with researchers active in the field and these centres throughout their PhD. The strong connections between the group, The Pandemic Institute, and the National Measurement Laboratory will facilitate a dynamic training programme in complementary immunocompatibility and metrology; areas related to complex medicines and model development.

As part of their partnership, NML and TPI have co-funded this PhD studentship, with the outputs expected to support LNP design by identifying the optimal characteristics of LNPs for vaccine delivery and pandemic preparedness, focusing on the delivery system rather than just the payload. At UoL, we possess a comprehensive suite of human immunological assays to delineate responses to such delivery systems and full training will be provided. NML will support the metrological aspects of the studentship, including an assessment of physicochemical characteristics and the application of metrology approaches essential for translating new materials. This will also present a valuable training opportunity at the academic-industrial interface, facilitated by clinical considerations via The Pandemic Institute.

-Applications should be made to the primary project supervisor (Prof. Neill Liptrott) in the first instance via CV and cover letter. This is for all applications. Only when a candidate has been selected following interview will a formal online application be required.