Developing a novel platform for single dose vaccine delivery

Project Overview

Figure 1: Monodisperse phospholipid coated microspheres (diameter 150 um) produced using a ...

Figure 2: Multilayered capsule (120um diameter) produced using a multistream PDMS device.

Almost all current subunit vaccines require administration in two or three doses and at specific time intervals for full efficacy. Inadequate immunisation coverage is a long-standing problem in vaccination programmes worldwide, leading to avoidable deaths and debilitating disease in millions of children and adults, and risking new outbreaks of vaccine preventable diseases.

This project aims to develop a new technology for vaccine delivery that would allow multiple (prime-boost) immunisations to be combined into a single-dose vaccine while retaining full efficacy. The boost dose(s) would be encapsulated into polymer microcapsules for a delayed delivery within the body and administered together with the priming vaccine thus mimicking the conventional prime-boost immunisation. If successful, this approach would have a big impact both in the developing and the developed countries, from increasing vaccine coverage through minimising the impact of vaccination non-compliance, to reducing the costs and logistics associated with vaccine distribution, storage and administration. This could enhance vaccine delivery for a wide range of infectious diseases including malaria, influenza, outbreak pathogens, pertussis, HIV, meningitis and pneumococcal disease.  Once developed, the same technology could be applied to veterinary vaccines, resulting in many economic and healthcare benefits.

We have preliminary data suggesting that a delayed in vivo delivery could be achievable using a ‘core-shell’ type particle consisting of dense outer shell with a viscous gel centre. In this project we will further develop these particles and additionally investigate slow continuous and triggered release formulations to establish the optimal kinetics for single dose administration efficacy. Initially we will optimise microencapsulation using a model antigen and will then move to testing the process using two of the most promising types of future vaccines: virus like particles (VLPs) and viral vectors (as used in the recently developed Ebola vaccine).

We anticipate each of these objectives to result in a peer-reviewed publication with the overall project leading to a patentable novel immunisation platform. While the project will initially focus on vaccine delivery, this technology could also be applied to the field of drug or small molecule delivery. The candidate should ideally have a background in pharmacology, pharmaceutics, immunology, biochemistry or bioengineering with a strong interest in vaccine development.

Training Opportunities

The Jenner Institute has a strong track record in developing new vaccines, from the basic concept to clinical trials, with over 100 staff involved in active research and vaccine development in preclinical and clinical settings. It offers many excellent training opportunities, including molecular biology techniques for vaccine production using different platforms such as VLPs and viral vectors, in vivo evaluation of vaccine immunogenicity, a variety of imaging techniques, in vitro methods for assessing vaccine loading and stability and more. In addition, we have several well-established disease challenge animal models for testing the immunogenicity and efficacy of our vaccine candidates in vivo. Further information on the research activities at the Jenner Institute can be found at www.jenner.ac.uk

This is an interdisciplinary project and the successful candidate will work in collaboration with Prof. Eleanor Stride’s group at the Institute of Biomedical Engineering (IBME), which is co-located with the Jenner Institute on the University’s medical research campus adjacent to the Churchill Hospital. Prof. Stride’s laboratory is equipped with facilities for the preparation and characterisation of micro and nanoparticles for drug encapsulation (see Figures 1&2). The former include standard “wet chemistry” techniques in addition to systems for microfluidic and electrohydrodynamic fabrication. The latter include instruments for advanced particle sizing, spectroscopic and chromatographic analysis as well as state-of-the-art microscopy techniques. More information about IBME and its research programmes may be found at www.ibme.ox.ac.uk.

Theme

Immunology & Infectious Disease and Tropical Medicine & Global Health

Admissions

Project reference number: 771

Funding and admissions information

Supervisors

Name Department Institution Country Email
Dr Anita Milicic Jenner Institute Oxford University, Old Road Campus Research Building GBR anita.milicic@ndm.ox.ac.uk
Professor Adrian VS Hill Jenner Institute Oxford University, Old Road Campus Research Building GBR adrian.hill@ndm.ox.ac.uk
Professor Eleanor Stride Engineering Science University of Oxford GBR eleanor.stride@eng.ox.ac.uk

Walters AA, Krastev C, Hill AV, Milicic A. 2015. Next generation vaccines: single-dose encapsulated vaccines for improved global immunisation coverage and efficacy. J. Pharm. Pharmacol., 67 (3), pp. 400-8. Read abstract | Read more

OBJECTIVES: Vaccination is considered the most successful health intervention; yet incomplete immunisation coverage continues to risk outbreaks of vaccine preventable diseases worldwide. Vaccination coverage improvement through a single-dose prime-boost technology would revolutionise modern vaccinology, impacting on disease prevalence, significantly benefiting health care and lowering economic burden of disease. KEY FINDINGS: Over the past 30 years, there have been efforts to develop a single-dose delayed release vaccine technology that could replace the repeated prime-boost immunisations required for many current vaccines. Biocompatible polymers have been employed to encapsulate model vaccines for delayed delivery in vivo, using either continuous or pulsed release. Biomaterial considerations, safety aspects, particle characteristics and immunological aspects of this approach are discussed in detail. SUMMARY: Despite many studies showing the feasibility of vaccine encapsulation for single-dose prime-boost administration, none have been translated into convincing utility in animal models or human trials. Further development of the encapsulation technology, through optimising the particle composition, formulation, antigen loading efficacy and stability, could lead to the application of this important approach in vaccine deployment. If successful, this would provide a solution to better global vaccination coverage through a reduction in the number of immunisations needed to achieve protection against infectious diseases. This review provides an overview of single-dose vaccination in the context of today's vaccine needs and is derived from a body of literature that has not been reviewed for over a decade. Hide abstract

Labbaf S, Ghanbar H, Stride E, Edirisinghe M. 2014. Preparation of multilayered polymeric structures using a novel four-needle coaxial electrohydrodynamic device. Macromol Rapid Commun, 35 (6), pp. 618-23. Read abstract | Read more

Coaxial four-needle electrohydrodynamic forming is applied for the first time to prepare layered structures in both particle and fiber form. Four different biocompatible polymers, polyethylene glycol, poly (lactic-co-glycolic acid), polycaprolactone, and polymethylsilsesquioxane, are used to generate four distinct layers confirmed using transmission and scanning electron microscopy combined with focused ion beam milling. The incorporation and release of different dyes within the polymeric system of four layers are demonstrated, something that is much desired in modern applications such as the polypill where multiple active pharmaceutical ingredients can be combined to treat numerous diseases. Hide abstract

Parhizkar M, Stride E, Edirisinghe M. 2014. Preparation of monodisperse microbubbles using an integrated embedded capillary T-junction with electrohydrodynamic focusing. Lab Chip, 14 (14), pp. 2437-46. Read abstract | Read more

This work investigates the generation of monodisperse microbubbles using a microfluidic setup combined with electrohydrodynamic processing. A basic T-junction microfluidic device was modified by applying an electrical potential difference across the outlet channel. A model glycerol air system was selected for the experiments. In order to investigate the influence of the electric field strength on bubble formation, the applied voltage was increased systematically up to 21 kV. The effect of solution viscosity and electrical conductivity was also investigated. It was found that with increasing electrical potential difference, the size of the microbubbles reduced to ~25% of the capillary diameter whilst their size distribution remained narrow (polydispersity index ~1%). A critical value of 12 kV was found above which no further significant reduction in the size of the microbubbles was observed. The findings suggest that the size of the bubbles formed in the T-junction (i.e. in the absence of the electric field) is strongly influenced by the viscosity of the solution. The eventual size of bubbles produced by the composite device, however, was only weakly dependent upon viscosity. Further experiments, in which the solution electrical conductivity was varied by the addition of a salt indicated that this had a much stronger influence upon bubble size. Hide abstract