Ebola virus pseudotypes as tools for investigation of immunity, infectivity, diagnostics and therapeutic evaluation
Dr Simon Scott
Dr N Temperton
No more applications being accepted
Funded PhD Project (European/UK Students Only)
Ebola is a haemorrhagic disease exhibiting high mortality rates but with no licensed vaccines or antivirals. Existing ELISAs measure Ebola-specific antibodies stimulated by infection but not specifically those inducing virus neutralization, a correlate of protection. Neutralization assays using wild type Ebola virus are performed under high biological containment (BSL-4), severely restricting where they can be conducted. However, pseudotype viruses (PVs) can be employed as surrogates in neutralization assays, but are non-infectious particles with the ‘core’ of one virus and envelope glycoprotein (env) of the study virus. They can be used to investigate natural infections and vaccine or antiviral efficacy. Dr Wright recently generated data on production of PVs for both Ebola and related Marburg filoviruses, both of which feature on the current WHO priority disease list. These have been employed in antiviral drug screening (Long et al. F1000 2015), diagnostic development (EbolaCheck; Moschos Exp Rev Mol Diagn 2015) and establishment of an international serological standard for Ebola in collaboration with the National Institute for Biological Standards and Control (NIBSC, UK). However, compared to other PV families generated, these are low titre, limiting use for larger-scale research.
We previously demonstrated that filovirus PVs retain their functionality following lyophilisation (Mather et al. JVM 2014) and have also multiplexed PV assays (Wright et al. Virology 2010). These ideas will be combined in a collaboration with the Institute for Translational Vaccinology (www.intravacc.nl), to develop a commercial kit for use in-field and in low-resource laboratories. University of Kent Innovation & Enterprise have overseen a signed work agreement between Dr Scott and Intravacc, who will provide €10K for project consumables. The student would also spend time at Intravacc in the later project period, up-scaling kit production and validation.
1) Increase Ebola PV titres by: enhancing env expression utilising alternative gene promoter sequences; env cleavage site mutations; env transmembrane signal sequences; other viral ‘cores’ which influence PV titres.
2) Identification of immunodominant and infectivity-enhancing glycoprotein domains and epitopes for design of pan-Ebolavirus immunogens, via targeted mutation.
3) Development of a lyophilised multiplex PV diagnostic kit able to identify the three Ebola species that have caused major human outbreaks, plus Marburg filovirus.
Drs Scott, Temperton & Wright are PIs in the Viral Pseudotype Unit (www.viralpseudotypeunit.info), a collaboration between the Universities of Kent and Westminster, interfacing between academia, industry and public health laboratories. The timely nature of this project is highlighted by Dr Wright’s grant funding (Wellcome Trust and Department for International Development) to develop EbolaCheck and novel antibody-based treatments. These grants would support the proposed project, in addition to Intravacc funding. NIBSC will provide serological standards. The scholarship would support MSoP research strategy by creating a new link with a European pharmaceutical company conducting international healthcare R&D, in a high profile field, leading to high impact scientific publications and a potentially marketable product.
This 3 year project is a collaboration between the PhD primary supervisor Dr Simon Scott and secondary supervisor Dr Nigel Temperton (University of Kent) and Dr Edward Wright (University of Westminster), allPIs of the Viral Pseudotype Unit and Dr Ivo Ploemen of the Institute for Translational Vaccinology (Bilthoven, Netherlands). The intention is to develop a lyophilised, EboPV-based antibody neutralization kit for commercial use. Consumables (10k EURO total) will be funded through sponsorship by InTraVacc.
There is also a Graduate Teaching Assistantship component (see link below). This training and experience will lead to a qualification to add to your CV.