Kimberley Steeds

Antibody correlates of protection for Ebola virus infection: Effects of mutations within the viral GP on virus cell entry and immune escape

Personal Statement:

Kimberley is a final year PhD student based at Public Health England (PHE) Porton Down, and supported by the Institute of Infection and Global Health at the University of Liverpool (UoL). Kimberley was awarded a BSc degree in Applied Biology with first-class honours from the University of Bath, where she then worked as a laboratory technician for two years.  

 

She has since worked at Porton Down for over seven years, gaining experience in infectious disease research and immunology.  Various deployments to West Africa during the 2013-2016 EBOV outbreak, including work within an EBOV diagnostic laboratory, and collecting immunological samples for an Ebola vaccine trial, encouraged her decision to undertake a doctorate degree within this particular area of research.

          

 

Ksteeds

   

Lay Summary:

It is thought that Ebola virus disease (EVD) survivors are protected against subsequent infection with Ebola virus (EBOV), and that neutralising antibodies to the viral surface glycoprotein (GP) are involved.  Convalescent therapy has been used to treat infected individuals, and several vaccines are based on EBOV GP.

During virus infection, and transmission from person to person, EBOV may evolve, and mutations within EBOV GP may affect the ability of antibodies from convalescent patients, or those induced by vaccines, to protect against new variants of the virus. 

This project will use a psuedotyped virus (PV) system to study the effects of mutations within the EBOV GP on escape from neutralising antibodies.

A PV is a replication-defective chimeric virion that comprises the structural and enzymatic core of one virus, bearing the envelope protein of another, and encodes a quantifiable reporter gene.  PVs can be created by co-transfection of producer cells using a three-plasmid system.  The first plasmid encodes the genes responsible for manufacture and enzymatic processing of the core structural proteins.  The second plasmid encodes the envelope glycoprotein gene from the virus of interest, and the third plasmid encodes the chosen reporter gene, which becomes packaged into the core.

PVs can be used as surrogates for infectious virus in neutralisation assays to measure neutralising antibodies against the envelope glycoprotein.  If binding and infection of target cells by the PV is successful, the genome is transferred to the target cell and the reporter gene is expressed.  However, if neutralising antibodies to the surface glycoprotein are present, the PV does not infect the target cell, and the reporter gene is not expressed.

We will generate a panel of mutant EBOV GP PVs, and will test these in neutralisation assays using plasma from EVD survivors, to determine to presence of escape mutants.

Supervisors:

  • Miles Carroll - NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Public Health England
  • Georgios Pollakis – Institute of Infection and Global Health, University of Liverpool
  • Julian Hiscox – NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool

Publications:

Tree, J.A., Hall, G., Pearson, G., Rayner, E., Graham, V.A., Steeds, K., Bewley, K.R., Hatch, G.J., Dennis, M., Taylor, I., Roberts, A.D., Funnell, S.G.P. and Vipond, J.  Sequence of Pathogenic Events in Cynomolgus Macaques Infected with Aerosolized Monkeypox Virus.  Journal of Virology. 2015, 89(8), 4335-4344
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442344/

Graham, V.A., Hatch, G.J., Bewley, K.R., Steeds, K., Lansley, A., Bate, S.R. and Funnell, S.G.P.  Efficacy of Primate Humoral Passive Transfer in a Murine Model of Pneumonic Plague Is Mouse Strain-Dependent.  Journal of Immunology Research, 2014, 807564, 11 pages
https://www.hindawi.com/journals/jir/2014/807564/

Hatch, G.J., Graham, V.A., Bewley, K.R., Tree, J.A., Dennis, M., Taylor, I., Funnell, S.G.P., Bate, S.R., Steeds, K., Tipton, T., Bean, T., Hudson, L., Atkinson, D.J., McLuckie, G., M Charlwood, M., Roberts, A.D.G. and Vipond, J.  Assessment of the protective effect of Imvamune and Acam2000 vaccines against aerosolized monkeypox virus in cynomolgus macaques.  Journal of Virology. 2013, 87(14), 7805-7815
http://jvi.asm.org/content/87/14/7805.full