Prof Sarah Gilbert

Prof Sarah Gilbert
Address:

The Jenner Institute, Old Road Campus Research Building
Roosevelt Drive, Oxford OX3 7DQ

Tel:

+44 (0)1865 617605

Email:

Principal areas of research

T cell vaccines, DNA, MVA and fowlpox vaccines, tuberculosis and influenza vaccines.

After a first degree in Biological Sciences at the University of East Anglia, specializing in Microbiology, I moved to the Biochemistry Department at the University of Hull. The subject of my PhD thesis was the biochemistry of lipid accumulation in oleaginous yeasts. I then spent a year investigating pentose metabolism in brewing yeasts at the Brewing Research Foundation in Surrey and two years at the Leicester Biocentre where I learned molecular biology techniques and investigated promoters suitable for heterologous protein expression in yeast. I then joined Delta Biotechnology in Nottingham, working on production of recombinant human blood proteins in yeast before moving to Adrian Hill’s group at the University of Oxford in 1994.

Research

My chief research interest is the development of vaccines that work by inducing strong and protective T cell responses. This has included work on DNA vaccines and virus-like protein particles carrying multiple T cell epitopes on their surface, as well as the viral vaccine vectors Modified Vaccinia virus Ankara (MVA), fowlpox and adenovirus. Having discovered that heterologous prime-boost immunisation, in which the same antigen is delivered in first one vector and then another, is highly immunogenic in pre-clinical studies, I produced DNA, MVA and fowlpox vaccines which were then manufactured for clinical trials.

The majority of the clinical trials that I have been involved with have utilized the METRAP antigen, which I constructed. This consists of a string of defined human T cell epitopes (Multiple Epitope) taken from pre-erythrocytic antigens of Plasmodium falciparum, fused in frame to the complete coding sequence of the Thrombospondin Related Adhesive Protein (TRAP), which is also a P. falciparum antigen expressed during the pre-erythrocytic stage of infection. In volunteers immunized with these vaccines in prime-boost regimes (DNA prime MVA boost, or fowlpox prime, MVA boost) strong T cell responses were induced. Challenge studies, in which volunteers are immunized and then deliberately infected with P. falciparum, have also been carried out. We have been able to demonstrate partial efficacy of the vaccines, killing a proportion of liver stage parasites in some of the volunteers, and complete protective efficacy in a small number of volunteers.

Field trials of the vaccines in The Gambia and Kenya showed the vaccines to be safe and immunogenic, but no efficacy could be demonstrated. Pre-clinical development has continued in parallel with the field trials, and we are now ready to begin clinical trials with a replication-deficient adenovirus vectored vaccine, again expressing METRAP. Detailed immunological analysis after clinical trials has demonstrated increased efficacy correlating with increased CD8+, rather than CD4+ T cell responses. In pre-clinical studies vaccination with adenovirus vectors induces high levels of CD8+ T cell responses to the recombinant antigen, and we now need to test if this result is replicated in clinical studies, and if this results in increased protective efficacy.

In addition I have been involved in the development and clinical trial of new vaccines against tuberculosis, and more recently have begun to apply the same principles of vaccine development, pre-clinical and clinical testing to new vaccines against influenza. The currently available ‘flu vaccines work by inducing antibodies to highly variable surface proteins of the virus, and slightly different versions have to be manufactured each year to keep up with changes in the virus. However the internal proteins of the ‘flu virus, which are produced inside infected cells, are well conserved, not only from one year to the next, but also between seasonal ‘flu viruses and those normally found only in avian species. Using these antigens, it should be possible to make a vaccine that protects against all subtypes of influenza, and ultimately, to stop a new pandemic in its tracks.

Lifelong exposure to malaria results in low-level immunity which is quickly lost when exposure ceases. Vaccine development must therefore aim to achieve far more than can be achieved by natural infection. In contrast, a single infection with influenza results in a protective immune response which is effective for some years after the infection, but then wanes. Boosting these naturally acquired T cell responses to the conserved antigens of the virus by vaccination could therefore result in continued cross-reactive immunity, maintained by subsequent booster doses. This is the concept that I am now aiming to test in clinical trials.

Key Publications

1. Hill, A.V., A. Jepson, M. Plebanski, and S.C. Gilbert, Genetic analysis of host-parasite coevolution in human malaria. Philos Trans R Soc Lond B Biol Sci, 1997. 352(1359): p. 1317-25.
2. Hill, A.V., W. Reece, P. Gothard, V. Moorthy, M. Roberts, K. Flanagan, M. Plebanski, C. Hannan, J.T. Hu, R. Anderson, P. Degano, J. Schneider, E. Prieur, E. Sheu, and S.C. Gilbert, DNA-based vaccines for malaria: a heterologous prime-boost immunisation strategy. Dev Biol (Basel), 2000. 104: p. 171-9.
3. Gilbert, S.C., Virus-like particles as vaccine adjuvants. Mol Biotechnol, 2001. 19(2): p. 169-77.
4. Taracha, E.L., R. Bishop, A.J. Musoke, A.V. Hill, and S.C. Gilbert, Heterologous priming-boosting immunization of cattle with Mycobacterium tuberculosis 85A induces antigen-specific T-cell responses. Infect Immun, 2003. 71(12): p. 6906-14.
5. Vordermeier, H.M., S.G. Rhodes, G. Dean, N. Goonetilleke, K. Huygen, A.V. Hill, R.G. Hewinson, and S.C. Gilbert, Cellular immune responses induced in cattle by heterologous prime-boost vaccination using recombinant viruses and bacille Calmette-Guerin. Immunology, 2004. 112(3): p. 461-70.
6. Andrews, L., R.F. Andersen, D. Webster, S. Dunachie, R.M. Walther, P. Bejon, A. Hunt-Cooke, G. Bergson, F. Sanderson, A.V. Hill, and S.C. Gilbert, Quantitative real-time polymerase chain reaction for malaria diagnosis and its use in malaria vaccine clinical trials. Am J Trop Med Hyg, 2005. 73(1): p. 191-8.
7. Young, K., A. Frodsham, O.K. Doumbo, S. Gupta, A. Dolo, J.T. Hu, K.J. Robson, A. Crisanti, A.V. Hill, and S.C. Gilbert, Inverse associations of human leukocyte antigen and malaria parasite types in two West African populations. Infection and Immunity, 2005. 73(2): p. 953-5.
8. Cottingham, M.G., R.F. Andersen, A.J. Spencer, S. Saurya, J. Furze, A.V. Hill, and S.C. Gilbert, Recombination-mediated genetic engineering of a bacterial artificial chromosome clone of modified vaccinia virus Ankara (MVA). PLoS One, 2008. 3(2): p. e1638.
9. Cottingham, M.G. and S.C. Gilbert, Rapid generation of markerless recombinant MVA vaccines by en passant recombineering of a self-excising bacterial artificial chromosome. Journal of virological methods, 2010. 168(1-2): p. 233-6.
10. Berthoud, T.K., M. Hamill, P.J. Lillie, L. Hwenda, K.A. Collins, K.J. Ewer, A. Milicic, H.C. Poyntz, T. Lambe, H.A. Fletcher, A.V. Hill, and S.C. Gilbert, Potent CD8+ T-cell immunogenicity in humans of a novel heterosubtypic influenza A vaccine, MVA-NP+M1. Clin Infect Dis, 2011. 52(1): p. 1-7.
11. Gilbert, S.C., T-cell-inducing vaccines - what's the future. Immunology, 2012. 135(1): p. 19-26.
12. Gilbert, S.C., Advances in the development of universal influenza vaccines. Influenza Other Respi Viruses, 2012.
13. Gilbert, S.C., Influenza vaccines and immunopathology. Expert Rev Vaccines, 2012. 11(8): p. 873-5.
14. Lambe, T., A.J. Spencer, C.E. Mullarkey, R.D. Antrobus, L.M. Yu, P. de Whalley, B.A. Thompson, C. Jones, J. Chalk, S. Kerridge, A.V. Hill, M.D. Snape, A.J. Pollard, and S.C. Gilbert, T-Cell Responses in Children to Internal Influenza Antigens, 1 Year after Immunization with Pandemic H1N1 Influenza Vaccine, and Response to Revaccination with Seasonal Trivalent Inactivated Influenza Vaccine. Pediatr Infect Dis J, 2012.
15. Lillie, P.J., T.K. Berthoud, T.J. Powell, T. Lambe, C. Mullarkey, A.J. Spencer, M. Hamill, Y. Peng, M.E. Blais, C.J. Duncan, S.H. Sheehy, T. Havelock, S.N. Faust, R.L. Williams, A. Gilbert, J. Oxford, T. Dong, A.V. Hill, and S.C. Gilbert, Preliminary assessment of the efficacy of a T-cell-based influenza vaccine, MVA-NP+M1, in humans. Clin Infect Dis, 2012. 55(1): p. 19-25.
6. Science advisor on "Bio-Punk - Stories from the Far Side of Research", edited by Ra Page. A collection of science fiction stories based on real science: http://www.commapress.co.uk/?section=books&page=BioPunk