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Be part of launching a new scientific field – translating PK/PD modelling to immunostimulation/ immunodynamic (IS/ID) modelling - to accelerate vaccine development


   London Interdisciplinary Biosciences Consortium (LIDo)

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  Prof R White  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Vaccines, once developed, are one of the cheapest ways of saving human lives. But, developing a new vaccine can take decades, and cost around a billion dollars. The current scientific methods used to identify the right amount of vaccine dose are empirical and antiquated. In contrast, mathematical model-based drug development (PK/PD) is regularly used to predict the best size and schedule of dose to use.

We are translating the modelling techniques used for drug development, to vaccine development, and launching a new scientific field - immunostimulation/ immunodynamic (IS/ID) modelling.

You will create novel statistical and mechanistic models, parameterised using empirical data from Vaccitech mouse vaccine experiments and the literature, to help design new pre-clinical and clinical studies performed at Vaccitech.

You will build on our previous dose-response mathematical modelling work, to focus on adenoviral constructs and Modified vaccinia Ankara, two viral vectors which are often used in combination to induce T cells responses. A “prime-boost combination” has been widely used in animals and humans, including in advanced studies of tuberculosis, HIV, Ebola, RSV, HCV, and even prostate cancer. However, minimal work has been carried out to understand the best doses of vaccines when used in combination, and there is poor understanding of the timing of vaccination, and if one or more primes or boosts should be given.

The exact PhD research questions will be adapted to the interests of the student, and feasibility will be continually monitored during the project, but the PhD scope could be:
Aim 1: First, you will use existing experimental data to create and parameterise novel statistical/mechanistic models to make predictions for the vaccine dose/immunological response relationship in mice. Will include a 3-month Vaccitech placement.
Aim 2: Second, you will improve the statistical/mechanistic model dose-response predictions, by making predictions for the best design of new empirical mouse experiments, to maximise the dose-response information gained, and minimising the number of mice used. Will include a 3-month Vaccitech placement.
Aim 3: Third, using an allometric scaling assumption and statistical/mechanistic modelling, you will make initial predictions for the most immunogenic dose-response relationship in humans, based on the mouse data. These predictions will be evaluated in new empirical clinical experiments carried out at Vaccitech. Will include a 2-month Vaccitech placement.
Aim 4: Within the period of this PhD, the modelling evidence you will create will be used to improve the design of a human trial of the Vaccitech adenoviral constructs and Modified vaccinia Ankara viral vectors. Will include a 1-month Vaccitech placement.

In additional to the creation of new knowledge, the project has a route to impact on vaccine development policy, and wider economic and societal impact.

Supervisory team
Prof White is Prof of Infectious Disease Modelling at the London School of Hygiene and Tropical Medicine (LSHTM) and leads the LSHTM TB Modelling Group and the international TB Modelling and Analysis Consortium. Dr Rhodes is an expert in mathematical and IS/ID modelling. Dr Evans is an expert in vaccine product development, and is the former CSO and CEO of the Aeras (Vaccine) Product Development Partnership, who has worked closely with many products in the TB vaccine space, including those included in this proposal. Dr Fletcher has extensive experience in vaccine immunology and is head of the LSHTM TB Centre. Joe Standing, UCL, is an expect PK/PD modeller.

Environment
LSHTM (Richard White, Helen Fletcher, Sophie Rhodes) is a leading establishment LSHTM is a top global public health centre, with a reputation for international quality multidisciplinary research, and active research programmes in immunology, epidemiology and mathematical modelling. LSHTM is home to the Centre for the Mathematical Modelling of Infectious Diseases and the TB Modelling Group. Vaccitech (Tom Evans) is a clinical stage biotechnology company spun out of the Jenner Vaccine Institute of Oxford University, and is a leader in the use of viral vectors for prophylactic and therapeutic vaccines. UCL hosts weekly meetings of the London Pharmacometrics Interest Group.

Training
Training will suit the needs of the student, but could include:
-Mechanistic math modelling: Introduction to Infectious disease modelling (LSHTM). The primary supervisor is the primary organiser of this course, who will give additional training.
-Immunology: Immunology of Infectious Diseases module (LSHTM) and further immunological guidance by Helen Fletcher.
-An external course in PK/PD modelling skills: ADME, Pharmacokinetics & Pharmacodynamics (Kings College, London) would also be offered to the student.
-Vaccitech will make available business-related training, including project-management, business strategy and finance.

Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £16,553. Students from the EU are welcome to submit an application for funding, any offers will be subject to BBSRC approval and criteria. The studentship includes £55,000 funding from Vaccitech to support animal studies, and some accommodation, consumable, equipment and conference expenses.

References

• Rhodes, S. J., C. Sarfas, G. M. Knight, A. White, A. A. Pathan, H. McShane, T. G. Evans, H. Fletcher, S. Sharpe and R. G. WHITE (2017). “Using Data from Macaques To Predict Gamma Interferon Responses after Mycobacterium bovis BCG Vaccination in Humans: a Proof-of-Concept Study of Immunostimulation/Immunodynamic Modeling Methods.” Clinical and Vaccine Immunology 24(3).

• Fletcher, H.A. ; Snowden, M.A. ; Landry, B. ; Rida, W. ; Satti, I. ; Harris, S.A. ; Matsumiya, M. ; Tanner, R. ; O'Shea, M.K. ; Dheenadhayalan, V. ; Bogardus, L. ; Stockdale, L. ; Marsay, L. ; Chomka, A. ; Harrington-Kandt, R. ; Manjaly-Thomas, Z.R. ; Naranbhai, V. ; Stylianou, E. ; Darboe, F. ; Penn-Nicholson, A. ; Nemes, E. ; Hatheril, M. ; Hussey, G. ; Mahomed, H. ; Tameris, M. ; McClain, J.B. ; Evans, T.G. ; Hanekom, W.A. ; Scriba, T.J. ; McShane, H. ; T-cell activation is an immune correlate of risk in BCG vaccinated infants. Nat Commun (2016) 7:11290; DOI: 10.1038/ncomms11290; PMID: 27068708 Open Access

• Fletcher, H.A.; Filali-Mouhim, A.; Nemes, E.; Hawkridge, A.; Keyser, A.; Njikan, S.; Hatherill, M.; Scriba, T.J.; Abel, B.; Kagina, B.M.; Veldsman, A.; Agudelo, N.M.; Kaplan, G.; Hussey, G.D.; Sekaly, R.P.; Hanekom, W.A.; BCG study team, .; COLLABORATORS;Minnies, D. ; Tanner, R. ; Chung, C.K. ; Cameron, M.J. ; Goulet, J.P. ; Gaujoux, R. ; Hughes, J. ; Gelderbloem, S. ; Iloni, K. ; Buchanan, M. ; van der Merwe, L. ; Burger, A. ; Denation, L. ; Mlanjeni, S. ; Abrahams, S. ; Shepherd, R. ; Geldenhuys, M. ; Seoighe, C. ; Soares, A. ; Gamieldien, H. ; Sidibana, M. ; Mahomed, H. ; McShane, H. ; Hill, A.V. ; Human newborn bacille Calmette-Guérin vaccination and risk of tuberculosis disease: a case-control study. BMC Med (2016) 14(1):76; DOI: 10.1186/s12916-016-0617-3; PMID: 27183822 Open Access

• Rhodes, S.J. ; Knight, G.M. ; Fielding, K. ; Scriba, T.J. ; Pathan, A.A. ; McShane, H. ; Fletcher, H. ; White, R.G. ; Individual-level factors associated with variation in mycobacterial-specific immune response: Gender and previous BCG vaccination status. Tuberculosis (Edinb) (2016) 96:37-43; DOI: 10.1016/j.tube.2015.10.002; PMID: 26786653 Open Access
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