Defining the infant immune response to BCG vaccination in human and non-human primates

Project Overview

Bacille Calmette Guerin (BCG) is the only currently licensed vaccine available to counter the on-going tuberculosis (TB) pandemic. BCG is administered during infancy in TB endemic areas and is highly effective against disseminated disease in children. Protection wanes as individuals age, however, and efficacy against pulmonary TB in adolescents and adults is highly variable.  Understanding the immune response that confers early protection against disseminated disease and what changes lead to the loss of protection is a crucial step that will facilitate the development of improved vaccines. This project will characterise the early response to BCG in non-human primates (NHPs) from birth to three years via blood sample analysis at pre-determined intervals, comparing results to age-matched non-vaccinated controls. This will potentially lead to the identification of immune correlates of protection and identification of how or why protection begins to wane. In addition, the project seeks to confirm the legitimacy of the NHP model for future use by directly comparing existing human samples, taken after BCG in South African infants and post-BCG from UK adults, to those collected from the NHPs.

Training Opportunities

Helen McShane at Oxford and Sally Sharpe at PHE will lead the project, and both will serve as supervisors and mentors for the student. Dr Iman Satti will provide hands on lab supervision for the duration of the project. All 3 supervisors will meet regularly with the student to assist and address any issues or questions that may arise. The student will use and become familiar with numerous laboratory techniques, including flow cytometry, mycobacterial growth inhibition assays, antibody profiling, and cytokine release assays. The student will participate in departmental seminars, have access to field experts, and receive assistance from laboratory staff at both the University of Oxford and Public Health England to ensure competency and adequate progress.

Theme

Immunology & Infectious Disease and Tropical Medicine & Global Health

Admissions

Project reference number: 716

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor Helen McShane Jenner Institute Oxford University, Old Road Campus Research Building GBR helen.mcshane@ndm.ox.ac.uk
Dr Iman Satti The Jenner Institute University of Oxford GBR iman.satti@ndm.ox.ac.uk
Dr Sally Sharpe Public Health England, Porton Down GBR

Sibley L, Dennis M, Sarfas C, White A, Clark S, Gleeson F, McIntyre A, Rayner E, Pearson G, Williams A, Marsh P, Sharpe S. 2016. Route of delivery to the airway influences the distribution of pulmonary disease but not the outcome of Mycobacterium tuberculosis infection in rhesus macaques. Tuberculosis (Edinb), 96 pp. 141-9. Read abstract | Read more

Non-human primates (NHP) provide a key component in the preclinical assessment pathway for new TB vaccines. In the established models, Mycobacterium tuberculosis challenge is typically delivered to airways of macaques either by aerosol or bronchoscopic instillation and therefore, an understanding of these delivery routes would facilitate the comparison of data generated from models using different challenge methods. This study compared the clinical effects, antigen-specific IFNγ response profiles and disease burden following delivery of comparable doses of M. tuberculosis to the lungs of rhesus macaques by either aerosol or bronchoscopic instillation. The outcome of infection in terms of clinical effects and overall disease burden was comparable between both routes of challenge. However, the pathology in the lungs differed as disease was localised to the site of inoculation following bronchoscopic instillation while aerosol exposure resulted in lesions being evenly distributed through the lung. Whilst the IFNγ response to PPD was similar, responses to CFP10 and ESAT6 peptide pools measured with an ex vivo ELISPOT differed with regards to responses to the N-terminal regions depending on the route of infection. Both challenge routes therefore provide valid and comparable models for evaluation of new TB vaccines, although subtle differences in host responses may occur. Hide abstract