Characterisation of the Infant Immune System and the Influence and Immunogenicity of BCG Vaccination in Infant and Adult Rhesus Macaques

In countries where tuberculosis (TB) is endemic, BCG is recommended close after birth to protect infants from severe forms of TB. BCG has variable efficacy and provides limited protection against adult pulmonary TB, with guidance recommending that it is not administered to adults over 35 years. Most animal models used to study novel TB vaccine candidates rely on the use of adult animals, despite studies showing differences in the infant immune system that continues to change during ageing. The aim of this thesis was to characterise BCG-specific immune responses in rhesus macaques vaccinated in infancy and compare those to similarly vaccinated adults. BCG-specific immune responses were detected in macaques vaccinated in infancy from six weeks after immunisation indicating that neonatal macaques are able to generate a functional cellular response to BCG. However, responses measured were significantly lower than those observed following vaccination in adults. Infant profiles were skewed towards the activation and attraction of macrophages and monocytes and the release of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. The frequency of specific immune cell populations changed significantly as macaques progressed to adulthood. Notably, the CD4:CD8 ratio significantly declined as macaques aged. The frequency of T-cells expressing memory marker CD95, and memory subset populations increased significantly as animals matured. Macaques vaccinated in infancy possessed a significantly higher frequency of classical monocytes and granulocytes which remained higher throughout the first three years of life compared to unvaccinated age-matched animals. This project highlights differences in the phenotypic profile and functional ability of the immature host immune system when compared to that of adults which leads to an altered response to BCG. This provides an insight into the mechanism by which BCG vaccination provides protection in infants and is critical for our understanding of appropriate model use for the testing of vaccines