Paediatrics (RCH) - Theses

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Author: RITZ, NICOLE × End date: 2009 × Start date: 2006 × Type: PhD thesis ×

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    The influence of BCG vaccine strain on the immune response and protection against tuberculosis
    RITZ, NICOLE ( 2009)
    More than 100 million doses of Bacille-Calmette-Guérin (BCG) vaccine are given each year to protect infants against tuberculosis (TB). BCG is a live attenuated strain derived from Mycobacterium bovis. Subsequent to its development and first use in 1921, BCG was distributed to laboratories worldwide. Culture under dissimilar conditions led to the evolution of more than 20 BCG vaccine strains in different countries. Phenotypic differences between these BCG vaccine strains were first recognised in the 1920s and, more recently, molecular studies have defined their genomic differences. Although several animal and human studies suggest that the particular BCG vaccine strain used for immunisation influences the mycobacterial-specific immune response, there is currently insufficient data to favour or recommend one BCG vaccine strain. The principal aim of this thesis was to investigate the influence of BCG vaccine strain on the mycobacterial-specific cellular immune response in infants. Related to this, three additional studies addressed questions that provided critical information for the design and interpretation of the main study. These studies investigated: (i) the BCG vaccine strains used in each country worldwide, (ii) the susceptibility of different BCG vaccine strains to antimycobacterial drugs; and (iii) the difference in the immune response induced by BCG immunisation in children and adults. For the main study in this thesis, newborns were randomly allocated to be immunised soon after birth with one of the three BCG vaccine strains currently most commonly used worldwide (BCG-Denmark, BCG-Japan or BCG-Russia). Ten weeks after BCG immunisation, the mycobacterial-specific cellular immune response was investigated using a comprehensive panel of immunological assays. This comprised flow cytometric analysis of intracellular cytokines and cytotoxicity in T cells, as well as the measurement of cytokines and chemokines in supernatants, from in vitro whole blood stimulation assays. Data from 167 BCG-immunised infants was included in the final analysis. Infants immunised with BCG-Denmark or BCG-Japan had significantly higher proportions of multifunctional CD4 T cells than infants immunised with BCG-Russia. Similarly, infants immunised with BCG-Japan had significantly higher levels of Th1 cytokines in supernatants than infants immunised with BCG-Denmark or BCG-Russia. These findings are particularly important in the light of recent evidence from animal studies that the frequency of multifunctional CD4 T cells induced by immunisation correlates with protection against intracellular pathogens such as Mycobacterium tuberculosis. This suggests that immunisation with BCG-Denmark or BCG-Japan is associated with better protection against TB than immunisation with BCG-Russia. Until correlates of protection against TB are determined in humans, cautious interpretation of these findings is warranted. Nonetheless, the findings from this thesis have important implications. The use of a BCG vaccine strain with even a moderately higher protective efficacy would have a large effect on TB morbidity and mortality in infants on a global scale. This thesis may therefore inform future BCG immunisation policy worldwide.