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Title: Carriage of Streptococcus pneumoniae in young children following pneumococcal conjugate vaccination and exploration of the role of human dendritic cells in causing between-serotype immunogenicity differences
Author: Tocheva, Anna Stoyanova
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2011
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Streptococcus pneumoniae (pneumococcus) is a common coloniser of the human nasopharynx. Annually, invasive pneumococcal disease (IPD) kills approximately 800,000 children worldwide. Prior to introduction of the heptavalent pneumococcal conjugate vaccine (PCV-7) to the children's vaccination schedule in 2006, vaccine serotypes 4, 6B, 9V, 14, 18C, 19F and 23F accounted for 75% of paediatric IPD in the UK. PCV-7 implementation resulted in a 41% decline in IPD in =5 year olds by 2008. However, the incidence of replacement disease caused by non-vaccine serotypes increased. It is unknown whether serotype replacement is also mirrored in carriage. The long-term effects of PCV-7 implementation on carried pneumococcal serotypes and genetic clones in children <5 years was investigated. Data from the current study demonstrated that carriage of PCV-7 serotypes and related genetic clones declined significantly three years after vaccine implementation, due to significant decreases of serotypes 6B and 19F. However, this decline coincided with marked elevations of non-vaccine serotypes 6C, 11A, 19A and 22F, and expansions of related genetic clones. Based on these observations, we investigated whether biochemical changes in the structure of pneumococcal capsular polysaccharide (cps) were linked to alterations in immune processing of pneumococci that may possibly assist bacterial adaptation and facilitate serotype replacement. The in vitro interaction of human monocyte-derived dendritic cells (mo-DC) with clinical serotype 1, 3 and 6B S. pneumoniae isolates and with a laboratory reference strain D39 (serotype 2 ) and its unencapsulated and pneumolysin toxin-deficient mutants was investigated. There were no significant differences in the human mo-DC response to live pneumococci expressing distinct cps. Increasing concentrations of live pneumolysinsufficient pneumococci were cytotoxic to mo-DC with the unencapsulated mutant and serotype 6B being most lethal. Cytotoxicity and inhibition of mo-DC activation by live bacteria may be mediated by pneumolysin toxin as the live pneumolysin-deficient strain did not cause cell death and significantly activated human mo-DC compared to its parent strain. Furthermore, active pneumolysin-containing lysates did not inhibit human naïve CD4+ T cell proliferation. Heat-inactivation of the strains enhanced mo-DC responses in a dose-dependent manner, as shown by cytokine secretion and surface marker expression. In summary, the present study demonstrated that PCV-7 intervention resulted in a significant reduction of vaccine-associated serotypes in paediatric carriage. However, the dynamics of carried pneumococci changed following PCV-7 implementation resulted in an an increase of non-vaccine serotypes. Differences in cps structure were not a factor influencing human mo-DC activation. However, expression of the poreforming pneumococcal toxin pneumolysin enhanced cell death and abrogated mo-DC activation.
Supervisor: Christodoulides, Myron ; Faust, Saul ; Clarke, Stuart Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available