ETD Collection

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Has files: YesSubject: search.filters.subject.Pneumococcal Vaccines

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    Pre-clinical evaluation of pneumococcal vaccine candidate molecules in a mouse pneumococcal pneumonia model
    (2016) Lebogo, Kgomotso Welheminah
    Background: Streptococcus pneumoniae (pneumococcus) is a major cause of morbidity and mortality in young children. Pneumococcal conjugate vaccines are restricted in their serotype coverage, and hence, focus has been directed towards common protein-based antigens. However, there have been problems associated with testing protein-based antigens in animal models. These include inhumane endpoints, use of large sample sizes, and the inability to detect subtle differences between antigens. This study describes a novel intranasal pneumonia co-inoculation model conducted in mouse and aims to address some of these limitations. Methods: Eighty female NMRI mice were equally distributed into the vaccinated and placebo groups. The mice were subcutaneously inoculated with recombinant PspC or PpmA or adjuvant (control). Both groups were co-inoculated with 50 μL of a bacterial suspension containing D39:: rpsL (serotype 2) or PJ351:: rpsL (serotype 1) wild-type strains and their isogenic knockout strains containing a trimethoprim resistance marker. Mice (n = 5 per group) were terminated at 0, 6, 12 and 24 hours post-inoculation. Bacterial samples were obtained from nasopharyngeal washings, bronchoalveolar lavage fluid (BAL fluid) and homogenised lung tissue. Bacterial counts were obtained from selective media containing either streptomycin or trimethoprim, and the ratios of wild-type and knockout were determined. Serum was collected by cardiac puncture and ELISA was used to monitor the levels of IgG antibodies. To further refine the model, a single time point (T = 24h) in which events were more pronounced was chosen for the rest of the experiments and the number of mice was scaled down to 20 mice per experimetal procedure. A group of 20 mice (10 in placebo and 10 in vaccinated mice) were subcutaneously vaccinated with either recombinant PspA, IgA protease and SlrA or adjuvant (control). Both vaccinated and adjuvant groups were co-inoculated with 50 μL of a bacterial suspension containing D39:: rpsL (serotype 2) or PJ351:: rpsL (serotype 1) wild-type strains and their isogenic knockout strains. Bacterial samples were collected from mice as described above. Results: Pneumococcal knockouts of D39 and PJ351 lacking the genes encoding PpmA and PspC were attenuated in their ability to colonise the nasopharynx, BAL fluid and lungs of mice. Knockouts deficient in PspA, IgA bacterial protease and SlrA in the PJ351 background were attenuated in all sites sampled, whereas knockouts in the D39 background were attenuated only in the nasopharynx. PspC IgG antibodies were able to elicit clearance of PspC producing wild-type D39 and PJ351 strains more effectively compared to PspC deletion knockouts, which were able to persist in the nasopharynx, BAL fluid and lungs. Responses in PpmA vaccinated mice were dependent on the genetic background of the inoculation strains. Clearance of D39 wild-type strains was more noticeable in the nasopharynx than in the BAL fluid and lungs, whereas the wild-type PJ351 was cleared more efficiently than the knockout in the BAL fluid and lungs, compared to the nasopharynx. Responses in IgA bacterial protease vaccinated mice were also dependent on the genetic background of the inoculation strains, with a clearance of the D39 wild-type strain being more noticeable in the nasopharynx. PspA and SlrA IgG antibodies were not protective against infection with both strains of the pneumococcus in the mouse model. Conclusion: Using PspC, PpmA, PspA, IgA bacterial protease and SlrA as examples, we demonstrated that this mouse co-colonisation model could effectively detect subtle differences in the clearance of wild-type and knockout bacteria in the presence of antibodies against non-essential surface antigens. The model is humanely more acceptable, as it uses far fewer animals than conventional testing, with greater sensitivity. Further, it relies on measurements of bacterial density, rather than fatal disease as endpoints. The model also provides additional benefits in terms of monitoring the virulence characteristics of the target antigens.
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    Impact of the pneumococcal conjugate vaccine on culture-confirmed pulmonary tuberculosis in hospitalized children
    (2015-09-04) Mammen, Vijay
    Children hospitalized with culture-confirmed pulmonary tuberculosis (PTB) frequently present with acute symptoms, possibly because underlying PTB may predispose to superimposed bacterial pneumonia. Immunization of children with pneumococcal conjugate vaccine (PCV) could protect against such superimposed bacterial pneumonia and reduce the incidence of PTB hospitalization. OBJECTIVE We studied the temporal association of childhood immunization with pneumococcal conjugate vaccine on the incidence of hospitalization for culture-confirmed PTB in children. METHODS A retrospective study on the incidence of hospitalization for culture-confirmed childhood PTB at Chris Hani Baragwanath Academic Hospital was undertaken from 2005 to 2012. This included a pre-PCV era (2005-2008) and a PCV era (2011-2012). RESULTS Overall, there was a 69.2% (95% CI: 62.8-74.6%) decline in the incidence of hospitalization for culture-confirmed PTB when comparing the PCV and pre-PCV-eras, with the decline in HIV-uninfected children only significant in the 3-11 month age category and the decline in HIV-infected significant across all age categories. There was a trend for reduced pneumococcal bacteraemia in the PCV era compared to the pre-PCV era, with the odds of having a blood culture positive for pneumococcus being 1.91-fold (95% CI, 0.26-84.56) greater in the Pre-PCV era. CONCLUSION There has been a significant decline in culture-confirmed PTB hospitalization in children comparing the pre-PCV to the PCV-era. However, the incidence of culture-confirmed PTB prior to the introduction of PCV had been reduced to low levels due to antiretroviral therapy. This confounder together with the retrospective ecological study design and other several possible confounders limited any robust estimate as to whether there was a temporal association between PCV immunization and incidence of culture-confirmed PTB hospitalization in our study setting.
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    The impact of routine pmeumococcal conjugate immunisation on bacterial meningitis in Sowetan children-a time-series analysis
    (2013) Hauptfleisch, Marc Peter Kedzlie
    Introduction Invasive pneumococcal disease, including meningitis, caused by Streptococcus pneumoniae is a major cause of morbidity and mortality world-wide. The introduction of pneumococcal polysaccharide-protein conjugate vaccine (PCV) in the United States has resulted in a reduction in incidence of pneumococcal meningitis. PCV was introduced into the South African expanded programme on immunization (EPI) in 2009. Objective We evaluated the temporal association which the introduction of PCV into the South African EPI had on the incidence of pneumococcal meningitis in children. Methods The study was undertaken in Soweto. All children admitted to Chris Hani Baragwanath Academic Hospital (CHBAH) <14 years of age with meningitis from January 2006 to November 2011 were identified through an electronic database and their microbiological records reviewed to identify the causative bacteria. The results were time framed into two groups: prior to introduction of PCV 1 January 2006 to 31 March 2009 (pre-vaccine era) and post PCV-introduction 1 April 2009 to 30 November 2011 (post-vaccine era). Results 783 patients were admitted with suspected meningitis during the study period, of these 243 (31.0%) met the criteria for bacterial meningitis. The incidence of pneumococcal meningitis was decreasing in the CHBAH in-patient paediatric population by 4.7% per annum prior to the introduction of the vaccine in April 2009. The decline in incidence after PCV introduction accelerated to 18% per annum post-vaccine introduction (P=0.391). In the population most at risk for pneumococcal meningitis, children <1 year of age, the annual reduction in incidence of pneumococcal meningitis accelerated from 1.1% in the pre-vaccine era to 43.4% following PCV introduction (P= 0.011). Conclusions The introduction of PCV resulted in a decline in the incidence of pneumococcal meningitis in all age groups. This decline was most dramatic in the <1 year age group.