Browsing by Author "Kimuda, Simon"

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    The Effect of Current Schistosoma Mansoni Infection on the Immunogenicity of A Candidate TB vaccine, MVA85A, in BCG Vaccinated Adolescents: An open-label trial
    (PLoS neglected tropical diseases, 2017) Wajja, Anne; Kizito, Dennison; Nassanga, Beatrice; Nalwoga, Angela; Kabagenyi, Joyce; Kimuda, Simon; Galiwango, Ronald; Mutonyi, Gertrude; Vermaak, Samantha; Tukahebwa, Edridah; McShane, Helen
    Helminth infection may affect vaccine immunogenicity and efficacy. Adolescents, a target population for tuberculosis booster vaccines, often have a high helminth burden. We investigated effects of Schistosoma mansoni (Sm) on the immunogenicity and safety of MVA85A, a model candidate tuberculosis vaccine, in BCG-vaccinated Ugandan adolescents.In this phase II open label trial we enrolled 36 healthy, previously BCG-vaccinated adolescents, 18 with no helminth infection detected, 18 with Sm only. The primary outcome was immunogenicity measured by Ag85A-specific interferon gamma ELISpot assay. Tuberculosis and schistosome-specific responses were also assessed by whole-blood stimulation and multiplex cytokine assay, and by antibody ELISAs.Ag85A-specific cellular responses increased significantly following immunisation but with no differences between the two groups. Sm infection was associated with higher pre-immunisation Ag85A-specific IgG4 but with no change in antibody levels following immunisation. There were no serious adverse events. Most reactogenicity events were of mild or moderate severity and resolved quickly.The significant Ag85A-specific T cell responses and lack of difference between Sm-infected and uninfected participants is encouraging for tuberculosis vaccine development. The implications of pre-existing Ag85A-specific IgG4 antibodies for protective immunity against tuberculosis among those infected with Sm are not known. MVA85A was safe in this population.
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    Effect of isoniazid preventive therapy on immune responses to mycobacterium tuberculosis: an open label randomised, controlled, exploratory study
    (BMC infectious diseases, 2015) Andia Biraro, Irene; Egesa, Moses; Kimuda, Simon; Smith, Steven G.; Toulza, Frederic; Levin, Jonathan; Joloba, Moses; Katamba, Achilles; Cose, Stephen; Hazel M., Dockrell; Elliott, Alison M.
    With the renewed emphasis to implement isoniazid preventive therapy (IPT) in Sub-Saharan Africa, we investigated the effect of IPT on immunological profiles among household contacts with latent tuberculosis. Methods: Household contacts of confirmed tuberculosis patients were tested for latent tuberculosis using the QuantiFERON®-TB Gold In-Tube (QFN) assay and tuberculin skin test (TST). HIV negative contacts aged above 5 years, positive to both QFN and TST, were randomly assigned to IPT and monthly visits or monthly visits only. QFN culture supernatants from enrolment and six months’ follow-up were analysed for M.tb-specific Th1, Th2, Th17, and regulatory cytokines by Luminex assay, and for M.tb-specific IgG antibody concentrations by ELISA. Effects of IPT were assessed as the net cytokine and antibody production at the end of six months. Results: Sixteen percent of contacts investigated (47/291) were randomised to IPT (n = 24) or no IPT (n = 23). After adjusting for baseline cytokine or antibody responses, and for presence of a BCG scar, IPT (compared to no IPT) resulted in a relative decline in M.tb-specific production of IFN gamma (adjusted mean difference at the end of six months (bootstrap 95 % confidence interval (CI), p-value) -1488.6 pg/ml ((−2682.5, −294.8), p = 0.01), and IL- 2 (−213.1 pg/ml (−419.2, −7.0), p = 0.04). A similar decline was found in anti-CFP-10 antibody levels (adjusted geometric mean ratio (bootstrap 95 % CI), p-value) 0.58 ((0.35, 0.98), p = 0.04). We found no effect on M.tb-specific Th2 or regulatory or Th17 cytokine responses, or on antibody concentrations to PPD and ESAT-6. Conclusions: IPT led to a decrease in Th1 cytokine production, and also in the anti CFP-10 antibody concentration. This could be secondary to a reduction in mycobacterial burden or as a possible direct effect of isoniazid induced T cell apoptosis, and may have implications for protective immunity following IPT in tuberculosis-endemic countries.
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    The Use of Interferon Gamma Inducible Protein 10 as a Potential Biomarker in the Diagnosis of Latent Tuberculosis Infection in Uganda
    (PLoS ONE, 2016) Biraro, Irene Andia; Kimuda, Simon; Egesa, Moses; Cose, Stephen; Webb, Emily L.; Joloba, Moses; Smith, Steven G.; Elliott, Alison M.; Dockrell, Hazel M.; Katamba, Achilles
    In the absence of a gold standard for the diagnosis of latent tuberculosis (TB) infection (LTBI), the current tests available for the diagnosis of LTBI are limited by their inability to differentiate between LTBI and active TB disease. We investigated IP-10 as a potential biomarker for LTBI among household contacts exposed to sputum positive active TB cases. Methods Active TB cases and contacts were recruited into a cohort with six months’ follow-up. Contacts were tested for LTBI using QuantiFERON1-TB Gold In-Tube (QFN) assay and the tuberculin skin test (TST). Baseline supernatants from the QFN assay of 237 contacts and 102 active TB cases were analysed for Mycobacterium tuberculosis (MTB) specific and mitogen specific IP-10 responses. Results Contacts with LTBI (QFN+TST+) had the highest MTB specific IP-10 responses at baseline, compared to uninfected contacts (QFN-TST-) p<0.0001; and active cases, p = 0.01. Using a cut-off of 8,239 pg/ml, MTB specific IP-10 was able to diagnose LTBI with a sensitivity of 87.1% (95% CI, 76.2–94.3) and specificity of 90.9%(95% CI, 81.3–96.6). MTB specific to mitogen specific IP-10 ratio was higher in HIV negative active TB cases, compared to HIV negative latently infected contacts, p = 0.0004. Concentrations of MTB specific IP-10 were higher in contacts with TST conversion (negative at baseline, positive at 6-months) than in those that were persistently TST negative, p = 0.001. Conclusion IP-10 performed well in differentiating contacts with either latent or active TB from those who were uninfected but was not able to differentiate LTBI from active disease except when MTB specific to mitogen specific ratios were used in HIV negative adults. In addition, IP-10 had the potential to diagnose ‘recent TB infection’ in persons classified as having LTBI using the TST. Such individuals with strong IP-10 responses would likely benefit from chemoprophylaxis.