Papers by Gillian F Black
Background: The article analyses the policy engagement component of a research project on climate... more Background: The article analyses the policy engagement component of a research project on climate resilience in vulnerable communities that took place in Cape Town, South Africa. Conducted in 2022, the engagement included community and stakeholder events in three research sites, and a cross-cutting policy event with municipal officials, held at the end of the project. Importantly, this policy engagement process occurred in a context of political marginalisation, that is, one characterised by low trust, and little meaningful representation or even communication between these vulnerable communities and the city. Aims and objectives: This article examines the impact of policy engagement on political relations between local government and vulnerable communities. Methods: The overall methodology of the article is qualitative, using an illustrative case-study research design to unpack the subjective experiences of both government officials and residents of vulnerable communities. Primary data included many primary documents, direct observation of the engagements and post-event interviews. Findings: First, the engagement process created new 'invented' spaces for the representation of community perspectives to the city, and the city's perspective to the community. Second, the engagement facilitated community self-representation through educating community members to advocate for their ideas in these new invented spaces. Third, this engagement tended to be more constructive and deliberative than polarising and confrontational. Discussion and conclusions: Drawing on the theoretical framework of 'political mediation', the policy engagement process is characterised as a positive instance of democratic mediation through 'empowered representation', with some specified limitations.
Tuberculosis, 2008
An increase in interferon-gamma (IFN-gamma) production to Mycobacterium tuberculosis purified pro... more An increase in interferon-gamma (IFN-gamma) production to Mycobacterium tuberculosis purified protein derivative (Mtb PPD), as measured in the cultured diluted whole blood assay, is one indicator of a protective immune response to BCG vaccine. We have explored the potential for this assay to be improved by measuring IFN-gamma responses to more defined antigens of M. tuberculosis (short-term and mid-term culture filtrates, ESAT-6, 38 kDa), Mycobacterium bovis (MPB70), M. bovis BCG (Antigen 85) and Mycobacterium leprae (35 kDa), in UK teenagers before and 1 year after BCG vaccination (or no vaccination as controls). There was a significant increase in response to the culture filtrates post-vaccination, but this was no greater than that to Mtb PPD. Many teenagers responded to the purified antigens, in particular to Antigen 85, prior to vaccination, and BCG vaccination could only augment this pre-existing response to a limited extent; prior exposure to environmental mycobacteria can thus induce cross-reactive responses to antigens which complicate interpretation of in vitro assays of vaccine response. In contrast, ESAT-6 was recognised by only one teenager prior to vaccination, and, as expected, responses were not boosted by BCG. We therefore conclude that Mtb PPD is the antigen preparation of choice for assessing the immunogenicity of BCG vaccination.
Mediators of Inflammation, 2015
Elevated antibody responses to Mycobacterium tuberculosis antigens in individuals with latent inf... more Elevated antibody responses to Mycobacterium tuberculosis antigens in individuals with latent infection (LTBI) have previously been linked to an increased risk for progression to active disease. Studies in the field focussed mainly on IgG antibodies. In the present study, IgA and/or IgG responses to the mycobacterial protein antigens AlaDH, NarL, 19 kDa, PstS3, and MPT83 were determined in a blinded fashion in sera from 53 LTBI controls, 14 healthy controls, and 42 active TB subjects. Among controls, we found that elevated IgA levels against all investigated antigens were not randomly distributed but concentrated on a subgroup of < 30%-with particular high levels in a small subgroup of ∼ 5% comprising one progressor to active TB. Based on a specificity of 100%, anti-NarL IgA antibodies achieved with 78.6% sensitivity the highest accuracy for the detection of active TB compared to healthy controls. In conclusion, the consistently elevated IgA levels in a subgroup of controls suggest higher mycobacterial load, a risk factor for progression to active TB, and together with high IgG levels may have prognostic potential and should be investigated in future large scale studies. The novel antigen NarL may also be promising for the antibody-based diagnosis of active TB cases.
PubMed, Jul 1, 2001
Setting: Rural northern Malawi, where vaccination with BCG Glaxo (1077) provides protection again... more Setting: Rural northern Malawi, where vaccination with BCG Glaxo (1077) provides protection against leprosy but not against pulmonary tuberculosis. Objective: To evaluate the patterns of responsiveness to purified protein derivative of Mycobacterium tuberculosis (PPD) in terms of delayed type hypersensitivity (DTH) and interferon-gamma (IFN-gamma) production. Design: IFN-gamma was measured in 6 day whole blood cultures diluted 1 in 10, stimulated with PPD RT48, and the results compared to the DTH response to PPD RT23. A total of 633 individuals aged 12 to 28 years, without prior BCG vaccination, were recruited. Results: Overall, 63% of subjects made a positive IFN-gamma response (defined as >62 pg/ml), and 37% gave a DTH induration of >5 mm. A strong correlation between skin test and IFN-gamma responses was observed, although with interesting exceptions: 13/270 individuals with zero DTH showed IFN-gamma responses >500 pg/ml, and 7/53 individuals with >10 mm induration showed IFN-gamma responses < or = 62 pg/ml. The prevalence of skin test responsiveness increased with age, and was higher among older males than females; age-sex patterns were less clear for IFN-gamma production. Conclusion: The 6 day IFN-gamma response to PPD correlates well with Mantoux skin test induration. The discordant individuals may represent important subsets in terms of protective immunity and risk of clinical tuberculosis.
Journal of Infection, Dec 1, 2014
Accurate, simple and cost-effective diagnostic tests are needed for diagnosis of active tuberculo... more Accurate, simple and cost-effective diagnostic tests are needed for diagnosis of active tuberculosis (TB). Serodiagnosis is attractive as it can be harnessed for point-of-care tests. We evaluated, in a blinded fashion, the sensitivity and specificity of serologic immunoglobulin (Ig)G, IgA and/or IgM responses to Apa, heat shock protein (HSP) 16.3, HSP20, PE35, probable thiol peroxidase Tpx and lipoarabinomannan (LAM) in 42 HIV-negative South African pulmonary TB patients and 67 control individuals. The status of latent Mycobacterium tuberculosis infection (LTBI) among controls was defined through the TST and IFN-γ release assays (IGRAs). We evaluated 47 definite LTBI (IGRA(+)/LTBI), 8 putative LTBI (IGRA(-)/TST(+)) and 12 TB-uninfected (non-LTBI) subjects. In contrast to anti-PE35 IgA, anti-PE35 IgG and particularly anti-Apa IgA, performances of anti-LAM IgG and selected anti-protein antibodies were less affected by inclusion of LTBI participants into the analysis. Anti-LAM IgG showed with a sensitivity/specificity of 71.4%/86.6% (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) the best discrimination between TB and non-TB subjects. Selected five-antibody-combinations (including anti-LAM IgG, anti-LAM IgA and anti-Tpx IgG) further improved this performance to an accuracy exceeding 86%. Antibody responses to some Mycobacterium tuberculosis antigens often also reflect latent infection explaining the poor performance of antibody-based tests for active TB in TB-endemic settings. Our results suggest that rather a combination of serological responses against selected protein and non-protein antigens and different Ig classes should be investigated for TB serodiagnostics.
Microbes and Infection, 1999
Vaccine, Dec 1, 2010
One third of the world's population is infected with Mycobacterium tuberculosis (M.tb). A vaccine... more One third of the world's population is infected with Mycobacterium tuberculosis (M.tb). A vaccine that would prevent progression to TB disease will have a dramatic impact on the global TB burden. We propose that antigens of M.tb that are preferentially expressed during latent infection will be excellent candidates for post-exposure vaccination. We therefore assessed human T cell recognition of two such antigens, Rv2660 and Rv2659. Expression of these was shown to be associated with non-replicating persistence in vitro. After six days incubation of PBMC from persons with latent tuberculosis infection (LTBI) and tuberculosis (TB) disease, Rv2660 and Rv2659 induced IFN-γ production in a greater proportion of persons with LTBI, compared with TB diseased patients. Persons with LTBI also had increased numbers of viable T cells, and greater specific CD4 + T cell proliferation and cytokine expression capacity. Persons with LTBI preferentially recognize Rv2659 and Rv2660, compared with patients with TB disease. These results suggest promise of these antigens for incorporation into post-exposure TB vaccines.
Clinical Infectious Diseases, Jun 25, 2013
Background. Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as ... more Background. Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as exemplified by the highly increased risk of tuberculosis disease among individuals receiving TNF-blocker therapy. Methods. We determined the extent of TNF production after stimulation with BCG or BCG plus interferon gamma (IFN-γ) using a whole blood assay in 392 children belonging to 135 nuclear families from an area hyperendemic for tuberculosis in South Africa. We conducted classical univariate and bivariate genome-wide linkage analysis of TNF production using the data from both stimulation protocols by means of an extension of the maximum-likelihoodbinomial method for quantitative trait loci to multivariate analysis. Results. Stimulation of whole blood by either BCG or BCG plus IFN-γ resulted in a range of TNF release across subjects. Extent of TNF production following both stimulation protocols was highly correlated (r = 0.81). We failed to identify genetic linkage of TNF release when considering each stimulus separately. However, using a multivariate approach, we detected a major pleiotropic locus (P < 10 −5) on chromosome region 11p15, termed TNF locus 1 (TNF1), that controlled TNF production after stimulation by both BCG alone and BCG plus IFN-γ. Conclusions. The TNF1 locus was mapped in the vicinity of the TST1 locus, previously identified in the same family sample, that controls tuberculin skin test (TST) negativity per se, that is, T-cell-independent resistance to Mycobacterium tuberculosis infection. This suggested that there is a connection between TST negativity per se and TNF production.
The Journal of Infectious Diseases, 2010
Philosophical Transactions of the Royal Society B, Sep 29, 1997
Tubercle and Lung Disease, 1997
Setting: A study of multicase tuberculosis pedigrees from Northern Brazil. Objective: To determin... more Setting: A study of multicase tuberculosis pedigrees from Northern Brazil. Objective: To determine the model of inheritance for genetic susceptibility to tuberculosis, and to test the hypothesis that TNFA and NRAMP1 are candidate susceptibility genes. Design: The study sample included 98 pedigrees, 704 individuals and 205 nuclear families. Segregation analyses were performed using the programs POINTER and COMDS. Combined segregation and linkage analysis was carried out within COMDS. Non-parametric linkage analyses were performed using BETA. Results: A sporadic model for disease distribution in families was strongly rejected, as were polygenic and multifactodal models. A codominant single gene model provided the best fit (P< 0.001) to the data using POINTER. COMDS extended the analysis to compare single-gene and two-gene models. A general two-locus model for disease control was marginally favoured (0.01 < P< 0.05) over the codominant single-gene model. No evidence was found for linkage between susceptibility to disease per se and the TNF gene cluster. Weak linkage was observed using COMDS for genes (IL8RB, P= 0.039; D2S1471, P= 0.025) tightly linked (<150 kb) to NRAMP1, but not for NRAMP1 itself. Conclusions: Tuberculosis susceptibility in this region of Brazil is under oligogenic control. Although a minor role for TNFA and NRAMP1 cannot be excluded, our data suggest that neither is a major gene involved in this oligogenic control.
Background. BCG vaccination of infants is thought to provide good protection in all settings. Thi... more Background. BCG vaccination of infants is thought to provide good protection in all settings. This study investigated whether Malawian infants made weaker responses across a cytokine panel after BCG vaccination, compared with UK infants. Methods. Diluted whole-blood samples were cultured with Mycobacterium tuberculosis purified protein derivative for 6 days from BCG-vaccinated infants 3 months (n 5 40 Malawi, 28 UK) and 12 months (n 5 34 Malawi, 26 UK) after vaccination, and also from UK unvaccinated infants (n 5 9 at 3 months, n 5 10 at 12 months). Forty-two cytokines were measured in supernatants using a multiplex bead array assay. Principal component analysis was used to summarize the overall patterns in cytokine responses. Results. We found differences in median responses in 27 of the 42 cytokines: 7 higher in the UK and 20 higher in Malawi. The cytokines with higher responses in the UK were all T helper 1 related. The cytokines with higher responses in Malawi included innate proinflammatory cytokines, regulatory cytokines, interleukin 17, T helper 2 cytokines, chemokines, and growth factors. Principal component analysis separated the BCG-vaccinated infants from Malawi from the UK vaccinated infants and from the unvaccinated infants. Conclusions. Malawian infants make cytokine responses following BCG vaccination, but the cytokine profile is different from that in the UK. The different biosignatures following BCG vaccination in the 2 settings may indicate variability in the protective efficacy of infant BCG vaccination.
Clinical and Experimental Immunology, Dec 1, 2006
We report a large study of the effect of BCG vaccination on the in vitro 6-day whole blood interf... more We report a large study of the effect of BCG vaccination on the in vitro 6-day whole blood interferon-gamma (IFN-g) response to antigens from eight species of mycobacteria among schoolchildren in southeastern England, where bacille Calmette-Guérin (BCG) vaccination is highly protective against pulmonary tuberculosis, and among young adults in northern Malawi, where BCG vaccination is not protective. In the UK children, BCG induced an appreciable increase in IFN-g response to antigens from most species of mycobacteria. The degree of change was linked to the relatedness of the species to Mycobacterium bovis BCG, and provides further evidence of the cross-reactivity of mycobacterial species in priming of the immune system. IFN-g responses to purified protein derivatives (PPDs) from M. tuberculosis and environmental mycobacteria were more prevalent in the Malawian than the UK group prior to vaccination; BCG vaccination increased the prevalence of responses to these PPDs in the UK group to a level similar to that in Malawi. There was no evidence that the vaccine-induced change in IFN-g response was dependent upon the magnitude of the initial response of the individual to environmental mycobacteria in the United Kingdom or in Malawi. These observations should assist the development and interpretation of human clinical trials of new vaccines against M. tuberculosis in areas of both low and high exposure to environmental mycobacteria.
immuneACCESS
Study team* & GC6-74 Consortium* Antigen-specific, MHC-restricted αβ T cells are necessary for pr... more Study team* & GC6-74 Consortium* Antigen-specific, MHC-restricted αβ T cells are necessary for protective immunity against Mycobacterium tuberculosis, but the ability to broadly study these responses has been limited. In the present study, we used single-cell and bulk T cell receptor (TCR) sequencing and the GLIPH2 algorithm to analyze M. tuberculosis-specific sequences in two longitudinal cohorts, comprising 166 individuals with M. tuberculosis infection who progressed to either tuberculosis (n = 48) or controlled infection (n = 118). We found 24 T cell groups with similar TCR-β sequences, predicted by GLIPH2 to have common TCR specificities, which were associated with control of infection (n = 17), and others that were associated with progression to disease (n = 7). Using a genome-wide M. tuberculosis antigen screen, we identified peptides targeted by T cell similarity groups enriched either in controllers or in progressors. We propose that antigens recognized by T cell similarity groups associated with control of infection can be considered as high-priority targets for future vaccine development. Antigen-specific CD4 T cells are necessary for protective immunity against M. tuberculosis, the etiological agent of tuberculosis (TB) 1,2. Experimental and clinical evidence shows that the primary T cell mediators of this protection are interferon (IFN)-γ-expressing helper type 1 T cells (T H 1 cells), although recent evidence from nonhuman primates implicates T H 1/T H 17 cells as probable correlates of protection 3-6. Comprehensive delineation of αβ T cell responses in M. tuberculosisinfected humans has been hampered by the complexity and heterogeneity of clinical phenotypes in TB 7,8 , the high interindividual diversity of the major histocompatibility complex (MHC), which restricts antigen presentation to T cells, and the marked diversity of TCRs 9,10 , even within single hosts. Recent advances in single-cell and bulk TCR-sequencing technologies enable characterization of the antigen-specific TCR repertoire with unprecedented throughput and efficiency 11,12. In addition, advances in analytic approaches, particularly GLIPH 12 and GLIPH2 (ref. 13), allow grouping of TCR sequences that share conserved sequences and motifs in the CDR3 region, which is primarily responsible for the recognition of antigenic peptides bound to molecules of the MHC 9,14,15. This allows rapid clustering of thousands or millions of TCRs into similarity groups, without having to know for what antigens these TCRs are specific. This enables a broad profiling of T cell specificities, despite the complexity of these responses across individuals and groups 13,15,16. Together, these tools provide the opportunity to analyze the pathogen-specific T cell
Background: We evaluated the role that selected variants in serotonin transporter (5-HTT), dopami... more Background: We evaluated the role that selected variants in serotonin transporter (5-HTT), dopamine receptor 2 (DRD2) and brain-derived neurotrophic factor (BDNF) genes play in PTSD symptom severity in an at-risk population. We also investigated the interaction between the genetic variants to determine whether these variables and the interactions between the variables influenced the severity of PTSD symptoms. Methods: PTSD symptoms were quantitatively assessed using the Davidson Trauma Scale (DTS) in 150 participants from an at-risk South African population. All participants were genotyped for the 5-HTTLPR, DRD2 Taq1A and BDNF Val66Met polymorphisms. Gene– gene interactions were investigated using various linear models. All analyses were adjusted for age, gender, major depressive disorder diagnosis, level of resilience, level of social support and alcohol dependence. Results: A significant interaction effect between DRD2 Taq1A and BDNF Val66Met variants on DTS score was observed. On...
Nature Communications, 2018
New biomarkers of tuberculosis (TB) risk and disease are critical for the urgently needed control... more New biomarkers of tuberculosis (TB) risk and disease are critical for the urgently needed control of the ongoing TB pandemic. In a prospective multisite study across Subsaharan Africa, we analyzed metabolic profiles in serum and plasma from HIV-negative, TB-exposed individuals who either progressed to TB 3–24 months post-exposure (progressors) or remained healthy (controls). We generated a trans-African metabolic biosignature for TB, which identifies future progressors both on blinded test samples and in external data sets and shows a performance of 69% sensitivity at 75% specificity in samples within 5 months of diagnosis. These prognostic metabolic signatures are consistent with development of subclinical disease prior to manifestation of active TB. Metabolic changes associated with pre-symptomatic disease are observed as early as 12 months prior to TB diagnosis, thus enabling timely interventions to prevent disease progression and transmission.
The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010
The extent of immune reactivity measured by the tuberculin skin test (TST) and interferon-gamma (... more The extent of immune reactivity measured by the tuberculin skin test (TST) and interferon-gamma (IFN-gamma) T-cell assays is usually not analysed. To determine the impact of age and sex on assay positivity and on the extent of reactivity of both TST and T-cell assays in young persons in an area of South Africa with high TB transmission. Age had a strong impact on assay positivity for all seven immune phenotypes tested (P < 0.0007). Among positive responders, the extent of purified protein derivative (PPD) triggered IFN-gamma release (P < 0.003) was sensitive to age. ESAT-6 triggered IFN-gamma release (day 7, P = 0.03) and the frequency of PPD-specific IFN-gamma(+)CD4(+) (P = 0.03) and IFN-gamma(+)CD8(+) cells (P = 0.04) were weakly dependent on age. By contrast, the extent of TST induration was insensitive to age (P > 0.05), and sex had no significant impact on any phenotype measured (P > 0.05). The high proportion of positive responders in the 1-10 year age-group observ...
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Papers by Gillian F Black