Publications by authors named "Hassan Mahomed"

77 Publications

Tackling missed opportunities for vaccination in a new era of immunisation.

Lancet 2021 Jun 2. Epub 2021 Jun 2.

Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town 7925, South Africa; Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa; Division of Epidemiology and Biostatistics, Department of Global Health, Stellenbosch University, Cape Town, South Africa.

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http://dx.doi.org/10.1016/S0140-6736(21)01226-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172164PMC
June 2021

Estimating vaccine confidence levels among healthcare students and staff of a tertiary institution in South Africa: protocol of a cross-sectional survey.

BMJ Open 2021 05 13;11(5):e049877. Epub 2021 May 13.

Division of Health Systems and Public Health, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, Western Cape, South Africa.

Introduction: The outbreak of novel COVID-19 caught the world off guard in the first quarter of 2020. To stem the tide of this pandemic, there was acceleration of the development, testing and prelicensure approval for emergency use of some COVID-19 vaccine candidates. This led to raised public concern about their safety and efficacy, compounding the challenges of vaccine hesitancy. The onus of managing and administering these vaccines to a sceptical populace when they do become available rests mostly on the shoulders of healthcare workers (HCWs). Therefore, the vaccine confidence levels of HCWs become critical to the success of vaccination endeavours. This proposed study aims to estimate the level of vaccine confidence and the intention to receive a COVID-19 vaccine among future HCWs and their trainers at a specific university in Cape Town, South Africa, and to identify any vaccination concerns early for targeted intervention.

Methods And Analysis: This proposed study is a cross-sectional survey study. An online questionnaire will be distributed to all current staff and students of the Faculty of Medicine Health Sciences of Stellenbosch University in Cape Town, South Africa. No sampling strategy will be employed. The survey questionnaire will consist of demographic questions (consisting of six items) and vaccine confidence questions (comprising six items in Likert scale format). Log binomial models will be employed to identify factors associated with vaccine confidence and intention. The strength of association will be assessed using the OR and its 95% CI. Statistical significance will be defined at a p value <0.05.

Ethics And Dissemination: Ethics approval has been obtained for the study from Stellenbosch University (Human Research Ethics Committee reference number S19/01/014 (PhD)). The results will be shared with relevant health authorities, presented at conferences and published in a peer-reviewed journal.
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http://dx.doi.org/10.1136/bmjopen-2021-049877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126322PMC
May 2021

Contact Tracing and the COVID-19 Response in Africa: Best Practices, Key Challenges, and Lessons Learned from Nigeria, Rwanda, South Africa, and Uganda.

Am J Trop Med Hyg 2021 Feb 11. Epub 2021 Feb 11.

20Fogarty International Center, National Institutes of Health, Bethesda, Maryland.

Most African countries have recorded relatively lower COVID-19 burdens than Western countries. This has been attributed to early and strong political commitment and robust implementation of public health measures, such as nationwide lockdowns, travel restrictions, face mask wearing, testing, contact tracing, and isolation, along with community education and engagement. Other factors include the younger population age strata and hypothesized but yet-to-be confirmed partially protective cross-immunity from parasitic diseases and/or other circulating coronaviruses. However, the true burden may also be underestimated due to operational and resource issues for COVID-19 case identification and reporting. In this perspective article, we discuss selected best practices and challenges with COVID-19 contact tracing in Nigeria, Rwanda, South Africa, and Uganda. Best practices from these country case studies include sustained, multi-platform public communications; leveraging of technology innovations; applied public health expertise; deployment of community health workers; and robust community engagement. Challenges include an overwhelming workload of contact tracing and case detection for healthcare workers, misinformation and stigma, and poorly sustained adherence to isolation and quarantine. Important lessons learned include the need for decentralization of contact tracing to the lowest geographic levels of surveillance, rigorous use of data and technology to improve decision-making, and sustainment of both community sensitization and political commitment. Further research is needed to understand the role and importance of contact tracing in controlling community transmission dynamics in African countries, including among children. Also, implementation science will be critically needed to evaluate innovative, accessible, and cost-effective digital solutions to accommodate the contact tracing workload.
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http://dx.doi.org/10.4269/ajtmh.21-0033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045625PMC
February 2021

From Easing Lockdowns to Scaling Up Community-based Coronavirus Disease 2019 Screening, Testing, and Contact Tracing in Africa-Shared Approaches, Innovations, and Challenges to Minimize Morbidity and Mortality.

Clin Infect Dis 2021 01;72(2):327-331

Department of Infection, Division of Infection and Immunity, Centre for Clinical Microbiology, University College London, London, United Kingdom.

The arrival of coronavirus disease 2019 (COVID-19) on the African continent resulted in a range of lockdown measures that curtailed the spread of the infection but caused economic hardship. African countries now face difficult choices regarding easing of lockdowns and sustaining effective public health control measures and surveillance. Pandemic control will require efficient community screening, testing, and contact tracing; behavioral change interventions; adequate resources; and well-supported, community-based teams of trained, protected personnel. We discuss COVID-19 control approaches in selected African countries and the need for shared, affordable, innovative methods to overcome challenges and minimize mortality. This crisis presents a unique opportunity to align COVID-19 services with those already in place for human immunodeficiency virus, tuberculosis, malaria, and non communicable diseases through mobilization of Africa's interprofessional healthcare workforce. By addressing the challenges, the detrimental effect of the COVID-19 pandemic on African citizens can be minimized.
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http://dx.doi.org/10.1093/cid/ciaa695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314180PMC
January 2021

A framework for implementation of community-orientated primary care in the Metro Health Services, Cape Town, South Africa.

Afr J Prim Health Care Fam Med 2020 Dec 18;12(1):e1-e5. Epub 2020 Dec 18.

Division of Family Medicine and Primary Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town.

In South Africa, the national policy on re-engineering primary health care (PHC) supports the implementation of ward-based outreach teams with community health workers. In the Western Cape, a community-orientated primary care (COPC) approach has been adopted in provincial goals for 2030 and the key strategies for the improvement of district health services. This approach is expected to improve health and also save costs. A task team was established in the Metropolitan Health Services to develop an implementation framework for COPC. The framework was developed in an iterative process with four learning sites in the metropole over a period of 18 months. The framework consists of 10 inter-related elements: geographic delineation of PHC teams, composition of PHC teams, facility-based and community-based teamwork, partnership of government and non-government organisations, scope of practice, information system, community engagement, stakeholder engagement, training and development of PHC teams, system preparation and change management. This framework was implemented at the four learning sites and is now being taken to scale and further assessed in the metropole.
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http://dx.doi.org/10.4102/phcfm.v12i1.2632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756660PMC
December 2020

Risk factors for COVID-19 death in a population cohort study from the Western Cape Province, South Africa.

Clin Infect Dis 2020 Aug 29. Epub 2020 Aug 29.

Health Programmes Directorate, Western Cape Government: Health.

Background: Risk factors for COVID-19 death in sub-Saharan Africa and the effects of HIV and tuberculosis on COVID-19 outcomes are unknown.

Methods: We conducted a population cohort study using linked data from adults attending public sector health facilities in the Western Cape, South Africa. We used Cox-proportional hazards models adjusted for age, sex, location and comorbidities to examine the association between HIV, tuberculosis and COVID-19 death from 1 March-9 June 2020 among (i) public sector "active patients" (≥1 visit in the 3 years before March 2020), (ii) laboratory-diagnosed COVID-19 cases and (iii) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19 comparing HIV positive vs. negative adults using modelled population estimates.

Results: Among 3,460,932 patients (16% HIV positive), 22,308 were diagnosed with COVID-19, of whom 625 died. COVID-19 death was associated with male sex, increasing age, diabetes, hypertension and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR] 2.14; 95% confidence interval [CI] 1.70-2.70), with similar risks across strata of viral load and immunosuppression. Current and previous tuberculosis were associated with COVID-19 death (aHR [95%CI] 2.70 [1.81-4.04] and 1.51 [1.18-1.93] respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95%CI 1.96-2.86); population attributable fraction 8.5% (95%CI 6.1-11.1).

Conclusion: While our findings may over-estimate HIV- and tuberculosis-associated COVID-19 mortality risks due to residual confounding, both HIV and current tuberculosis were independently associated with increased COVID-19 mortality. The associations between age, sex and other comorbidities and COVID-19 mortality were similar to other settings.
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http://dx.doi.org/10.1093/cid/ciaa1198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499501PMC
August 2020

Prevention, Management and Risk Factors for Diarrhoeal Disease in under-Fives in Cape Town.

J Trop Pediatr 2020 Jul 26. Epub 2020 Jul 26.

Metro Health Services, Western Cape Government: Health, Bellville Health Park, c/o Mike Pienaar Boulevard and Frans Conradie Drive, Cape Town, South Africa, 7505.

Background: In South Africa, Cape Town's health facilities are stretched by the volume of cases of diarrhoea during the summer months, particularly with severely dehydrated children, who often require complex inpatient management. The prevalence of severe disease in children living in the settlements around Cape Town is particularly high.

Methods: An observational study of a systematic sample of children under 5 who presented to any primary care facility in Khayelitsha, an informal settlement of Cape Town, with diarrhoea and referred to secondary care between 1 November 2015 and 30 April 2016. We recruited participants from the sub-district office and identified risk factors associated with the index presentation, captured the triage and management of patients in primary care and investigated post-discharge follow-up.

Results: We recruited 87 children into the study, out of a total of 115 cases of severe dehydration. There was a significantly higher number of households in this group with no income than in Khayelitsha overall (65% vs. 47.4%; p < 0.001). In the sample, HIV-exposed, uninfected children were younger than unexposed children (median 9.44 months in exposed vs. 17.36 months in unexposed; p = 0.0015) and were more likely to be malnourished (weight-for-age Z-score; WAZ score < -2) [13 cases exposed vs. 8 cases unexposed (p = 0.04)]. Outreach staff were able to trace only 33.3% of children at home following discharge, yet 65% of children attended follow-up appointments in clinics.

Conclusions: This cohort of children with diarrhoeal disease complicated by severe dehydration was a particularly socially deprived group. The results demonstrating zero vertical transmission of HIV in this very socioeconomically deprived area of Cape Town are encouraging. In the HIV-exposed, uninfected group, children were younger and had a higher prevalence of malnutrition, which should be the subject of future research, especially given existing evidence for immunological differences in children exposed to HIV in utero. Locating children with severe diarrhoea post-discharge was challenging and further research is needed on the cost-effectiveness and outcomes of different follow-up approaches.
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http://dx.doi.org/10.1093/tropej/fmaa036DOI Listing
July 2020

Current tools available for investigating vaccine hesitancy: a scoping review protocol.

BMJ Open 2019 12 11;9(12):e033245. Epub 2019 Dec 11.

Cochrane South Africa, South African Medical Research Council, Cape Town, Western Cape, South Africa.

Introduction: Vaccine hesitancy, defined as the delay in acceptance or refusal of vaccination despite availability of vaccination services is responsible in part for suboptimal levels of vaccination coverage worldwide. The WHO recommends that countries incorporate plans to measure and address vaccine hesitancy into their immunisation programmes. This requires that governments and health institutions be able to detect concerns about vaccination in the population and monitor changes in vaccination behaviours. To do this effectively, tools to detect and measure vaccine hesitancy are required. The purpose of this scoping review is to give a broad overview of currently available vaccine hesitancy measuring tools and present a summary of their nature, similarities and differences.

Methods And Analysis: The review will be conducted using the framework for scoping review proffered by Arksey and O'Malley. It will comply with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews' guidelines. The broader research question of this review is: what vaccine hesitancy measuring tools are currently available?Search strategies will be developed using controlled vocabulary and selected keywords. PubMed, Web of Science, Scopus and reference lists of relevant publications will be searched. Titles and abstracts will be independently screened by two authors and data from full-text articles meeting the inclusion criteria will be extracted independently by two authors using a pretested data charting form. Discrepancies will be resolved by discussion and consensus. Results will be presented using descriptive statistics such as percentages, tables, charts and flow diagrams as appropriate. Narrative analysis will be used to summarise the findings of the review.

Ethics And Dissemination: Ethics approval is not required for the review. It will be submitted as part of a doctoral thesis, presented at conferences and published in a peer-reviewed journal.

Trial Registration Number: https://osf.io/x8fjk/.
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http://dx.doi.org/10.1136/bmjopen-2019-033245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924801PMC
December 2019

Cytomegalovirus infection is a risk factor for tuberculosis disease in infants.

JCI Insight 2019 12 5;4(23). Epub 2019 Dec 5.

The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a case-control analysis to identify drivers of immune activation and disease risk. Among 49 infants who developed TB disease over the first 2 years of life, and 129 healthy matched controls, we found the cytomegalovirus-stimulated (CMV-stimulated) IFN-γ response to be associated with CD8+ T cell activation (Spearman's rho, P = 6 × 10-8). A CMV-specific IFN-γ response was also associated with increased risk of developing TB disease (conditional logistic regression; P = 0.043; OR, 2.2; 95% CI, 1.02-4.83) and shorter time to TB diagnosis (Log Rank Mantel-Cox, P = 0.037). CMV+ infants who developed TB disease had lower expression of NK cell-associated gene signatures and a lower frequency of CD3-CD4-CD8- lymphocytes. We identified transcriptional signatures predictive of TB disease risk among CMV ELISpot-positive (area under the receiver operating characteristic [AUROC], 0.98, accuracy, 92.57%) and -negative (AUROC, 0.9; accuracy, 79.3%) infants; the CMV- signature was validated in an independent infant study (AUROC, 0.71; accuracy, 63.9%). A 16-gene signature that previously identified adolescents at risk of developing TB disease did not accurately classify case and control infants in this study. Understanding the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.
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http://dx.doi.org/10.1172/jci.insight.130090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962026PMC
December 2019

'Doing more with less': a qualitative investigation of perceptions of South African health service managers on implementation of health innovations.

Health Policy Plan 2019 Mar;34(2):132-140

Alcohol, Tobacco and Other Drug Research Unit, South African Medical Research Council, Francie Van Zijl Drive, Parow Valley, Cape Town, South Africa.

Building resilience in health systems is an imperative for low- and middle- income countries. Health service managers' ability to implement health innovations may be a key aspect of resilience in primary healthcare facilities, promoting adaptability and functionality. This study investigated health service managers' perceptions and experiences of adopting health innovations. We aimed to identify perceptions of constraints to adoption and emergent behaviours in response to these constraints. A convenience sample of 34 facility, clinical service and sub-district level managers was invited to participate. Six did not respond and were not contactable. In-depth individual interviews in a private space at participants' place of work were conducted with 28 participants. Interviews were audio recorded and transcribed verbatim. NVivo 11 was used to store data and facilitate framework analysis. Study participants described constraints to innovation adoption including: staff lack of understanding of potential benefits; staff personalities, attitudes and behaviours which lead to resistance to change; high workload related to resource constraints and frequent policy changes inducing resistance to change; and suboptimal communication through health system structures. Managers reported employing various strategies to mitigate these constraints. These comprised (1) technical skills including participatory management skills, communication skills, community engagement skills and programme monitoring and evaluation skills, and (2) non-technical skills including role modelling positive attitudes, understanding staff personalities, influencing perceptions of innovations, influencing organizational climate and building trusting relationships. Managers have a vital role in the embedding of service innovations into routine practice. We present a framework of technical and non-technical skills that managers need to facilitate the adoption of health innovations. Future efforts to build managers' capacity to implement health innovations should target these competencies.
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http://dx.doi.org/10.1093/heapol/czz017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481285PMC
March 2019

Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease.

PLoS Pathog 2017 11 16;13(11):e1006687. Epub 2017 Nov 16.

The Center for Infectious Disease Research, Seattle, WA, United States of America.

Our understanding of mechanisms underlying progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease in humans remains limited. To define such mechanisms, we followed M. tuberculosis-infected adolescents longitudinally. Blood samples from forty-four adolescents who ultimately developed tuberculosis disease (“progressors”) were compared with those from 106 matched controls, who remained healthy during two years of follow up. We performed longitudinal whole blood transcriptomic analyses by RNA sequencing and plasma proteome analyses using multiplexed slow off-rate modified DNA aptamers. Tuberculosis progression was associated with sequential modulation of immunological processes. Type I/II interferon signalling and complement cascade were elevated 18 months before tuberculosis disease diagnosis, while changes in myeloid inflammation, lymphoid, monocyte and neutrophil gene modules occurred more proximally to tuberculosis disease. Analysis of gene expression in purified T cells also revealed early suppression of Th17 responses in progressors, relative to M. tuberculosis-infected controls. This was confirmed in an independent adult cohort who received BCG re-vaccination; transcript expression of interferon response genes in blood prior to BCG administration was associated with suppression of IL-17 expression by BCG-specific CD4 T cells 3 weeks post-vaccination. Our findings provide a timeline to the different immunological stages of disease progression which comprise sequential inflammatory dynamics and immune alterations that precede disease manifestations and diagnosis of tuberculosis disease. These findings have important implications for developing diagnostics, vaccination and host-directed therapies for tuberculosis.

Trial Registration: Clincialtrials.gov, NCT01119521.
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http://dx.doi.org/10.1371/journal.ppat.1006687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689825PMC
November 2017

Training and support to improve ICD coding quality: A controlled before-and-after impact evaluation.

S Afr Med J 2017 May 24;107(6):501-506. Epub 2017 May 24.

Division of Health Systems and Public Health, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Western Cape Government: Health, Cape Town, South Africa.

Background: The proposed National Health Insurance policy for South Africa (SA) requires hospitals to maintain high-quality International Statistical Classification of Diseases (ICD) codes for patient records. While considerable strides had been made to improve ICD coding coverage by digitising the discharge process in the Western Cape Province, further intervention was required to improve data quality. The aim of this controlled before-and-after study was to evaluate the impact of a clinician training and support initiative to improve ICD coding quality.

Objective: To compare ICD coding quality between two central hospitals in the Western Cape before and after the implementation of a training and support initiative for clinicians at one of the sites.

Methods: The difference in differences in data quality between the intervention site and the control site was calculated. Multiple logistic regression was also used to determine the odds of data quality improvement after the intervention and to adjust for potential differences between the groups.

Results: The intervention had a positive impact of 38.0% on ICD coding completeness over and above changes that occurred at the control site. Relative to the baseline, patient records at the intervention site had a 6.6 (95% confidence interval 3.5 - 16.2) adjusted odds ratio of having a complete set of ICD codes for an admission episode after the introduction of the training and support package. The findings on impact on ICD coding accuracy were not significant.

Conclusion: There is sufficient pragmatic evidence that a training and support package will have a considerable positive impact on ICD coding completeness in the SA setting.
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http://dx.doi.org/10.7196/SAMJ.2017.v107i6.12075DOI Listing
May 2017

Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study.

Lancet Respir Med 2017 04 16;5(4):282-290. Epub 2017 Feb 16.

South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.

Background: The value of quantitative interferon-γ release assay results for predicting progression from Mycobacterium tuberculosis infection to active disease is unknown. We aimed to investigate the relation between QuantiFERON-TB Gold In-Tube (QFT) conversion interferon-γ values and risk of subsequent active tuberculosis disease and of QFT reversion.

Methods: We analysed data from a reported vaccine efficacy trial of the tuberculosis vaccine MVA85A in South Africa. QFT negative, HIV uninfected young children aged 18-24 weeks were enrolled. We stratified participants by quantitative QFT result (interferon-γ <0·35 IU/mL, 0·35-4·00 IU/mL, and >4·00 IU/mL) at the intermediate study visit (day 336) and determined risk of progression to active tuberculosis disease over the subsequent 6-24 months. No QFT differences were observed between placebo and MVA85A groups at day 336 or end of study; therefore, both groups were included in analyses. Study clinicians were not masked to QFT values, but strict case definitions were used that excluded QFT results. We used generalised additive models to evaluate the quantitative relation between day 336 QFT value and subsequent disease risk, and we compared disease rates between QFT strata using a two-sample Poisson test.

Findings: Among 2512 young children with QFT tests done at day 336, 172 (7%) were positive; 87 (7%) of 1267 in placebo group and 85 (7%) of 1245 in the MVA85A group (p=1·00). Compared with QFT non-converters (tuberculosis disease incidence 0·7 per 100 person-years [95% CI 0·4-1·1]), children with QFT conversion at interferon-γ values between 0·35-4·00 IU/mL did not have significantly increased risk of disease (2·5 per 100 person-years [95% CI 0·4-9·4]; incidence rate ratio (IRR) 3·7 (95% CI 0·4-15·8; p=0·23). However, QFT conversion at interferon-γ values higher than 4·00 IU/mL was associated with substantially increased disease incidence (28·0 per 100 person-years [95% CI 14·9-45·7]) compared with non-converters (IRR 42·5 [95% CI 17·2-99·7]; p<0·0001), and compared with children with interferon-γ values between 0·35-4·00 IU/mL (IRR 11·4 [95% CI 2·4-107·2]; p=0·00047). Among 91 QFT converters who were given a repeat test, 53 (58%) reverted from positive to negative. QFT reversion risk was inversely associated with interferon-γ value at QFT conversion and was highest with interferon-γ values less than 4·00 IU/mL (47 [77%] of 61).

Interpretation: In young children, tuberculosis disease risk was not significantly increased, and QFT reversion was common, following QFT conversion at interferon-γ values up to 10 times the recommended test threshold (0·35 IU/mL). By contrast, QFT conversion at very high interferon-γ values (>4·00 IU/mL) warrants intensified diagnostic and preventive intervention because of the extremely high risk of tuberculosis disease in these young children.

Funding: Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC) were the funders of the MVA85A 020 Trial. National Institute of Allergy and Infectious Diseases supported this analysis.
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http://dx.doi.org/10.1016/S2213-2600(17)30060-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350938PMC
April 2017

H1:IC31 vaccination is safe and induces long-lived TNF-αIL-2CD4 T cell responses in M. tuberculosis infected and uninfected adolescents: A randomized trial.

Vaccine 2017 01 18;35(1):132-141. Epub 2016 Nov 18.

South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, South Africa. Electronic address:

Background: Control of the tuberculosis epidemic requires a novel vaccine that is effective in preventing tuberculosis in adolescents, a key target population for vaccination against TB.

Methods: Healthy adolescents, stratified by M. tuberculosis-infection status, were enrolled into this observer-blinded phase II clinical trial of the protein-subunit vaccine candidate, H1:IC31, comprising a fusion protein (H1) of Ag85B and ESAT-6, formulated with the IC31 adjuvant. Local and systemic adverse events and induced T cell responses were measured after one or two administrations of either 15μg or 50μg of the H1 protein.

Results: Two hundred and forty participants were recruited and followed up for 224days. No notable safety events were observed regardless of H1 dose or vaccination schedule. H1:IC31 vaccination induced antigen-specific CD4 T cells, co-expressing IFN-γ, TNF-α and/or IL-2. H1:IC31 vaccination of M.tb-uninfected individuals preferentially drove the emergence of Ag85B and ESAT-6 specific TNF-αIL-2CD4 T cells, while H1:IC31 vaccination of M.tb-infected individuals resulted in the expansion of Ag85B-specific but not ESAT-6-specific TNF-αIL-2CD4 T cells.

Conclusions: H1:IC31 was safe and immunogenic in uninfected and M.tb-infected adolescents. Two administrations of the 15μg H1:IC31 dose induced the greatest magnitude immune response, and was considered optimal (South African National Clinical Trials Register, DoH-27-0612-3947; Pan African Clinical Trial Registry, PACTR201403000464306).
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http://dx.doi.org/10.1016/j.vaccine.2016.11.023DOI Listing
January 2017

Student experiences of participating in five collaborative blended learning courses in Africa and Asia: a survey.

Glob Health Action 2016;9:28145. Epub 2016 Oct 6.

Department of Family Medicine, Centre for Studies in Family Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.

Background: As blended learning (BL; a combination of face-to-face and e-learning methods) becomes more commonplace, it is important to assess whether students find it useful for their studies. ARCADE HSSR and ARCADE RSDH (African Regional Capacity Development for Health Systems and Services Research; Asian Regional Capacity Development for Research on Social Determinants of Health) were unique capacity-building projects, focusing on developing BL in Africa and Asia on issues related to global health.

Objective: We aimed to evaluate the student experience of participating in any of five ARCADE BL courses implemented collaboratively at institutions from Africa, Asia, and Europe.

Design: A post-course student survey with 118 students was conducted. The data were collected using email or through an e-learning platform. Data were analysed with SAS, using bivariate and multiple logistic regression. We focused on the associations between various demographic and experience variables and student-reported overall perceptions of the courses.

Results: In total, 82 students responded to the survey. In bivariate logistic regression, the course a student took [=0.0067, odds ratio (OR)=0.192; 95% confidence interval (CI): 0.058-0.633], male gender of student (=0.0474, OR=0.255; 95% CI: 0.066-0.985), not experiencing technical problems (<0.001, OR=17.286; 95% CI: 4.629-64.554), and reporting the discussion forum as adequate for student needs (=0.0036, OR=0.165; 95% CI: 0.049-0.555) were found to be associated with a more positive perception of BL, as measured by student rating of the overall helpfulness of the e-learning component to their studies. In contrast, perceiving the assessment as adequate was associated with a worse perception of overall usefulness. In a multiple regression, the course, experiencing no technical problems, and perceiving the discussion as adequate remained significantly associated with a more positively rated perception of the usefulness of the online component of the blended courses.

Discussion: The results suggest that lack of technical problems and functioning discussion forums are of importance during BL courses focusing on global health-related topics. Through paying attention to these aspects, global health education could be provided using BL approaches to student satisfaction.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056983PMC
http://dx.doi.org/10.3402/gha.v9.28145DOI Listing
October 2016

Temperature Variability and Occurrence of Diarrhoea in Children under Five-Years-Old in Cape Town Metropolitan Sub-Districts.

Int J Environ Res Public Health 2016 08 29;13(9). Epub 2016 Aug 29.

Division of Community Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7505, South Africa.

This paper describes the relationship between temperature change and diarrhoea in under five-year-old children in the Cape Town Metropolitan Area (CTMA) of South Africa. The study used climatic and aggregated surveillance diarrhoea incidence data of two peak periods of seven months each over two consecutive years. A Poisson regression model and a lagged Poisson model with autocorrelation was performed to test the relationship between climatic parameters (minimum and maximum temperature) and incidence of diarrhoea. In total, 58,617 cases of diarrhoea occurred in the CTMA, which is equivalent to 8.60 cases per 100 population under five years old for the study period. The mixed effect overdispersed Poisson model showed that a cluster adjusted effect of an increase of 5 °C in minimum and maximum temperature results in a 40% (Incidence risk ratio IRR: 1.39, 95% CI 1.31-1.48) and 32% (IRR: 1.32, 95% CI: 1.22-1.41) increase in incident cases of diarrhoea, respectively, for the two periods studied. Autocorrelation of one-week lag (Autocorrelation AC 1) indicated that a 5 °C increase in minimum and maximum temperature led to 15% (IRR: 1.46, 95% CI: 1.09-1.20) and 6% (IRR: 1.06, 95% CI: 1.01-1.12) increase in diarrhoea cases, respectively. In conclusion, there was an association between an increase in minimum and maximum temperature, and the rate at which diarrhoea affected children under the age of five years old in the Cape Town Metropolitan Area. This finding may have implications for the effects of global warming and requires further investigation.
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http://dx.doi.org/10.3390/ijerph13090859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036692PMC
August 2016

The acceptability of three vaccine injections given to infants during a single clinic visit in South Africa.

BMC Public Health 2016 08 8;16:749. Epub 2016 Aug 8.

Division of Community Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Background: The Expanded Programme on Immunisation (EPI) has increased the number of antigens and injections administered at one visit. There are concerns that more injections at a single immunisation visit could decrease vaccination coverage. We assessed the acceptability and acceptance of three vaccine injections at a single immunisation visit by caregivers and vaccinators in South Africa.

Methods: A mixed methods exploratory study of caregivers and vaccinators at clinics in two provinces of South Africa was conducted. Quantitative and qualitative data were collected using questionnaires as well as observations of the administration of three-injection vaccination sessions.

Results: The sample comprised 229 caregivers and 98 vaccinators. Caregivers were satisfied with the vaccinators' care (97 %) and their infants receiving immunisation injections (93 %). However, many caregivers, (86 %) also felt that three or more injections were excessive at one visit. Caregivers had limited knowledge of actual vaccines provided, and reasons for three injections. Although vaccinators recognised the importance of informing caregivers about vaccination, they only did this sometimes. Overall, acceptance of three injections was high, with 97 % of caregivers expressing willingness to bring their infant for three injections again in future visits despite concerns about the pain and discomfort that the infant experienced. Many (55 %) vaccinators expressed concern about giving three injections in one immunisation visit. However, in 122 (95 %) observed three-injection vaccination sessions, the vaccinators administered all required vaccinations for that visit. The remaining seven vaccinations were not completed because of vaccine stock-outs.

Conclusions: We found high acceptance by caregivers and vaccinators of three injections. Caregivers' poor understanding of reasons for three injections resulted from limited information sharing by vaccinators for caregivers. Acceptability of three injections may be improved through enhanced vaccinator-caregiver communication, and improved management of infants' pain. Vaccinator training should include evidence-informed ways of communicating with caregivers and reducing injection pain. Strategies to improve acceptance and acceptability of three injections should be rigorously evaluated as part of EPI's expansion in resource-limited countries.
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http://dx.doi.org/10.1186/s12889-016-3324-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977687PMC
August 2016

BCG and New Preventive Tuberculosis Vaccines: Implications for Healthcare Workers.

Clin Infect Dis 2016 05;62 Suppl 3:S262-7

Office of the Director General, World Health Organization, Geneva, Switzerland.

Healthcare workers (HCWs) are at high risk of Mycobacterium tuberculosis (Mtb) infection and tuberculosis disease, but also play a crucial role in implementing healthcare. Preexposure tuberculosis vaccination, including revaccination with BCG, might benefit Mtb-uninfected HCWs, but most HCWs in tuberculosis-endemic countries are already sensitized to mycobacteria. A new postexposure tuberculosis vaccine offers greatest potential for protection, in the setting of repeated occupational Mtb exposure. Novel strategies for induction of mycobacteria-specific resident memory T cells in the lung by aerosol administration, or induction of T cells with inherent propensity for residing in mucosal sites, such as CD1-restricted T cells and mucosa-associated innate T cells, should be explored. The need for improved protection of HCWs against tuberculosis disease is clear. However, health systems in tuberculosis-endemic countries would need significantly improved occupational health structures to implement a screening and vaccination strategy for HCWs.
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http://dx.doi.org/10.1093/cid/ciw025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845890PMC
May 2016

T-cell activation is an immune correlate of risk in BCG vaccinated infants.

Nat Commun 2016 04 12;7:11290. Epub 2016 Apr 12.

Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.

Vaccines to protect against tuberculosis (TB) are urgently needed. We performed a case-control analysis to identify immune correlates of TB disease risk in Bacille Calmette-Guerin (BCG) immunized infants from the MVA85A efficacy trial. Among 53 TB case infants and 205 matched controls, the frequency of activated HLA-DR(+) CD4(+) T cells associates with increased TB disease risk (OR=1.828, 95% CI=1.25-2.68, P=0.002, FDR=0.04, conditional logistic regression). In an independent study of Mycobacterium tuberculosis-infected adolescents, activated HLA-DR(+) CD4(+) T cells also associate with increased TB disease risk (OR=1.387, 95% CI=1.068-1.801, P=0.014, conditional logistic regression). In infants, BCG-specific T cells secreting IFN-γ associate with reduced risk of TB (OR=0.502, 95% CI=0.29-0.86, P=0.013, FDR=0.14). The causes and impact of T-cell activation on disease risk should be considered when designing and testing TB vaccine candidates for these populations.
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http://dx.doi.org/10.1038/ncomms11290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832066PMC
April 2016

A blood RNA signature for tuberculosis disease risk: a prospective cohort study.

Lancet 2016 Jun 24;387(10035):2312-2322. Epub 2016 Mar 24.

Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.

Background: Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat the tuberculosis epidemic. We aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease.

Methods: In this prospective cohort study, we followed up healthy, South African adolescents aged 12-18 years from the adolescent cohort study (ACS) who were infected with M tuberculosis for 2 years. We collected blood samples from study participants every 6 months and monitored the adolescents for progression to tuberculosis disease. A prospective signature of risk was derived from whole blood RNA sequencing data by comparing participants who developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex quantitative real-time PCR (qRT-PCR), the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. Participants of the independent cohorts were household contacts of adults with active pulmonary tuberculosis disease.

Findings: Between July 6, 2005, and April 23, 2007, we enrolled 6363 participants from the ACS study and 4466 from independent South African and Gambian cohorts. 46 progressors and 107 matched controls were identified in the ACS cohort. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% CI 63·2-68·9) and a specificity of 80·6% (79·2-82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA sequencing and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6-64·3) and a specificity of 82·8% (76·7-86) in the 12 months preceding tuberculosis.

Interpretation: The whole blood tuberculosis risk signature prospectively identified people at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease.

Funding: Bill & Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union, and the South African Medical Research Council.
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http://dx.doi.org/10.1016/S0140-6736(15)01316-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392204PMC
June 2016

Are central hospitals ready for National Health Insurance? ICD coding quality from an electronic patient discharge record for clinicians.

S Afr Med J 2016 Jan 8;106(2):181-5. Epub 2016 Jan 8.

Division of Community Health, Department of Interdisciplinary Health Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa; Western Cape Government Department of Health, Cape Town, South Africa.

Background: South Africa (SA)'s planned National Health Insurance reforms require the use of International Statistical Classification of Diseases (ICD) codes for hospitals to purchase services from the proposed National Health Authority. However, compliance with coding at public hospitals in the Western Cape Province has been challenging. A computer application was developed to aid clinicians in integrating ICD coding into the patient hospital discharge process.

Objective: To evaluate the quality of ICD codes captured using the application and predictors thereof in a single hospital department.

Methods: After 6 months, the quality of ICD codes was determined by comparing ICD code descriptors with medical concepts in a random sample of original patient records selected over a 6-week period. Patient and personnel characteristics influencing quality of coding, derived from a theoretical framework, were collected.

Results: Of 223 patient records, 45.3% (95% confidence interval (CI) 38.8 - 51.9) had complete ICD codes. Primary ICD code accuracy was 74.0% (95% CI 67.8 - 79.5). Patient characteristics such as female gender, younger age group and fewer comorbidities, as well as seniority of clinician rank, were significantly associated with ICD coding being complete on adjusted analysis.

Conclusion: The results of this study describe ICD coding quality at a central hospital in SA supported by a computer application and the factors influencing this. More interventions are required to achieve reliable coding data, such as additional ICD coding validation tools, training and oversight of junior clinicians.
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http://dx.doi.org/10.7196/SAMJ.2016.v106i2.10079DOI Listing
January 2016

Evaluation of Xpert® MTB/RIF Assay in Induced Sputum and Gastric Lavage Samples from Young Children with Suspected Tuberculosis from the MVA85A TB Vaccine Trial.

PLoS One 2015 10;10(11):e0141623. Epub 2015 Nov 10.

South African Tuberculosis Vaccine Initiative, Institute of Infectious Diseases and Molecular Medicine, and Department of Pediatrics and Child Health, University of Cape Town, Cape Town, South Africa.

Objective: Diagnosis of childhood tuberculosis is limited by the paucibacillary respiratory samples obtained from young children with pulmonary disease. We aimed to compare accuracy of the Xpert® MTB/RIF assay, an automated nucleic acid amplification test, between induced sputum and gastric lavage samples from young children in a tuberculosis endemic setting.

Methods: We analyzed standardized diagnostic data from HIV negative children younger than four years of age who were investigated for tuberculosis disease near Cape Town, South Africa [2009-2012]. Two paired, consecutive induced sputa and early morning gastric lavage samples were obtained from children with suspected tuberculosis. Samples underwent Mycobacterial Growth Indicator Tube [MGIT] culture and Xpert MTB/RIF assay. We compared diagnostic yield across samples using the two-sample test of proportions and McNemar's χ2 test; and Wilson's score method to calculate sensitivity and specificity.

Results: 1,020 children were evaluated for tuberculosis during 1,214 admission episodes. Not all children had 4 samples collected. 57 of 4,463[1.3%] and 26 of 4,606[0.6%] samples tested positive for Mycobacterium tuberculosis on MGIT culture and Xpert MTB/RIF assay respectively. 27 of 2,198[1.2%] and 40 of 2,183[1.8%] samples tested positive [on either Xpert MTB/RIF assay or MGIT culture] on induced sputum and gastric lavage samples, respectively. 19/1,028[1.8%] and 33/1,017[3.2%] admission episodes yielded a positive MGIT culture or Xpert MTB/RIF assay from induced sputum and gastric lavage, respectively. Sensitivity of Xpert MTB/RIF assay was 8/30[26.7%; 95% CI: 14.2-44.4] for two induced sputum samples and 7/31[22.6%; 11.4-39.8] [p = 0.711] for two gastric lavage samples. Corresponding specificity was 893/893[100%;99.6-100] and 885/890[99.4%;98.7-99.8] respectively [p = 0.025].

Conclusion: Sensitivity of Xpert MTB/RIF assay was low, compared to MGIT culture, but diagnostic performance of Xpert MTB/RIF did not differ sufficiently between induced sputum and gastric lavage to justify selection of one sampling method over the other, in young children with suspected pulmonary TB.

Trial Registration: ClinicalTrials.gov NCT00953927.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141623PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640848PMC
June 2016

T Cell Responses against Mycobacterial Lipids and Proteins Are Poorly Correlated in South African Adolescents.

J Immunol 2015 Nov 14;195(10):4595-603. Epub 2015 Oct 14.

Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98109;

Human T cells are activated by both peptide and nonpeptide Ags produced by Mycobacterium tuberculosis. T cells recognize cell wall lipids bound to CD1 molecules, but effector functions of CD1-reactive T cells have not been systematically assessed in M. tuberculosis-infected humans. It is also not known how these features correlate with T cell responses to secreted protein Ags. We developed a flow cytometric assay to profile CD1-restricted T cells ex vivo and assessed T cell responses to five cell wall lipid Ags in a cross-sectional study of 19 M. tuberculosis-infected and 22 M. tuberculosis-uninfected South African adolescents. We analyzed six T cell functions using a recently developed computational approach for flow cytometry data in high dimensions. We compared these data with T cell responses to five protein Ags in the same cohort. We show that CD1b-restricted T cells producing antimycobacterial cytokines IFN-γ and TNF-α are detectable ex vivo in CD4(+), CD8(+), and CD4(-)CD8(-) T cell subsets. Glucose monomycolate was immunodominant among lipid Ags tested, and polyfunctional CD4 T cells specific for this lipid simultaneously expressed CD40L, IFN-γ, IL-2, and TNF-α. Lipid-reactive CD4(+) T cells were detectable at frequencies of 0.001-0.01%, and this did not differ by M. tuberculosis infection status. Finally, CD4 T cell responses to lipids were poorly correlated with CD4 T cell responses to proteins (Spearman rank correlation -0.01; p = 0.95). These results highlight the functional diversity of CD1-restricted T cells circulating in peripheral blood as well as the complementary nature of T cell responses to mycobacterial lipids and proteins. Our approach enables further population-based studies of lipid-specific T cell responses during natural infection and vaccination.
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http://dx.doi.org/10.4049/jimmunol.1501285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637215PMC
November 2015

Risk of Disease After Isoniazid Preventive Therapy for Mycobacterium tuberculosis Exposure in Young HIV-uninfected Children.

Pediatr Infect Dis J 2015 Nov;34(11):1218-22

From the *South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town; †Western Cape Government; ‡Stellenbosch University, Cape Town, South Africa; §Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; and ¶Aeras, Rockville, Maryland.

Background: The risk of developing tuberculosis (TB) disease in HIV-uninfected children after isoniazid preventive therapy (IPT) for a positive QuantiFERON-TB Gold In-Tube test (QFT-GIT) is unknown. The aim of this study was to evaluate risk of TB disease after IPT in young HIV-uninfected children with a positive QFT-GIT result, or household TB contact.

Methods: HIV-uninfected South African infants aged 4-6 months were screened for enrolment in a TB vaccine trial. Baseline household TB contact and positive QFT-GIT result were exclusion criteria, and these infants were referred for IPT. Outcome data are reported for 36 months after IPT referral.

Results: Four thousand seven hundred forty-nine infants were screened. Household TB contact was reported in 131 (2.8%) infants; 279 (6.0%) were QFT-GIT positive, and 138 of these 410 infants (34.0%) started IPT. Forty-four cases of TB disease (11.0%) were recorded within 991 child years of observation. TB disease incidence was 4.8 versus 3.6 per 100 child years in household exposed versus QFT-GIT-positive children [incidence rate ratio: 1.35; 95% confidence interval (CI): 0.67-2.88] and 2.4 versus 5.5 per 100 child years in children who received versus did not receive IPT, respectively (incidence rate ratio: 0.44; 95% CI: 0.17-0.96). Adjusted hazard ratio (Cox regression) for TB disease was 0.48 (95% CI: 0.21-1.05) for those who received IPT.

Conclusion: In young HIV-uninfected children, the effect of IPT on risk of TB disease is similar, whether TB exposure was defined by household contact history or by positive QFT-GIT result. International IPT guidelines for HIV-uninfected children with a positive QFT-GIT result should be updated.
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http://dx.doi.org/10.1097/INF.0000000000000874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604652PMC
November 2015

The Role of Clinical Symptoms in the Diagnosis of Intrathoracic Tuberculosis in Young Children.

Pediatr Infect Dis J 2015 Nov;34(11):1157-62

From the *South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease & Molecular Medicine (IDM), Department of Pediatrics & Child Health, University of Cape Town; †Vaccines for Africa (VACFA), Institute of Infectious Disease & Molecular Medicine, University of Cape Town; ‡Division of Community Health, Stellenbosch University and Western Cape Government: Health, Cape Town, South Africa; §Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; and ¶Aeras, Rockville, Maryland.

Background: Childhood tuberculosis (TB) is usually Mycobacterium tuberculosis (MTB) culture negative. Furthermore, clinical presentation may be altered by active case finding, isoniazid prophylaxis and early treatment. We aimed to establish the value of presenting symptoms for intrathoracic TB case diagnosis among young children.

Methods: Healthy, HIV-uninfected, South African infants in an efficacy trial of a novel TB vaccine (MVA85A) were followed for 2 years for suspected TB. When suspected, investigation followed a standardized algorithm comprising symptom history, QuantiFERON Gold-in-Tube, chest radiography (CXR), MTB culture and Xpert MTB/RIF from paired gastric lavage and induced sputa. Adjusted odds ratios and 95% confidence intervals describe the associations between symptoms and positive MTB culture or Xpert MTB/RIF, and CXR compatible with intrathoracic TB.

Results: Persistent cough was present in 172/1017 (16.9%) of the children investigated for TB. MTB culture/Xpert MTB/RIF was positive in 38/1017 children (3.7%); and CXR was positive, that is, compatible with intrathoracic TB, in 131/1017 children (12.9%). Children with persistent cough had more than triple the odds of a positive MTB culture/Xpert MTB/RIF (adjusted odds ratios: 3.3, 95% confidence interval: 1.5-7.0) and positive CXR (adjusted odds ratios: 3.5, 95% confidence interval: 2.2-5.5). Persistent cough was the only symptom that differentiated children with severe (56.5%) from nonsevere intrathoracic TB disease (28.2%; P = 0.001).

Conclusion: Persistent cough was the cardinal diagnostic symptom associated with microbiologic and radiologic evidence, and disease severity, of intrathoracic TB. Symptom-based definitions of TB disease for diagnostic, preventive and therapeutic studies should prioritize persistent cough above other symptoms compatible with childhood TB.
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http://dx.doi.org/10.1097/INF.0000000000000847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604651PMC
November 2015

First-in-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults.

Vaccine 2015 Aug 19;33(33):4130-40. Epub 2015 Jun 19.

South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine (IDM), School of Child and Adolescent Health, University of Cape Town, University of Cape Town, Cape Town, South Africa; Vaccines for Africa Initiative, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa.

Background: H56:IC31 is a candidate tuberculosis vaccine comprising a fusion protein of Ag85B, ESAT-6 and Rv2660c, formulated in IC31 adjuvant. This first-in-human, open label phase I trial assessed the safety and immunogenicity of H56:IC31 in healthy adults without or with Mycobacterium tuberculosis (M.tb) infection.

Methods: Low dose (15 μg H56 protein in 500 nmol IC31) or high dose (50 μg H56, 500 nmol IC31) vaccine was administered intramuscularly thrice, at 56-day intervals. Antigen-specific T cell responses were measured by intracellular cytokine staining and antibody responses by ELISA.

Results: One hundred and twenty-six subjects were screened and 25 enrolled and vaccinated. No serious adverse events were reported. Nine subjects (36%) presented with transient cardiovascular adverse events. The H56:IC31 vaccine induced antigen-specific IgG responses and Th1 cytokine-expressing CD4(+) T cells. M.tb-infected vaccinees had higher frequencies of H56-induced CD4(+) T cells than uninfected vaccinees. Low dose vaccination induced more polyfunctional (IFN-γ(+)TNF-α(+)IL-2(+)) and higher frequencies of H56-specific CD4(+) T cells compared with high dose vaccination. A striking increase in IFN-γ-only-expressing CD4(+) T cells, displaying a CD45RA(-)CCR7(-) effector memory phenotype, emerged after the second high-dose vaccination in M.tb-infected vaccinees. TNF-α(+)IL-2(+) H56-specific memory CD4(+) T cells were detected mostly after low-dose H56 vaccination in M.tb-infected vaccinees, and predominantly expressed a CD45RA(-)CCR7(+) central memory phenotype. Our results support further clinical testing of H56:IC31.
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http://dx.doi.org/10.1016/j.vaccine.2015.06.051DOI Listing
August 2015

The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: A randomized controlled trial.

Vaccine 2015 Jul 3;33(30):3592-9. Epub 2015 Jun 3.

Sanofi Pasteur, Swiftwater, PA, USA.

Background: New, more effective vaccines to prevent tuberculosis (TB) disease are needed urgently. H4:IC31 is an investigational vaccine that contains a fusion protein of the immunodominant antigens TB10.4 and Ag85B, formulated in IC31 adjuvant. We assessed the safety and immunogenicity of H4:IC31 in South African adults from a TB endemic setting.

Methods: In this double blind, placebo controlled, phase I trial, Mycobacterium tuberculosis-uninfected, HIV-uninfected, healthy adults with a history of childhood BCG vaccination were randomly allocated to two intramuscular vaccinations with 5, 15, 50 or 150 μg H4 formulated in 500nmol IC31, two months apart. Vaccinees were followed for six months to assess safety; immunogenicity was measured by ELISpot and intracellular cytokine staining assays.

Results: Thirty-two participants received H4:IC31 and 8 received placebo. Injection site adverse events were common but mild; mild fatigue was the most common systemic adverse event. Frequencies of adverse events did not differ between dosage groups. Detectable antigen-specific CD4 T cell responses were induced by all doses of H4:IC31, but doses below 50 μg induced the highest frequencies of CD4 T cells, comprised predominantly of IFN-γ(+)TNF-α(+)IL-2(+) or TNF-α(+)IL-2(+) cells. These memory responses persisted up to the end of follow up, on study day 182.

Conclusions: H4:IC31 demonstrated an acceptable safety profile and was immunogenic in South African adults. In this trial, the 15 μg dose appeared to induce the most optimal immune response.
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http://dx.doi.org/10.1016/j.vaccine.2015.05.036DOI Listing
July 2015

COMPASS identifies T-cell subsets correlated with clinical outcomes.

Nat Biotechnol 2015 Jun 25;33(6):610-6. Epub 2015 May 25.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Advances in flow cytometry and other single-cell technologies have enabled high-dimensional, high-throughput measurements of individual cells as well as the interrogation of cell population heterogeneity. However, in many instances, computational tools to analyze the wealth of data generated by these technologies are lacking. Here, we present a computational framework for unbiased combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS). COMPASS uses a Bayesian hierarchical framework to model all observed cell subsets and select those most likely to have antigen-specific responses. Cell-subset responses are quantified by posterior probabilities, and human subject-level responses are quantified by two summary statistics that describe the quality of an individual's polyfunctional response and can be correlated directly with clinical outcome. Using three clinical data sets of cytokine production, we demonstrate how COMPASS improves characterization of antigen-specific T cells and reveals cellular 'correlates of protection/immunity' in the RV144 HIV vaccine efficacy trial that are missed by other methods. COMPASS is available as open-source software.
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http://dx.doi.org/10.1038/nbt.3187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569006PMC
June 2015