ANNUAL REPORT 2019 - satvi.uct.ac.za · from UCT with an MBChB degree in 1980. She worked for many years in the public health sector in Cape Town and in Worcester. In 2003 she joined

ANNUAL REPORT 2019

https://www.uct.ac.za/

vision and mission

Our VisionA World Without TB Innovative and High Quality

TB Vaccine Research

to impact the

Global Epidemic

Innovation I Respect I Employee

Recognition I Accountability

Communication I Commitment

Honesty

Our Mission Our Values

contents Director’s Foreword 2 About SATVI 3 Governance 4 Senior Clinical Research Team 6 Research Highlights from 2019 8 Selection of Clinical and Immunology Research conducted 10 Research Outputs 20 Awards, Honours and Accreditations 24 Postgraduate Students and Postdoctoral Fellows 25 Our Staff 26 Our Community 28 Funders 30 Collaborators 31

2 SATVI ANNUAL REPORT 2019

director’s foreword2019 was an extraordi-narily busy and produc-tive period for SATVI. The year ended with the close of the CORTIS trial, a large multi-centre effort to test a strategy for biomarker-targeted

TB preventive therapy. Data from this trial, which enrolled 2,923 HIV-uninfected adult volunteers, and a parallel obser-vational study in HIV-infected individuals, are now being anal-ysed and are expected to be released in the first quarter 2020. These exciting results will guide the further development of host blood transcriptional biomarkers for the diagnosis and prediction of TB, and inform the field if short-course TB pre-ventive therapy can prevent progression to disease in bio-marker-positive individuals.

The year was also punctuated by the release of final results of a multi-site trial that tested whether the vaccine candidate M72/AS01E could prevent progression to TB in individuals who were M. tuberculosis-infected at the time of vaccination. The landmark results (Tait et al, NEJM 2019) confirm 50% efficacy against TB disease, which was durable through 3 years. This important finding must now be tested in other geographies and key populations, including adolescents without M. tuberculosis infection, and adults with HIV infection. A second key finding was the publication of safety and immunogenicity findings for the novel live

attenuated M. tuberculosis vaccine MTBVAC (Tameris et al, Lancet Respiratory Medicine 2019), which have informed entry of this vaccine candidate into two dose-finding studies in infants and adults.

Three major projects began recruiting in 2019, including CORTIS KIDS, a study to evaluate transcriptomic, proteomic and flow cytometric biomarkers for the diagnosis and prognosis of TB in young children with household exposure. This study, funded by the US National Institutes of Health, is the logical continuation of the CORTIS biomarker effort. BCG REVAX, a large multi-site clinical trial funded by the Gates Medical Research Institute, seeks to confirm whether BCG revaccination of M. tuberculosis-uninfected adolescents can provide durable protection against sustained IGRA conversion; recruitment started in October 2019. A third large trial, PHOENIx, is a multi-centre, cluster-randomized controlled trial which seeks to compare the safety and efficacy of Delamanid compared with Isoniazid in the prevention of active TB disease in high risk household contacts of adult patients with MDR-TB.

It was pleasing that this considerable research activity, both at the field site and in the immunology laboratory, was accompanied by a number of high impact research outputs. SATVI authors published 36 papers in 2019, including 16

papers with a first or senior SATVI author, in journals that included the New England Journal of Medicine, Nature Reviews Immunology, Nature Medicine, Lancet Respiratory Medicine, Lancet Infectious Diseases, Clinical Microbiology Review, PLoS Medicine, JAMA Pediatrics, and the American Journal of Respiratory and Critical Care Medicine.

SATVI continues to invest in the development of mid-career researchers who will form the leadership of the future and this year was rewarded with the ad hominem promotion of Dr Elisa Nemes to Associate Professor, and Dr Michele Tameris and Dr Angelique Luabeya to Senior Clinical Researcher. Finally, SATVI’s community engagement and TB awareness education programme, which is critical to the success of our research in a community heavily burdened by TB and central to our ethos of “paying forward”, was recognised by the Vice Chancellor’s Social Responsiveness Award.

We look forward to working closely with the greater Worcester community, national stakeholders, our collaborators and funders, in a number of exciting new vaccine and biomarker projects in 2020 and beyond.

Professor Mark HatherillDirector, SATVI

3SATVI ANNUAL REPORT 2019

about SATVI

The South African Tuberculosis Vaccine Initiative (SATVI) is a tuberculosis (TB) research group with a research scope that spans several disciplines including paediatrics, infectious diseases, epidemiology, public health, immunology, systems biology and clinical sciences. Our research focus is understanding the risk for, and protection against, M. tuberculosis infection and TB disease, in order to develop more effective vaccines and preventive strategies.

SATVI was established in 2001 at the University of Cape Town (UCT) and has developed into a sophisticated, world-class TB clinical research centre with state-of-the-art immunology laboratories located within the Institute of Infectious Disease and Molecular Medicine (IDM) of the University of Cape Town. SATVI is regarded as a leader

in TB vaccine and prevention research worldwide and is the largest dedicated TB vaccine research group on the African continent. Our laboratories are accredited and adhere to the highest international standards. In addition to our well-established track record in TB vaccine development, our recent work builds on discovery and validation of prognostic biomarkers for TB disease to test screen-&-treat strategies, based on biomarker-targeted TB preventive therapy.

SATVI has a large and well-developed clinical field site in the Boland Overberg region, with the core facility on the premises of the Brewelskloof TB Hospital in Worcester, from where most clinical/epidemiological studies and clinical trials are conducted.

The clinical trials research is led by SATVI Director, Professor Mark Hatherill, and the immunology and laboratory-based research is led by SATVI Deputy Director, Professor Tom Scriba.

Our clinical trial programme has been extraordinarily productive over the past 19 years. SATVI has conducted 28 Phase I–IV trials of BCG and 9 novel TB vaccine candidates among more than 30,000 research participants, and published 313 papers, the majority of these with a SATVI first or senior author. Our active postgraduate student programme has produced 10 PhD graduates and several Master’s graduates during the same period.


governanceExecutive Committee

PROFESSOR MARK HATHERILL, DIRECTOR

Dr Mark Hatherill (MD, FCPaed) is a specialist paediatrician and clinical trialist who is active in the design and implementation of innovative trials of new TB vaccines and TB preventive therapy strategies, through several consortia. His current academic focus includes evaluation of biomarker-targeted interventions and several clinical trials of novel TB vaccine candidates. He is a full member of the Institute of Infectious Disease & Molecular Medicine (IDM) at UCT; member of the WHO IVR Working Group on TB Vaccines and Co-Chair of the Regional Prospective Observational Research in Tuberculosis (RePORT) South Africa consortium. Dr Hatherill is funded by institutional research grants from the Bill & Melinda Gates Foundation (BMGF), the Gates Medical Research Institute, the SA Medical Research Council (SAMRC), US National Institutes of Health, the European & Developing Countries Clinical Trials Partnership and Aeras/IAVI.

THE SATVI EXECUTIVE COMMITTEE IS COMPRISED OF:

Director: Professor Mark Hatherill

Deputy Director: Professor Tom Scriba

Chief Operations Officer: Dr Masooda Kaskar

Field Site Manager: Marwou de Kock


PROFESSOR TOM SCRIBA, DEPUTY DIRECTOR IMMUNOLOGY

Dr Tom Scriba (PhD) directs the clinical immunology laboratory at SATVI. He was trained in biological sciences at Stellenbosch University and obtained a DPhil (PhD) in T cell Immunology at Oxford University. He returned to South Africa in 2006 to complete a postdoctoral fellowship in paediatric and clinical immunology in TB and vaccinology at the IDM, UCT. Dr Scriba is a full member of the IDM, member of the STOP TB Partnership Working Group for New Diagnostics Biomarkers Taskforce and the Collaboration for TB Vaccine Discovery of the BMGF. Dr Scriba is funded by competitive grants from the BMGF, the National Research Foundation (NRF), SAMRC, US National Institutes of Health and the European Union.

DR MASOODA KASKAR, CHIEF OPERATIONS OFFICER

Dr Masooda Kaskar joined SATVI’s senior leadership team in 2016 to advance organisational excellence and drive innovation and growth. Her leadership experience spans corporate, public and philanthropic sectors with a focus on strategic business development, governance and operations. In her current role she is a key driver of SATVI’s transformation efforts and risk management plans to ensure growth and long-term sustainability of the organisation. Dr Kaskar previously occupied several senior leadership positions within the pharmaceutical industry. At Novartis she was instrumental in developing and implementing transformational growth plans that resulted in establishing Novartis’s leadership position within the industry. She holds an MBChB degree from the University of Cape Town and an MBA degree from UCT, Graduate School of Business.

MARWOU DE KOCK, FIELD SITE MANAGER

Marwou de Kock holds a Master’s degree in Clinical Research Administration from UCT, as well as degrees in biomedical science and laboratory management. She has worked at SATVI since 2002 and has intricate knowledge of the site, the people and procedures in the laboratory, clinical operations and community engagement. She helped establish the SATVI Field Site laboratory and developed it into a world class facility that received SANAS accreditation in 2010. She is currently responsible for managing the SATVI Field Site, overseeing and managing service delivery for all operations, as well as coordinating and implementing multiple research projects.


senior clinical research teamASSOCIATE PROFESSOR ELISA NEMES, INVESTIGATOR

Dr Elisa Nemes completed her PhD in HIV-specific T-cell Immunology in Italy and France in 2008. She then worked on paediatric immune responses to HIV and TB in Cameroon. She joined SATVI in 2011,

where she has been involved in basic immunology studies, immuno-diagnostics, clinical trials of new TB vaccines and studies of host correlates of risk of TB disease in BCG-vaccinated infants; and of BCG/TB immune reconstitution inflammatory syndrome (IRIS) in HIV+ children. She is funded by competitive grants from the Center for AIDS Research (CFAR) and the US National Institutes of Health. Dr Nemes was promoted to Associate Professor ad hominem in 2019.

DR MICHÈLE TAMERIS, SENIOR CLINICAL RESEARCHER

Dr Michèle Tameris graduated from UCT with an MBChB degree in 1980. She worked for many years in the public health sector in Cape Town and in Worcester. In 2003 she joined SATVI as a clinical researcher and since 2005

has been an Investigator on 15 vaccine trials, 6 as Principal Investigator, including 9 trials of novel TB vaccines and the first Phase 2b infant efficacy trial of a new TB vaccine (MVA85A). Dr Tameris has been awarded two Wellcome Trust International Engagement awards (2012 and 2014) for projects using drama to improve community understanding of TB clinical research. She is a member of the Stop TB Working Group on New Vaccines.

DR ANGELIQUE LUABEYA, SENIOR CLINICAL RESEARCHER

Dr Angelique Kany Kany Luabeya graduated as a medical doctor in 1996 from the University of Kinshasa (DR Congo) and holds a Master’s degree in Epidemiology from the London School of Tropical

Medicine (LSHTM). She joined SATVI in 2009 as a clinical investigator from the Africa Centre for Health and Population Studies at University of KwaZulu-Natal and has been involved as Principal Investigator in the implementation and conduct of clinical trials of new TB vaccines (AERAS C035-456, IDRI-TBVPx-203, and VPM1002-ZA-2.13TB) in healthy adults, TB patients and new-borns, respectively. Dr Luabeya has a research interest in the design and conduct of novel diagnostic studies (TB case-finding by oral swab PCR) and health systems operational research in the area of TB prevention in young children.


DR JUSTIN SHENJE, INVESTIGATOR

Dr Justin Shenje graduated as a Medical doctor in 2004 from the University of Zimbabwe and holds a Master’s degree in Clinical Epidemiology from the University of Pretoria. He joined SATVI in 2015 as a clinical investigator and

leads the AIDS Clinical Trials Group (ACTG) trials, serving as Principal Investigator for the following tuberculosis (TB) drug studies; A5300B, A5343 and A5349 (TBTC Study 31). Dr Shenje is also the principal investigator for the A-055 study, a prevention of recurrence study investigating the efficacy of the novel TB vaccine H56:IC31. He is also a member of the ACTG TB Vaccine Working Group, a team working to develop clinical trials for novel TB vaccines for the ACTG network.

DR SIMON MENDELSOHN, INVESTIGATOR

Dr Simon Mendelsohn graduated from the University of Cape Town as a medical doctor in 2011, and read for two Master’s degrees at the University of Oxford on a Rhodes Scholarship, in

Immunology (2015) and International Health and Tropical Medicine (2016), and obtained a Diploma in Tropical Medicine and Hygiene from the Royal College of Physicians (London). Simon joined SATVI on a PhD Fellowship in 2017 and also works as a clinical trial Investigator. He has experience in HIV and TB clinical medicine, most recently with Médecins Sans Frontières implementing an HIV and TB programme in Malawi prisons. Simon Mendelsohn was awarded a Fogarty HIV-associated TB Training Program Clinician Scientist PhD Fellowship and South African Medical Association PhD Scholarship in 2019.

DR HENNIE GELDENHUYS, INVESTIGATOR

Dr Hennie Geldenhuys trained in Family Medicine and joined SATVI in 2007. He has fulfilled the role of Principal Investigator on a number of clinical trials. His current focus is coaching and training

in private practice, but he remains associated with SATVI as a sessional Sub-Investigator, based at the field site in Worcester, and as clinical quality management consultant for clinical trials.


research highlightsA PHASE IIB, DOUBLE-BLINDED, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY AND IMMUNOGENICITY OF M72:ASO1E AGAINST TB DISEASE, IN ADULTS AGED 18-50 YEARS, LIVING IN A TB ENDEMIC REGION

SATVI Principal Investigator: Mark HatherillSATVI Investigator: Michèle TamerisStudy Coordinator: Danelle Van AsFunders: - GlaxosmithKline (GSK)- Bill and Melinda Gates Foundation (BMGF) - International AIDS Vaccine Initiative (IAVI)- United Kingdom Department for International

Development - Government of the Netherlands Directorate-

General for International Cooperation- Australian AID Foundation

were published in the New England Journal of Medicine (Tait et al. 2019) and presented at the TB Science 2019 conference, in Hyderabad, India.

The primary objective of this study, which was conducted at 11 sites in Kenya, South Africa and Zambia, including SATVI and CIDRI-Africa at the University of Cape Town, was to evaluate the efficacy of the M72/AS01

E candidate vaccine against pulmonary TB in previously M. tuberculosis infected adults. A total of 3,575 HIV-negative, latently infected adults aged 18 to 50 years received two doses of either the M72/AS01

E vaccine or a placebo and were followed for three years for evidence of pulmonary TB. Of these, 13 participants in the vaccine group and 26 participants in the placebo group developed pulmonary TB, with overall vaccine efficacy of 50%.

The results of this final analysis are consistent with results of the primary analysis (at year two year of follow-up), which were published in the New England Journal of Medicine in September 2018 (Van Der Meeren et al. 2018). These exciting final results confirmed the previously reported acceptable safety profile of the M72/AS01

E vaccine and also showed that the vaccine induced immune responses that persisted for three years. ClinicalTrials.gov: NCT01755598

The final results of this trial, which assessed the safety and efficacy of M72/AS01E TB vaccine in adults with latent M. tuberculosis infection against progression to TB disease

Professor Hatherill presenting results at TB Science 2019.

Professor Scriba presenting results at the TB Science 2019.


August 2019. The trial demonstrated that vaccination with MTBVAC induced a long-lasting immune response of greater magnitude than that of BCG at a comparable dose.

MTBVAC was also shown to induce dose-dependent conversion and later reversion of the QuantiFERON test (QFT), a diagnostic tool originally designed to detect infection with M. tuberculosis. This is not surprising since MTBVAC is a live, attenuated M. tuberculosis vaccine and may be seen as anencouraging sign of stimulating immune responses againstM. tuberculosis. However, this effect on interpretation of QFTresults in MTBVAC recipients prevents a diagnostic challenge, since identification of M. tuberculosis-infected individuals forpreventive antibiotic treatment is compromised. Ongoingphase 2a and future efficacy studies in TB endemic countrieswill allow more extensive evaluation of QFT dynamics ininfants, and encourage the development of new diagnostictests to differentiate the MTBVAC-induced response fromnatural M. tuberculosis infection. ClinicalTrials.gov: NCT02729571

DOSE-ESCALATION SAFETY AND IMMUNOGENICITY STUDY TO COMPARE MTBVAC TO BCG IN NEWBORNS WITH A SAFETY ARM IN ADULTS (MTBVAC 201)

The novel vaccine MTBVAC, is the first recombinant live whole cell M. tuberculosis vaccine in clinical testing, intended as a BCG replacement vaccine in new-borns, or as booster to BCG in older individuals.

In this trial we first sought to test the safety of MTBVAC in 18 BCG-vaccinated, TB-uninfected adults. After establishing safety in adults, the safety and immunogenicity of 3 different dose levels of MTBVAC were tested in 36 BCG-naïve new-borns, compared against BCG. The safety and immunogenicity results for MTBVAC in BCG-naive South African infants, were published in the Lancet Respiratory Medicine in

Investigator: Dr Michèle TamerisFunders: - European and Developing Countries Clinical

Trials Partnership (EDCTP)- Biofabri- University of Zaragoza

GSK/M72 Study team with PI Dr Michèle Tameris

MTBVAC infant study team with Dr Michèle Tameris

...continued M72:ASO1E


selection of major clinical and immunology researchTB VACCINE STUDIES

MTBVAC PHASE 1B/2A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED, SAFETY, IMMUNOGENICITY, AND DOSE-ESCALATION STUDY IN ADULTS WITH AND WITHOUT LATENT TUBERCULOSIS INFECTION IN SOUTH AFRICA.

This is a Phase 1b/2a, double-blind, randomized, BCG-controlled, dose-escalation safety and immunogenicity study in 144 healthy adults with and without Latent TB infection. All participants have received previous BCG vaccination in infancy. Participants meeting the inclusion/exclusion criteria are randomized within a study cohort to receive a single dose of MTBVAC or BCG revaccination administered intradermally on Study Day 0. The investigational product is MTBVAC at four dose levels: 5 x 10^3 CFU, 5 x 10^4 CFU, 5 x 10^5 CFU, and 5 x 10^6 CFU. The active control is BCG (5 x 10^5 CFU).

Principal Investigator: Angelique Luabeya Funders: National Institutes of Health, Congress Directed Medical Research Program (CDMRP)Sponsor: IAVI

The study started in January 2019 and 125 participants have been enrolled with no safety concerns have been reported at this stage. Participants are followed for 12 months after vaccination and the estimated study duration (from first participant vaccinated to completion of data collection) is approximately 24 months. Data is expected in 2022.Clinicaltrials.gov Identifier: NCT02933281

MTBVAC adult study team with PI Dr Angelique Luabeya.


PHASE I/II, SAFETY AND IMMUNOGENICITY STUDY OF A RECOMBINANT PROTEIN TUBERCULOSIS VACCINE (H4:IC31) IN BCG-PRIMED INFANTS (P1113, AERAS C-015-404)

This multisite study of 211 participants evaluated the H4:IC31 vaccine, designed as a booster to BCG to provide protection against M. tuberculosis infectionand/or TB disease early inlife. The trial compareddifferent doses and numberof administrations of thevaccine, in infants ofdifferent ages. Enrolmentand follow up is completeat all sites.

We anticipate the results of this trial will be made available in Q1 of 2020.

Clinicaltrials.gov Identifier: NCT01861730

SATVI Principal Investigator: Michèle TamerisFunders/Sponsors: IAVI, NIAID, NICHD, IMPAACT

STUDY TO EVALUATE THE SAFETY AND IMMU-NOGENICITY OF VPM1002 IN COMPARISON WITH BCG IN HIV-EXPOSED/-UNEXPOSED NEW-BORN INFANTS IN SOUTH AFRICA

BCG is currently the only licensed TB vaccine, but it provides incomplete protection against pulmonary TB in children and variable protection in adults. It is also contraindicated for HIV-positive persons due to the high risk of adverse events. This multi-site trial of 416 infants evaluated the safety and immunogenicity of the candidate recombinant BCG vaccine VPM1002, in HIV exposed and unexposed neonates, compared with BCG. Enrolment and follow up at participating sites (Desmond Tutu TB Centre, Children’s

Infectious Diseases Clinical Research Unit and Respiratory and Meningeal Pathogens Research Unit) is now complete. Results are expected in Quarter 1 of 2020.Clinicaltrials.gov Identifier: NCT02391415.

SATVI Principal Investigator: Michèle TamerisFunders: Serum Institute of India, Ltd (PI Cotton)

BCG REVACCINATION OF HEALTHY ADOLESCENTS FOR THE PREVENTION OF MYCOBACTERIUM TUBERCULOSIS SUSTAINED INFECTION (BCG REVAX)

The purpose of this study is to demonstrate the efficacy of Bacille Calmette Guerin (BCG) revaccination against sustained M. tuberculosis infection versus a placebo in previously BCG vaccinated QuantiFERON®-TB Gold Plus (QFT) negative, healthy adolescents. The study started in November 2019 and is actively enrolling.Clinicaltrials.gov Identifier: NCT04152161BCG

Principal Investigator: Angelique Luabeya Funders: BMGF


A PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF H56:IC31 IN REDUCING THE RATE OF TB DISEASE RECUR-RENCE IN HIV-NEGATIVE ADULTS SUCCESS-FULLY TREATED FOR DRUG-SUSCEPTIBLE PULMONARY TUBERCULOSIS (A-055).

The A-055 study is a double blind, randomized placebo-controlled trial, which seeks to evaluate the safety and efficacy of the H56:IC31 vaccine in preventing the recurrence of TB in HIV-negative individuals who have recently completed a 6 months of TB treatment successfully. H56:IC31 is a novel TB vaccine and early clinical trials have shown it to be safe and to illicit immunogenic reaction. The study plans to enrol 900 participants, each participant will have the vaccine administered twice, the first at enrolment and the second, 56 days after enrolment. Participants will then be followed-up for 421 days and the outcome measures for the study will be confirmed TB, probable TB and immunogenicity. The study commenced in February 2019 is expected to be completed in September 2022. Clinicaltrials.gov Identifier: NCT03512249

Principal Investigator: Justin ShenjeFunder: EDCTP

NEW TB DRUGS AND REGIMENS

USING BIOMARKERS TO PREDICT TB TREATMENT DURATION (PREDICT)

This is a prospective, randomized, Phase 2b non-inferiority trial in drug-sensitive pulmonary TB participants. Eligible participants initially receive Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E) for 8 weeks, then switch to Isoniazid and Rifampicin (HR). Early treatment completion criteria will be evaluated for each participant using all available data at week 16 including GeneXpert results, adherence data and PET/CT scan results. Those who do not meet the early treatment completion criteria at enrolment will be assigned to Arm A and receive standard of care ie 24 weeks of treatment; those who meet early treatment completion criteria, will be randomised at week 16, either to continue therapy to week 24 (Arm B) or to complete

Investigator: Dr Michèle TamerisFunders: BMGF, EDCTP, International Collaborations in Infectious Disease Research (ICIDR), RePORT South Africa (PI: Walzl)

therapy early at week 16 (Arm C). All participants will be followed for 18 months from entering the study, with the primary endpoint of treatment success being evaluated at 18 months. SATVI currently has 65 participants enrolled of whom 24 have completed the study followup of 18 months. Enrolment on this study across all sites is expected to be complete by July 2020 and follow up by January 2022.Clinicaltrials.gov Identifier: NCT02821832

A RANDOMIZED, PARTIALLY-BLINDED, CLINICAL TRIAL OF ISONIAZID AND RIFAPENTINE (3HP) THERAPY TO PREVENT PULMONARY TUBERCULOSIS IN HIGH-RISK INDIVIDUALS IDENTIFIED BY A TRANSCRIPTOMIC CORRELATE OF RISK.

CORTIS builds on a decade-long project to develop a host blood RNA (transcriptomic) signature that predicts whether a person is at risk of developing TB, based on the human immune response (Zak et al, Lancet 2016 ). In this large clinical trial, we evaluated whether an 11-gene RNA signature can identify those with undiagnosed TB disease and those who are at risk of progression to incident disease. The trial also evaluates if targeted preventive therapy for people with a positive RNA signature can stop them from developing TB. This international collaboration is led by SATVI in partnership with the Aurum Institute, the Stellenbosch University Immunology Research Group, the Centre for the

National Principal Investigator: Mark HatherillSATVI Principal Investigator: Michèle TamerisFunders: BMGF, South African Medical Research Council


AIDS Programme of Research in South Africa (CAPRISA), the London School of Hygiene and Tropical Medicine (LSHTM) and the Fred Hutchinson Cancer Research Center (FHCRC).

The trial recruited 2,923 HIV-uninfected adult volunteers from communities with high TB burden at 5 sites in South Africa, who were randomised to either preventive therapy (RNA signature+) or active surveillance (RNA signature+ or -). All participants were screened for TB disease at baseline, and through 15 months of follow-up, to evaluate the signature for diagnosis of prevalent TB and prognosis of incident TB. Efficacy of preventive therapy (3 months of once-weekly, high dose Isoniazid and Rifapentine) for protection against incident TB will be evaluated in RNA signature + participants in the preventive therapy vs active surveillance arms.

If successful, CORTIS would provide proof of concept for mass campaigns using a ‘TB screen and treat’ strategy, which has potential for impact on the global epidemic. Preliminary indications suggest a very high prevalence of TB disease in the CORTIS study population, which is enriched for RNA signature+ persons.

Results are expected in early 2020.Clinicaltrials.gov Identifier: NCT02735590

CORRELATE OF RISK TARGETED INTERVENTION STUDY: HIGH RISK (CORTIS-HR)

CORTIS-HR is an observational study of the diagnostic and prognostic performance of the host blood 11-gene RNA signature of TB in HIV-infected persons. This multi-site study enrolled 860 participants and followed them up over a 15-month period to determine if the transcriptomic signature can identify prevalent and incident TB in this population. This ground-breaking study will show if this predictive screening tool can identify those individuals at highest risk of progression from M. tuberculosis infection to TB disease, avoiding unnecessary treatment of people who would otherwise remain healthy despite being positive for conventional tests that suggest infection with M. tuberculosis.

Results are expected in early 2020.

National Principal Investigator: Mark Hatherill SATVI Principal Investigator: Michèle TamerisFunders: BMGF, South African Medical Research Council

PROTECTING HOUSEHOLDS WITH EXPOSURE TO NEWLY DIAGNOSED INDEX MULTIDRUG-RESISTANT TUBERCULOSIS PATIENTS (PHOENIX MDR-TB)

The PHOENIx MDR-TB study is a multi-centre, cluster-randomized controlled trial which seeks to compare the safety and efficacy of Delamanid compared with Isoniazid in the prevention of active TB disease in high risk household contacts (HHC) of adult patients with MDR-TB. The study plans to enrol 3,452 HHC, who will receive 26 weeks of either Delamanid or Isoniazid and will be followed-up for a total of 96 weeks. Delamanid is a new anti-TB drug which has been shown to be highly efficacious in the treatment of MDR-TB. Isoniazid is the most widely used TB prophylaxis drug, but there are important concerns about drug resistance when Isoniazid is used for prophylaxis in high risk HHC of patients with MDR-TB. High-risk HHC are those with HIV or non-HIV immunosuppression, latent M. tuberculosis infection, and young children below the age of 5 years. The study commenced recruitment in October 2019 and is expected to run till September 2026.Clinicaltrials.gov Identifier: NCT03568383

Investigator: Dr Justin ShenjeFunder: AIDS Clinical Trials Group (ACTG)


SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF BEDAQUILINE AND DELAMANID, ALONE AND IN COMBINATION, AMONG PARTICIPANTS TAKING MULTIDRUG TREATMENT FOR DRUG-RESISTANT PULMONARY TUBERCULOSIS (ACTG 5343)

Bedaquiline and Delamanid are drugs for the treatment of Multi-drug resistant (MDR) tuberculosis (TB). Both these drugs have been shown to be efficacious and safe when administered alone with the standard MDR TB treatment. However, the safety of combining these two drugs with the standard MDR treatment has not been investigated, especially for their effects on the heart. This trial, which is being conducted at 3 global sites including SATVI,

Principal Investigator: Justin ShenjeFunders: ACTG, Division of AIDS (DAIDS)

evaluates the safety and efficacy of each drug (Bedaquiline and Delamanid) alongside standard MDR TB treatment and compares with the combination of Bedaquiline and Delamanid alongside standard MDR TB treatment.

The participants will be followed-up with intensive monitoring for electrocardiogram (ECG) changes and other safety events. Participant enrolment is complete, and the study is now in the follow-up phase.Clinicaltrials.gov Identifier: NCT02583048

RIFAPENTINE-CONTAINING TREATMENT SHORTENING REGIMENS FOR PULMONARY TUBERCULOSIS: A RANDOMIZED, OPEN-LABEL, CONTROLLED PHASE 3 CLINICAL TRIAL (ACTG STUDY A5349)

A5349/S31 study is a multi-centre, randomized controlled TB drug trial, led by ACTG and the Tuberculosis Trials Consortium (TBTC), which seeked to enrol 2500 participants to compare the standard treatment for drug-sensitive TB with novel shortened regimens, which contain Rifapentine and Moxifloxacin. Outcome measures of the study include microbiological and clinical treatment success and non-recurrence of disease, as well as safety parameters. Participant enrolment is complete, and the study is now in the follow-up phase.Clinicaltrials.gov Identifier: NCT02410772

Principal Investigator: Justin ShenjeFunders: ACTG, DAIDS, Tuberculosis Trials Consortium (TBTC)

DIAGNOSTIC AND OBSERVATIONAL STUDIES

TUBERCULOSIS CASE-FINDING BY ORAL SWAB POLYMERASE CHAIN REACTION (PCR)

This study evaluated the feasibility of oral swab analysis (OSA) for the diagnosis of TB disease. Oral swabs were collected from adult patients including GeneXpert® MTB/RIF (GeneXpert)-confirmed TB patients (N=138), sputum GeneXpert-negative but culture-positive TB patients (N=10), ill non-TB patients (N=37) and healthy QuantiFERON-negative controls (N=34). Relative to all laboratory-diagnosed TB, the

Principal Investigator: Angelique LuabeyaFunders: University of Washington, National Institutes of Health (NIH), BMGFSponsor: University of Washington (PI: Professor Cangelosi)


sensitivity of sputum GeneXpert (1 sample per subject) and OSA (2 samples per subject) were similar at 83.1% and the specificity of OSA was 91.5%. The results confirm and significantly expand our previous finding that M. tuberculosis DNA and/or cells accumulate in the oral cavity of TB patients in amounts that are sufficient to enable non-sputum-based diagnosis of TB.

HOST BLOOD BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS AND TREATMENT RESPONSE OF CHILDHOOD TB (CORTIS KIDS)

The CORTIS KIDS study is an observational study which seeks to evaluate the performance of diagnostic and prognostic host biomarkers of TB in child household contacts under five years of age of drug-sensitive adult TB patients. TB in children of this age group is difficult to diagnose and has a higher incidence of poor outcomes when compared to adult populations. The 11-gene host blood transcriptomic RNA signature has been shown to accurately diagnose and predict TB in case-control studies in adults. This study will evaluate the performance of the RNA signature, a proteomic risk signature, and a T-cell Antigen-Specific Activation assay for the diagnosis and prognosis of TB in children who have household exposure to TB. The study commenced during Quarter 3 of 2019 and aims to enrol 490 participants.

Principal Investigator: Justin ShenjeFunders: NIH

TRANSMISSION OF TUBERCULOSIS IN HIGH SCHOOL STUDENTS IN WORCESTER, SOUTH AFRICA

This project examined the epidemiological burden of tuberculosis (TB) among adolescents in a high TB burden community in South Africa (Worcester) over the decade 2005–2015 to determine epidemiological trends and impact of TB control efforts. Overall adolescent LTBI prevalence remained high and relatively unchanged (44–49%) between 2005–2015. However, adolescent TB disease notification rates fell 45% (662 to 361 per 100,000) in the same community over the same period. Despite this decrease, TB disease prevalence remains high and is three–fold higher in older (15–19 years) than younger (10–14 years) adolescents (566 vs. 151 per 100,000 in 2015), consistent with ongoing medium–term transmission.

Principal Investigator: Mark Hatherill, Erick Bunyasi (PhD student)Funder: Stanford University (PI Andrews)

SELECTION OF IMMUNOLOGY STUDIES

COLONISATION OR INFECTION WITH RESPIRATORY VIRUSES IS ASSOCIATED WITH ELEVATED TUBERCULOSIS TRANSCRIPTOMIC SIGNATURE OF RISK SCORES

A blood-based test that can accurately discriminate between TB disease and other diseases, in addition to predicting who will develop TB disease after M. tuberculosis-infection is needed to identify those who need treatment. As mentioned earlier, we discovered and validated an 11-gene transcriptomic signature of TB risk (RISK11), based on mRNA expression of 11 IFN stimulated genes (ISG). RISK11 prospectively differentiates between incident TB cases and

Principal Investigator: Mark Hatherill and Thomas ScribaProject Scientist: Humphrey MulengaFunder: National Research Foundation (NRF), NIH


healthy controls up to a year before disease diagnosis. However, little is known about the effects of respiratory pathogens, such as viral or bacterial infections, on the RISK11 score.

The aim of this project was to identify respiratory pathogens other than M. tuberculosis that are associated with high RISK11 scores and to test whether RISK11 differentiates between individuals with and without respiratory pathogens.

In collaboration with the Division of Medical Microbiology at UCT, we collected 1000 nasopharyngeal and 1000 oropharyngeal samples from HIV-uninfected, asymptomatic participants of a cross-sectional study nested in the Correlate of Risk Targeted Intervention Study (CORTIS). Samples were tested using multiplex real-time PCR to detect 33 pathogens including bacteria, viruses and fungi.

Participants with viral colonization or infection in the upper respiratory tract had significantly elevated RISK11 scores, suggesting induction of interferon responses that are detectable in peripheral blood. Infection or colonization with respiratory viruses is likely to result in false positive results for RISK11 and other transcriptomic signatures of tuberculosis based on ISGs.

DISCOVERY OF PROTECTIVE M. TUBERCULOSIS -SPECIFIC T-CELL RESPONSES THROUGH T CELL RECEPTOR REPERTOIRE PROFILING

T-cells are an essential component of the adaptive immune system, which detects and defends against infection and disease. M. tuberculosis-specific T-cells can recognize

Principal Investigator: Thomas ScribaProject Scientist: Munyaradzi MusvosviFunder: BMGF

bacterial protein fragments using a diverse set of cell surface receptors known as T-cell receptors (TCR). When a M. tuberculosis-specific T-cell recognizes such bacterial protein fragments, it becomes activated and clonally expands to produce thousands of identical copies of itself, so that an army of T-cells that can identify M. tuberculosis can fight the infection. This project aimed to discover the array of TCR’s used by M. tuberculosis-specific T-cells from individuals who either successfully control their M. tuberculosis infection (controls) or those who progress to TB disease (progressors). Together with Mark Davis, Huang Huang and colleagues at Stanford University, we isolated and sequenced thousands of individual T-cells and compared their abundance in progressors and controls.

Multiple different groups of related TCR’s that were associated with individuals who successfully controlled their infection and may thus be “protective” T-cells, were identified. We also identified multiple groups of related TCR’s that were associated with individuals who progressed to TB disease, which we consider “ineffective” T-cells. We are now conducting experiments to determine if these associations are reproducible in an independent group of controls and progressors. In addition, we are identifying the protein fragments (bacterial targets) that these TCR’s recognize. Incorporation of the bacterial targets recognized by “protective” TCR’s into new TB vaccine candidates may improve their potential to protect against TB.


A HOST BIOMARKER FOR RECENT M. TUBERCULOSIS INFECTION

Enhanced control of TB requires better implementation of preventative TB therapy provision to individuals who are at high risk of developing TB. Recent M. tuberculosis infection is associated with a high risk of disease progression. This risk drops markedly in those with remote infection that occurred more than 2-3 years ago. Identifying the high-risk individuals with recent infection is challenging because current immunodiagnostic tools fail to distinguish these infection states.

In this project we measured activation, memory and functional kinetics of M. tuberculosis-specific CD4 T cells in a longitudinal adolescent cohort of recent QuantiFERON (QFT) converters, who had no evidence of M. tuberculosis-sensitisation at baseline (before infection). Persistent QFT-positive individuals were studied as a comparator group. We identified CD4 T cell activation as a promising biomarker of recent M. tuberculosis infection. This biomarker has previously been shown to identify individuals with active TB disease by Adekambi et al., Riou et al., and others, and thus appears to identify individuals with active M. tuberculosis replication, who could benefit from preventative TB therapy.

We are currently performing replication experiments to determine the diagnostic accuracy of this biomarker for identifying individuals with recent infection.

Principal Investigator: Elisa NemesProject Scientist: Cheleka MpandeFunder: NIH


DOES BCG VACCINATION ACTIVATE AND EXPAND DONOR UNRESTRICTED T CELL RESPONSES?

Vaccination with BCG has been part of the global vaccination programme for almost 50 years. However, BCG does not consistently and sufficiently protect against pulmonary TB, especially in adolescents and adults, who are thought to be important drivers of M. tuberculosis transmission. Better TB vaccines are thus urgently required. However, rational vaccine development is constrained by limited understanding of immunological protection against M. tuberculosis.

Most current TB vaccine strategies aim to induce MHC-restricted CD4 or CD8 T-cell responses to mycobacterial peptide antigens. A different class T cell subsets, the so-called “donor unrestricted T” (DURT) cells, which recognize non-peptidic antigens presented by non-polymorphic antigen presenting molecules, have not been extensively evaluated in humans. DURT cells include MR1-reactive MAIT cells, CD1b-reactive GEM T cells, HLA-E-reactive CD8 T cells, CD1d-reactive NKT cells, and γδ T cells.

We aimed to determine the extent to which DURTs expand in number after vaccination and whether such expansions are durable such that they might be considered part of immunological memory. This project was conducted in collaboration with the larger DURT working group of the Collaboration for TB Vaccine Discovery (CTVD).

We measured frequencies and activation profiles of MAIT cells, GEM T cells, NKT cells and γδ T cells in infants who

Principal Investigator: Thomas ScribaProject Scientist: Anele GelaFunder: IAVI

received BCG or not, and before and after BCG vaccination in adults.

Our results indicate that BCG administration did not significantly modulate frequencies or activation profiles of

these DURT cell subsets. Our findings do not preclude the role of BCG vaccination in shaping the qualitative aspects of these cells, including their functional capacity and/or TCR repertoire.


MODULATION OF NK RESPONSES BY BCG VACCINATION

BCG vaccination confers protection against severe forms of TB in infants but efficacy against pulmonary TB is variable. The lack of known immune correlates of protection against TB is a major obstacle to designing more efficacious vaccines. Infant BCG vaccination induces MHC-restricted CD4 and CD8 T cells and these have been extensively studied. However, immune responses beyond these classical T cells, including natural killer (NK) cells, require more investigation. BCG has been shown to induce epigenetic reprogramming of innate cells such as monocytes. This reprogramming is termed trained immunity and can lead to higher production of proinflammatory cytokines and increased antimicrobial activity. Recent studies suggest that NK cells can also be epigenetically reprogrammed and contribute to control of unrelated infections. However, evidence that NK cells may be directly ‘trained’ by BCG is scarce and contradictory.

We sought to investigate whether neonatal BCG vaccination modulates NK responses to mycobacteria and to identify the underlying mechanisms. We analysed samples from an infant cohort in which BCG vaccination was either administered at birth or delayed to 5 or 9 weeks of age. Analysis of samples collected prior to delayed BCG

Principal Investigators: Elisa Nemes and Thomas Scriba Project Scientist: Melissa Murphy Funder: NIH

administration allowed a cross-sectional comparison between age-matched BCG-vaccinated and unvaccinated infants. Whole blood from infants was stimulated with BCG and the phenotype and function of NK cell subsets measured by flow cytometry. In addition, secreted cytokines associated with trained immunity were measured in culture supernatants. Our results suggest that BCG vaccination leads to significant increases in frequencies of IFNγ expressing NK cells, which may result from epigenetic reprogramming. In follow-up experiments, we are now performing assays to detect BCG-induced epigenetic modifications in infant NK cells. We expect that this study will reveal that NK cell function can be modulated by whole cell vaccination. If these effects are sufficiently long-lived, NK cells should be investigated as novel targets for TB vaccine candidates.

RISK6, A 6-GENE TRANSCRIPTOMIC SIGNATURE OF TUBERCULOSIS RISK

Non-sputum-based tests that predict progression from M. tuberculosis infection to clinical disease or that can detect individuals with undiagnosed disease are urgently needed. With the application of sophisticated blood transcriptional profiling technologies, bioinformatics and systems biology approaches, substantial progress in the discovery and

Principal Investigator: Thomas Scriba Project Scientists: Stanley M. Kimbung, Simon MendelsohnFunders: BMGF, CRDF GLOBAL

validation of concise transcriptomic signatures has been made in the last decade. Such transcriptomic signatures show potential for integration into accurate, rapid diagnostic devices for use at the point of care.

As part of a long-standing collaboration with Dan Zak’s team, formerly at the Centre for Infectious Disease Research, we sought to develop a concise transcriptomic signature of TB risk. We studied whole blood samples from adolescents who were followed over a two-year period and either developed TB (progressors) or who remained infected with M. tuberculosis but did not develop disease (non-progressors). We identified 86 differentially expressed mRNA junctions from genome-wide RNA expression profiles and compared relative abundance of all possible junction pairs in any combination of upregulated and downregulated mRNAs when measured by RT-qPCR. An optimal set of 6 mRNA transcripts (the RISK6 signature) were found to best discriminate between progressors and non-progressors.

We have completed blind validation studies of RISK6 performance in 7 independent cohorts across the world, drawn from Brazil, South Africa, Gambia and Peru. The results demonstrate that RISK6 is a robust and simple PCR-based test for multiple applications, including identification of individuals at risk of incident disease, as a screening test for subclinical or clinical TB, and for monitoring TB treatment. The performance of RISK6, along with 5 published, concise transcriptomic signatures, is currently also being assessed in the CORTIS and CORTIS-HR studies. Results are expected in the second quarter of 2020.


research outputs1. Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis. Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, Van Brakel E, Salaun B, Scriba TJ, Akite EJ, Ayles HM, Bollaerts A, Demoitié MA, Diacon A, Evans TG, Gillard P, Hellström E, Innes JC, Lempicki M, Malahleha M, Martinson N, Mesia Vela D, Muyoyeta M, Nduba V, Pascal TG, Tameris M, Thienemann F, Wilkinson RJ, Roman F. New England Journal of Medicine, 381(25):2429-2439.

2. Moving tuberculosis vaccines from theory to practice. Andersen P, Scriba TJ. Nature Reviews Immunology, 19(9):550-562.

3. Protection against tuberculosis by mucosal BCG administration. Scriba TJ, Nemes E. Nature Medicine, 25(2):199-201.

4. Paediatric tuberculosis transmission outside the household: challenging historical paradigms to inform future public health strategies. Martinez L, Lo NC, Cords O, Hill PC, Khan P, Hatherill M, Mandalakas A, Kay A, Croda J, Horsburgh CR, Zar HJ, Andrews JR. Lancet Respiratory Medicine, 7(6):544-552.

5. Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial. Tameris M, Mearns H, Penn-Nicholson A, Gregg Y, Bilek N, Mabwe S, Geldenhuys H, Shenje J, Luabeya AKK, Murillo I, Doce J, Aguilo N, Marinova D, Puentes E, Rodríguez E, Gonzalo-Asensio J, Fritzell B, Thole J, Martin C, Scriba TJ, Hatherill M; MTBVAC Clinical Trial Team. Lancet Respiratory Medicine, 7(9):757-770.

6. Advances in the understanding of Mycobacterium tuberculosis transmission in HIV-endemic settings. Peters JS, Andrews JR, Hatherill M, Hermans S, Martinez L, Schurr E, van der Heijden Y, Wood R, Rustomjee R, Kana BD. Lancet Infectious Diseases, 19(3): e65-e76.

7. Tuberculosis Vaccine Development: Progress in Clinical Evaluation. Sable SB, Posey, JE Scriba TJ. Clinical Microbiology Review, 18;33(1):e00100-19.

8. Discovery and validation of a prognostic proteomic signature for tuberculosis progression: A prospective cohort study. Penn-Nicholson A, Hraha T, Thompson EG, Sterling D, Mbandi SK, Wall KM, Fisher M, Suliman S, Shankar S, Hanekom WA,

Janjic N, Hatherill M, Kaufmann SHE, Sutherland J, Walzl G, De Groote MA, Ochsner U, Zak DE, Scriba TJ; ACS and GC6–74 cohort study groups. PLoS Medicine, 16;16(4).

9. Safety and Immunogenicity of Early Bacillus Calmette-Guérin Vaccination in infants who are Preterm and/or have low birth weights: A Systematic Review and Meta-analysis. Badurdeen S, Marshall A, Daish H, Hatherill M, Berkley JA. JAMA Pediatrics, 1;173(1):75-85.

10. Dose Optimization of H56:IC31 Vaccine for Tuberculosis-Endemic Populations. A Double-Blind, placebo-controlled, Dose-Selection Trial. Suliman S, Luabeya AKK, Geldenhuys H, Tameris M, Hoff ST, Shi Z, Tait D, Kromann I, Ruhwald M, Rutkowski KT, Shepherd B, Hokey D, Ginsberg AM, Hanekom WA, Andersen P, Scriba TJ, Hatherill M; H56-035 Trial Group. American Journal Respiratory and Critical Care Medicine, 199(2):220-231.

11. Addressing critical needs in the fight to end tuberculosis with innovative tools and strategies. Hatherill M, Chaisson RE, Denkinger CM. PLoS Medicine, 16(4):e1002795.


12. Select sequencing of clonally expanded CD8+ T cells reveals limits to clonal expansion. Huang H, Sikora MJ, Islam S, Chowdhury RR, Chien YH, Scriba TJ, Davis MM, Steinmetz LM. Proceedings of the National Academy of Sciences of the USA, 30;116(18):8995-9001.

13. Diagnostic Accuracy of Early Secretory Antigenic Target-6-Free Interferon-gamma Release Assay Compared to QuantiFERON-TB Gold In-tube. Nemes, E., Abrahams D, Scriba TJ, Ratangee F, Keyser A, Makhethe L, Erasmus M, Mabwe S, Bilek N, Rozot V, Geldenhuys H, Hatherill M, Lempicki MD, Holm LL, Bogardus L, Ginsberg AM, Blauenfeldt T, Smith B, Ellis RD, Loxton AG, Walzl G, Andersen P, Ruhwald M. Clinical Infectious Diseases, 69(10):1724-1730.

14. Batf2 differentially regulates tissue immunopathology in Type 1 and Type 2 diseases.Guler R, Mpotje T, Ozturk M, Nono JK, Parihar SP, Chia JE, Abdel Aziz N, Hlaka L, Kumar S, Roy S, Penn-Nicholson A, Hanekom WA, Zak DE, Scriba TJ, Suzuki H, Brombacher F. Mucosal Immunology, 12(2):390-402.

15. FDG-PET/CT as a no-invasive biomarker for assessing adequacy of treatment and predicting relapse in patients treated for pulmonary tuberculosis. Lawal I, Fourie B, Mathebula M, Moagi I, Lengana T, Moeketsi N, Nchabeleng M, Hatherill M, Sathekge M. Journal of Nuclear Medicine, pii: jnumed.119.233783.

16. A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates. Rodo MJ, Rozot V, Nemes E, Dintwe O, Hatherill M, Little F, Scriba TJ. PLoS Pathogens, 4: 15(3).

17. Cytomegalovirus infection is a risk factor for TB disease in Infants.Müller J, Tanner R, Matsumiya M, Snowden MA, Landry B, Satti I, Harris SA, O’Shea MK, Stockdale L,Marsay L, Chomka A, Harrington-Kandt R, Manjaly Thomas ZR, Stylianou E, Naranbhai V, Mbandi SK, Hatherill M, Hussey G, Mahomed H, Tameris M, McClain JB, Hanekom WA, Evans TG, Scriba TJ, McShane H, Fletcher HA. Journal of Clinical Investigation Insight, 4(23).

18. Targeting innate immunity for tuberculosis vaccination. Khader SA, Divangahi M, Hanekom W, Hill PC, Maeurer M, Makar KW, Mayer-Barber KD, Mhlanga MM, Nemes E, Schlesinger LS, van Crevel R, Vankalayapati R, Xavier RJ, Netea MG; Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group 18.Journal of Clinical Investigation, 129(9):3482-3491.

19. MR1-Independent Activation of Human Mucosal-Associated Invariant T Cells by Mycobacteria. Suliman S, Murphy M, Musvosvi M, Gela A, Meermeier EW, Geldenhuys H, Hopley C, Toefy A, Bilek N, Veldsman A, Hanekom WA, Johnson JL, Boom WH, Obermoser G, Huang H, Hatherill M, Lewinsohn DM, Nemes E, Scriba TJ. Journal of Immunology, (11):2917-2927.

20. Plasma Type I IFN Protein Concentrations in Human Tuberculosis. Llibre A, Bilek N, Bondet V, Darboe F, Mbandi SK, Penn-Nicholson A, Hatherill M, Rozenberg F, Scriba TJ, Duffy D. Frontiers in Cellular Infection Microbiology, 22;9:296.

21. Immunometabolic signatures predict risk of progression to active Tuberculosis and disease outcome. Duffy FJ, Weiner J 3rd, Hansen S, Tabb DL, Suliman S, Thompson E, Maertzdorf J, Shankar S, Tromp G, Parida S, Dover D, Axthelm MK, Sutherland JS, Dockrell HM, Ottenhoff THM, Scriba TJ, Picker LJ, Walzl G, Kaufmann SHE, Zak DE; GC6-74 Consortium. Frontiers Immunology, 22;10:527.

22. HIV infection is associated with downregulation of BLTA expression on Mycobacterium tuberculosis-specific CD4 T cells in active Tuberculosis disease. Barham MS, Abrahams DA, Khayumbi J, Ongalo J, Tonui J, Campbell A, de Kock M, Ouma SG, Odhiambo FH, Hanekom WA, Gandhi NR, Day CL.Frontiers Immunology, 10:1983.

23. A Population Pharmacokinetic Analysis Shows that Arylacetamide Deacetylase (AADAC) Gene Polymorphism and HIV Infection Affect the Exposure of Rifapentine. Francis J, Zvada SP, Denti P, Hatherill M, Charalambous S, Mungofa S, Dawson R, Dorman S, Gupte N, Wiesner L, Jindani A, Harrison TS, Olagunju A, Egan D, Owen A, McIlleron HM. Antimicrobial Agents and Chemotherapy, 27;63(4). pii: e01964-18.


24. Non-invasive Detection of Tuberculosis by Oral Swab Analysis.Luabeya AK, Wood RC, Shenje J, Filander E, Ontong C, Mabwe S, Africa H, Nguyen FK, Olson A, Weigel KM, Jones-Engel L, Hatherill M, Cangelosi GA. Journal of Clinical Microbiology, 57(3).

25. A prospective study of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected children from high prevalence countries.Cotton MF, Rabie H, Nemes E, Mujuru H, Bobat R, Njau B, et al. (2019) A prospective study of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected children from high prevalence countries. PLoS One, 14(7):e0211155.

26. Multinomial modelling of TB/HIV co-infection yields a robust predictive signature and generates hypotheses about the HIV+TB+ disease state. Duffy FJ, Thompson EG, Scriba TJ, Zak DE. PLoS One, 14(7): e0219322.

27. Toll-like receptor chaperone HSP90B1 and the immune response to Mycobacteria. Graustein AD, Misch EA, Musvosvi M, Shey M, Shah JA, Seshadri C, Aguoju A, Bowman K, Mulenga H, Veldsman A, Hanekom WA, Hatherill M, Scriba TJ, Hawn TR. PLoS One, 13(12): e0208940.

28. Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy. Darboe F, Mbandi SK, Naidoo K, Yende-Zuma N, Lewis L, Thompson EG, Duffy FJ, Fisher M, Filander E, van Rooyen M, Bilek N, Mabwe S, McKinnon LR, Chegou N, Loxton A, Walzl G, Tromp G, Padayatchi N, Govender D, Hatherill M, Karim SA, Zak DE, Penn-Nicholson A, Scriba TJ, SATVI Clinical Immunology Team. Frontiers in Microbiology, 26;10:1441.

29. The effect of antiretroviral treatment on selected genes in whole blood from HIV-infected adults sensitised by Mycobacterium tuberculosis. Jhilmeet N, Lowe DM, Riou C, Scriba TJ, Coussens A, Goliath R, Wilkinson RJ, Wilkinson KA. PLoS One, 13(12): e0209516.

30. Performance of host blood transcriptomic signatures for diagnosing and predicting progression to tuberculosis disease in HIV-negative adults and adolescents: a systematic review protocol. Mulenga H, Bunyasi EW, Mbandi SK, Mendelsohn SC, Kagina B, Penn-Nicholson A, Scriba T, Hatherill M. British Medical Journal Open, 9(5): e026612.

31. Potential population level impact on tuberculosis incidence of using an mRNA expression signature correlate-of-risk test to target tuberculosis preventive therapy. Sumner T, Scriba TJ, Penn-Nicholson A, Hatherill M, White RG.Scientific Reports, 9(1):11126.

32. Beyond memory T cells: mechanisms of protective immunity to tuberculosis infection.Steigler P, Verrall AJ, Kirman JR.Immunology and Cell Biology, 97(7):647-655.

33. Temporal trends in the prevalence of Mycobacterium tuberculosis infection in South African adolescents. Bunyasi EW, Geldenhuys H, Mulenga H, Shenje J, Luabeya AKK, Tameris M, Nemes E, Mahomed H, Rozot V, Wood R, Scriba T, Andrews JR, Hatherill M.International Journal of Tuberculosis Lung Diseases, 23(5):571-578.

34. Preferred product characteristics for therapeutic vaccines to improve tuberculosis treatment outcomes: Key considerations from World Health Organization. Vekemansa J, Brennan MJ, Hatherill M, Schragera L, Fritzelld B, Rutkowskie K, De Vosd B, Zignola M, Thiryd G, Ginsberge AM, Walker B. Vaccine, (19)31461-6, doi: 10.1016/j.vaccine.2019.10.072.


35. Feasibility of Identifying Household Contacts of Rifampin- and Multidrug-resistant Tuberculosis Cases at High Risk of Progression to Tuberculosis Disease.Gupta A, Swindells S, Kim S, Hughes MD, Naini L, Wu X, Dawson R, Mave V, Sanchez J, Mendoza A, Gonzales P, Kumarasamy N, Comins K, Conradie F, Shenje J, Fontain SN, Garcia-Prats A, Asmelash A, Nedsuwan S, Mohapi L, Lalloo UG, Ferreira ACG, Mugah C, Harrington M, Jones L, Cox S, Smith B, Shah NS, Hesseling AC, Churchyard G, ACTG 5300/IMPAACT I2003 PHOENIx Feasibility study team.Clinical Infectious Diseases, ciz235. doi: 10.1093/cid/ciz235.

36. Willingness to Take Multidrug-Resistant Tuberculosis (MDR-TB) Preventive Therapy among Adult and Adolescent Household Contacts of MDR-TB Index Cases: An International Multi-Site Cross-Sectional Study.Suryavanshi N, Murrill M, Gupta A, Hughes M, Hesseling A, Kim S, Naini L, Jones L, Smith B, Gupte N, Dawson R, Mave V, Meshram S, Mendoza-Ticona A Sanchez J, Kumarasamy N11, Comins K, Conradie F, Shenje J, Nerette Fontain S, Garcia-Prats A, Asmelash A16, Nedsuwan S, Mohapi L, Lalloo U, Ferreira ACG, Okeyo E, Swindells S, Churchyard G Shah NS; A5300/I2003 Study Team.Clinical Infectious Diseases, ciz254. doi: 10.1093/cid/ciz254.

Chapters in book:

Between representing and intervening: Diagnosing childhood tuberculosis during a vaccine trial in South Africa.Dixon J, Tameris M. 2019. In Macdonald, H., Harper, I (ed), Understanding tuberculosis and its control, First edition. Routledge Press, Oxon & New York.


awards, honours & accreditations

Elisa Nemes was promoted ad hominem to Associate Professor.

Dr Michèle Tameris was promoted to Senior Clinical Researcher.

Dr Angelique Luabeya was promoted to Senior Clinical Researcher and awarded a rating from the South African Research Foundation.

SATVI was awarded the 2018 UCT Vice Chancellor’s Social Responsiveness Award for a series of community engagement and TB awareness projects in the Worcester community.

OTHER

SATVI colleagues who have been appointed to ACTG committees have included Dr Justin Shenje (Protocol Development and Implementation Subcommittee (PDISC), Dr Chris Hikuam (Site Management and Clinical Care Committee (SMCCC), Marcia Steyn (Laboratory Technologist), Thelma Leopeng (Site Operations Subcommittee (SOS), Ashly Veldsman (Site Operations Subcommittee (SOS),


postgraduate students & postdoctoral fellows

KEYSTONE SYMPOSIUM UCT VACCINOLOGY STUDENTS

Cheleka Mpande featured in a Keystone Symposium video in which she explained the paper titled “Functional, antigen-specific stem cell memory (TSCM) CD4+ T cells are induced by human M. tuberculosis infection”.

During April SATVI hosted postgraduate students enrolled for the vaccinology module of the BSc Honours degree in Infectious Disease and Immunology at UCT.

POSTDOCTORAL FELLOWSDr Anele GelaDr Agano KiravuDr Claire ImbrattaDr Munyaradzi Musvosvi

PHD STUDENTSDr Eric BunyaseCarli YoungCheleka MpandeHumphrey MulengaMelissa MurphyMiguel RodoDr Pia SteiglerRichard BagumaDr Simon Mendelsohn

MASTERS STUDENTSDango MwambeneTessa Lloyid


our staffSAD NEWS GRADUATIONS WOMEN’S DAY

Rose Ockhuis Dr Chris Hikuam

SATVI marked Women’s Day by joining the “Doek on Fleek Lifestyle Women’s Day”.

During 2019 the SATVI family tragically lost two clinical research workers, Rose Ockhuis and Bongiwe Vazana, from the team.

Dr Chris Hikuam graduated with a Postgraduate Diploma in Management Practice from UCT.Thelma Leopeng, Clinical Assurance Specialist graduated with a Masters degree (distinction) in Clinical Research Administration from UCT.

Bongiwe Vasana

Thelma Leopeng


SATVI TEAMBUILDING, SEPTEMBER 2019

Staff team Brown

Staff team Red

Staff team Blue

Staff team Orange

Staff team Green

Staff team Black

Staff team Pink

Staff team Purple

Staff team Yellow


our community2018 VICE-CHANCELLOR SOCIAL RESPONSIVENESS AWARD

SATVI was presented with the UCT 2018 Vice Chancellor So-cial Responsiveness Award at the Faculty of Health Sciences graduation ceremony during April 2019.

The award was made in recognition of the role which SATVI has played, since its establishment in 2001, in engaging communities of the Cape Winelands through a portfolio of social responsiveness programmes, which aim to develop and advance TB prevention strategies by ensuring that communities are aware of TB and related health issues, and that they are empowered to take ownership of the problems and the solutions.

This role is managed by an active community engagement team under the leadership of Dr Michèle Tameris, communications manager Kelvin Vollenhoven and field site manager Marwou de Kock, drawing on the depth and breadth of expertise among SATVI staff, and the broader University community programs at Worcester and Cape Town.

Highlights of SATVI’s social responsiveness initiatives include two Wellcome Trust-funded drama productions, Carina’s Choice (Karina se Keuse) and Lienkie’s Lungs (Lienkie se

Longe); the Kick TB Schools Programme; and the “TB Under the Spotlight” Science Engagement initiative.

RESEARCH NIGHT, NETWORK FOR ITALIAN RESEARCHERS, CAPE TOWNAssociate Professor Elisa Nemes, presented a talk at a research night organised by the Network for Italian researchers in the Cape during September 2019.

SCHOOLS VISIT TO IDM, CAPE TOWN (IDM) During September 2019, Dr Michelle Fisher presented a workshop session on the work that SATVI does, to 93 senior secondary learners participating in the IDM School Outreach Program.

SOAPBOX SCIENCE, CAPE TOWNAssociate Professor Elisa Nemes participated in organising the first ever South African leg of Soapbox Science. This program, which is a novel public engagement

for promoting women scientists and their science, took place at the Victoria Alfred Waterfront, Cape Town during September 2019.

WORLD TB DAY THREE PEAKS CHALLENGE, CAPE TOWN

Cape TownFor World TB Day 2019 the SATVI team organised an endurance hike on Saturday 24 March 2019 involving ascending and descending “The Three Peaks”, Devil’s Peak, Table Mountain via Platteklip Gorge and Lions Head, all in one day. The event, which was organised to raise awareness about TB, also raised R 3200 which was donated to Ikamva Lethu, a Worcester-based community-based food security organisation.


TB Science Engage-ment on World TB DaySATVI partnered with the Western Cape Department Education and Stellenbosch University in hosting the TB under the Spotlight at Somerset High School, Worcester and reached 180 learners.

Table Mountain peak walkers

Devils Peak

Platteklip Gorge

Professor Tom Scriba with members of Ikamva Lethu

World TB Day Social Media Campaign

“World TB Day 2029: TB Science Engagement facilitators and learners of Somerset High School, Worcester.

TB EDUCATIONAL TALKSDuring 2019 SATVI has facilitated several TB educational talks which have included:• Worcester Toevlug Rehabilitation Centre; a series of

monthly awareness workshops with adolescent patients in their substance abuse rehabilitation program.

• National Institute of the Deaf; a workshop with youth trainees at the National Institute of the Deaf.

• TB awareness program at De Doorns Clinic. • Various TB talk including the SANTA Western Cape

Annual General SATVI’s Meeting, South African Health Technology Advocacy Committee and at staff wellness programs of employers. COMMUNITY ADVISORY BOARD

The CAB was active in 2019, meeting regularly during the year and participating in a training program for new CAB members in August 2019.

The CAB participated in the annual ACTG meeting, with CAB chairperson, Belinda Ameterra invited to a HIV/AIDS Networking Coordinating (HANC) meeting and CAB member Hilda Fredricks elected to the ACTG Community Scientific Subcommittee.


funders


collaborators


South African Tuberculosis Vaccine Initiative (SATVI)

Institute of Infectious Disease and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town Werner and Beit - South Building, Anzio Road, Observatory, 7925

T: +27 21-406 6791 / +27 21 406 6014 / +27 21 406 603

www.satvi.uct.ac.za www.facebook.com/satviuct

CREDITSPhotos: Sydelle Willow-Smith, Matt Feldman, Mike Hammond, Fabio Julies, Jihaan Opperman, Kelvin VollenhovenDTP: Samantha Mouton

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ANNUAL REPORT 2019 - satvi.uct.ac.za · from UCT with an MBChB degree in 1980. She worked for many years in the public health sector in Cape Town and in Worcester. In 2003 she joined