Terms of Reference

The Working Group will be requested to review the scientific evidence and relevant programmatic considerations to formulate proposed recommendations on the use of BCG vaccines for consideration by SAGE to inform a revision of the global policy on the use of BCG, and for subsequent updating of the WHO Position Paper on BCG and related materials.

Specifically the Working Group (WG) will be asked to review the following elements:

1. country practices in the use of BCG including that of targeted vaccination in low TB prevalence countries as well as the threshold applied to decide on stopping vaccination;
2. TB epidemiology as well as the epidemiology of leprosy;
3. trends in antibiotic resistance and their implications for BCG use;
4. the safety and effectiveness of BCG (in a strain specific analysis) in different age groups and according to HIV status and for different outcomes (i.e. death, pulmonary disease and infection);
5. assessment of the duration of protection and need for revaccination (including a comparison of the effect of revaccination with that of alternative protective approaches e.g. isoniazid preventive therapy);
6. the effect of BCG co-administration with other vaccines administered at birth (OPV, hepatitis B) or later (e.g. co-administration with DTP containing and specifically pentavalent vaccine);
7. the economic burden of TB and cost-effectiveness of vaccination as well as modelling data to inform BCG vaccination strategies (including vaccination in the context of other control strategies);
8. the potential role of BCG in the control of leprosy.

In addition the WG will be briefed for their information on the TB vaccine candidates’ development status, including BCG improvement strategies that may have implications for beneficial non-specific vaccine effects of the current BCG.

The vaccine has several non-specific effects (NSE) which should be discussed, but which should not be the immediate focus of the Working Group since this issue of NSE is being addressed by the Immunization and Vaccines-Related Implementation Research Advisory Committee (IVIR-AC).

Composition

SAGE Members

• Charles Shey Wiysonge: South African Medical Research Council, South Africa (Chair of the Working Group)
• Kari Johansen: European Centre for Disease Prevention and Control, Sweden

Experts

• Safaa Al-Khawaja: Ministry of Health, Bahrain
• Pamela Bakkabulindi: Ministry of Health, Uganda
• Sang Nae Cho: Yonsei University College of Medicine, South Korea
• Nigel Curtis: University of Melbourne, Australia
• Mark Hatherill: University of Cape Town, South Africa
• Guangxue He: Chinese Center for Disease Control and Prevention, China
• Helen McShane: University of Oxford, England
• Elizabeth Obimbo: University of Nairobi, Kenya
• Jeffrey Starke: Baylor College of Medicine, USA

WHO Secretariat

• Philippe Duclos
• Malin Finkernagel

Declaration of interests

Four members reported relevant interests. All interests were assessed to not constitute a conflict of interest. It was concluded that all members could take part in full in all of the discussions. The reported relevant interests are summarized below:

Helen McShane

• Her research institution1 receives a grant from the US National Institutes of Health (NIH) for the characterization of mycobacterial induced immunity in HIV-infected and uninfected individuals (2016-2019).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 currently receives a grant from the Biotechnology and Biological Sciences Research Council for a reverse vaccinology approach to a bTB vaccine (2015-2019).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 currently receives 2 grants from the Bill & Melinda Gates Foundation for an experimental medicine study to assess feasibility of pulmonary administration of BCG for vaccination and human challenge models (2015-2018). The second grant is for research on the heterologous effects of BCG (2014-2016).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 currently receives a grant from the National Centre for the Replacement, Refinement and Reduction of Animals in Research for the developing and validating an in-vitro mycobacterial challenge model to facilitate TB vaccine research and minimize in-vivo challenge experiments (2015-2018).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 currently receives a grant from the Tuberculosis Vaccine Initiative (TBVI) for a phase I trial to compare the safety and immunogenicity in M.tb infected adult subjects of MVA85A vaccination given by the aerosolized and intramuscular route (2015-2017).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 currently receives a grant from Medical Research Council Confidence in Concept (MRC CiC)/ Liverpool School of Tropical Medicine (LSTM) for the evaluation of new antigens for subunit vaccines against Mycobacterium tuberculosis (2015-2016).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 currently receives a grant from The EU Framework Programme for Research and Innovation Horizon 2020 (EC H2020) on TBVAC2020 for the vaccine development for poverty-related and neglected infectious diseases (2015-2019).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 currently receives a grant from Tuberculosis Vaccine Initiative (TBVI)/ Norwegian Agency for Development Cooperation (NORAD) for the preclinical clinical development of new promising TB vaccine candidates (2015-2016).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 currently receives a grant from Aeras for the investigation of mycobacterial growth inhibition assays (MGIA) in TB animal models (2014-2016).
  This interest was assessed as non-personal, non-specific and financially significant*.
• Her research institution1 received two grants from Aeras for a BCG challenge trial (2013-2015) and for a mycobacterial assay for growth inhibition (2010-2013).
  This interest was assessed as non-personal, non-specific and financially significant*.
• Her research institution1 received a grant from by Aeras/FDA for a novel approach for identifying biological and immunological biomarkers for TB vaccines (2010-2013).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 currently receives a grant from European Research Infrastructures for Poverty Related Diseases (EURIPRED FP7) for the analysis of the European Research Infrastructures for Poverty Related Diseases (2015-2019).
  This interest was assessed as non-personal, non-specific and financially significant*.
• Her research institution1 currently receives a grant from Wellcome Trust for a clinical Research Fellowship on the evaluation of innovative TB vaccination strategies in preclinical and clinical models (2011-2016).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 received a grant from Wellcome Trust for a Phase IIb proof-of-concept efficacy trial with MVA85A in infants in South Africa (Strategic Award) (2008-2014).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 received a grant from TBVI/NORAD for research of Biomarkers (2013-2015).
  This interest was assessed as non-personal, non-specific and financially significant*.
• Her research institution1 received 2 grants from The European & Developing Countries Clinical Trials Partnership (EDCTP), for the collaboration and integration of tuberculosis vaccine trials in Europe & Africa (TBTEA) (2011-2013) and for a proof-of-concept study on a phase IIb clinical trial to evaluate the protective efficacy of a booster MVA85A vaccination administered to healthy, HIV-infected adults in South Africa, Senegal and the Gambia (2009-2014).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 received a grant from the discovery and preclinical development of new generation tuberculosis vaccines (NEWTBVAC 2,EU 7th Framework) in the framework of an EU TB Consortium on the discovery and preclinical development of new generation tuberculosis vaccines (2010-2014).
  This interest was assessed as non-personal, specific and financially significant*.
• Her research institution1 received a grant from the European Network of Vaccine Research and Development (TRANSVAC,EU 7th Framework) with a grant on EU Vaccine Consortium: European network of vaccine research and development (2009-2013).
  This interest was assessed as non-personal, specific and financially significant*.

Mark Hatherill

• Mark Hatherill reported that he was reimbursed as a consultant for his work on the Advisory Board on therapeutic tuberculosis vaccines of GSK in 2014.
  This interest was assessed as personal, specific and financially significant*.
• His research institution2 currently receives 3 grants from the Bill & Melinda Gates Foundation for the validation of correlates of risk of TB disease in high risk populations (2016-2019), for a clinical trial on a correlate of risk targeted screen and treat strategy to impact TB control (2015-2019) and for a project entitled, “Systems Immunology Consortium: Systems Biology” (2013-2016).
  This interest was assessed as non-personal, specific and financially significant*.
• His research institution2 received a grant from the Bill & Melinda Gates Foundation for a project on the planning for a risk-targeted intervention to reduce TB transmission (2014-2015).
  This interest was assessed as non-personal, specific and financially significant*.
• His research institution2 currently receives a grant from the National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS (DAIDS) / Medical Research Council of South Africa (SA MRC) for the analysis of the advancement of TB biomarker targeted interventions (TBTI) (2016-2018).
  This interest was assessed as non-personal, non-specific and financially significant*.
• His research institution2 currently receives a grant from United Kingdom Department for International Development (DFID)/ Medical Research Council (MRC)/ Wellcome Trust Joint Global Health Trials for the investigation of MVA85A tuberculosis vaccine prime and selective delayed BCG boost in infants of HIV infected mothers, a randomized controlled, double blind, safety and immunogenicity trial of newborn MVA85A prime and selective, delayed BCG boost in HIV exposed uninfected infants (2012-2016).
  This interest was assessed as personal, specific and financially significant*.
• His research institution2 currently receives two grants from Aeras for a randomized, placebo controlled, partially blinded phase II study to evaluate safety, immunogenicity, and prevention of infection with mycobacterium tuberculosis of AERAS-404 and BCG revaccination in healthy adolescents (2014-2016) and for a phase IIb, double-blind, randomized, placebo controlled study to evaluate the efficacy, safety and immunogenicity of GSK Biologicals’ candidate tuberculosis (TB) vaccine GSK 692342 against TB disease, in healthy adults aged 18- 50 years, living in a TB endemic region (2014-2018).
  This interest was assessed as non-personal, specific and financially significant*.
• His research institution2 received a grant from Aeras for a phase 1b, randomized, double-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of the ID93 + GLA-SE vaccine in BCG-vaccinated healthy adults, and a phase I/IIa double-blind, randomized, placebo-controlled, dose-finding study to evaluate the safety and immunogenicity of AERAS-456 in HIV-negative adults with and without latent tuberculosis infection (2013-2015).
  This interest was assessed as non-personal, specific and financially significant*.
• His research institution2 currently receives a grant from Wellcome Trust for a Clinical development of a therapeutic vaccine for tuberculosis (a phase 2a, randomized, double-blind, placebo-controlled, clinical trial to evaluate the safety and immunogenicity of the ID93 + GLA-SE vaccine in HIV uninfected adult TB patients after treatment completion) (2014-2018).
  This interest was assessed as non-personal, specific and financially significant*.
• The University of Cape Town Clinical Trials Unit (UCTCTU) currently receives a grant from NIH for HIV clinical trials related to new prevention modalities and new strategies for the management of HIV, tuberculosis and related infections (2013-2020).
  This interest was assessed as non-personal, specific and financially significant*.
• His research institution2 currently receives a grant from MRC Clinical Sciences Centre for the project entitled “Systems immunology of ID93 vaccine---induced protection against recurrent TB disease” (2014-2017).
  This interest was assessed as non-personal, non-specific and financially significant*.
• His research institution2 received a grant from NIH, NIAID for a project on the biology and biosignatures of anti-tuberculosis treatment response (2015).
  This interest was assessed as non-personal, non-specific and financially significant*.
• His research institution2 received a grant from NIH, NIAID/ Division of Microbiology and Infectious Diseases (DMID) for a phase I study of whether preclearance of latent M. tuberculosis (MTB) infection with isoniazid (INH) enhances specific immune responses to MTB following subsequent BCG revaccination in healthy, HIV-uninfected, tuberculin skin test positive adults (2010-2014).
  This interest was assessed as non-personal, specific and financially significant*.
• His research institution2 received a grant from NIH, NIAID for a double-blind, randomized controlled phase IIb trial of safety and immunogenicity of MVA85A, given as an adjunctive TB vaccine for prevention of recurrent TB disease, in HIV uninfected adults (R34 planning grant) (2013-2014).
  This interest was assessed as non-personal, specific and financially significant*.
• His research institution2 currently receives a grant from AIDS Clinical Trials Group (ACTG) and International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) for a study of MDR TB cases and their household contacts: Operational feasibility to inform PHOENIx trial design (2015-2016).
  This interest was assessed as non-personal, specific and financially significant*.
• His research institution2 received a grant from the InterTB Consortium (EDCTP) for an international multicentre controlled clinical trial to evaluate high dose Rifapentine and a quinolone in the treatment of pulmonary tuberculosis (2010-2013).
  This interest was assessed as non-personal, non-specific and financially significant*.

Nigel Curtis

• His research institution3 currently receives three grants from the Australian National Health & Medical Research Council (NHMRC) for extending the Melbourne Infant Study: BCG for Allergy & Infection Reduction randomized trial of BCG to prevent childhood allergy and infection (2016-2020), for a systems-biology approach to understanding the beneficial heterologous effects of neonatal BCG vaccination in a Melbourne-based randomized controlled trial (2016-2018), and for a BCG immunization to prevent the development of allergy in infants: a randomized trial (2013-2016).
  This interest was assessed as non-personal, specific and financial significant*.

Sang Nae Cho

• Sang Nae Cho reported that he received a Research Service Contract from the Green Cross Company (South Korea) on the “Evaluation of protective efficacy of the secondary seed lot K-1 of BCG Pasteur 1173P2 in a mouse model of M. tuberculosis infection” in 2015.
  This interest was assessed as personal, specific and financially significant*.

1 University of Oxford, Jenner Institute, Research Group on Tuberculosis
2 University of Cape Town, South African Tuberculosis Vaccine Initiative
3 University of Melbourne, Murdoch Children's Research Institute, Research Group on Infectious Diseases & Microbiology

* According to WHO's Guidelines for Declaration of Interests (WHO expert), an interest is considered "personal" if it generates financial or non-financial gain to the expert, such as consulting income or a patent. "Specificity" states whether the declared interest is a subject matter of the meeting or work to be undertaken. An interest has "financial significance" if the honoraria, consultancy fee or other received funding, including those received by expert's organization, from any single vaccine manufacturer or other vaccine-related company exceeds 5,000 USD in a calendar year. Likewise, a shareholding in any one vaccine manufacturer or other vaccine-related company in excess of 1,000 USD would also constitute a “significant shareholding”.