Terms of Reference

WHO’s Strategic Advisory Group of Experts (SAGE) has requested the WHO Secretariat to review the evidence concerning the possible non-specific effects of vaccines included in the routine infant immunization schedule.

Preparatory to such a review of the evidence by SAGE in 2013, it is necessary to:

1. systematically review all published and grey literature concerning epidemiological studies addressing “non-specific” effects of BCG, measles and, DTP-containing vaccines on survival/all-cause mortality in children under five years of age and,
2. critically appraise the evidence using the WHO Strategic Advisory Group of Experts (SAGE) guidelines.

The Working Group will be asked to determine if the current evidence is sufficient to lead to adjustments in policy recommendations or to warrant further scientific investigation, and if so, to define the path towards obtaining unequivocal evidence on these issues that would support future robust, evidence-based adjustments in immunization policies, if warranted.

Guidance for the development of evidence-based vaccine related recommendations.

The Working Group will specifically be asked to:

1. Review and provide guidance on the protocol for two independent systematic reviews (one on epidemiological studies and one on immunological factors) on the evidence of selected vaccines on child survival/ deaths by all causes in children less than 5 years of age.
2. Review the available evidence that addresses the effect of BCG, DTP and measles-containing vaccines on survival/all-cause mortality in children less than five years of age and, the outcomes of the above mentioned reviews and related GRADE tables.
3. Determine if the current evidence on non-specific effects of vaccines is sufficient to lead to adjustments in policy recommendations or to warrant further scientific investigation.

Composition

SAGE Members

• Terry Nolan (Chair of the Working Group), Head, University of Melbourne School of Population and Global Health, Melbourne, Australia
• Zufiqar Bhutta, Department of Paediatrics & Child Health, The Aga Khan University Medical Center, Karachi, Pakistan
• Kate O’Brien, Center for American Indian Health, Johns Hopkins Bloomberg School Public Health, Baltimore, USA

Experts

• Christine Stabell Benn, Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Denmark
• Mike Brennan, Senior Adviser, Global Affairs. AERAS, Washington D.C., USA
• Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene and Tropical Medicine, UK
• Paul Fine, Professor of Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, UK
• Brad Gessner, Scientific Director, Association pour la Medicine Preventive (AMP), Ferney-Voltaire, France
• Diane Griffin, University Distinguished Service Professor Alfred and Jill Sommer Chair W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health; Professor, Medicine and Neurology, Johns Hopkins University School of Medicine, USA
• Jaleela Sayed Jawad, Head of Immunization Group and EPI Manager Ministry of Health, Manama, Bahrain
• Martin Mermikuwu, Professor of Pediatrics, University of Calabar, Nigeria
• Walter A. Orenstein, Professor of Medicine, Infectious Diseases, Emory University, USA
• Dipika Sur, Deputy Director, NICED, ICMR, Kolkata, India

WHO Secretariat

• Ana-Maria Henao-Restrepo

Declarations of Interest

All members completed a declaration of interests. Eight members reported relevant interests summarized below:

Terry Nolan

• Received consultancy fees for participating in meetings and for data analysis and interpretation as member of Data and Safety Monitoring Board (DSMB) and Independent Data Monitoring Committee (IDMC) on Human Papilloma Virus vaccine from GlaxoSmithKline (GSK).The consultancy was ceased by the 17th October 2012. This interest was assessed as personal, non-specific and financially insignificant*. In the time from 2008-2012 his institution received research support for vaccine trials implemented in Australia from a number of companies (including GSK, Wyeth, Novartis Vaccines, Sanofi Pasteur and CSL Ltd).These trials concern a number of vaccines (MenACWY, MenB, MenC, HibMenC Adult and peadiatric TIV, H1N1 and H5N1 vaccine and DTPa-Hib-hepB-IPV-MenC vaccine). This interest was assessed as non-personal, non-specific and financially significant*.
• His institution receives research support to conduct a clinical trial on paediatric Quadrivalent Influenza Vaccine from Sanofi Pasteur. Further travel costs and participation fees in scientific meetings were covered. This interest was assessed as non-personal, non-specific and financially significant*.
• Received consultancy fees in 2011 from GSK for providing expert opinion to European jurisdiction in respect of clinical trial data from studies conducted by himself in the early 1990s sponsored by CSL ltd. This interest was assessed as personal, non-specific and financially insignificant*.
• His institution receives research support to conduct a follow-up clinical trial on a birth dose of Pertussis Vaccination from GSK. This interest was assessed as non-personal, non-specific and financially significant*.
• Receives travel grants for planning of a new QIV Phase II study which is planned for 2013. This interest was assessed as personal, non-specific and financially insignificant*.
• Serves on Australian Technical Advisory Group on Immunisation (ATAGI) and receives payments from the Australian Government. This interest was assessed as personal, non-specific and financially significant*.

Kate O’Brien

• Her institution received consultancy fees from Sanofi Pasteur in 2010 and 2011 on pneumococcal vaccine. This interest was assessed as non-personal, non-specific and financially insignificant*.
• Her institution provided consultancy to Pfizer in 2011 on PCV13. This interest was assessed as personal, non-specific and financially insignificant*.
• Her institution provides consultancy to Merck on pneumococcal vaccine. This interest was assessed as non-personal, non-specific and financially insignificant*.
• Received consultancy fees from GSK in 2011 on PCV10. This interest was assessed as personal, non-specific and financially insignificant*.
• Serves currently as member of DSMB on malaria RTSS vaccine funded by PATH-Malaria Vaccine Initiative. This interest was assessed as non-personal, non-specific and financially significant*.
• Serves currently as member of DSMB on maternal influenza vaccine funded by Bill and Melinda Gates Foundation (BMGF). This interest was assessed as personal, non-specific and financially insignificant*.
• Her institution currently receives research grants from GSK, BMGF, National Institutes on Health (NIH), and GAVI regarding pneumococcal vaccine, PCV13, PCV and rotavirus vaccine. This interest was assessed as non-personal, non-specific and financially significant*.
• Her institution received a research grant from Pfizer until 31.Oct.2012 regarding PCV13. This interest was assessed as non-personal, non-specific and financially significant*.
• Her institution received a research grant from MedImmune in 2011 regarding RSV-motavizumab. This interest was assessed as non-personal, non-specific and financially significant*.
• Her institution currently receives a research grant from BMGF regarding PCV serotype replacement. This interest was assessed as non-personal, non-specific and financially significant*.

Zulfiqar Bhutta

• His department received in March 2011 a research grant from Novartis Global Health Institute on a Phase II trial of typhoid Vi conjugate vaccination. This interest was assessed as non-personal, non-specific and financially significant*.

Paul Fine

• Received research support, travel support and contribution to salary from WHO on various projects in regard to vaccine schedules. This interest was assessed as personal, specific and financially significant*.
• Received travel support from the Danish National Science Foundation in 2005 to attend a meeting on the non-specific effects of vaccines. This interest was assessed as personal, specific and financially insignificant*.

Christine Stabell Benn

• Serves as the leader of the Research Center for Vitamins and Vaccines which aims to study non-specific effects of vaccines. This interest was assessed as non-personal, specific and financially significant*.

Diane Griffin

• Serves on the advisory board for HIV and until 2012 received grants by Novartis Vaccines. This interest was assessed as personal, non-specific and financially insignificant*.
• Member of the collaboration on patented DNA measles vaccine by Vical Inc. No funding is related to this. This interest was assessed as personal, non-specific and financially insignificant*.

Mike Brennan

• His institution, funded mainly by the BMGF, facilitates the development of new TB vaccines. This interest was assessed as personal, non-specific and financially significant*.
• Is inventor of a novel recombinant BCG vaccine with a pending patent. This interest was assessed as personal, non-specific and financially insignificant*.
• Since 2008 in regard to his work for AERAS provided regulatory advice on Tb vaccines to various agencies including FDA and MCC. This interest was assessed as non-personal, non-specific and financially significant*.

Brad Gessner

• His institution is mainly funded by the Bill & Melinda Gates Foundation WHO, UNICEF, Save the Children and the French Ministry of Foreign Affairs. This interest was assessed as non-personal, non-specific and financially significant*.
• His institution receives funding by Pfizer on pneumococcal surveillance in Togo and Prevenar-13 immunogenicity among children in the meningitis belt in Burkina Faso, both as investigator initiated research grants. This interest was assessed as non-personal, non-specific and financially significant*.
• Serves as the main epidemiologist on a study on pneumococcal carriage in Hajj pilgrims in Saudi Arabia; his institution sub-contracts with the Saudi Ministry of Health, which in turn receives funding by Pfizer through an investigator initiated grant. This interest was assessed as non-personal, non-specific and financially significant*.
• His institution receives funding by GSK on global malaria vaccine pharmacovigilance and rotavirus epidemiology. This interest was assessed as non-personal, non-specific and financially significant*.
• His institution receives funding by Crucell on the evaluation of logistic and anthropologic issues associated with pentavalent vaccine delivered through Uniject in Senegal and Vietnam. This interest was assessed as non-personal, non-specific and financially significant*.
• His institution received funding in 2011 by Sanofi-aventis for the organization of a conference on acellular pertussis. This interest was assessed as non-personal, non-specific and financially significant*.
• His institution received funding ending in 2012 by Merck for research on the anthropology of HPV vaccine in Kenya and Vietnam. This interest was assessed as non-personal, non-specific and financially significant*.

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* 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 10,000 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”.