The Global Action Plan for Influenza Vaccines

Report of the ninth meeting of the Advisory Group of the WHO Global Action Plan for Influenza Vaccines

Dubai, United Arab Emirates, 27 March 2014

Ordering code: WHO/HIS/PHI/TTI/14.1

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2 Contents

Abbreviations and Acronyms ...... 4

Executive Summary ...... 5

1. Welcome and objectives ...... 6

2. Update on progress and global activities in support of GAP ...... 7

3. GAP partnership offices: report on activities ...... 9 3.1 CDC ...... 9 3.2 BARDA: Dr Rick Bright ...... 9 3.3 Other Partnership Offices ...... 10

4. Deployment ...... 11

5. Interactions of PIP–GAP advisory groups ...... 12

6. Recommendations by the Advisory Group ...... 13 6.1 Strengthen activities to increase appropriate use of seasonal influenza vaccines ...... 13 6.2 Explore additional Partnership Offices ...... 13 6.3 Continue and intensify PIP-GAP interactions ...... 13 6.4 Start to prepare the GAP III Consultation in 2016 ...... 13

7. List of Participants ...... 14

Report of the ninth meeting of the Advisory Group of the WHO Global Action Plan for Influenza Vaccines— 27 March 2014 3

Abbreviations and Acronyms

AFRO WHO Regional Office for Africa AG Advisory Group BoD Burden of Disease BARDA Biomedical Advanced Research and Development Authority CDC Centers for Disease Control and Prevention, Atlanta, USA ERL Essential Regulatory Laboratories EPI Expanded Programme on Immunization GAP Global Action Plan for Influenza Vaccines GAVI Global Alliance for Vaccines and Immunization GSD Genetic Sequence Data IFPMA-IVS International Federation of Pharmaceutical Manufacturers & Associations- Influenza Vaccine Supply LAIV Live Attenuated Influenza Vaccines NIBSC National Institute for Biological Standards and Control NRA National Regulatory Authority PIP Pandemic Influenza Preparedness Framework PIVI Partnership for Influenza Vaccine Introduction SAGE Strategic Advisory Group of Experts on Immunization SMTA Standard Material Transfer Agreement TEWG Technical Expert Working Group

4 Executive Summary

The Advisory Group (AG) reviewed progress and challenges as reported in the 2006-2013 GAP Interim Progress Report and based on information presented in the meeting with International Partners. Specific attention was paid to deployment and logistical challenges on the basis of lessons learned after the 2009 (A)H1N1 pandemic.

The AG considered the progress on the Pillar 2 and Pillar 3 objectives as satisfactory but called for more attention to Pillar 1. Reasons for concern include weak implementation of the 2012 SAGE recommendations on seasonal influenza vaccination of priority groups.

Current and potential future synergies between GAP and Pandemic Influenza Preparedness (PIP) Framework were discussed given that the PIP Framework aims to improve and strengthen the sharing of influenza viruses with human pandemic potential, and increase access of developing countries to vaccines and other pandemic related supplies, while GAP is focused on enhancing a stable global influenza vaccine supply so that vaccine will be available to as many as possible in the next pandemic. To that end, a number of elements in PIP that support the increase of vaccine production capacity were highlighted, including work to be undertaken under the 2013-2016 PIP Framework Partnership Contribution Implementation Plan which covers burden of disease studies and regulatory capacity building in both producing and non-producing (vaccine importing) countries.

The AG recommended to: • strengthen activities aimed at fully implementing the 2012 SAGE recommendation • explore additional Partnership Offices • continue and intensify PIP-GAP interactions • start preparing the GAP III Consultation in 2016

Report of the ninth meeting of the Advisory Group of the WHO Global Action Plan for Influenza Vaccines— 27 March 2014 5

1. Welcome and objectives

Dr Marie-Paule Kieny welcomed two new members to this 9th meeting of the GAP AG: Dr John Watson from the UK and Dr Ziad Memish from Saudi Arabia. She also thanked Dr Bruce Gellin for accepting to remain the Chairman of this Group for another two years.

As in other years, having the meeting back-to-back with the International Partners’ meeting enables AG members to discuss face-to-face, the activities and challenges of both producers and NRAs from developing countries.

6 2. Update on progress and global activities in support of GAP

The Secretariat presented an update of progress and challenges using a monitoring and evaluation framework developed with the support of the AG and covering the three GAP objectives and the activities required to achieve them.

Several of the activities to be financed under the PIP Partnership Contribution Implementation Plan (PCIP), coincide with GAP objectives on regulatory capacity strengthening and laboratory surveillance, while others are complementary such as strengthening of risk communication capacity.

A summary of the main progress as was reported in the 2006-20013 Interim Progress Report:

• Potential global vaccine production capacity increased from 500 million doses in 2006 to 1.5 billion doses in 2013. • The geographical distribution of the seasonal vaccine manufacturing base has expanded significantly, with 16 low and middle income countries working to establish production capacity. Fourteen of these are being directly supported by WHO under GAP. Collectively, these new manufacturers have now a pandemic vaccine production capacity of 330 million doses, which is predicted to reach 795 million by 2016. • Regulatory capacity in these countries has also increased. At present, 9 out of 14 WHO supported countries have a functional national regulatory authority (NRA), up from 5 in 2006. • Since the 2009 H1N1 influenza pandemic four of the GAP-supported manufacturers have been able to produce and register H1N1 pandemic vaccines. In addition, since the emergence of H7N9 avian influenza viruses in human populations in China in March 2013, four GAP grantees – in India, Viet Nam, Brazil and Indonesia – are in the process of developing H7N9 candidate vaccines. • Between 2007 and 2012 the number of countries with seasonal policies to vaccinate at least one at risk population group has increased from 46 to 72, with significant progress in the Region of the Americas. • Since 2007, the number of pandemic vaccine candidates in clinical trials has increased six- fold, to over 380 trials being conducted worldwide, demonstrating an active pipeline and continued commitment to develop new and improved influenza vaccines.

Discussion It was reiterated that the Pillar 1 objective (increase of evidence-based seasonal influenza vaccination) is fully in line with the 2012 SAGE recommendations which aim to reduce significant annual morbidity and mortality due to influenza. In that perspective, concern was expressed about the slow vaccine uptake globally and about the uneven implementation of the 2012 SAGE recommendations.

It appears challenging for example in Europe to implement the recommendation to immunize pregnant women. Influenza is not seen as a severe disease and only a very small percentage of health care workers actually recommend vaccination. On the other hand, in the US coverage increased from 20 to 50% due to an increased perception of risk following the 2009 A(H1N1) pandemic.

In addition to better epidemiological data to strengthen national policy-making, efforts are needed at many levels to communicate the benefits of vaccination.

A need was expressed for an updated survey on national policy-making and implementation of seasonal influenza vaccination. It would be relevant to collect country data in each WHO region on current and planned vaccination policies and related experiences.

Report of the ninth meeting of the Advisory Group of the WHO Global Action Plan for Influenza Vaccines— 27 March 2014 7

The AG observed that the main challenges are not about scientific evidence or production capacity, but that they are about policy and implementation issues. For instance, in China, up to 30% of the current locally produced vaccines remain unused and the SAGE recommendations are not well known among national and regional level decision makers. The priority for the next few years should be to develop a new strategy for large developing countries, incorporating local burden of disease data and effective communication strategies.

8 3. GAP partnership offices: report on activities

GAP partnership offices are national institutes or agencies with an international footprint in influenza. They are intended to have an informal, yet recognized role in GAP based on their specific expertise.

3.1 CDC Dr Joe Bresee presented CDC activities in support of GAP objectives.

Under Pillar 1, CDC works to develop the evidence base for seasonal influenza vaccination by:

(1) developing and strengthening surveillance capacity, (2) understanding BoD at country, regional and global levels to drive communication messages, (3) understanding economic burden and cost effectiveness, and (4) understanding vaccine performance in countries or specific populations through vaccine effectiveness studies.

Two projects are targeting vaccine introductions in particular:

1. the Partnership for Influenza Vaccine Introduction project (PIVI, as reported in the Partners’ meeting), to support countries that aspire to introduce flu vaccines; they are assisted for a time limited period in the generation of data to help decision making towards sustainable introduction. Vaccine donations have been given to Laos and Nicaragua under PIVI.

2. a project to support policy development in 5 countries (Vietnam, China, Morocco, Uganda, Kenya) assisting in the generation and use of BoD and epidemiological data for policy development and implementation.

For Pillar 2, CDC plays a role in the LAIV vaccine development by functioning as a backup to the Institute of Experimental Medicine from Russia in the preparation of annual candidate viral vaccine materials for distribution to LAIV manufacturers.

3.2 BARDA: Dr Rick Bright Dr Rick Bright presented BARDA's work, which falls under GAP objectives 2 and 3.

BARDA is fully committed to the target of reaching 400–500 million pandemic vaccine capacity among manufacturers assisted by GAP by 2016.

BARDA supports vaccine development in the US, resulting in three key licensures that may also support outside US technologies and licensures: the cell based vaccine by Novartis, an oil-in -water adjuvanted (pre-) pandemic H5N1 vaccine from GSK and the recombinant-based vaccine from Protein Sciences. These new platforms and technologies will provide lessons on the development, regulatory science and clinical pathways towards more effective vaccines for seasonal and perhaps to the goal of a universal flu vaccine.

Further, the US has set up three centres for innovation and advanced manufacturing and three centres to provide surge capacity to 150 million doses in 4 months after the onset of a pandemic.

Awards were given for 5 different sites to develop and conduct clinical studies: not only to evaluate seasonal and pandemic viral vaccines and antiviral drugs, but also to have standardized protocols on

Report of the ninth meeting of the Advisory Group of the WHO Global Action Plan for Influenza Vaccines— 27 March 2014 9 the shelf and systems in place to collect data in the event of a pandemic. Data on effectiveness and on safety will be collected real time.

BARDA also works with NIBSC, the international ERLs and industry to advance the technology to make influenza vaccines. A recent advancement is a reduction in the time needed to do a sterility assay time from 2-3 weeks till 5-6 days. This is a non-proprietary test and will be rolled out to all manufacturers. Work is also done on potency assay improvements and yield improvement technologies with a view to standardization for all flu vaccines.

In the Partners’ meeting, BARDA supported H7N9 clinical vaccine development has been reported. H7N9 appears to be slightly less immunogenic than H5N1 and is clearly less immunogenic than seasonal. The data reiterate the essential need to understand safety and impact of adjuvants in all age groups. Lastly, a plan is developed to produce massive amounts of H7N9 doses, if it becomes a global issue. In that case, adjuvants will be needed.

Looking forward, BARDA plans to allocate significant funding, time and efforts into more effective universal influenza vaccines. The conserved stalk region-approach is seen as a prime candidate for further development.

Another important area where BARDA plans to provide funding is the development of monoclonal antibodies and modulators for immune therapy and antiviral drugs for severely ill hospitalized patients.

3.3 Other Partnership Offices In addition to CDC and BARDA, the Secretariat tried over the past year to identify additional Partnership Offices in different countries/ regions to achieve a wider global participation to the programme. Informal talks were held with China and Japan however no concrete commitments have been made. In view of GAP’s limited lifespan, the AG was asked to advise whether these efforts should be continued and, if so, for guidance on suggestions for institutions to be approached.

Discussion The AG suggested to continue the efforts for China and Japan, since after 2016 there will still be a need for a global partnership structure on influenza vaccines as established by GAP.

The Secretariat will explore the interest of the Institute Pasteur in France, in view of their large international presence in developing countries.

10 4. Deployment

WHO presented lessons learned on the deployment of 2009 (A) H1N1 2009 pandemic vaccines. There were considerable delays in the processes related to receipt of Letters of Intent and Letters of Acceptance from States wishing to receive pandemic vaccine. There were also significant delays in the preparation of national deployment plans. One Letter of Acceptance was received in July 2010, one year after the start of the pandemic. At the peak, the delivery was about 14 million doses a month.

There were concerns in accepting pandemic vaccines in all WHO regions, the overarching concern being safety, and to a lesser extent efficacy. One of the main bottlenecks was at the regulatory level: 38 countries needed national regulatory approval; only two had a previous registration. Two countries required additional clinical trials. Most countries see WHO prequalification as a first needed step for a national registration.

The situation has now improved as most countries have a national deployment plan. WHO is working towards:

(1) a common deployment approach. Scenario planning has started for 92 eligible countries. Under the assumption of a real-time vaccine availability of 8 million doses per week, 192 million doses could be provided to 92 countries in 24 weeks. In 2009/2010, 77 million doses were supplied to 78 countries.

(2) a common regulatory approach for emergency uptake: because of the limited time-frame, a model dossier for each product should be developed, and its use solicited in advance signed agreements.

Discussion It was noted that the planning should include a 2-dose vaccine schedule. It may be useful to make a deployment scenario based on current existing licensed vaccines. The details of distribution of doses to be donated through the PIP SMTA2 are not part of the agreement, and are to be worked out at the time. The number of eligible countries may also have to be revised, as in 2009 it depended on available local production and evidence of advance purchase agreements in place.

Under the PIP Framework, manufacturers commit to supply 10% of their real time pandemic vaccine capacity for WHO. What may not be clear at present for each Member State is how large manufacturers with multiple production sites in different countries will meet this commitment. In theory, committed donations to the international community could interfere with bilateral commercial agreements between manufacturers and countries.

Report of the ninth meeting of the Advisory Group of the WHO Global Action Plan for Influenza Vaccines— 27 March 2014 11

5. Interactions of PIP–GAP advisory groups

Dr Ampofo reported on progress under the PIP Framework. He drew attention to the recent PIP Partnership Contribution Implementation Plan 2013 – 2016 (PCIP), released January 2014, which allocates significant funding to strengthen global preparedness capacities through, among others, burden of diseases studies, regulatory capacity building, laboratory and surveillance capacity strengthening, enhancing risk communications, and planning for deployment of pandemic supplies. Some of these activities contribute to the achievement of GAP Pillar 1 objectives. Most of these activities will be implemented through WHO Regional Offices.

One issue with relevance for GAP is the potential to use synthetic seeds for candidate vaccine virus generation. The use of genetic sequence data (GSD) can now replace viruses in the synthesis of influenza vaccine viruses through (patented) new technologies.

As this raises issues on traceability and benefit sharing for viruses with human pandemic potential under the PIP Framework, the PIP Advisory Group convened a Technical Expert Working Group (TEWG) on GSD to provide background and technical information on areas related to the use and handling of GSD. The work of the TEWG will enable the PIP AG to formulate guidance to the WHO Director General on the best process for further discussion and resolution of issues relating to the handling of GSD under the PIP Framework.

12 6. Recommendations by the Advisory Group

6.1 Strengthen activities to increase appropriate use of seasonal influenza vaccines • Consider a global survey on seasonal influenza vaccination policies and implementation. • Strengthen immunization through implementation research, distribution and systems strengthening. • Consider additional progress indicators measuring global pandemic readiness, such as the number of updated national deployment plans and the number signed SMTA2 agreements under PIP. • Better articulate why developing countries should develop and implement policies on seasonal influenza vaccination. • Communication: o consider an additional regional workshop on communication for AFRO. o engage EPI key decision makers in country/regional workshops.

6.2 Explore additional Partnership Offices The GAP Secretariat should continue to seek engagement of Partnership Offices in China, Japan, and Europe and also explore the potential for such collaborations in Africa.

6.3 Continue and intensify PIP-GAP interactions • The PIP and GAP Secretariats should continue to work together. • Explore opportunities for the PIP Framework to help sustain GAP-related progress in global influenza vaccine production.

6.4 Start to prepare the GAP III Consultation in 2016 The Secretariat should start preparing the 2016 GAP III Consultation in 2014. A concept note for discussion in AG teleconferences should be developed and could include scenario development on what could happen were a pandemic to strike again on the basis of what is now realistically known about global production capacity and deployment experiences from the 2009 (A)H1N1 pandemic.

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7. List of Participants

MEMBERS Dr William Kwabena Ampofo, Senior Research Fellow & Head - Virology, Noguchi Memorial Institute for Medical Research, Legon Accra, Ghana

Professor Daniel Camus, Institut Pasteur de Lille, Lille, France

Dr Supamit Chunsuttiwat, Senior Medical Officer, Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand (Unable to attend)

Dr Bruce Gellin, Director, National Vaccine Programme, Department of Health and Human Services, Washington, DC, United States of America

Dr Hajime Inoue, Director, Office of Pandemic Influenza Preparedness and Response, Ministry of Health, Labour and Welfare, Tokyo, Japan

Dr Rosanna Lagos, Coordinadora, Centro para vacunas en Desarrollo-Chile, Hospital de Niños Roberto del Rio, Santiago, Chile

Dr Ziad Memish, Deputy Minister of Health, Ministry of Health, Riyadh, Saudi Arabia

Dr Firdausi Qadri, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh (unable to attend)

Professor John Watson, Deputy Chief Medical Officer, Department of Health, United Kingdom of Great Britain & Northern Ireland

Professor Hongjie Yu, Director, Division for Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China

OBSERVERS Dr Joseph S. Bresee, Chief, Epidemiology and Prevention Branch, Influenza Division, Centers of Disease Control, Atlanta, United States of America

Dr Rick Bright, Director, Influenza Division, Office of Biomedical Advanced Research & Development Authority (BARDA), US Department of Health and Human Services (HHS), Washington, United States of America

WHO SECRETARIAT Ms Florence Barthelemy, Team Assistant, Technology Transfer Initiative, Essential Medicines and Health Products, Health Systems and Innovation, Geneva, Switzerland

Dr Martin Friede, Scientist, Technology Transfer Initiative, Essential Medicines and Health Products, Health Systems and Innovation, Geneva, Switzerland

Mr Jan T. Hendriks, Scientist, Technology Transfer initiative, Essential Medicines and Health Products, Health Systems and Innovation, Geneva, Switzerland

Dr Marie-Paule Kieny, Assistant Director-General, Health Systems and Innovation (HIS), Geneva, Switzerland

14 Ms Claudia Nannei, Technical Officer, Public Health, Innovation and Intellectual Property, Essential Medicines and Health Products, Health Systems and Innovation, Geneva, Switzerland

Dr Justin Ortiz, Technical Officer, Initiative for Vaccine Research, Family, Women's and Children's Health, Geneva, Switzerland

Mr James Pfitzer, Technical Officer, Technology Transfer initiative, Essential Medicines and Health Products, Health Systems and Innovation, Geneva, Switzerland

Ms Erin Sparrow, Project Officer, Technology Transfer initiative, Essential Medicines and Health Products, Health Systems and Innovation, Geneva, Switzerland

Report of the ninth meeting of the Advisory Group of the WHO Global Action Plan for Influenza Vaccines— 27 March 2014 15

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