Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to Developing Country Vaccine

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1 Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to Developing Country Vaccine Manufacturers Belgrade, Serbia, March 2012

2 WHO Library Cataloguing-in-Publication Data Report of the fifth meeting with international partners on prospects for influenza vaccine technology transfer to developing country vaccine manufacturers, Belgrade, Serbia, March Influenza vaccines - standards. 2.Influenza vaccines - supply and distribution. 3.Technology, Pharmaceutical - standards. 4.Disease outbreaks. 5.Developing countries. 6.International cooperation. I.World Health Organization. ISBN (NLM classification: WC 515) World Health Organization 2012 All rights reserved. Publications of the World Health Organization are available on the WHO web site ( or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: ; fax: ; bookorders@who.int). Requests for permission to reproduce or translate WHO publications whether for sale or for noncommercial distribution should be addressed to WHO Press through the WHO web site ( The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This publication does not necessarily represent the decisions or policies of the World Health Organization. Printed in Switzerland. 2

3 CONTENTS Abbreviations and Acronyms INTRODUCTION AND OBJECTIVES Second Consultation on the Global Action Plan for Influenza Vaccines BARDA International Influenza Program bridging the GAP UPDATES... 8 SAGE Working Group for Influenza Vaccine and Immunization... 8 Meeting on Influenza vaccines that induce broad spectrum and long-lasting immune responses, November Workshop on enhancing the global workforce for vaccine manufacturing... 9 Workshop on international regulatory capacity enhancement for influenza vaccines... 9 Session 1. Sustainable pandemic influenza vaccine manufacturing in developing countries... 9 Session 2. Sustainability through production of veterinary vaccines in human facilities Production of veterinary vaccines from eggs Regulatory challenges to production of veterinary influenza vaccines in human facilities Session 3. Reverse genetics issues Summary of existing reverse genetics methods and their limitations for production of influenza candidate vaccine viruses Reverse genetics technology patent portfolio Session 4. Gathering evidence on vaccine use Demand for influenza vaccine: economic analysis and burden of disease assessment Session 5. Regulatory pathways and processes for influenza vaccines Regulatory capacity strengthening and institutional development plans: relevance to influenza vaccines New grantee projects Development of the technology for manufacturing a seasonal trivalent influenza split vaccine at the Research Institute for Biological Safety Problems (RIBSP), Kazakhstan Establishing influenza manufacturing capacity at the Biovac Institute in South Africa DAY 2 - TECHNICAL ISSUES From start to approval: lessons learnt in the Serum Institute of India (SII) Section 6. LAIV development Update on LAIV studies at the Institute of Experimental Medicine, Russian Federation Lessons learnt on LAIV development: Government Pharmaceutical Organization, Thailand PATH's LAIV program: clinical trials, delivery devices and formulation work Market Authorization Options for Live Attenuated Influenza Vaccines Session 7. Technical issues Eggs and the production of H5N1 at IVAC, Viet Nam The inactivation process at Torlak Institute of Virology, Vaccines and Sera, Serbia Whole or split? International Technology Platform for Influenza Vaccines (ITPIV) Purification by column chromatography to replace ultracentrifugation Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 3 Developing Country Vaccine Manufacturers March 2012

4 Development of influenza vaccine production with use of chromatographic methods at Microgen 18 Influenza vaccine, Instituto Butantan, Brazil Column chromatography for the development of pandemic and seasonal influenza vaccines at RIBSP Session 8. Panel session on training The RIVM as knowledge and training centre (the Netherlands) Biomanufacturing Training and Education Center's (BTEC) International Influenza Vaccine Manufacturing Training Program (South Carolina, USA) Center for Integrated Biosystems, Utah State University (USA) The Vaccine Formulation Laboratory (VFL), University of Lausanne, Switzerland Adjuvant technology for pandemic influenza vaccines, IDRI (USA) Closing session

5 ABBREVIATIONS AND ACRONYMS BARDA BTEC DCVM DNA FDA GAP GMP GPO HA HAI HHS HPAI HPNAI IDRI IgA IgG IEM ITPIV IIV IPR IVAC LAIV NRA OIE PATH PIP RIBSP RIVM RNA RNPs SAGE SII SOP WHO VFL VLP Biomedical Advanced Research Development Authority Biomanufacturing Training and Education Center (USA) developing country vaccine manufacturers deoxyribonucleic acid United States Food and Drug Administration Global Action Plan for Influenza Vaccines good manufacturing practice Governmental Pharmaceutical Organization (Thailand) haemagglutination haemagglutination inhibition United States Department of Health and Human Services high pathogenicity avian influenza viruses high pathogenicity notifiable avian influenza viruses Infectious Disease Research Institute immunoglobulin A immunoglobulin G Institute of Experimental Medicine (Russian Federation) International Technology Platform for Influenza Vaccines inactivated influenza vaccine intellectual property rights Institute of Vaccines and Medical Biologicals (Viet Nam) live attenuated influenza vaccine national regulatory authorities World Organisation for Animal Health Program for Appropriate Technology in Health Pandemic Influenza Preparedness Framework Research Institute for Biological Safety Problems (Kazakhstan) National Institute for Public Health and the Environment (the Netherlands) ribonucleic acid ribonucleoprotein complexes Strategic Advisory Group of Experts on Immunization Serum Institute of India standard operating procedure World Health Organization Vaccine Formulation Laboratory (Switzerland) virus-like particle Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 5 Developing Country Vaccine Manufacturers March 2012

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7 1. INTRODUCTION AND OBJECTIVES The fifth meeting with International partners on prospects for influenza vaccine technology transfer to developing country vaccine manufacturers was held on March 2012 in Belgrade, Serbia, following the convention to convene each time in one of the WHO grantee countries. On behalf of their co-hosting institutions, Drs Branislav Lazic, Managing Director of Torlak and Marie-Paule Kieny, Assistant Director-General of WHO, extended a warm welcome to participants, who were encouraged to contribute actively to the discussions. In addition to reviewing progress and sharing experiences, the objectives of the meeting were to review and discuss a series of scientific and technical topics (see Agenda and List of Participants in Annex 1 and 2, respectively). The meeting was co-chaired by Drs Jaspal Sokhey and Jim Robertson. 2. SECOND CONSULTATION ON THE GLOBAL ACTION PLAN FOR INFLUENZA VACCINES Dr Marie-Paule Kieny summarized the conclusions of this consultation held in July It was agreed that the original GAP-I objectives remained valid and that GAP has been the catalyst for a significant expansion in global influenza vaccine production capacity. However, this has not equally benefited all regions. To reach its goals, GAP-II needs to expand its areas of action beyond those of GAP-I. The following opportunities were identified for GAP-II along the three pillars. Pillar 1: Increase seasonal vaccine use Data on the burden of disease must be generated in countries and in different population groups, and evidence on the effectiveness of vaccination communicated widely. In addition, commitments from governments in moderate resource countries would contribute to the sustainability of the facilities. Pillar 2: Increase production capacity The substantial increase in production capacity in a growing number of developing countries has not been without major challenges, especially sustaining supply demand and regulatory issues. New technologies, especially for surge capacity, and production strategies are thus among priorities. Pillar 3: Further research and development Numerous influenza vaccines are being developed that may greatly enhance equitable access to vaccine. However, research is urgently required on issues such as alternative correlates of protection, needle-free delivery methods and those with potential for dose sparing. In addressing these issues, GAP II should focus particularly on promoting evidence-based policies to increase seasonal vaccine use, and on the sustainability of vaccine production. Effective messages must be developed to attract funding for these GAP activities. 3. BARDA INTERNATIONAL INFLUENZA PROGRAM BRIDGING THE GAP Dr Rick Bright recalled BARDA's objectives, activities and core expertise as a major GAP partner in building sustainable influenza vaccine production capacity worldwide. Since the launch of the GAP, BARDA has invested some US$ 60 million in this objective, including grants and clinical and manufacturing training for developing country vaccine manufacturers as part of the WHO Technology Transfer programme. This has resulted in adjuvant production capability in two countries, clinical Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 7 Developing Country Vaccine Manufacturers March 2012

8 trials in seven countries, four licensed pandemic vaccines and, most importantly, reduced burden of disease and enhanced global pandemic preparedness: an excellent return on investment. In , BARDA will focus on GAP pillars 1 and 2. Projects include international training and other workshops, and the initiation of clinical trials in India, Indonesia, Romania and Viet Nam, covering traditional as well as much needed adjuvanted and live attenuated influenza vaccines. 4. UPDATES SAGE Working Group for Influenza Vaccine and Immunization Dr John Tam (WHO) summarized the findings of an extensive evidence-based review on seasonal influenza vaccination, to be presented to SAGE in April Using a conceptual matrix, the Working Group examined data on burden of disease, vaccine performance, cost-effectiveness and several operational issues for five target risk groups, focusing on whether sufficient data exist and could be extrapolated from high- to lower-income countries. Members were also tasked to consider a possible revision in coverage goals; gaps in knowledge (e.g. the use of LAIV and adjuvanted vaccines); and options for a potential WHO pandemic influenza vaccine stockpile. In this regard, the Working Group took account of assessments and recommendations from other WHO expert groups that focus on vaccine safety. Based on the background document, SAGE may recommend an update of the 2005 WHO Vaccine Position Paper on seasonal influenza vaccination, as well as a revision of the coverage goals outlined in World Health Assembly resolution WHA Discussion This review analysed the evidence for several age groups in lower-income countries, although it is countries that will decide on target groups to vaccinate and coverage goals, based on their priorities and disease burden data. Clarification was provided on how seed funding from the Technology Transfer Programme encouraged confidence and commitment from public and private sectors to complement investment in local vaccine production, which in turn can attract further funding and networking opportunities. However, attention to developing strong communication and assessment tools such as cost-benefit data was reiterated if investment in influenza is to be convincing and sustainable, particularly in Africa. Other points discussed were the breakdown of data for the broad age group "children", achievable coverage goals and WHO approaches to redress low seasonal vaccine use in developing countries. Meeting on Influenza vaccines that induce broad spectrum and long-lasting immune responses, November 2011 Dr Tam explained that meetings of this group were now combined with the annual review of influenza vaccine clinical trials. They continue to be a valuable platform for public and private entities to share the latest data and challenges on novel vaccines and promising delivery mechanisms for potential pandemic use, a summary table of which is posted on the WHO website (a distinct summary of the seasonal influenza vaccine pipeline will also be posted from April The broad agenda included advances in T-cell clinical development, challenge studies, anti-ha and NA strategies, studies on adjuvants and LAIV and novel approaches to broad spectrum vaccines such as synthetic vaccines. However, assays for correlates of protection for novel vaccines, safety data, and regulatory pathways remain significant hurdles to the accelerated development of novel technologies. 8

9 Workshop on enhancing the global workforce for vaccine manufacturing Dr Claudia Nannei (WHO) presented the objectives of the HHS-WHO workshop, held in Cape Town, South Africa in December More than 100 participants from public and private sectors shared experiences in recruiting, training and retaining specialists for sustained influenza vaccine manufacture. Investment in local vaccine production can only be successful if the benefits are clear for the government, the local manufacturers and the population. Key parameters to ensure a local skilled workforce comprise a validated education system, adequate resources, employment prospects, and training with monitoring and evaluation. Regional priorities and certified training courses may also be explored. Finally, the importance of integrating skilled human resources in the initial business plan was highlighted. Workshop on international regulatory capacity enhancement for influenza vaccines Dr Claudia Alfonso described overall objective of this HHS-WHO workshop, held in Sao Paulo, Brazil in June 2011, to improve the mutual understanding of regulators and policy-makers of their needs and challenges, and thus to develop stronger partnerships. The complexity of influenza vaccines poses specific challenges for regulators, who often work within unclear legislative frameworks and with inadequate SOPs. Policy-makers had learnt from the 2009 H1N1 pandemic the importance of coordination and communication, both within the government, with NRAs and the public. Proposals to enhance harmonization among stakeholders in general and regulatory capacity in particular included political commitment, understanding of regulatory requirements at all levels, improved surveillance, and earmarking a percentage manufacturing support to regulatory activities. SESSION 1. SUSTAINABLE PANDEMIC INFLUENZA VACCINE MANUFACTURING IN DEVELOPING COUNTRIES Dr Robert Huebner (BARDA) presented the interim results of a survey on the feasibility of multiproduct facilities in developing countries. A major barrier to sustainable influenza vaccine manufacture is a limited perception of the relevance of influenza vaccination against other health priorities. Resources and access to highly specialized skills are two other hurdles. The survey sought models that might be sustainable in developing countries. Multi-product facilities are more cost-effective in settings with limited physical space and human resources, although this approach has been largely the remit of contract manufacturing organizations. Regarding the option of vaccines that could be produced in facilities which are also used for influenza vaccine production, considerations covered market demand, the adaptability of facilities, technology transfer and developmental stage of the technology. For example, recombinant vaccines derived from microbial or insect cells may be of great interest since these technologies could also make other vaccines, but are of higher risk as currently no licenced influenza vaccine exists using these technologies. Manufacturing scenarios to develop egg-based and microbial vaccines were presented, the former suggesting yellow fever, measles or rabies as companion vaccines, depending on the size of the facility, or even liposomes or phospholipids. In conclusion, long-term sustainability depends on a careful assessment of needs, risks and resources. Discussion Issues raised covered the training of staff in more than one technology, options to reduce the expense of egg production, the risks of switching production between vaccines in one facility, and the critical importance of pharmacovigilance. Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 9 Developing Country Vaccine Manufacturers March 2012

10 SESSION 2. SUSTAINABILITY THROUGH PRODUCTION OF VETERINARY VACCINES IN HUMAN FACILITIES Production of veterinary vaccines from eggs Dr Martin Friede (WHO) summarized the available knowledge, gleaned from experts in this field, to determine the feasibility of producing veterinary and human egg-derived vaccines in the same facility. While national legislation does not support the production of human vaccines in a veterinary facility, the reverse may be possible. However, global veterinary influenza vaccine production, although in billions of doses, currently meets demand and these vaccines have low profit margins. Given the additional regulatory requirements for human vaccine facilities, particularly GMP and the very different downstream processing, making veterinary vaccines in human vaccine facilities may not be cost-effective. Since the yield is undefined approval being based on challenge studies and not HA content it is not possible to predict the yield and cost-of-goods per dose without undertaking exploratory studies with different seed strains. In addition, access to these seed strains may not be secure. In conclusion, a location-specific evaluation of regulatory, economic and human resource issues, as well as practical determination of yield and cost need to be conducted before veterinary eggderived vaccines could be produced in the same facility. Discussion GMP standards for upstream processes appeared equivalent for egg-based veterinary and human vaccine; equine, porcine or multivalent vaccines were not considered viable options by the veterinary experts. Initial discussions suggest that Newcastle disease vaccine might be an option to complement influenza provided the process is the same, i.e. inactivated for both. Regarding costs, it was agreed that sustainability, not profit, was the objective of the analysis, although it was suggested that the full veterinary vaccine cost may be underestimated. Having different regulatory authorities and standards may also pose challenges, as well as maintaining high-level training in purification processes. Regulatory challenges to production of veterinary influenza vaccines in human facilities Dr Laszlo Palkonyay (WHO) noted that the significant increase in pandemic influenza vaccine production capacity over last five years had not been matched by uptake of seasonal vaccine. He reiterated the assumptions for combining veterinary and human influenza vaccines in the same location, adding that many newer manufacturers have their own chicken farms. The World Organisation for Animal Health (OIE) has developed the concept of high vs low pathogenicity notifiable avian influenza viruses, which affects subtype H5 and H7 prone to turn pathogenic. OIE requires that HPNAI viruses are not used as seed viruses and that conventional live influenza vaccines are not recommended against any subtype of avian influenza. Requirements also exist on the use of eggs. Dr Palkonyay noted that many avian influenza strain banks have been established and, given that the composition of the vaccine does not need to be adjusted, stockpiling is highly economical. He agreed that the upstream process for both vaccines are similar, as is the quality of eggs required, and the master and working seed preparation. Finally, it was stressed that the facility and the vaccines must comply with the veterinary and human regulatory authorities (including biosafety containment requirements), which are often under different ministries, and those considering the approach should therefore discuss their plans at the outset. Discussion Discussion confirmed that multi-purpose facilities should focus on one technology, i.e. live attenuated or inactivated vaccines, as it is very expensive to install equipment and train staff for both, and would require large facilities. As 95% of global veterinary influenza vaccine production is inactivated, combination with live attenuated veterinary vaccines is not an option. The various definitions of quality eggs were clarified, and that both veterinary and human vaccines need the same high quality. To protect poultry in a pandemic situation, WHO could facilitate access to several strains for selection of the optimal strain in countries. Options for access to seed strains included WHO Collaborating Centres and the OIE. 10

11 SESSION 3. REVERSE GENETICS ISSUES This Session, moderated by Dr Martin Friede, reviewed the discussions of a WHO meeting on reverse genetics that looked at the science, methods and patent barriers to access to the technology for the production of influenza candidate vaccine viruses. Summary of existing reverse genetics methods and their limitations for production of influenza candidate vaccine viruses Dr Othmar Engelhardt (NIBSC) explained reverse genetics as enabling the generation and genetic manipulation of influenza virus from cloned DNA, which is particularly useful to generate candidate vaccine viruses from highly pathogenic avian viruses. He presented the technical underpinnings of reverse genetic systems. The ability to focus on a single segment in influenza viruses has implications for reverse genetics, enabling the combination of segments to generate a new virus. The two categories described were helper virus-dependent and helper virus-independent systems. In the former, RNPs can be made in vitro or reconstituted in a cell. Advantages of this technology are that it is the best known and in its simplest form is off-patent. On the other hand, it requires a selection system, and the laborious purification process may affect reproducibility and effectiveness under quality control conditions. For helper virus-independent systems, the major methods are plasmid/vector based or RNP transfection systems, using different promoters to express the RNA in the cell. No infectious influenza virus is required to generate new virus and no selection system is required. Advantages are their efficiency, reproducibility and relative ease of use. They are well established and have been used to generate candidate vaccine viruses. IPR are the major barrier. In conclusion, and subject to regulatory acceptance, the rationale for using reverse genetics to generate candidate vaccine viruses is the independence from egg isolates; the DNA phase can clean up any virus and depathogenise/attenuate HPAI viruses, tailor and improve viruses to specific requirements, and is potentially quicker and more reliable than conventional reassortment. At least six laboratories are currently developing candidate vaccine viruses using this technology. Reverse genetics technology patent portfolio Dr David Marks (PATH) complemented the above presentation by describing the scope, rights conferred and options related to the reverse genetics patent portfolio, and the objectives of PATH to enhance access to influenza vaccine in the public sector in developing countries. The historical owners and current licence holders of patents on the technology, along with the broad international claims filed by licensees on reverse genetics helper-dependent and -independent systems, were described. It was cautioned, however, that information on where a specific patent is issued requires direct contact with each patent office. Moreover, patent claims aim to prevent others from making, selling or using not only the method, but the viral seed stock and vaccine, which is not limited to influenza. A summary of known patents filed in various jurisdictions was given, along with an indication of those that have expired or due to expire within the next decade. Current options might be to sublicense, access seed strains from authorized laboratories, or use laboratories where no patents exist. Discussion Although IP-free, the classical reassortment technology is labour-intensive and presents regulatory, economic, political and training hurdles. It was confirmed that the currently-used reverse genetics process is patented in many countries, which impacts the use of the final product. Existing agreements with the owners of the IP may need to be revisited to ensure that these are suitable in pandemic situations. Compulsory licensing approaches are not applicable in this situation. Topics also covered Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 11 Developing Country Vaccine Manufacturers March 2012

12 biosafety standards; comparison with conventional reassortants; live vs inactivated virus strains; how the Pandemic Influenza Preparedness (PIP) framework could integrate with the GAP objectives in this area; and experience of reverse genetics during the H1N1 pandemic. SESSION 4. GATHERING EVIDENCE ON VACCINE USE Demand for influenza vaccine: economic analysis and burden of disease assessment Dr Daniel Miller (HHS) presented an analysis on potential regional, independent and sustainable influenza vaccine manufacture to allow surge capacity in developing countries in a pandemic event. The success of this approach would depend on a combination of strategies to meet public health goals. Studies to obtain disease burden data are critical to increase use of seasonal vaccine and bridge gaps in knowledge, ideally based on specific risk groups and clear laboratory samples. New data are becoming available in a growing number of developing countries and show, for example, that the rate of influenza as a cause of pneumonia in children <5 years of age is 20 times that of developed countries. The economic burden of disease includes not only the direct costs, but out-of-pocket expenses and significant indirect costs such as absenteeism. These are powerful arguments for decision-makers. In conclusion, disease burden data will inform whether influenza is an issue, and comparison with other diseases and costing studies will determine national priorities. Discussion Tools to assess disease burden and costs are fundamental, but the evidence needs to be translated into a political decision. In Thailand, the trigger to consider local vaccine production was not solely costor evidence-based, but to assure national security in the face of a pandemic, and led to major government investment over a five-year period. Consideration of therapeutic over preventive vaccines was noted as advantageous in large countries such as China. SESSION 5. REGULATORY PATHWAYS AND PROCESSES FOR INFLUENZA VACCINES Regulatory capacity strengthening and institutional development plans: relevance to influenza vaccines Dr Claudia Alfonso (WHO) highlighted advances in vaccine development over the last decades and the challenges this has posed for vaccine regulation. On the one hand, the number of vaccines has increased, along with demand and heightened public awareness of vaccine quality and safety. On the other, quality control systems and standards remain inconsistent in developing countries. The lengthy and complex vaccine regulatory process from pre- to post-marketing was briefly outlined as well as WHO activities to strengthen NRAs at all phases to become fully functional. WHO has six regulatory requirements to assure the quality of vaccines, either procured through the UN system, or produced or imported by the country. To date, a team of 350 assessors have assessed 101 WHO Member States, 60 of which now have a functional NRA with an institutional development plan and staff trained through WHO. Analyses compared the percentage of low- to high-income countries with functional NRAs, and the growing percentage of vaccines produced in emerging economies by volume, although not by value. Interestingly, countries with high potential to account for 70-80% of global vaccine production are largely those selected by the WHO Technology Transfer Project. In summary, NRAs are a critical and integral component in the development and availability of safe and effective vaccines, and a very cost-effective investment that enhances confidence and credibility in national immunization programmes. 12

13 Discussion A survey being carried out on NRA assessments identified training as the major shared need, and WHO has organized hands-on courses to address the specific needs. Details were also given on WHO prequalified pandemic and seasonal influenza vaccines. It was clarified that NRA training is totally separate to WHO product prequalification for sale within the UN procurement system, although a functional NRA in the producing country would be a prerequisite. Regarding biosafety, participants were invited to review the standards adopted by the Expert Committee on Biological Standardization on the WHO web site. Lastly, training options and responsibilities was discussed, particularly the need for integrated training models appropriate for developing countries, and expanding funding sources. NEW GRANTEE PROJECTS Development of the technology for manufacturing a seasonal trivalent influenza split vaccine at the Research Institute for Biological Safety Problems (RIBSP), Kazakhstan Dr Berik Khairullin of the RIBSP presented safety and immunogenicity data from Phase II trials of their inactivated whole virion H5N1 and H1N1 candidate vaccines. Results showed both vaccines to be safe and well tolerated and to meet international criteria for immunogenicity, and have therefore been submitted for registration for vaccination in adults. The WHO project to support the manufacture of 6 million doses a year of seasonal trivalent split influenza vaccine was initiated in December The current status of the project, related to quality and safety standards and the construction of a dedicated facility, was described. Optimization of methods and development of master and working seed lots has led to the preparation of six experimental batches of H1N1. In parallel, assessment plans for the production facility have been completed by WHO experts. Immediate objectives of the Institute are to secure financial commitment and to advance the design plans of the production facility. Longer-term milestones up to 2015 are to certify and validate the plant, and develop a fully trained influenza vaccine workforce. Establishing influenza manufacturing capacity at the Biovac Institute in South Africa Dr Tippoo presented an overview of Biovac's influenza vaccine activities, noting that WHO support complements the Institute's own investment to upgrade facilities. For example, Biovac has built a new quality control laboratory with warehousing and cold chain capability and more recently has invested in the production facility. The WHO project is an opportunity to initiate influenza vaccine manufacturing capacity in sub-saharan Africa. The two-track project aims to (a) establish capability to fill/finish imported seasonal and pandemic bulk vaccine; and (b) manufacture antigen at Biovac. It was estimated that the 5-step activities towards obtaining a licence to fill-finish imported bulk vaccine could be completed in 3-4 years. Antigen manufacture will require much longer-term planning and financial commitment. The status of both arms of the project was summarized: discussions with the technology transfer partner were at an advanced stage; multi-product formulation and filling capacity in vials is on track; equipment should be ordered and training carried out in the coming months; and the NRA invited for inspection in the third quarter of the year. Regarding antigen manufacture, results of the feasibility study to determine the best options should be available soon. Discussion RIBSP clarified that their poultry and experimental lots for human vaccines are produced in completely separate parts of the plants. The Institute intended to produce vaccine for the domestic market as well as for neighbouring countries in Central Asia. Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 13 Developing Country Vaccine Manufacturers March 2012

14 The estimated demand in South and southern Africa is low, although detailed projection studies and discussions with other African nations such as Nigeria to increase demand were underway. Biovac noted that finalization of their business case will accelerate conclusion of the agreement with the technology partner, and that use of the existing bacterial fermentation-based platform for antigen production would be examined before looking into the construction of a new plant. It was agreed that for seasonal vaccine, it may be better to import bulk or finished product until a less voluminous antigen production technology becomes available. Data from a WHO survey confirm that this would not meet pandemic demand. A major challenge in transferring bulk vaccine is the need to demonstrate a large enough market. Demand in new African countries is not expected to be high, although the use of live attenuated technology for yellow fever (produced by Institut Pasteur Senegal) may facilitate the production of influenza vaccine. Options to improve surge capacity were regional production, the sharing of virus strains through the PIP framework, WHO access to a percentage of international supply, tiered pricing mechanisms and an adjuvant stockpile. Manufacturers interested in the latter should initiate negotiations with potential partners in the interpandemic period to obtain a licence in a timely fashion. DAY 2 - TECHNICAL ISSUES FROM START TO APPROVAL: LESSONS LEARNT IN THE SERUM INSTITUTE OF INDIA (SII) Recalling the challenges faced during the initial phase of influenza vaccine development, Dr Rajeev Dhere underlined the challenge of sustainability in this second stage of development. When India started the project in 2006, demand for seasonal vaccine was minimal. The H1N1 pandemic precipitated access to LAIV technology via a sublicense with WHO to fast-track pandemic vaccine for the large Indian population. Many challenges from public and regulatory perspectives were overcome, including delays to import the live virus strain, achieving sufficient titres, stabilization and the freezedrying process, and the delivery device and labelling. Data from HAI, NM, IgG and IgA tests along with ferret challenge data and extensive data from IEM were pivotal to overcome the lack of international standards for correlates of protection to approve their HINI LAIV. SII is also developing a seasonal, trivalent influenza vaccine, which has completed a Phase I clinical trial and now entering Phase II/III clinical trials. Unresolved issues include options for sustainable influenza vaccine production, including patent barriers to the use of reverse genetics systems and the choice of northern or southern formulations. SECTION 6. LAIV DEVELOPMENT Update on LAIV studies at the Institute of Experimental Medicine, Russian Federation Dr Larissa Rudenko summarized the work of the Institute of Experimental Medicine to develop LAIV and prepare reassortants for developing countries under an agreement with WHO. Reconstruction of a laboratory with capacity, inter alia, to manipulate HPAI is nearing completion. In collaboration with PATH, preclinical testing of an H7N3 candidate vaccine has shown good immunological response after two doses in ferrets and clinical trials are expected to start in April Similarly, very promising preclinical results obtained in an H5N1 strain will lead to trials of the A/17/turkey/Turkey strain in humans in Q Details were also provided on advances and challenges in the development of a new prepandemic candidate LAIV H2N2, and the preparations to license this vaccine. 14

15 IEM highlighted the strong collaboration with partners, which has led to the transfer of its LAIV technology to a growing number of developing country manufacturers. Lessons learnt on LAIV development: Government Pharmaceutical Organization, Thailand Dr Sit Thirapakpoomanunt underlined the political commitment of the Government of Thailand to national pandemic preparedness, which led to the allocation in 2007 of US$ 42 million for a five-year project to build an influenza vaccine facility. This complemented WHO grants to establish manufacturing capacity for seasonal and pandemic vaccines at GPO. Dr Sit presented the key achievements to date to complete the industrial-scale IIV plant and to develop their H1N1 and H5N2 LAIV, and described regional outreach and the target groups for seasonal vaccination. Lessons learnt were that health security could leverage government support for vaccines of high quality, not lower price. Moreover, increasing demand for seasonal influenza vaccine using disease burden and cost-effectiveness data is the approach for sustainability. Thailand realized that building the capacity of the manufacturer must be matched by strengthening the NRA and disease control agency. Technical support from international partners, regular monitoring, media communication, and opportunities from the H1N1 pandemic to accelerate knowledge- and confidence-building among policy-makers, partners and the public, were other critical components to the success of the project. Outstanding issues relate to the coproduction of IIV and LAIV and generating evidence to ensure that future supply-demand is met for different age groups. PATH's LAIV program: clinical trials, delivery devices and formulation work Dr Kathleen Neuzil noted that PATH worked collaboratively and strategically towards the GAP goals. She described the scientific and logistic reasons for PATH support to the development of LAIV and paid tribute to IEM, which had facilitated the achievements of so many others in this field. Clinical trials: Dr Neuzil noted that, despite extensive data using LAIV in children since 1986, evidence was needed on use of the vaccine in younger children in a community with known high influenza incidence. PATH is thus supporting a Phase II clinical trial in children aged months in Bangladesh using the SII trivalent LAIV. The aim of the study is to collect additional safety and immunogenicity data in this age group, including wheezing, and to demonstrate efficacy and burden of illness/risk-benefit ratios in a low-resource population. The placebo-controlled, randomized trial in 300 children should provide data to inform potential continuation into Phase III and age de-escalation. Delivery devices: a major lesson learnt from the H1N1 pandemic was reliance on the delivery device to deliver the vaccine. PATH thus commissioned a landscape analysis of intranasal devices for use with live attenuated vaccines. The complex parameters for the selection of a device and the pros and cons of available models were listed. The most common hurdles encountered were cost, compatibility and scalability. Unpublished data from a recent trial comparing quadravalent prefilled drops with a trivalent spray device were presented, using HAI GMT as the primary endpoint. Both devices showed comparable immunogenicity, solicited symptoms, adverse events, as well as recipient satisfaction. In conclusion, an evaluation may be warranted of a simple dropper delivery method that is affordable and scalable for LAIV administration in a pandemic event. Formulations: A study was presented that aimed to improve significantly the stability of subunit and LAIV, and develop a process that is easy to implement in pilot scale, toxicology, and Phase I testing. The project studied freeze-, spray- and foam-drying processes using the SII LAIV monovalent bulk frozen liquid. The pros and cons of each process were discussed. Results showed that foam-drying improved stability up to 10-fold compared to freeze- and spray-drying for up to 6 months at 37 C. After 3 months, no loss of stability has been observed at 2-8 C. Data for spray-drying were inferior, but consistently better than freeze-drying. Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 15 Developing Country Vaccine Manufacturers March 2012

16 Market Authorization Options for Live Attenuated Influenza Vaccines In reviewing options for market authorization, Dr Laszlo Palkonyay distinguished between newly developed seasonal influenza vaccine and their pandemic equivalent, and LAIVs developed by adapting a licensed technology and using the same reassortant master seeds as the parent vaccine. While the standardized HAI test has been widely used since the 1970s to license IIVs, HAI response following LAIV provides biologically relevant, strain-specific functional immune response, but not a correlation with protection. The lack of a measurable efficacy marker that could be used as a correlate of protection points to reliance on large-scale efficacy studies for "new" LAIV for market authorization. Vaccines adapted from licensed LAIV as described above do not have this requirement since efficacy data already exist. Market authorization is thus based on quality considerations, biological equivalence with the licensed vaccine and safety studies, a process analogous with the annual approval of strains in licensed LAIV. Discussion Participants recommended that, following endless debate on correlates of protection for LAIV, it was urgent that WHO issue clear guidance that can inform licensing and pre-qualification pathways for this technology. LAIV is such an important vaccine that it was considered essential to identify an alternative to large-scale efficacy trials for market approval. The European Union discussions on regulatory requirements for LAIV should proceed in tandem with the development of the WHO guidelines, based on safety data and potentially post-market effectiveness trials, from which increasing data were becoming available. SII described the constraints of freeze-drying, the drawbacks of spray-drying and noted that, for foamdrying, the scalability and thermostability data in different strains are next steps to investigate after the positive preliminary data obtained at laboratory scale. It was confirmed that foam- and freeze-drying uses the same equipment and takes the same amount of time. Other issues were the need to include delivery devices early in the regulatory pathway and minimize their cost for developing countries. Manufacturers responded to questions related to the availability of their vaccines and their production capability, and IEM noted that it was not necessary to repeat trials of reassortants for seasonal vaccines each year except if a safety issue had been identified. SESSION 7. TECHNICAL ISSUES Eggs and the production of H5N1 at IVAC, Viet Nam Dr Le Kim Hoa noted that after the successful clinical trials of H1N1, high endotoxin levels were detected in their H5N1 vaccine. Data from the H1N1 trial using eggs of between weeks showed lows levels of endotoxin, while the levels in H5N1 batches, using week-old eggs, were very high. These data correlate the quality of eggs with the age of the flock, and support the industry recommendation to use eggs only from flocks of up to 40 weeks old. Other factors such as climate may also affect the quality of eggs. Studies carried out to compare the older IVAC eggs with week-old eggs procured from a local farm showed that the local farm eggs produced batches of H5N1 with much lower endotoxic and bioburden levels. Monitoring of IVAC eggs was carried out using internal SOPs, the results of which were satisfactory, except for the detection of contaminated eggs. Following an audit, new quality control tests have been implemented. The first flock has now been culled. The second, 22-week-old flock will now produce eggs for use in three commissioning batches of H5N1 vaccine; the production process is fixed and ready for material preparation for clinical trials in August

17 The inactivation process at Torlak Institute of Virology, Vaccines and Sera, Serbia Dr Aleksandar Radojevic of Torlak informed that following reconstruction of its facilities to meet GMP requirements in 2010, the Institute continues to produce whole virus inactivated seasonal influenza vaccine under fully optimized conditions. It is also able to produce monovalent vaccine for pandemic use, and has capacity to meet national needs and those of neighbouring countries. The upstream process was first described in detail, during which Torlak also works with live active virus. Following inactivation using formaldehyde, the downstream process was presented up to the point where the final monovalent bulk is stored in refrigerators ready for blending with other bulk and finalization. All processes are carried out in line with European Pharmcopaeia specifications. The timing, substances used and conditions for the critical inactivation process were described in depth, along with specific production parameters of the Institute and the validation control tests carried out. In summary, the inactivation validation process led Torlak to use 0.005% CH2O for B strain, 0.01% for H1N1 and 0.02% for H3N2, followed by 7, 5 and 5 days refrigeration, respectively. Discussion Dr Radojevic responded to questions on the choice of formaldehyde as the inactivation agent, the mixing and validation parameters, Torlak's production scale and rotation of strains, and the production process which necessitates extra storage time in refrigerators after inactivation. Whole or split? International Technology Platform for Influenza Vaccines (ITPIV) Dr Renée van Boxtel presented the activities of the ITPIV to develop and transfer influenza vaccine production capacity to developing countries. ITPIV had chosen to develop whole virion vaccines primarily for their higher immunogenicity, without the need for adjuvants, and the ease of transfer to new manufacturers. Dr Boxtel presented results after six months of their Phase I double-blind, parallel, randomized, placebo-controlled trial to compare two whole virion candidate vaccines (seasonal H3N2 and pandemic H5N1) with a commercial trivalent split vaccine. Adverse events in the 120 adults were mild and comparable in all groups; safety data showed less reactogenicity in whole virion groups than previously reported; and the immunogenicity results were excellent. Discussion It was discussed whether the excellent immunogenicity results, particularly with H5N1, were strain related or because it was a whole virion vaccine. Phase II studies, or studies on other viruses, were not planned since the purpose of the Phase I trial was to validate the process within the technology transfer project, and not with a view to licensing the vaccine. The need to plan with local authorities in the grantee countries for the timely importation of the appropriate vaccine virus strains was raised. It was agreed that, while the process was intended to be simple and affordable, the advantages of adjuvants were undeniable. This technology is increasingly available to new manufacturers from many sources and may be a good option as experience is gained in the development of highly immunogenic vaccines. Two grantees were receiving adjuvant technology transfer from the University of Lausanne, and a further grantee from IDRI. Aluminium adjuvants have not been shown to be effective with whole virion H5N1 vaccines, and would need to be split, especially for use in children. In India, H1N1 clinical trials in humans were successful using aluminium phosphate at only 10ug. Several countries have licensed alum-adjuvanted vaccines for both seasonal and pandemic use, and it was proposed that interested manufacturers consider including a group with and without alum in their trials. Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 17 Developing Country Vaccine Manufacturers March 2012

18 Purification by column chromatography to replace ultracentrifugation Development of influenza vaccine production with use of chromatographic methods at Microgen Dr Igor Krasilnikov of Microgen noted that chromatography was developed in the Russian Federation to overcome the lack of significant centrifuge capacity, and has been used to produce influenza vaccine for over 20 years. It is also used in vaccines against rabies, tick-borne encephalitis and hepatitis B. The elution profile of influenza viruses and the production process were described in detail. Adsorption chromatography on macroporous silica of the whole virion inactivated virus in allantoic fluids in a column is purified over two stages up to 99.7%. The virus is then concentrated by ultrafiltration and gel permeated chromatography, and adsorbed on aluminium hydroxide to achieve purified and concentrated virus at 0.5ml/dose. Gel chromatography has also been used to develop an inactivated avian influenza split virosomal vaccine adjuvanted with aluminium hydroxide (AviFlu). The prepandemic candidate vaccine is based on an H5N1 strain with a high-growth reassortant H5N2 strain. Results of the Phase I double-blind randomized trial in healthy adults comparing 15ug and 30ug doses showed that two doses showed low reactogenicity and induced strong antibody responses to the homologous vaccine strains. In addition, they promoted broad and persistent cross-clade immunity. Dr Krasilnikov also presented a recent comparative study in mice immunized with novel inactivated (whole and split) and live influenza vaccine prototypes with or without adjuvants after challenge with an HPAI H5N1 strain. Results showed that both H5 and H1 LAIV formulations completely protected mice from challenge. For the inactivated strains, 100% protection was seen in the whole virus H5N1 group and 58% of mice in the split H5N1 group survived. All mice died in the whole virus H1N1 and the control groups. All adjuvanted split formulations showed higher protectivity (adjuvant based on fish caviar-like particles had higher rates of protection than alum formulations). Discussion It was clarified that WHO had started to explore this technology following overwhelming difficulties in introducing centrifugation equipment to certain grantee manufacturers. Microgen gave further clarification on the how the different processes functioned, and how chromatographic methods were less expensive, simpler, and allow a more stabilized process. Influenza vaccine, Instituto Butantan, Brazil Dr Cosue Miyaki traced Butantan's history of influenza vaccine production from the initial technology transfer agreement with sanofi-pasteur to their current blending, filling and packing facility, and construction of an industrial production plant. Following pilot scale production, the Institute has produced A/H1N1 pandemic vaccine (split and whole) and working seeds for seasonal vaccine, and produced 20 million doses for the influenza campaigns. This production uses centrifugation. This presentation focused on the testing of split vs whole virus vaccines (H5N1, H1N1, H3N2 and B viruses) and an evaluation of column chromatography. The different processes used to produce split and whole vaccine were illustrated, and details of the tests for whole virus using gel filtration chromatography provided. The whole viruses gave significantly more doses per egg than the split vaccines, as did the H5N1 split vaccine with and without adjuvant compared to the other strains. Results of a Phase I clinical trial of A/H1N1 in 250 participants showed that four formulations met requirements for seroprotection: one 15ug non-adjuvanted, a 7.5ug and two 3.75ug vaccines. This showed the importance of adjuvants in accelerating the production of influenza vaccines. 18

19 Discussion Butantan explained that increasing the diameter of the column had enabled scale-up to processing large quantities from allantoic fluid; Column chromatography for the development of pandemic and seasonal influenza vaccines at RIBSP Dr Olga Chervyakova presented the work of the Research Institute for Biological Safety Problems in Kazakhstan. The process for pandemic H5N1 and H1N1 vaccine production was illustrated: after inactivation with formaldehyde, purification and filtration using Sepharose size-exclusion chromatography is carried out before the vaccine is formulated with adjuvant. Results of Phase I/II clinical trials in the age group show both vaccines to be well tolerated, safe and meet requirements on immunogenicity of inactivated influenza vaccines. Applications for government registration of Refluvac (3.75μg/dose) for A/H1N1v and Kazfluvac (7.5μg/dose) have been filed. The same technology is being used to develop a seasonal vaccine, with a modified purification process to obtain higher yields. Optimization studies on the chromatographic purification and sterilization steps have resolved the high ovalbumin concentration and virus loss experienced. Specifications of their purified vaccine bulk currently show 99.0% removal of protein, ovalbumin content <2 µg/ml; and HA yields >30%. It was concluded that tangential diafiltration in combination with column chromatography can be successfully used for influenza virus purification. The method and chromatographic profiles were the same for all virus subtypes tested. Discussion The HA yields were considered satisfactory and comparable to centrifugation, and optimization to address HA loss was experienced by other manufacturers. Discussion focused on the comparative duration of the processes, the variation in yield and purity of the various runs done on the same batch of allantoic fluid, the number of batches that a chromatography column could process before replacement, the relevance of the gel used in gel chromatography filtration, and whether the eluent used is an indicator of yield between centrifugation and chromatographic methods. Participants voiced their concerns about the high degree of variability between runs with the same batch indicating some lack of control of some parameters, and also the challenges that will be faced with different strains of influenza and upscaling. Participants agreed that chromatographic methods could be useful for the production of influenza vaccines. Studies should further compare in parallel centrifugation with chromatographic methods and the reproducibility of the process across batches and challenges to upscaling. SESSION 8. PANEL SESSION ON TRAINING Dr Claudia Nannei (WHO) moderated this session, highlighting the range of partners involved in training activities relevant to developing country vaccine manufacturers. The RIVM as knowledge and training centre (the Netherlands) Dr Marit Holleman presented the training courses offered by the National Institute of Public Health and the Environment (RIVM) in support of the GAP. Whether generic, tailored or through bilateral agreements, RIVM provides technical, process and production technology, documentation and clinical support to developing country vaccine manufacturers, with emphasis on hands-on learning. To date, 65 training courses have been carried out involving 85 institutes, more recently including the production of split vaccines. Future courses will focus on NRAs and start-up biotechnology Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 19 Developing Country Vaccine Manufacturers March 2012

20 companies, and on critical quality attributes for the preparation of influenza vaccines and assay validation. Biomanufacturing Training and Education Center's (BTEC) International Influenza Vaccine Manufacturing Training Program (South Carolina, USA) Dr Ruben Carbonell described BTEC's process development and analytical services to prepare an industry-ready workforce through hands-on training. The facilities, launched at Research Triangle Park, USA in 2007 are extensive and cover small- to industrial-scale capacity. Dr Carbonell described the comprehensive syllabus on fundamental cgmp influenza manufacturing, and courses on advanced downstream and upstream processes, the latter focusing on cell processes. Regulatory aspects are included in all courses, which are continuously assessed, and a visit to a neighbouring operating plants is included. The Centre has also initiated comprehensive on-line tools and customized courses. Center for Integrated Biosystems, Utah State University (USA) Dr Kamal Rashid presented the training programme of the Centre, as well as its research and core facility services such as genomics, procurement and bioprocessing. Since 2010, under the auspices of BARDA, the Institute for Antiviral Research has been developing novel influenza virus vaccines. A highly qualified and experienced team provides training in egg and cell cultures, with a particular emphasis on chromatographic methods. The comprehensive courses cover start-up to downstream activities, including an adjuvant programme, with a significant hands-on content, and are suitable for all levels of students from undergraduate to FDA specialists. The Vaccine Formulation Laboratory (VFL), University of Lausanne, Switzerland Dr Nicolas Collin illustrated the objective of the Adjuvant Hub and Training Centre on Vaccine Formulation to develop the sustainable manufacture of adjuvanted pandemic vaccines in developing countries. One year after launching the transfer of a squalene-in-water adjuvant technology to BioFarma, Indonesia, stability tests on initial lots produced under GMP and QC conditions are very good. The Institute is now optimizing the process development, producing new adjuvant lots, and has evaluated an adjuvanted BioFarma H5N1 vaccine in preclinical trials. Since this initial BARDA project, the VFL has expanded its staff, its collaborative activities and its adjuvant portfolio. Dr Collin summarized the support that the VFL platform can provide to vaccine developers, whether in the choice of adjuvant, advice on its formulation with the antigen, quality control or preclinical trials. Adjuvant technology for pandemic influenza vaccines, IDRI (USA) Dr Chris Fox described IDRI's capabilities and accomplishments related to adjuvants and formulations in the state-of-the-art facilities in Seattle. Complementing the VLP goals, Dr Fox reiterated the benefits of adjuvants and how IDRI facilitated public sector access to the technology and formulation know-how in developing countries. Two clinical trials of GLA-SE adjuvant for influenza have been completed, and many more are in the pipeline. Increased and broadened HAI antibody responses were achieved in a study in mice in an inactivated influenza vaccine adjuvanted with an oil-in-water emulsion. Significantly, clinical data showed that a GLA-SE adjuvanted H5N1 recombinant vaccine required >30 times less protein to achieve a far superior immune response. The technology transfer model for adjuvants starts with selection of the appropriate adjuvant and establishment of the necessary infrastructure. While awaiting completion of this stage, staff are trained with decreasing supervision to become proficient in producing adjuvant lots and the mixing process with locally-produced antigen. Dr Fox summarized the transfer of a complete oil-in-water emulsion technology to Cantacuzino in Romania, a project that with a minimum budget has rapidly progressed to preclinical evaluation of adjuvanted vaccine with its own antigen. This experience and others in developing countries have informed a working technology transfer model that can be applied in other institutes. 20

21 Discussion It was emphasized that most training courses, and all technology transfer projects, were tailor-made. Questions related to access to the technologies; the use of immunostimulants; the need for harmonized guidelines on adjuvanted vaccines for regulatory approval; the relevance of cell-culture training for developing countries; and different approaches to measuring impact. Opportunities for training national control laboratories and regulatory authorities in parallel to manufacturers were also discussed. WHO invited DCVMs to a one-to-one session with the panel of training centres on 29 March with a view to discuss specific training needs and tailoring available courses to them. CLOSING SESSION The Chair summarized the major avenues that had been explored during this 5 th meeting of partners of the WHO Technology Transfer Initiative. While applauding the achievements towards the overall objectives, Dr Robertson noted that sustainability was an issue of growing concern. Increasing demand for influenza vaccine, along with exploring parallel production options for facilities were areas for priority attention. A critical area identified during the technical sessions was the urgent need for WHO guidelines to accelerate market authorization of LAIVs. Other technical areas for further research included devices and the promising avenue of chromatographic methods for purification of the virion. The Chair thanked all participants, the speakers and WHO for organizing the meeting, particularly Dr Kieny and her team. In her closing remarks, Dr Kieny felt that all the partners working together to achieve the goals of the GAP should be proud of their achievements. She extended her thanks to members of the GAP Advisory Group, who will review the progress with vaccine manufacturing capacity within the broader objectives of the GAP; and to members of the Technical Advisory Group for their oversight and individual support to each project. Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 21 Developing Country Vaccine Manufacturers March 2012

22 ANNEX I FIFTH MEETING WITH INTERNATIONAL PARTNERS ON PROSPECTS FOR INFLUENZA VACCINE TECHNOLOGY TRANSFER TO DEVELOPING COUNTRY VACCINE MANUFACTURERS March 2012 Hotel Hyatt Regency, Belgrade, Serbia AGENDA Chair: J. Sokhey DAY 1 SUSTAINABILITY 8:00 8:45 Registration 8:45 9:15 Welcome address and opening remarks MP Kieny, B. Lazic 9:15 9:30 Second Consultation on the Global Action Plan for Influenza Vaccines MP Kieny 9:30 9:50 BARDA international influenza programmes R. Bright 9:50 10:30 Updates 9:50 10:00 SAGE J. Tam 10:00 10:10 5th Meeting on Influenza Vaccines that Induce Broad Spectrum and J. Tam Long-lasting Immune Responses (16-17 November 2011) 10:10 10:20 Workshop on Enhancing the Global Workforce for Vaccine Manufacturing (30 Nov - 2 Dec 2011, Cape Town, South Africa) C. Nannei 10:20 10:30 Workshop on international regulatory capacity enhancement for influenza C. Alfonso vaccines (8-10 June 2011, São Paulo, Brazil) 10:30 11:00 Session 1 - Sustainability and multiuse facilities 10:30 10:50 Multiproduct Vaccine Manufacturing Facility feasibility study R. Huebner 10:50 11:00 Discussion 11:00 11:30 Coffee break 11:30 12:30 Session 2 - Sustainability through production of veterinary vaccines in human facilities 11:30 11:45 Production of chicken vaccines from eggs. Flu, Newcastle disease, others M. Friede 11:45 12:05 Regulatory challenges to production of veterinary vaccines in human L. Palkonyay facilities 12:05 12:30 Discussion on other technical issues, e.g. access/supply of avian seed All strains, economics 12:30 14:00 Lunch 14:00 15:00 Session 3 - Reverse genetics issues (human and veterinary) Chair: M. Friede 14:00 14:20 Summary of existing reverse genetics methods and their limitations for O. Engelhardt production of influenza candidate vaccine viruses 14:20 14:50 IP landscape D. Marks 14:50 15:00 Discussion 15:00 15:30 Coffee break 15:30 16:00 Session 4 - Gathering evidence on vaccine use 15:30 15:50 Demand for Influenza Vaccine Economic Analysis and Burden of Disease Assessment 15:50 16:00 Discussion 16:00 16:30 Session 5 - Regulatory pathways and processes for influenza vaccines 16:00 16:20 WHO Regulatory capacity strengthening and institutional development plans: relevance to the regulatory oversight of influenza vaccines D. Miller C. Alfonso 16:20 16:30 Discussion 16:30 16:50 New grantees projects 16:30 16:40 Presentation by RIBSP, Kazakhstan B. Khairullin 16:40 16:50 Presentation by BIOVAC, South Africa P. Tippoo 16:50 17:00 Wrap-up Chair 17:00 End of Day 1 22

23 ANNEX I FIFTH MEETING WITH INTERNATIONAL PARTNERS ON PROSPECTS FOR INFLUENZA VACCINE TECHNOLOGY TRANSFER TO DEVELOPING COUNTRY VACCINE MANUFACTURERS March 2012 Hotel Hyatt Regency, Belgrade, Serbia AGENDA Chair: J. Robertson DAY 2 - TECHNICAL ISSUES 9:00 9:20 From start to approval: lessons learnt - SII R. Dhere 9:20 11:00 Session 6 - LAIV development 9:20 9:40 New developments in LAIV L. Rudenko 9:40 9:55 Lessons learnt - GPO S. Thirapakpoomanunt 9:55 10:10 PATH LAIV development pathway (forthcoming trials) K. Neuzil 10:10 10:25 Devices (nasal devices; spray vs drops)(stability and stabilization) K. Neuzil 10:25 10:40 Regulatory issues for LAIV vaccines L. Palkonyay 10:40 11:00 Discussion 11:00 11:30 Coffee Break 11:30 12:45 Session 7 - Technical issues 11:30 11:45 Eggs: ageing flocks Le Kim Hoa 11:45 12:00 Inactivation processes A. Radojevic 12:00 12:15 Whole or split? R. van Boxtel 12:15 12:45 Any other issues? Discussion All 12:45 14:15 Lunch - Regulators Networking Lunch 14:15 15:15 Session 7 cont'd - Technical issues Purification by Column Chromatography to replace Ultracentrifugation 14:15 14:30 Microgen experience I. Krasilnikov 14:30 14:45 Butantan experience C. Myiaki 14:45 15:00 RIBSP experience O.V. Chervyakova 15:00 15:15 Discussion 15:15 15:45 Coffee Break 15:45 16:45 Session 8 - Training Moderator: C. Nannei 15:45 16:40 Panel session with trainers M. Holleman K. Rashid R. Carbonell N. Collin C. Fox 16:40 16:45 Presentation of Trainer - Trainees session (29 March) 16:45 17:15 General discussion Chair 17:15 17:30 Wrap-up and conclusion Chair 17:30 17:30 Close of meeting Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 23 Developing Country Vaccine Manufacturers March 2012

24 ANNEX II FIFTH MEETING WITH INTERNATIONAL PARTNERS ON PROSPECTS FOR INFLUENZA VACCINE TECHNOLOGY TRANSFER TO DEVELOPING COUNTRY VACCINE MANUFACTURERS March 2012 Hotel Hyatt Regency, Belgrade, Serbia LIST OF PARTICIPANTS PARTICIPANTS/OBSERVERS Mr Christian Bachoffen, Mibiotec Ltd., Worblaufen, Switzerland Dr David Behnam, Pandemic Preparedness Initiative, Division for Health, Education, Social Protection, Deutsche Gesellschaft für Internationale Zusammenarbeit GmbH, Eschborn, Germany Dr John Boslego, Director, Vaccine Development Strategic Program, Program for Appropriate Technology in Health, Washington, United States of America Dr Joseph S. Bresee, Commissioned Corps (Medical OFC), Centers of Disease Control, Atlanta, United States of America Dr Rick Bright, Deputy Director, Influenza Division, Office of Biomedical Advanced Research & Development Authority (BARDA), US Department of Health and Human Services (HHS), Washington, United States of America Dr Iskandar Obih Buhori, President Director, PT Bio Farma (Persero), Bandung, Indonesia Professeur Daniel Camus, Institut Pasteur de Lille, Lille Cedex, France Dr Ruben Carbonell, Biomanufacturing Training and Education Center, North Carolina State University, Raleigh, United States of America Mr Rajko Cebedzic, Senior Adviser for Microbiological testing, Biological Laboratory, National Control Laboratory, Medicines & Medical Devices Agency of Serbia, Belgrade, Serbia Ms Sandra Cerin, Public Relations Manager, Institute of Virology, Vaccines and Sera Torlak, Belgrade, Serbia Dr Rocio Cervantes Rosales, Assistant Director General of Operations, Laboratorios de Biológicos y Reactivos de México S.A. de C.V. (BIRMEX), México, Mexico Dr Olga Victorovna Chervyakova, Senior Scientist, Research Institute for Biological Safety Problems, Gvardeiskiy, Kazakhstan Dr Nicolas Collin, Head, Vaccine Formulation Laboratory, University of Lausanne, Epalinges sur Lausanne, Switzerland Dr Otto de Boer, Cib/Vaccinology, National Institute for Public Health and Environment (RIVM), Bilthoven, Netherlands Mr Marshall Denton, COO, Wolfe Tory Medical, Salt Lake City, United States of America Dr Rajeev M. Dhere, Director, Vaccine Production, Serum Institute of India Ltd, Pune, India Dr Othmar Engelhardt, Principal Scientist, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom of Great Britain and Northern Ireland Dr Chris Fox, Infectious Disease Research Institute, Seattle, United States of America Dr Donald P. Francis, Executive Director, Global Solutions for Infectious Diseases, South San Francisco, United States of America Professor Hadi Famil Ghadakchi, Director General, Razi Vaccine & Serum Research Institute, Alborz, Iran (Islamic Republic of) Dr Mohammad Gheisarzadeh, Head of Biologic Department, Food and Drug Organization, Ministry of Health & Medical Education, Tehran, Iran (Islamic Republic of) Dr Gary Grohmann, (Adjunct Associate Professor-Immunology & Infectious Diseases-University of Sydney), Campbell, Australia Mr Henning Haltrup, Sales Director, NNE Pharmaplan, Soborg, Denmark Dr Norbert Hehme, IFPMA - IVS Chairman, Vice President, Global External Relations, GlaxoSmithKline Biologicals SA, Dresden, Germany Dr Klaus Hermansen, Senior Specialist, Consulting, NNE Pharmaplan, Soborg, Denmark 24

25 Dr Le Kim Hoa, Vice Director, Quality Control & Quality Assurance, Institute of Vaccine and Medical Biologicals, Nha Trang, Viet Nam Dr Marit Holleman, Advisor Strategy & Policy, National Institute for Public Health and Environment (RIVM), Bilthoven, Netherlands Dr Robert Huebner, Deputy Director - Influenza Division, Biomedical Advanced Research & Development Authority (BARDA), US Department of Health and Human Services (HHS), Washington, United States of America Mr Chuong Huynh, Project Officer, Division of Influenza, Office of Biomedical Advanced Research & Development Authority (BARDA), US Department of Health and Human Services (HHS), Washington, United States of America Dr Berik Khairullin, Deputy Director, Research Institute for Biological Safety Problems, Gvardeiskiy, Kazakhstan Dr Vesna Kovacevic Jovanovic, Executive Director, Institute of Virology, Vaccines and Sera Torlak, Belgrade, Serbia Dr Igor Krasilnikov, Consultant, Moscow, Russian Federation Dr Rosanna Lagos, Coordinadora, Centro para vacunas en Desarollo-Chile, Hospital de Niños Roberto del Rio, Santiago, Chile Mr Eric Laurent, Consultant, Geneva, Switzerland Dr Yupin Lawanprasert, Senior Adviser in Safety, Effectiveness and Use of Health Products, Food and Drug Administration, Nonthaburi, Thailand Dr Branislav R. Lazic, Managing Director, Institute of Virology, Vaccines and Sera Torlak, Belgrade, Serbia Mr Kritsada Limpananont, Pharmacist, Biological Products Section, Drug Control Division, Ministry of Public Health, Bangkok, Thailand Dr David Marks, Senior Commercialization Officer, Vaccine Development Global Program, Program for Appropriate Technology in Health, Seattle, United States of America Dr Mauricio Meros de Oliveira, Production Department, Fundação Butantan, São Paulo, Brazil Dr Daniel S. Miller, Director, International Influenza Unit, Department of Health and Human Services, Washington, United States of America Mr Robert Mischler, Mibiotec Ltd., Worblaufen, Switzerland Dr Cosue Miyaki, Production Department, Fundação Butantan, São Paulo, Brazil Dr Rajiv Modi, Managing Director, Cadila Pharmaceuticals Limited, Ahmedabad, India Dr Ali Akbar Mohammadi, Executive Director, Global Health & Security Consultants, Geneva, Switzerland Mrs Norma Morales Villa, Manager, Analysis and Immunologic and Biochemical Testing, Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS), Mexico City, Mexico Ms Tamara Music, Manager, Influenza Vaccines & Code Compliance, International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), Geneva, Switzerland Dr Abdulsalami Nasidi, Project Director, Nigeria Centre for Disease Control, Asokoro, Abuja, Nigeria Dr Jasminka Nedeljkovic, Head of Respiratory Department, Reference Laboratory for Respiratory Viruses, Institute of Virology, Vaccines and Sera Torlak, Belgrade, Serbia Dr Zsolt Nemeth, Director for International Cooperation, Omninvest Ltd, Budapest, Hungary Dr Kathleen Neuzil, Senior Clinical Adviser, Program for Appropriate Technology in Health (PATH), Seattle, United States of America Dr Nhung Hong Nguyen, Pharmacist, Drug Registration Division, Drug Administration of Vietnam, Hanoi, Viet Nam Dr Michael Perdue, Consultant, Hilo, United States of America Dr Yuri Pervikov, Consultant, Geneva, Switzerland Dr Herve Pinton, Expertise & Technical Innovation, Sanofi Pasteur, Marcy-l'Etoile, France Ms Lora Polowczuk, International Health Analyst, International Influenza Unit, US Department of Health and Human Services (HHS), Washington, United States of America Dr Samuel Ponce de Leon, General Director, Laboratorios de Biologicos y Reactivos de Mexico, S.A. de C.V, Mexico, Mexico (unable to attend) Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 25 Developing Country Vaccine Manufacturers March 2012

26 Ms Ljubica Popovic, Head, National Control Laboratory, Medicines & Medical Devices Agency of Serbia, Belgrade, Serbia Dr Firdausi Qadri, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh Dr Aleksandar Radojevic, Associate in Influenza Vaccine Production Department, Institute of Virology, Vaccines and Sera Torlak, Belgrade, Serbia Dr Kamal A. Rashid, Associate Director, Center for Integrated BioSystems, Utah State University, Logan, United States of America Dr Mohamed Refaat Abdelfattah, Inspector Pharmacist, Biological Products Inspectorate, Central Administration of Pharmaceutical Affairs, Cairo, Egypt Dr Emmanuel Regulier, R&D Manager, Biogenesis Bago S.A., Garin - Buenos Aires, Argentina Dr Daniel Reynders, Head of Service, International Relations, Federal Public Service, Brussels, Belgium (unable to attend) Dr James S. Robertson, Principal Scientist, Virology, National Institute for Biological Standards and Control (NIBSC), Health Protection Agency, Potters Bar, United Kingdom of Great Britain and Northern Ireland Professor Larisa Georgievna Rudenko, Head, Department of Virology, Uchrezdenie of Russian Academy of Medical Sciences, St. Petersburg, Russian Federation Dr Jennifer Ruiz, Utah State University, Logan, United States of America Dr Jean-François Saluzzo, Consultant, La-Gaude, France Dr Pathom Sawanpanyalert, Director, Department of Medical Sciences, Center for International Cooperation, National Institute of Health, Muang Nonthaburi, Thailand Dr Rumondang Simanjuntak, Senior GMP Inspector, Ministry of Health, Jakarta, Indonesia Ms Vera Simic, Senior Associate in Microbiological Testing, Biological Laboratory, National Control Laboratory, Medicines & Medical Devices Agency of Serbia, Belgrade, Serbia Dr Surinder Singh, Director, National Institute of Biologicals, Noida, Uttar Pradesh, India Dr Amine Slim, Head, Microbiology Department, National Influenza Centre, Charles Nicolle Hospital, Tunis, Tunisia Mrs Dragana Smidling-Koruga, Head of Biological Laboratory, National Control Laboratory, Medicines & Medical Devices Agency of Serbia, Belgrade, Serbia Dr Sam Soeharto, PT Bio Farma (Persero), Bandung, Indonesia Dr Jaspal Sokhey, Consultant, New Delhi, India Professor André Spiegel, Administrateur général, Institut Pasteur de Dakar, Dakar, Senegal Dr Marijana Stojanovic, Institute of Virology, Vaccines and Sera Torlak, Belgrade, Serbia Dr Mahendra Suhardono, Production Director, Bio Farma, Bandung, Indonesia Dr Kandaswamy Sumathy, Associate Director R&D, Bharat Biotech International Limited, Hyderabad, India Dr Teiji Takei, Director, International Cooperation Office, Ministry of Health, Labour and Welfare, Tokyo, Japan Dr Bart Tarbet, Institute for Antiviral Research, Utah State University, Logan, United States of America Ms Mirela Tavakol, Head of Biological Department, National Medicines Agency, Bucharest, Romania Dr Beverly Taylor, IFPMA - IVS SPR Coordinator, Head of Technology and Scientific Affairs, Novartis Vaccines & Diagnostics Ltd, Liverpool, United Kingdom of Great Britain and Northern Ireland Mr Sit Thirapakpoomanunt, Director of the Viral Division, The Government Pharmaceutical Organization, Bangkok, Thailand Mr Patrick Tippoo, R&D Manager, Biovac Institute, Pinelands, South Africa Dr Vadim Tsvetnitsky, Vaccine Development Global Program, PATH, Washington, United States of America Dr Renée van Boxtel, Clinical and Regulatory Research, National Institute for Public Health and the Environment, Bilthoven, Netherlands Dr Ruth Velazquez Fernandez, Head of Influenza Project, Laboratorios de Biologicos y Reactivos de Mexico, S.A. de C.V, Cuautitlán Izcalli, Mexico Dr Ana Vidmanic, Deputy Director Virological Production, OPV Production Department, Institute of Virology, Vaccines and Sera Torlak, Belgrade, Serbia Dr Niteen Wairagkar, Senior Program Officer, Infectious Diseases, Global Health Program, The Bill & Melinda Gates Foundation, Seattle, United States of America 26

27 Dr Suwit Wibulpolprasert, Senior Advisor on Health Economics, Ministry of Public Health, Nonthaburi, Thailand Dr Jinchang Wu, Director R&D, International Affairs, Changchun BCHT Biotechnology Co., Changchun, Jilin, People's Republic of China Dr Hamdallah H. Zedan, Chairman & CEO of EGYVAC, The Egyptian Organization for Biological Products and Vaccines (Vacsera), Cairo, Egypt Dr Gerd Zettlmeissl, Consultant, Vienna, Austria WHO SECRETARIAT Dr Claudia Alfonso, Scientist, Quality, Safety and Standards, Family, Women's and Children's Health, Geneva, Switzerland Ms Florence Barthelemy, Team Assistant, Technology Transfer Initiative, Innovation, Information, Evidence and Research, Geneva, Switzerland Ms Kay Bond, Consultant, Geneva, Switzerland (Rapporteur) Dr Martin Friede, Scientist, Technology Transfer Initiative, Innovation, Information, Evidence and Research, Geneva, Switzerland Dr Marie-Paule Kieny, Assistant Director-General, Innovation, Information, Evidence and Research, Geneva, Switzerland Dr Houda Langar, Regional Adviser, Essential Vaccines and Biologicals Policy, Division of Health Systems and Services Development, Cairo, Egypt Ms Claudia Nannei, Technical Officer, Public Health, Innovation and Intellectual Property, Innovation, Information, Evidence and Research, Geneva, Switzerland Dr Dorit Nitzan, WHO Representative, Belgrade, Serbia (unable to attend) Dr Laszlo Palkonyay, Scientist, Quality, Safety and Standards, Family, Women's and Children's Health, Geneva, Switzerland Dr Dina Pfeifer, Medical Officer, Vaccine Preventable Diseases and Immunization, Copenhagen, Denmark (unable to attend) Mr James Pfitzer, Technical Officer, Technology Transfer Initiative, Innovation, Information, Evidence and Research, Geneva, Switzerland Dr Analia Porras, Medicines and Health Technologies, Washington, United States of America Dr Yoshikuni Sato, Medical Officer, Expanded Programme on Immunization, Manila, Philippines Ms Erin Sparrow, Project Officer, Technology Transfer Initiative, Innovation, Information, Evidence and Research, Geneva, Switzerland Dr John S. Tam, Technical Officer, Initiative for Vaccine Research, Immunization, Vaccines and Biologicals, Family, Women's and Children's Health, Geneva, Switzerland Mr Guido Torelli, Administrative Officer, Technology Transfer Initiative, Innovation, Information, Evidence and Research, Geneva, Switzerland Report of the Fifth Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to 27 Developing Country Vaccine Manufacturers March 2012

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