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Report of the Second WHO Informal Consultation held in Geneva, Switzerland Influenza Vaccine Response during the Start of a Pandemic 21 July - 22 July 2016

Influenza Vaccine Response during the Start of a Pandemic · 2016. 7. 22. · Risk Management (PIRM) — WHO interim guidance (ref 1). The WHO PIRM framework provides flexibility

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Page 1: Influenza Vaccine Response during the Start of a Pandemic · 2016. 7. 22. · Risk Management (PIRM) — WHO interim guidance (ref 1). The WHO PIRM framework provides flexibility

Report of the Second WHO Informal Consultation held in Geneva, SwitzerlandInfluenza Vaccine Response during the Start of a Pandemic

21 July - 22 July 2016

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Ordering code: WHO/HSE/PED/GIP/EPI/2017.1

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i

Influenza Vaccine Response during the Start of a Pandemic

ContentsExecutive Summary i

1. Introduction and Scope of Meeting 1

2. Reports of key international pandemic influenza preparedness activities 2

3. Organization of the Consultation 5

4. Refinement of the process for pandemic vaccine response 5

5. Principles and bottlenecks in making the switch from seasonal to pandemic vaccine production 6

6. Key Outcomes of the Meeting and Next Steps 13

7. References 14

8. Abbreviations 14

9. Acknowledgements 15

10. Annexes 15

1. Scenarios2. Draft operational framework for pandemic vaccine response3. Timelines of pandemic vaccine production4. Process of the WHO vaccine response to an influenza pandemic or a potential pandemic5. Further activities: the “Parking Lot”6. List of Participants

Report of the Second WHO Informal Consultation held in Geneva, Switzerland – 21 July - 22 July 2016

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Executive Summary

i

In June 2015, the World Health Organization (WHO) held an Informal Consultation to bring together key stakeholders to address questions associated with vaccine response at the start of an influenza pandemic and, in particular, the strategic problems associated with switching from seasonal influenza vaccine production to pandemic vaccine production (switch). The 2015 Consultation clarified some of the complexities associated with the switch and identified key actions and challenges. However, several gaps remained in both knowledge and planning.

A second Informal Consultation was held by WHO in June 2016. The main goal of the 2016 consultation was to work to bridge these gaps by better understanding the complexities of the early stages of pandemic vaccine development; elaborating the principles that could guide the decision to switch; obtaining a better understanding of the evidence or data needed to support the decision-making process; and prioritizing the technical actions needed to overcome any bottlenecks in pandemic vaccine production.

The main outcomes of the meeting were:• The decision to switch is complex and multi-

faceted and will involve nearly all parts of the influenza community. An integrated approach could be achieved by establishing an international expert group tasked with making such a recommendation to WHO.

• Greater clarity and transparency is needed in the decision-making process, which will be enhanced by elaborating the principles involved in making such a decision. Several principles were proposed during the Consultation.

• National and international decision makers should be made aware of the complex issues associated with the decision to switch.

• As identified during the first consultation, there are several potential technical bottlenecks which could severely interfere with pandemic vaccine development. These were discussed and solutions were proposed. The next steps would be to convene expert groups in order to address potential solutions in greater depth.

• The feasibility of establishing a publicly funded small scale GMP pilot lot vaccine production facility should be explored. The facility could be used in the early stages of pandemic vaccine development by assessing CVV yield; assessing biosafety; producing pilot lots of vaccine for evaluation of process yield and for clinical evaluation; supplying antigen for potency reagents; and establishing diagnostic capacity.

• Three charts were finalized during the consultation (the operational framework for pandemic vaccine response; timelines of pandemic vaccine production; process of the WHO vaccine response to an influenza pandemic or a potential pandemic). These are intended for inclusion in the final version of the PIRM Framework document.

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Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT |

1. Introduction and Scope of the Meeting

1

In June 2013, WHO published a revision of the pandemic influenza preparedness and response guidance entitled Pandemic Influenza Risk Management (PIRM) — WHO interim guidance (ref 1). The WHO PIRM framework provides flexibility to countries for risk-based national response, including pandemic influenza vaccine response. In order to ensure rapid and adequate production anddeployment of pandemic influenza vaccines, taking into consideration seasonal epidemicswhich may be severe and occur concurrently at the start of a pandemic, there is apressing need to review the whole process from identification of the pandemic virus through to vaccines being available for use.

In June 2015, the first WHO Informal Consultation was held (http://www.who.int/influenza/resources/publications/influenzavaccineresponse_meeting01/en/) in order to bring together key stakeholders to address questions associated with pandemic vaccine response at the start of an influenza pandemic and to identify and discuss the strategic problems around switching from seasonal influenza vaccine production to pandemic vaccine production.

The Consultation clarified some of the enormous complexities at national, regional and global levels with the various public and private partners involved and an “operational framework for pandemic vaccine response was drafted”. While a common understanding of an effective pandemic vaccine response was established at the first Consultation, key

challenges were also identified including: risk assessment; availability of candidate vaccine viruses (CVVs) and reagents; clinical trials; regulatory procedures; bottlenecks involved in production of seasonal vaccines and in the switch to pandemic vaccine production; and programmatic issues involved in vaccine “roll out”. Also adding to the complexity was the possible need for the use of seasonal vaccines at the start of a pandemic.

One of the key recommendations from the first WHO Consultation was that WHO, through its advisory bodies, shall recommend the start of pandemic influenza vaccine production based on risk assessment. It was also recommended that the PIRM be updated from the earlier “interim” 2013 version and finalized based on the outcome of the WHO Consultation.

The Second Informal Consultation was held in June 2016. Its main objectives were to:

• Better understand the complexities and strategies for pandemic vaccine response at the start of a pandemic through discussion of different pandemic scenarios;

• Elaborate the principles that will guide the decision to switch from production of seasonal vaccine to pandemic vaccine;

• Better understand the evidence or data needed to support the decision-making process;

• Prioritize the technical actions needed to overcome any bottlenecks in pandemic vaccine production; and

• Finalize the draft “operational framework for a pandemic vaccine response” and use this to finalize the WHO PIRM Framework.

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This information considerably helped the discussions in 2015, but needed updating for the second consultation in 2016. In addition there were other activities that need some explanation in order that participants could fully contribute to the second consultation.

2.1 The key players in WHO decision- making at the start of pandemic influenza vaccine production

WHO will engage all expertise inside and outside of the organization needed for the decision making, including but not limited to the following WHO programmes and advisory bodies:• Global Influenza Programme including

WHO Global Influenza Surveillance and Response System (GISRS) and PIP Framework Secretariat

• Initiative for Vaccine Research including GAP

• Technologies Standards and Norms including vaccine regulation

• Global Capacities, Alert and Response including IHR

• Strategic Advisory Group of Experts (SAGE) on Immunization

• IHR Emergency Committee

2.2 Pandemic Influenza Risk Management (PIRM)

As reported in the first consultation, the WHO published in 2013 a revision of the influenza preparedness and response guidance, entitled “Pandemic Influenza Risk Management (PIRM) – WHO interim guidance”. The PIRM Framework provides high-level guidance on risk management of pandemic influenza, but

It was emphasized that both the first and the second consultations were designed specifically to address issues and difficulties in producing pandemic vaccines at the start of a pandemic and not to address other different but possibly related issues surrounding pandemic vaccine production and use.

Thirty-eight participants from 24 countries were drawn from WHO Collaborating Centres (WHO CCs), National Influenza Centers (NICs), WHO Essential Regulatory Laboratories (ERLs), academic research community, National Regulatory Authorities (NRAs), national/regional public health agencies, vaccine manufacturers, International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), Developing Countries Vaccine Manufacturers Network (DVVMN) and other stakeholders.

2. Reports of key international pandemic influenza preparedness activities

At the start of the first consultation, background information was provided to bring all participants up to date on some key international pandemic influenza preparedness activities:• WHO Pandemic Influenza Risk Management

(PIRM) Framework (ref 1)• The International Health Regulations

(IHR) 2005 (ref 2)• The Pandemic Influenza Preparedness

(PIP) Framework (ref 3)• The WHO Global Action Plan for Influenza

Vaccines (GAP) (ref 4)

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the section on pandemic influenza vaccines still needs completion. The two WHO consultations on Influenza Vaccine Response during the Start of a Pandemic should enable the PIRM Framework to be completed with the inclusion of the operational framework and the practical issues associated with pandemic vaccine development and, in particular, those associated with switching from seasonal vaccine to pandemic vaccine production.

2.3 Tool for Pandemic Influenza Risk Assessment (TIPRA) (http://www.who.int/influenza/areas_of_ work/human_animal_interface/tipra/en/)

One of the main components of the PIRM Framework is the country-specific risk assessment of the pandemic potential of a newly detected influenza virus, taking into account the global risk assessment conducted by WHO. TIPRA provides the means by which countries, regions and WHO (at a global level) can conduct standardized hazard assessment. TIPRA attempts to answer questions such as, “what is the risk of sustained human-to-human transmission of the virus; specifically, what is the likelihood and what is the likely impact?”. There are 11 steps in the TIPRA process and during its development, it has been tested several times in simulation exercises before Version 1 was launched in May 2016 (http://apps.who.int/iris/bitstream/10665/250126/1/WHO-OHE-PED-GIP-2016.3.pdf).

2.4 Global Action Plan for Influenza Vaccines (GAP)

As reported during the first consultation, the Global Action Plan for Influenza Vaccines (GAP) is a comprehensive strategy to reduce the global shortage of influenza vaccines for seasonal epidemics and pandemic influenza in all countries

through three major approaches:1. Increase in seasonal vaccine use.2. Increase in vaccine production capacity.3. Research into more effective vaccines. Another important component is sustainability of any improvements made.

GAP started in 2006 and there has been considerable progress since then, with nine approved new vaccines (6 pandemic and 3 seasonal vaccines) with some of the vaccines being prequalified for possible UN use. GAP will end in 2016, when there will be a review taking account of opinions from stakeholders around the world (http://www.who.int/influenza_vaccines_plan/en/).

2.5 Standard Material Transfer Agreements 2 (SMTA2) (http://www.who.int/influenza/pip/ benefit_sharing/smta2/en/)

Under the PIP Framework, a non-GISRS institution that receives PIP biological materials from a GISRS laboratory is required to complete a Standard Material Transfer Agreement 2 (SMTA2) with WHO. The SMTA2 is a legally-binding contract to ensure that manufacturers of vaccines, antivirals and diagnostic products and research institutions that receive PIP biological materials share with WHO some of the benefits arising from their access to the PIP biological materials. Possible benefits include pandemic influenza vaccines, antiviral medicines and other pandemic related products or technologies.

In terms of vaccine manufacturers, WHO strategy was first to reach agreement with manufacturers that had prequalified vaccines and had export experience. At the

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time of the second consultation, WHO had concluded or was in formal negotiation with seven large vaccine manufacturers and was in informal negotiations with two other manufacturers having prequalified vaccines. For manufacturers of diagnostic materials, WHO was in formal negotiations with two large manufacturers and a number of smaller manufacturers. Forty-seven academic and research institutions from around the world had already signed SMTA2s and 19 had agreed to provide some benefits. In addition, WHO will be consulting widely to examine the various options for effective deployment of influenza vaccines.

2.6 The IFPMA perspective on the initiation of pandemic vaccine production

Before the PIRM Framework was adopted, vaccine manufacturers had a clear signal to start pandemic vaccine production when WHO had declared pandemic phase 6 of the former WHO pandemic guidance was declared by WHO. At present, the PIRM Framework gives responsibility to countries and regions for pandemic response based on its own risk assessment, but the World Health Assembly clearly noted that the initiation of pandemic vaccine production is the responsibility of vaccine manufacturers (ref 6), leading to considerable uncertainty surrounding the decision to initiate pandemic vaccine production. Given the interconnected nature of vaccine manufacturers and countries, they need:

• A clear international signal of when to switch from seasonal to pandemic vaccine production;

• Clear identification of roles and responsibilities of key stakeholders involved in the decision-making process; and

• Clarity and transparency in the decision-making process.

2.7 The USA plan to mitigate vaccine mismatch risk

During the 2014-2015 northern hemisphere influenza season, there was late emergence of an influenza A (H3N2) virus which led to a vaccine mismatch and reduction in vaccine effectiveness (http://ecdc.europa.eu/en/publications/Publications/RRA-InfluenzaA-H3N2-Dec-2014.pdf http://www.nature.com/articles/srep15279). As a result of a USA government enquiry, the HHS organized an interagency consultation to try to develop a plan to mitigate the risk of a vaccine mismatch. There are elements of this plan that have synergy with improving the decision-making process for a pandemic vaccine switch, e.g. improving CVV and reagent availability and improving the yield of high-growth reassortants. The proposal from the consultation is that the USA decision on seasonal vaccine strains could be in stages, with the possibility of one vaccine strain decision being delayed until April 15th.

The most relevant message from the USA consultation is to take steps to be better prepared to make a vaccine strain change, whether it be seasonal or pandemic.

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3. Organization of the Consultation

After hearing the progress reports described above and in order to stimulate discussion to address the main objectives of the consultation, participants were provided with two different scenarios (Annex 1) for initiating a pandemic vaccine response during the early stages of a pandemic. Participants were tasked with assessing the type of data needs and the principles involved in making decisions about vaccine production following the emergence of a pandemic virus while seasonal influenza virus was still circulating and causing illness.

The discussions were enriched by the varied backgrounds and experiences of the participants and representatives from vaccine manufacturers. In addition, as with the first consultation, the discussions were aided by an external facilitator. The pandemic scenario discussions were invaluable for formulating ideas as participants moved on to the next tasks during the meeting and for different stakeholders to understand the challenges involved of various players. It was noticeable that during the second consultation, participants had a clearer understanding of the need for risk assessment and the procedures for producing a pandemic vaccine than they had one year earlier. Consequently, one of the tasks identified for participants during the second consultation was to identify the key principles and the data required for a decision to recommend the start of pandemic vaccine production so that key stakeholders will also be able to understand and follow the recommendation with more ease and with greater transparency.

The second focus of the consultation was to refine the description of the pandemic vaccine process, which was drafted during the first consultation. Three tables outlining the process were finalized by input from all participants.

The third activity was to build on earlier experience from the first consultation and identify principles that should be applied to decisions made to switch from seasonal to pandemic vaccine production and to address the various technical bottlenecks in pandemic vaccine production so that possible solutions could be identified.

During the first consultation, areas of concern that were outside the scope of the meeting but still needed attention were listed in a “parking lot”. Supplementary items identified during the second consultation were added to the list. (Annex 5).

Finally, the key outcomes and next steps were identified.

4. Refinement of the process for pandemic vaccine response

As noted above, three pandemic vaccine process charts were finalized during the consultation:• Operational framework for pandemic

vaccine response (i.e. who takes the actions?). (Annex 2)

• Timelines of pandemic vaccine production (i.e. when are actions taken?). (Annex 3)

• Process of the WHO vaccine response to influenza pandemic or potential pandemics (i.e. how are actions taken?). (Annex 4)

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The outcomes of the consultation will be referenced in the PIRM Framework document in order to better describe the complexities and interactions of different stakeholders in making a pandemic vaccine available.

It was particularly challenging to develop accurate and realistic timelines for pandemic vaccine production as so many of the activities had an impact on other activities. For example, if there are delays in producing a CVV, there will also be delays in vaccine clinical trials, vaccine production and ultimately in vaccine availability. The timelines developed during the two consultations therefore reflect pandemic vaccine production during ideal circumstances. If some activities do not go well, they may take longer and this is indicated in the hatched areas of the chart.

5. Principles and bottlenecks in making the switch from seasonal to pandemic vaccine production

Participants were invited to discuss and make proposals for the types of evidence, expertise and principles needed to make a decision to switch from producing seasonal vaccine to pandemic vaccine. Inevitably there are some aspects of the vaccine production process which could cause potential bottlenecks and delay vaccine availability and some of these were raised during the first consultation.

At the second consultation, participants were encouraged to develop proposals for solutions to the bottlenecks and identify who should be responsible for taking each issue forward.

It was noted, however, that these proposals only reflect the opinions of the participants during the consultation and the actual solutions may be different after further discussed among expert groups drawn together by WHO.

5.1 Principles

There are many challenges in switching from production of seasonal vaccine to pandemic vaccine and, as elaborated during the first consultation, they are:

• A switch that is too early may compromise the production of seasonal vaccine with possibly severe public health consequences.

• A switch that is too late could have significant public health consequences, particularly if the pandemic is severe.

• Influenza vaccine production facilities cannot produce seasonal and pandemic vaccines at the same time. If the decision to start pandemic vaccine production is made when a facility is in the middle of producing seasonal vaccine, the facility has to stop seasonal vaccine production and switch to pandemic vaccine production. In addition, many areas lack influenza vaccine production capacity.

• Risk assessment involves the virological, epidemiological and clinical aspects of the emerging pandemic as well as assessment of the risk of stopping seasonal vaccine production potentially resulting in not having enough seasonal vaccine for vulnerable people.

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• Few countries have a revised pandemic preparedness plan in place that includes country-specific risk assessment, risk management and vaccine response procedures.

With these challenges in mind, participants identified the following key principles in making a decision to start pandemic vaccine production:

• Any decision will be made on incomplete data. The amount and quality of data available in the early stages of a pandemic are likely to be different from those available in the later stages.

• There should be some built-in flexibility in order to review the decision to switch or not to switch as new data arise. But once the decision to switch is made, it will not be realistic to switch back immediately.

• There are different components to the advice and evidence needed:

o Technical (e.g. evidence, data). o Philosophical (e.g. ethics, transparency).o Structural (e.g. governance, expert advice).

• The declaration of a pandemic does not automatically trigger a switch to pandemic vaccine production. For example, a pandemic vaccine may be produced against the threat from a newly emerging, highly pathogenic virus, although it may not have reached pandemic proportions. Conversely, it may not be considered appropriate to produce a pandemic vaccine

if a pandemic has been declared, yet the virus causes only mild infections while ongoing seasonal influenza infections are severe and widespread. Considerations such as time of year, the geography of seasonal and pandemic virus circulation, and availability of CVVs will also play a role.

• The WHO recommendation should maximize global health and be guided by expert opinion.o The risks of mortality, morbidity and

economic consequences should be considered in order to minimize serious impact.

o The impact of not having enough seasonal vaccine available in case of a switch should be considered.

• Any decision or recommendation should be evidence-based and the process should be transparent and defensible. o There should be clarity of roles and

responsibilities for individuals and organizations making decisions.

o The information assessed should include a global map of influenza manufacturing capacity and relevant timelines for vaccine production.

• Different vaccine formulations should be an option (e.g. monovalent pandemic and monovalent seasonal vaccine; monovalent pandemic and bivalent seasonal vaccine) and these options should be evaluated by experts.

• The structure of the WHO Expert committee tasked with making recommendations on the start of

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pandemic vaccine production should be representative and include groups such as manufacturers.

• There should be clear, understandable and rapid communication of any decision or recommendation, equally accessible by all stakeholders.

5.2 Bottlenecks

As identified during the first consultation, there are several potential technical bottlenecks that could severely interfere with pandemic vaccine development. Each bottleneck was discussed by participants with a view to identifying the data needed to solve the problems and, where possible, to identify how the problem could be solved and by whom.

BOTTLENECK DATA NEEDED SOLUTIONS

Lack of suitable BSL3/GMP laboratories for early small scale work

Not enough labs producing CVVs especially from highly pathogenic (hp) viruses

Not enough high containment labs for making LAIV CVVs

Uncertainty of CVV status in terms of implications related to the Nagoya Protocol or PIP Framework*

Uncertainty about manufacturers’ obligations to share synthetic seed viruses and shipping requirements

Delays in access to CVVs

• Review number of suitable labs available

• None identified

• Review number of suitable labs available

• None identified

• None identified

• None identified

• Dedicated publicly funded pilot BSL3/GMP labs

• WHO to identify and establish more pandemic CVV labs

• Dedicated publicly funded pilot BSL3/GMP labs

• WHO to obtain clarification

• Manufacturers to start dialogue with WHO

• Manufacturers to obtain import permits (including GMO CVV) in advance; obtain agreement(s) with courier(s)

CVV Production/Availability

* After the Consultation, clarification has been obtained that CVVs are included within PIP Framework, i.e. not covered by Nagoya Protocol

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BOTTLENECK DATA NEEDED SOLUTIONS

Identification of the type of safety tests needed; availability of wt virus comparator; the need for ferret safety tests

Continued need for chicken pathogenicity tests of CVVs derived from hp viruses

Slow decision on biosafety and USDA Select Agent status; biosafety status could be country-specific

Uncertainty about biosafety status of synthetic CVVs especially with USDA Select Agent status

• WT virus risk assessment• Criteria for attenuation

and biosafety and utility of safety tests

• Historical review of chicken test data

• Review in vitro test data

• Information on pathogenicity

• Sequence especially HA/NA gene segments and including both egg and cell isolates

• Information on pathogenicity

• Sequence especially HA/NA gene segments and including both egg and cell isolates

• WHO to review guidance on safety testing of CVVs

• USDA to remove requirement for chicken pathogenicity test or remove hp influenza viruses from Select Agent status

• All CVV labs aiming to work with hp viruses should register with USDA in advance

• WHO to lead and coordinate bio-safety assessment and to speed up assessment

• WHO to provide feedback on IFPMA ‘white paper’ on CVV biocontainment

• Better coordination of CVV labs• Better communication between

CVV labs and manufacturers• CVV labs to standardize release

documents for CVVs• Future use of synthetic HA/NA CVVs

• Manufacturers to clarify status with human and agricultural safety authorities

• WHO to coordinate accumulation of data and liaison with human and agricultural safety authorities

Biocontainment for Wild Type Pandemic Virus and CVV

9

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BOTTLENECK DATA NEEDED SOLUTIONS

BOTTLENECK DATA NEEDED SOLUTIONS

Low yielding CVV; slow evaluation of CVV yield

Low downstream yield from CVV (i.e. vaccine processing)

Not enough CVVs to select one with high yield

Genetic/protein instability during downstream processing

Delay in availability of clinical trial vaccine lots, specifically related to vaccine potency assays

Delay due to GMO issues

Delay due to country-specific vaccine lot release

Delay in clinical trial protocol review

Delay in serology assays

• Small scale yield in eggs and cells

• Small scale processing yield

• None identified

• Genetic/amino acid sequencing

• Data from SRID and alternative potency assays

• Certificate of analysis

• Lot release data

• None identified

• Robustness and reproducibility of assays

• CVV labs and manufacturers to optimize rapid small scale yield assessment techniques

• Better high yield donor viruses• Dedicated publicly funded pilot

BSL3/GLP labs

• CVV labs and manufacturer to optimize rapid small scale yield and processing assessment techniques

• Dedicated publicly funded pilot BSL3/GMP labs

• WHO to identify and establish more possible pandemic CVV labs

• Sequence optimization to improve yield and stability

• WHO and ERLs to review and recommend alternative potency assays

• None identified

• WHO ERLs to coordinate pandemic vaccine lot release globally

• Harmonize clinical trial procedures

• Improvement, standardization and acceptance of assays

Yield and Manufacturing of CVVs

Clinical Trials for the First Pandemic Vaccines

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BOTTLENECK DATA NEEDED SOLUTIONS

BOTTLENECK DATA NEEDED SOLUTIONS

Delays in reagent supply will delay vaccine lot release and vaccine supply

• Availability of antigen and antiserum for use in reagent production

• Biosafety status of antigen• Which CVV is being used?• Suitability of existing

reagents, i.e. are new ones really needed?

• Review of regulatory requirements in different countries

• A basic set of criteria for seasonal and pandemic vaccine prequalification

• Requirements for donated vaccines in an emergency

• Confirmation of whether country NRAs meet published criteria for functionality

• Robustness of pandemic vaccine capability in countries

• Review of data on vaccine effectiveness

• Labelling requirements for emergency use of pandemic vaccine

• Review of pandemic vaccine lot release requirement in different countries

• Reagent supply needs better coordination and harmonization

• Alternative validated potency tests• Early start of antiserum production

(before CVV availability) • Allow use of heterologous reagent• Consider making panel of reagents

at risk

• Cross communication between regulatory authorities

• WHO to introduce prequalification for seasonal and pandemic influenza vaccines

• Continue to support regional regulatory harmonization in low and middle income countries

• M S to establish or strengthen NRAs:o Regulatory systems o Marketing Authorization

• Agreement on criteria for assessment of vaccine effectiveness

• Harmonization of labels and package inserts for pandemic vaccines

• Harmonization of pandemic vaccine lot release

Timing of SRID Reagents for Vaccine Potency Testing

Regulatory Harmonization

Lack of mutual recognition of regulatory procedures leading to delays in vaccine supply

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BOTTLENECK DATA NEEDED SOLUTIONS

BOTTLENECK DATA NEEDED SOLUTIONS

Delay in making a risk assessment of whether or not to make a vaccine switch

If pre-filled syringes are used, filling is slower and uses more antigen; if multidose vials are used, thiomersal will be used and this limits its use

• Potential impact of new virus versus that of seasonal virus, including: o Epidemiologyo Severityo Modellingo Impacto Ability to manufacture

vaccine

• Update of risk assessment as more data becomes available

• Criteria used by countries for selecting final presentation

• Formulation requirements to ensure required shelf life

• An understanding of the need for prefilled syringes for some groups, e.g. pregnant women, children

• Develop decision-making process including data, data source, data collecting channels, analytical methods, and communication channels.

• WHO to prepare formal output from risk assessments

• Review of risk assessment

methodology

• Evaluate different delivery methods

• Education on benefits of use of multidose vials

• Use USA model of a fill/finish network to optimize global filling capacity

Risk Assessment

Fill and Finish Capacity

12

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� There is a need for an integrated approach to the decision to switch or not to switch as there are many components to the decision process and they will involve nearly all parts of the influenza community. Such an integrated approach could be achieved by bringing together an international expert group tasked with making such a recommendation. The expert group should follow the principles as outlined during this consultation and should meet occasionally to work through switch scenarios in order to establish an effective working relationship.

� There is a need for greater clarity and transparency in the decision-making process and the elaboration during this consultation of the principles involved in making the decision will be a considerable help.

� As a result of the scenario exercises and resulting discussions, participants were now much better informed about the complex nature of the switch process and thus would be better equipped to make a recommendation and implement the decision. However, it is less likely that key national and international decision makers are fully aware of these issues. A critical outcome of the two consultations is to bring this information to key decision makers both within and outside of WHO.

� A main focus of the second consultation was to propose solutions to bottlenecks and problems that would interfere with making a timely switch and making pandemic vaccine available quickly. The next steps would be to follow up these proposals including identifying leading entities and convening expert groups in order to bring solutions closer. It was agreed at the consultation that small working groups, organized by WHO, would take this forward.

� One important outcome was the identification of solutions to the potential bottleneck where manufacturers are uncertain about clear signals being received concerning the need to escalate pandemic vaccine production (Bottleneck: Risk Assessment; Operational Flowchart: 1 Risk Assessment and Communications).

� One proposal that was placed in the “parking lot” during the first consultation was to establish a publicly funded small scale GMP pilot lot vaccine production facility. This proposal was repeated several times during the second consultation so that it was now regarded as one of the key outcomes. The facility could be used to assess CVV yield, assess biosafety, produce pilot lots of vaccine for evaluation of process yield, assess supply of antigen for potency reagent, establish diagnostic capacity and for training purposes. The facility would need to be in continuous use, e.g. as a training facility in non-pandemic period. Then in a pandemic emergency it would be used for influenza vaccine evaluation.

The main outcomes of the second consultation were:

6. Key Outcomes of the Consultation and Next Steps

13

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| Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT

8. Abbreviations

BLA Biologics License Application (USA regulatory mechanism)

BSL2+ Biosafety level 2+

CVV Candidate Vaccine Virus

DCVMN Developing Countries Vaccine Manufacturers Network

ERL WHO Essential Regulatory Laboratory

EUA Emergency Use Authorization (USA regulatory mechanism)

GAP WHO Global Action Plan for Influenza Vaccines

GISRS WHO Global Influenza Surveillance and Response System

6. Implementation of the International Health Regulations (2005) Report of the Review Committee on the Functioning of the International Health Regulations (2005) in relation to Pandemic (H1N1) 2009.

1. Pandemic Influenza Risk Management (PIRM) – WHO interim guidance

2. The International Health Regulations (IHR) 2005

3. The Pandemic Influenza Preparedness (PIP) Framework for the sharing of influenza viruses and access to vaccines and other benefits

7. References

http://www.who.int/influenza/preparedness/ pandemic/GIP_PandemicInfluenzaRisk ManagementInterimGuidance_Jun2013.pdf

http://whqlibdoc.who.int/publica-tions/2011/9789241503082_eng.pdf

http://apps.who.int/gb/ebwha/pdf_files/WHA64/A64_10-en.pdf

http://whqlibdoc.who.int/hq/2006/WHO_IVB_06.13_eng.pdf

http://whqlibdoc.who.int/publica-tions/2008/9789241580410_eng.pdf?ua=1

http://www.who.int/influenza/pip/smta2_eng.pdf?ua=1

� Following finalization of the operational framework for pandemic vaccine response, it will now be possible to finalize the PIRM Framework document. Following that, there should be consultation with member states on its implementation and periodically it should be reviewed and updated.

� As the expert working group progresses as mentioned above, WHO may consider organizing a third consultation on the same topic.

Further activities recognized during the first and second consultations and not considered directly within the scope of the consultations are listed in the “parking lot” (Annex 5).

14

4. Global Action Plan for Influenza Vaccines (GAP) to increase global influenza production capacity and supply

5. Standard Material Transfer Agreement 2 (SMTA2) outside the WHO global influenza surveillance and response system (GISRS)

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Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT |

Annexes

1. Scenarios2. Draft operational framework for pandemic

vaccine response3. Timelines of pandemic vaccine production4. Process of the WHO vaccine response to an

influenza pandemic or a potential pandemic5. Further activities: the “parking lot”6. List of Participants

12 15

GMO Genetically Modified Organism

GMP Good Manufacturing Practice

HHS USA Department of Health and Human Services

hp Highly pathogenic

IHR International Health Regulations (2005)

IFPMA International Federation of Pharmaceutical Manufacturers & Associations

IND Investigational New Drug (USA regulatory mechanism)

LAIV Live Attenuated Influenza Vaccine

MS WHO Member States

NIC WHO National Influenza Centre

NRAs National Regulatory Authorities

NRLs National Regulatory Laboratories

PIP Pandemic Influenza Preparedness

PIRM Pandemic Influenza Risk Management

RG Reverse Genetics

SAGE Strategic Advisory Group of Experts on immunization

9. Acknowledgements

The World Health Organization (WHO) wishes to acknowledge the contributions of all experts who participated in the preparation and in particular:

Derek Ellis (Canada), Susan Perry (Canada) and John Wood (United Kingdom) for peer review of the report.

SRID Single Radial Immunodiffusion

SMTA2 Standard Material Transfer Agreements 2

TIPRA Tool for Influenza Pandemic Assessment

WHO CCs WHO Collaborating Centres

wt Wild type

USA United States of America

USDA United States Department of Agriculture

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| Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT

ANNEX 1 – Scenarios

Scenario 1(Note: In discussing this scenario, note that the WHO GISRS network is continuously assessing and respond-ing to the risk of existing and emerging influenza viruses and that the WHO mechanisms including IHR and SAGE are functioning efficiently).

Week 1 GISRS has detected 12 human cases of H6N9 infection in the Netherlands during the month of December. The virus, originally detected in aquatic birds has acquired mutations in HA usually associated with mammalian adaptation.

Question 1 a) Do any additional communications need to be made? b) Do any additional actions need to be taken and by whom?

Week 2One hundred further cases of human H6N9 infection have been detected within the same region. All infections are clinically not as severe as those associated with seasonal H3N2 virus that is causing widespread human infection. An H6N9 CVV was prepared by GISRS one year earlier.

Question 2 a) Do extra CVVs need to be made? b) Do any additional actions need to be taken and by whom?

Week 6Within a month over 800 cases of H6N9 human infection have occurred across several countries. Cases were across all age groups.

Question 3 a) Is there a need to advance the development for a pandemic vaccine now? And if so, how far down

the development pathway should it go and by whom? b) Will national/regional contracts of seasonal vaccines be affected by activating pandemic APAs; if so,

how? c) When should pandemic vaccine production start? For all manufacturers or some - if only some, what

are the principles or assumption to consider when making this decision. Who decides what? d) Are there issues around seasonal versus pandemic vaccine availability? Are there any implications for

those needing seasonal vaccine?

Question 4 (Concluding Question): a) In this scenario, what would you recommend with regard to pandemic vaccine production vs.

seasonal vaccine production? b) On what basis is this recommendation to be made? Who are the stakeholders making the

recommendation? How should the recommendations be communicated?

16

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Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT |

ANNEX 1 – Scenarios

Scenario 2(Note: In discussing this scenario, note that WHO GISRS network is continuously assessing influenza isolates and novel viruses and that IHR and WHO expert committees such as SAGE are regularly informed).

Week 1 GISRS has detected the emergence of an antigenically drifted H3N2 in New Guinea.

Week 5The drifted H3N2 virus has spread to Fiji and Northern Australia, and the WHO VCM for the Southern Hemisphere has recommended the inclusion of the drifted H3N2 virus in the seasonal vaccine. There is evidence that infections are clinically severe with many patients being hospitalized.

Question 1 a) Do any additional communications need to be made? b) Do any additional actions need to be taken and by whom?

Week 6GISRS has detected 10 human cases of H10N2 virus in New guinea. One patient was hospitalised.

Week 7There is evidence of spread of H10N2 virus within the region but infections are clinically not as severe as the variant H3N2 virus infections. All age groups are affected.

Question 2 WHO (GISRS) is now ready to distribute CVVs to vaccine manufacturers for pandemic vaccine preparatory activities. a) When are manufacturers able to work with these CVV’s to produce clinical lots? b) Does working with CVVs and the production of clinical lots interfere with the production of seasonal vaccine?

Week 10 Within a month 1500 cases of H10N2 human infection have occurred across several countries and H3N2 infections continue to occur. All age groups were affected by both viruses.

Question 3 a) Should countries and stakeholders be informed on the progress of developing pandemic vaccine; and if so, how? b) How does WHO communicate with countries, industry and regulators? c) Would the presence of the N2 in the southern hemisphere vaccine provide any cross protective immunity and how would this influence

any decision to produce H10N2 vaccine?

Question 4 a) Is there a need to advance the development for a pandemic vaccine now? And if so, how far down the development pathway

should it go and by whom? b) Will national/regional contracts of seasonal vaccines be affected by activating pandemic APAs; if so, how? c) When should pandemic vaccine production start? For all manufacturers or some - if only some, what are the principles or assumption to consider

when making this decision. Who decides what? d) Are there issues around seasonal versus pandemic vaccine availability? Are there any implications for those needing seasonal vaccine? e) If both the H3 and H10 viruses were resistant to neuraminidase inhibitors, would this affect any of your decisions?

Weeks 12 - 15Within 3 months over 49 countries reported the spread of influenza, with many patients needing medical attention and some needing intensive care. Over 100,000 cases were reported with a 0.4% mortality rate. There were reports of severe challenges for the health care systems in most countries. There was also an increase in reports of absenteeism in front line health care workers. Laboratory tests on some 9200 samples showed that about 50% were of the new novel type A virus and nearly 50% were the new variant H3.

Question 5 (Concluding Question): a) In this scenario, what would you recommend with regard to pandemic vaccine production vs. seasonal vaccine production? b) Would your recommendation change in the face of increased morbidity and mortality which was over and above the normal seasonal

expectation. c) On what basis is this recommendation to be made? Who are the stakeholders making the recommendation? How should the recommendations

be communicated? d) In the situation of H3 dominating in some regions and H10 in others, what would your recommendations be?

17

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| Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT

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ccine

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ulatio

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inatio

n stra

tegy

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mun

icatio

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l plat

form

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webs

ite, p

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onfer

ence

s.

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ct co

mm

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tion w

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es1.

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rwar

d lo

okin

g ou

tcom

es w

ould

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esta

blis

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t of g

loba

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es a

nd

com

mon

regu

lato

ry p

roce

sses

to s

uppo

rt fa

st tr

acki

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er d

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to in

clud

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larit

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ansp

aren

cy, m

utua

l rec

ogni

tion,

rapi

d ac

cess

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ch W

HO

regi

on s

houl

d ha

ve s

uch

labo

rato

ries.

Mut

ual r

ecog

nitio

n pr

oced

ures

to b

e de

velo

ped.

Re

cogn

ized

sta

ndar

ds a

nd in

spec

tions

are

nee

ded,

EU

can

be

seen

as

as a

mod

el.

4.

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nce

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c hea

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ken

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catio

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18

Page 23: Influenza Vaccine Response during the Start of a Pandemic · 2016. 7. 22. · Risk Management (PIRM) — WHO interim guidance (ref 1). The WHO PIRM framework provides flexibility

Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT |

AN

NEX

2 –

Dra

ft o

pera

tiona

l fra

mew

ork

for

pand

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cine

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ken

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licat

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19

Page 24: Influenza Vaccine Response during the Start of a Pandemic · 2016. 7. 22. · Risk Management (PIRM) — WHO interim guidance (ref 1). The WHO PIRM framework provides flexibility

| Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT

OPE

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Page 25: Influenza Vaccine Response during the Start of a Pandemic · 2016. 7. 22. · Risk Management (PIRM) — WHO interim guidance (ref 1). The WHO PIRM framework provides flexibility

Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT |

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Page 26: Influenza Vaccine Response during the Start of a Pandemic · 2016. 7. 22. · Risk Management (PIRM) — WHO interim guidance (ref 1). The WHO PIRM framework provides flexibility

| Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT

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pean

Med

icin

es A

genc

yEU

A

Emer

genc

y U

se A

utho

rizat

ion*

FA

O

Food

and

Agr

icul

ture

Org

aniz

atio

n of

the

UN

FLU

COP

EU re

sear

ch c

onso

rtiu

m h

ttp:

//w

ww

.fluc

op.e

u/G

ACV

S W

HO

Glo

bal A

dviso

ry C

omm

ittee

on

Vacc

ine

Safe

tyG

AP

WH

O G

loba

l Act

ion

Plan

for I

nflue

nza

Vacc

ines

GIS

RS

Glo

bal I

nflue

nza

Surv

eilla

nce

& Re

spon

se S

yste

mG

MO

G

enet

ical

ly M

odifi

ed O

rgan

ismG

MP

Goo

d M

anuf

actu

ring

Prac

tice

HCW

H

ealth

Car

e W

orke

rIH

R In

tern

atio

nal H

ealth

Reg

ulat

ions

(200

5)IF

PMA

In

tern

atio

nal F

eder

atio

n of

Pha

rmac

eutic

al

Man

ufac

ture

rs &

Ass

ocia

tions

IND

In

vest

igat

iona

l New

Dru

g*

NCL

s N

atio

nal C

ontr

ol L

abor

ator

ies

NRA

s N

atio

nal R

egul

ator

y Au

thor

ities

OIE

W

orld

Org

aniz

atio

n fo

r Ani

mal

Hea

lthPH

EIC

Pu

blic

Hea

lth E

mer

genc

y of

Inte

rnat

iona

l Con

cern

PIP

Pand

emic

Influ

enza

Pre

pare

dnes

sPI

RM

Pand

emic

Influ

enza

Risk

Man

agem

ent

RG

Reve

rse

Gen

etic

sSA

GE

Stra

tegi

c Ad

viso

ry G

roup

of E

xper

ts o

n Im

mun

izat

ion

SRID

Si

ngle

Rad

ial I

mm

unod

iffus

ion

TIPR

A

Tool

for I

nflue

nza

Pand

emic

Risk

Ass

essm

ent

VRB

PAC

US

Vacc

ines

and

Rel

ated

Bio

logi

cal P

rodu

cts A

dviso

ry C

omm

ittee

US

NIH

/CD

C U

S N

atio

nal I

nstit

utes

of H

ealth

/Cen

tres

for D

iseas

e

Cont

rol a

nd P

reve

ntio

nW

HO

CCs

W

HO

Col

labo

ratin

g Ce

ntre

sW

HO

ERL

s W

HO

Ess

entia

l Reg

ulat

ory

Labo

rato

ry*

USA

regu

lato

ry m

echa

nism

22

AN

NEX

2 –

Dra

ft o

pera

tiona

l fra

mew

ork

for

pand

emic

vac

cine

res

pons

e

Page 27: Influenza Vaccine Response during the Start of a Pandemic · 2016. 7. 22. · Risk Management (PIRM) — WHO interim guidance (ref 1). The WHO PIRM framework provides flexibility

Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT |

CVV

DEVE

LOPM

ENT

RISK

ASS

ESSM

ENT

& CO

MM

UNIC

ATIO

N

REGI

STRA

TION

PROD

UCTI

ON

OPE

RATI

ON

AL

FRA

MEW

ORK

FO

R PA

ND

EMIC

VAC

CIN

E RE

SPO

NSE

Not

es1.

M

anuf

actu

rers

are

enc

oura

ged

to li

cens

e va

ccin

es a

ppro

ved

for e

mer

genc

y us

e.2.

Fo

rwar

d lo

okin

g ou

tcom

es w

ould

be

esta

blis

hmen

t of g

loba

l gui

delin

es a

nd c

omm

on re

gula

tory

pro

cess

es to

sup

port

fast

trac

king

/che

aper

dev

elop

men

t cos

ts.

3.

App

rova

l pro

cess

prin

cipl

es to

incl

ude:

cla

rity,

tran

spar

ency

, mut

ual r

ecog

nitio

n, ra

pid

acce

ss.

4.

Each

WH

O re

gion

sho

uld

have

suc

h la

bora

torie

s. M

utua

l rec

ogni

tion

proc

edur

es to

be

deve

lope

d.

Reco

gniz

ed s

tand

ards

and

insp

ectio

ns a

re n

eede

d, E

U c

an b

e se

en a

s as

a m

odel

.5.

In

crea

sed

confi

denc

e am

ong

HCW

and

pub

lic. E

nsur

e ca

se d

efini

tions

are

ava

ilabl

e fo

r AEF

Is.

Activ

ities

Coordinating Entities

Chan

nels

to

Com

mun

icate

th

e Out

com

esPa

rtici

patin

g En

titie

sOu

tcom

esDo

ssier

rout

e

See #

1 belo

w

WHO

, man

ufac

ture

rs,

natio

nal a

nd re

giona

l (e

.g. EM

A) re

gulat

ing

auth

oriti

es

WHO

, Re

gulat

ors

Appr

oval/

no ap

prov

al

Enha

nced

/fast-

track

ed

appr

oval

proc

ess

See #

2 belo

w

Guide

lines

Web

site

Wor

ksho

ps to

crea

te

unde

rstan

ding o

f the

pr

oces

ses

Emer

genc

y rou

teW

HO, m

anuf

actu

rers,

na

tiona

l and

regio

nal (e

.g.

EMA)

regu

lating

auth

oriti

es

WHO

, Re

gulat

ors

Appr

oval/

no ap

prov

al

Enha

nced

/fast-

track

ed

appr

oval

proc

ess

See #

3 belo

w

Guide

lines

Web

site

Wor

ksho

ps to

crea

te

unde

rstan

ding o

f the

pr

oces

ses

Regu

lator

y ove

rsigh

t to

assu

re th

e qua

lity o

f pa

ndem

ic va

ccine

s.

Exiti

ng lo

t rele

ase l

abs

includ

ing W

HO ER

Ls an

d NC

Ls

Regu

lator

y Ne

twor

k/W

HO

Deve

lopm

ent o

f a fo

rmal

netw

ork o

f rele

ase

labor

ator

ies to

enha

nce

avail

abilit

y of p

ande

mic

vacc

ine

Clear

set o

f assa

ys to

str

eam

line p

roce

ss

See #

4 belo

w

Web

sites

, wor

ksho

ps,

writt

en st

anda

rds,

mem

bersh

ip cri

teria

Risk

man

agem

ent,

safet

y mon

itorin

g, sig

nal

dete

ction

Vacc

ine eff

ectiv

enes

s qu

antifi

catio

n of a

dver

se

effec

ts, ex

posu

re da

ta

Bene

fit /

risk a

ssessm

ent

Healt

h car

e wor

kers,

re

gulat

ors,

publi

c hea

lth

imm

uniza

tion p

rogr

ams,

man

ufac

ture

rs

Natio

nal

Regu

lator

y Au

thor

ities

, W

HO

Impr

oved

safet

y asse

ssmen

t an

d mon

itorin

g sys

tem

Incre

ased

use o

f too

ls

(mod

els, e

tc.)

See #

5 belo

w

HCW,

publi

c hea

lth

orga

nizat

ions,

man

ufac

ture

rs,

inter

natio

nal e

xcha

nge o

f sa

fety d

ata/

signa

ls via

WHO

/SA

GE/G

ACVS

Distr

ibutio

n and

co

mm

unica

tions

Pand

emic

Vacc

ine

Deplo

ymen

t Plan

Healt

h aut

horit

ies

SAGE

Healt

h and

loc

al au

thor

ities

SAGE

Distr

ibutio

n,

avail

abilit

y, ea

rly AD

RsHe

alth a

utho

rities

and N

CLs

ERLs

via T

Cs or

email

or ot

her

chan

nels

Registration Process &Pre-qualification Process

Pharmacovigilance Vaccine RolloutLot Release5

REGI

STRA

TION

CLIN

ICAL

EV

ALUA

TION

GL

OSSA

RY

AD

R Ad

vers

e D

rug

Reac

tion

AEF

I Ad

vers

e Ev

ent F

ollo

win

g Im

mun

izat

ion

BLA

Bi

olog

ics L

icen

se A

pplic

atio

n*

BSL2

+ Bi

osaf

ety

leve

l 2+

CVV

Ca

ndid

ate

Vacc

ine

Viru

sD

CVM

N

Dev

elop

ing

Coun

trie

s Vac

cine

Man

ufac

ture

rs N

etw

ork

ECD

C Eu

rope

an C

entr

e fo

r Dise

ase

Prev

entio

n an

d Co

ntro

lEM

A

Euro

pean

Med

icin

es A

genc

yEU

A

Emer

genc

y U

se A

utho

rizat

ion*

FA

O

Food

and

Agr

icul

ture

Org

aniz

atio

n of

the

UN

FLU

COP

EU re

sear

ch c

onso

rtiu

m h

ttp:

//w

ww

.fluc

op.e

u/G

ACV

S W

HO

Glo

bal A

dviso

ry C

omm

ittee

on

Vacc

ine

Safe

tyG

AP

WH

O G

loba

l Act

ion

Plan

for I

nflue

nza

Vacc

ines

GIS

RS

Glo

bal I

nflue

nza

Surv

eilla

nce

& Re

spon

se S

yste

mG

MO

G

enet

ical

ly M

odifi

ed O

rgan

ismG

MP

Goo

d M

anuf

actu

ring

Prac

tice

HCW

H

ealth

Car

e W

orke

rIH

R In

tern

atio

nal H

ealth

Reg

ulat

ions

(200

5)IF

PMA

In

tern

atio

nal F

eder

atio

n of

Pha

rmac

eutic

al

Man

ufac

ture

rs &

Ass

ocia

tions

IND

In

vest

igat

iona

l New

Dru

g*

NCL

s N

atio

nal C

ontr

ol L

abor

ator

ies

NRA

s N

atio

nal R

egul

ator

y Au

thor

ities

OIE

W

orld

Org

aniz

atio

n fo

r Ani

mal

Hea

lthPH

EIC

Pu

blic

Hea

lth E

mer

genc

y of

Inte

rnat

iona

l Con

cern

PIP

Pand

emic

Influ

enza

Pre

pare

dnes

sPI

RM

Pand

emic

Influ

enza

Risk

Man

agem

ent

RG

Reve

rse

Gen

etic

sSA

GE

Stra

tegi

c Ad

viso

ry G

roup

of E

xper

ts o

n Im

mun

izat

ion

SRID

Si

ngle

Rad

ial I

mm

unod

iffus

ion

TIPR

A

Tool

for I

nflue

nza

Pand

emic

Risk

Ass

essm

ent

VRB

PAC

US

Vacc

ines

and

Rel

ated

Bio

logi

cal P

rodu

cts A

dviso

ry C

omm

ittee

US

NIH

/CD

C U

S N

atio

nal I

nstit

utes

of H

ealth

/Cen

tres

for D

iseas

e

Cont

rol a

nd P

reve

ntio

nW

HO

CCs

W

HO

Col

labo

ratin

g Ce

ntre

sW

HO

ERL

s W

HO

Ess

entia

l Reg

ulat

ory

Labo

rato

ry*

USA

regu

lato

ry m

echa

nism

23

AN

NEX

2 –

Dra

ft o

pera

tiona

l fra

mew

ork

for

pand

emic

vac

cine

res

pons

e

Page 28: Influenza Vaccine Response during the Start of a Pandemic · 2016. 7. 22. · Risk Management (PIRM) — WHO interim guidance (ref 1). The WHO PIRM framework provides flexibility

| Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT

AN

NEX

3 –

Tim

elin

es o

f pa

ndem

ic v

acci

ne p

rodu

ctio

n

19

VERS

ION

26.

10.2

016

TIM

ELIN

E O

F PA

ND

EMIC

VAC

CIN

E PR

OD

UC

TIO

N

1

2

3 4

5 6

7 8

9 10

11

12

13

14

15

16

17

18

19

20

21

2

2

23

24

ACTI

VITI

ES

ACTI

ONS

WEE

K NU

MBE

R SI

NCE W

HO R

ECOM

MEN

DATI

ON O

F PAN

DEM

IC VI

RUS

(gen

etic

sequ

ence

upl

oad)

ENTI

TIES

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

COM

MEN

TS A

ND P

OTEN

TIAL

ISSU

ES

Lin

eLin

eLin

e

14

Us

ed by

EU an

d cou

ntrie

s/NRA

s tha

t foll

ow th

e EMA

. Assu

mes

that

the m

anuf

actu

ring

proc

ess f

or th

e em

ergin

g pan

dem

ic vir

us w

ill be

the s

ame a

s tha

t for

seas

onal

vacc

ine vi

ruse

s. Ea

rly di

scus

sions

with

NRA

esse

ntial

.

15

Emer

genc

y use

appr

oval

may

be gi

ven p

rior t

o fina

l regis

tratio

n. Ea

rly di

scus

sions

wi

th N

RA es

sent

ial.

16

All m

anuf

actu

rers

shou

ld ide

ally s

eek r

egist

ratio

n of t

he va

ccine

not o

nly m

ock d

ossie

r app

rova

l an

d/or

emer

genc

y use

.

17

This

is th

e bat

ch re

lease

proc

ess.

Faste

r alte

rnat

ive te

sts su

ch as

ELISA

tests

could

also

be us

ed

in ad

dition

to SR

ID to

asse

ss po

tenc

y. En

doto

xin te

sts ar

e esse

ntial

as ar

e oth

er lo

t rele

ase

requ

irem

ents.

. Abo

ut 4

to 6

days

are n

eede

d.

18

AEFI

mon

itorin

g by t

he N

RA an

d oth

er sp

ecial

ist gr

oups

, web

-bas

ed re

porti

ng an

d sen

tinel

mon

itorin

g. Th

is wo

uld oc

cur b

eyon

d the

14 w

eek m

ark.

19

Distr

ibutio

n by p

rogr

amm

e man

ager

s to s

ites.

Roll-

out p

riorit

y to b

e det

erm

ined a

ccord

ing

to th

e pan

dem

ic pla

n. To

cont

inue b

eyon

d the

wee

k 14 m

ark.

CV

Vs ar

e sele

cted b

y the

WHO

CCs.

RG re

asso

rtant

s will

take

abou

t 19 d

ays,

classi

cal

reas

sorta

nts a

bout

21 da

ys. S

ynth

etic

seed

s may

also

be an

optio

n. Sa

fety t

estin

g TBD

, but

if th

e CVV

is de

rived

from

a hig

hly p

atho

genic

viru

s, it

will n

eed t

o be e

valua

ted f

or ex

clusio

n fro

m “S

elect

Agen

t” sta

tus i

n the

USA

and i

f the

CVV i

s der

ived b

y rev

erse

gene

tics i

t will

need

to

com

ply w

ith EU

GM

O re

gulat

ions.

CVVs

are g

ener

ally N

OT di

stribu

ted u

ntil S

teril

ity Te

st co

mple

te &

at le

ast a

1-wa

y HI b

ut in

a pa

ndem

ic sit

uatio

n the

y cou

ld be

distr

ibute

d pen

ding

HI an

d ste

rility

data

. WHO

will

give c

lear g

uidan

ce on

bioc

onta

inmen

t and

a ris

k asse

ssmen

t of

seve

rity,

trans

miss

ibilit

y and

epide

miol

ogy a

ssocia

ted w

ith th

e em

ergin

g viru

s.

2 Ch

eckin

g gen

e seq

uenc

es, g

ene c

onste

llatio

n and

perfo

rming

one a

nd tw

o way

tests

.

4

Poor

yield

s migh

t res

ult in

delay

s in v

accin

e sup

ply to

larg

e pop

ulatio

ns.

5 Es

sent

ial to

begin

a cli

nical

trial

if req

uired

(pha

se 1)

. Som

e cou

ntrie

s will

requ

ire a

clinic

al tri

al if t

he em

ergin

g pan

dem

ic su

btyp

e has

little

or no

clini

cal d

ata.

HA co

nten

t and

dosin

g sch

edule

will

not b

e kno

wn fo

r a ne

w su

btyp

e. Ad

ults a

nd ol

der a

dults

shou

ld be

inclu

ded i

n th

e tria

l. It i

s exp

ecte

d tha

t a ha

lf dos

e x 2

would

be gi

ven t

o chil

dren

as fo

r sea

sona

l vac

cine.

6 Th

e ear

ly sta

ges o

f plan

ning a

nd re

cruitm

ent w

ill ha

ve ta

ken p

lace e

arlie

r tha

n this

.

7

Base

line s

erolo

gy an

d the

n at 2

and 4

wee

ks af

ter in

jectio

n.

8

ADRs

need

to be

mon

itore

d esp

ecial

ly in

the fi

rst pa

rt of

the c

linica

l tria

l and

then

in th

e field

as

a pha

rmac

ovigi

lance

stud

y dep

endin

g on t

he N

RA. T

his w

ould

occu

r bey

ond t

he 14

wee

k mar

k.

9

Th

e pro

ducti

on of

a m

onov

alent

vacc

ine ca

n tak

e plac

e ear

ly wi

th ex

pecte

d lot

relea

se la

ter.

Man

ufac

ture

rs ne

ed to

supp

ly an

tigen

to ER

Ls as

soon

as po

ssible

for r

eage

nt pr

epar

ation

.

11/1

2

The p

rodu

ction

of sh

eep s

era i

s crit

ical a

nd a

majo

r bot

tlene

ck in

the p

roce

ss.

13

Idea

lly th

e 4 W

HO ER

Ls w

ould

calib

rate

the r

eage

nts.

But i

f tim

e is o

f the

esse

nce,

the r

eage

nt

can b

e cali

brat

ed lo

cally

to sa

ve ti

me,

e.g., b

etwe

en th

e ERL

and t

he m

anuf

actu

rer o

r ano

ther

co

mpe

tent

labo

rato

ry, th

e opt

ion to

prep

are a

nd ca

libra

te on

e set

of re

agen

ts to

redu

ce th

e wo

rkloa

d of c

ross

calib

ratio

n, an

d alte

rnat

ive te

sts su

ch as

ELISA

tests

to be

cons

idere

d pen

ding

relev

ant N

RA ap

prov

al.

COM

MEN

TS A

ND P

OTEN

TIAL

ISSU

ES

CO

MM

ENTS

AND

POT

ENTI

AL IS

SUES

1, 2,

3 and

4

{Th

is tim

eline

is in

idea

l circ

umsta

nces

whe

n eve

ryth

ing go

es w

ell. If

som

e acti

vities

do no

t go w

ell, t

hey m

ay ta

ke lo

nger

and t

his is

indic

ated

in th

e hat

ched

area

s of t

he ch

art.

Due t

o the

inte

r-rela

tedn

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24

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Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT |

ANNEX 4 – Process of the WHO vaccine response to an influenza pandemic or a potential pandemic

20

PROCESS FOR WHO PANDEMIC VACCINE RESPONSE TO INFLUENZA PANDEMICS/POTENTIAL PANDEMICS

DETECTION OF A NOVEL

VIRUS IN HUMANS

Preliminary global RA by GISRS including epidemiology, transmissibility and severity of

the disease associated with the virus

Selection of candidate viruses by GISRS

Biosafety assessment of CVVs by WHO

Further virus characterization by WHO CCs

IHR notification. Assessment of CVVs

by WHO and WHO CCs

Assessment of need for HGR development

Need to develop

Potentially significant to public health?

Development of high-growth reassortants by GISRSand other laboratories

Initiation of the development of potency reagents by GISRS

Distribution of high-growth reassortants

Yield evaluation by manufacturers and GISRS

RA on further vaccine development

Assessment if results warrant

production/use of pandemic/

pre-pandemic vaccines

Availability of potency reagents by GISRS

Clinical trials if needed

National/regional licensing/stockpiling as appropriate

Continuous update to SAGE; updates to member states, and other stakeholders as appropriate

WHO declaration of pandemic

Large-scale production/ release of vaccines for use by country/region

YES

NO

GLOSSARY

CVV Candidate Vaccine Virus

GISRS WHO Global Influenza Surveillance and Response System

HGRHigh growth reassortant

IHR International Health Regulations (2005)

RA Risk Assessment

SAGE WHO Strategic Advisory Group of Experts on Immunization

WHO CC WHO Collaborating Centre of GISRS

WHO ERL WHO Essential Regulatory Laboratory

Review of the use of pandemic/ pre-pandemicand seasonal vaccines by WHO, SAGE and other experts

Further vaccine

development/ licensing/

stockpiling

WHO recommendation on pandemic vaccine production and use

Y E S

YES

NO

VERSION 30.09.2016

Continuous assessment by WHOs IHR, SAGE and subject experts, as well as industry and stakeholders on:

1. Epidemiology, including severity assessment

2. Virology

3. Biosafety assessment

4. The status of seasonal vaccine production

5. The need for pandemic or pre-pandemic vaccines

6. The risks associated with switch from seasonal to pandemic production

7. The risks associated with switch back to seasonal vaccine production

NO

NO

YES

(a) HGR(s)(b) alternative

vaccine viruses?

1 Need a decision whether CVV is covered by Nagoya Protocol

1

25

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| Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT 2114

ANNEX 5Further Activities: the “Parking Lot”

The “parking lot” was a list of comments relevant to the informal consultation but not considered in depth. Some of the Parking Lot comments and proposals from the first Consultation have now been incorporated into Section 5.2 Bottlenecks of this report. The remaining Parking Lot items could be considered as part of forward agendas in future meetings. New proposals from the 2016 consultation are in italics.

Key proposals

Communication• Improve sharing of information including

genetic, sequence and epidemiological data.• Review how WHO communicates to

stakeholders in an emergency.

Research • Promote Gain of Function research.• Further surveillance information on the

spread of pandemic viruses and seasonal viruses concurrently. What is the likelihood of a pandemic virus displacing seasonal viruses?

Future meetings• Hold a specific consultation on research

and development of current and future pandemic vaccines.

Other activities• Finalize the risk assessment tool (TIPRA).• Update national pandemic preparedness

plans.• Consider adding administration procedures

in pandemic plans.

• What preservatives are to be recommended for pandemic vaccines?

• If an adjuvant is needed for pandemic vaccine and not all manufacturers have access to an effective adjuvant, what plans are in place to share adjuvants?

• What is the process to stop pandemic vaccine production?

Further proposals• Harmonize vaccine distribution, shipping,

logistics, and cold chain.• Include recombinant, cell based and

live vaccines in future consultations on pandemic vaccine response.

• Review new technology platforms to speed up production of current vaccines.

• Review the need and progress of potentially more effective vaccine, including adjuvanted and universal vaccines.

• Post-release observational vaccine effectiveness studies, especially among elderly vaccines, should be undertaken.

• Behavioural analysis: how do people actually behave in a pandemic? E.g., politicians, medical profession and the public.

• Pharmacovigilence should be strengthened globally.

26

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ANNEX 6 List of Participants

Dr Ian BarrWHO Collaborating Centre for Reference and Research on Influenza Peter Doherty Institute for Infection and Immunity 792 Elizabeth St, MelbourneVictoria 3000Australia

Dr William CracknellR&D Influenza OperationsbioCSL45 Poplar Road3052 - Parkville, VictoriaParkvilleAustralia

Dr Armen DonabedianInfluenza Division/Biomedical Advanced Research and Development Authority (BARDA)/HHS/ASPRDepartment of Health and Human Services330 Independence Avenue SW, Rm G640Washington, DC 20201USA

Dr Matthew DownhammManufacturing Science & TechnologyAstraZeneca OperationsRenaissance Way, Boulevard Industry ParkLiverpool L24 9JWUK

Mr Derek EllisConversArt Consulting1 Inwood DriveOttawa, Ontario K2M2A4Canada

Dr Othmar EngelhardtWHO Essential Regulatory LaboratoryDivision of VirologyNational Institute for Biological Standards and Control (NIBSC)Blanche Lane, South MimmsPotters BarHertfordshireEN6 3QGUK

Dr Bruce GellinNational Institutes of Health (NIH)National Vaccine Program Office (NVPO)U.S. Department of Health and Human Services200 Independence Avenue, S.W.Washington, DC 20201USA

Dr Kari JohansenExpert Influenza and other Vaccine Preventable DiseasesSurveillance and Response Support UnitEuropean Center for Disease Prevention and ControlSE 171 83 StockholmStockholmSweden

Dr Jacqueline KatzWHO Collaborating Centre for Surveillance Epidemiology and Control of InfluenzaCenters for Disease Control and Prevention (CDC)Influenza BranchMS G16, 1600 Clifton RoadAtlanta GA 30333USA

Dr Sam LeeSanofi PasteurPandemic & New Influenza ProductsDiscovery DriveSwiftwater, PA 18370-0187USA

22

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| Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT18

Dr John McCauleyCrick Worldwide Influenza CentreThe Francis Crick InstituteMill Hill LaboratoryThe Ridgeway, Mill HillLondon NW7 1AAUK

Dr Heidi MeyerPaul-Ehrlich-Institut International CooperationRegulatory Services HessenGermany

Dr Hartmut NedebockPandemic Influenza ResponseGlaxoSmithKline Vaccines20, Avenue Fleming, Building W231300 WavreBelgium

Dr Elisabeth NeumeierManufacturing Sciences & PLCMGlaxoSmithKline BiologicalsNL der SB Pharma GmbH & Co. KGZirkusstraße 40, 01069 DresdenGermany

Daniel NormandeauConversArt Consulting1651 promenade Autumn Ridge DriveOttawa, Ontario K1C 6Y1Canada Dr Bram PalacheInfluenza VacccinesAbbott BiologicalsC. J. van Houtenlaan 361381 CP - WeespThe Netherlands

Dr Pasi PenttinenDisease Programme for Influenza and other Respiratory VirusesEuropean Centre for Disease Prevention and Control (ECDC)Tomtebodavägen 11a171 83 StockholmSweden

Dr Jean-Luc SionEuropean CommissionDG SANTEUnit C3 Health ThreatsHITEC 02/95L-2920-Luxembourg Kirchberg

Dr Stepanie SonnbergScientist504 S. Rosa RdSuite 200Madison, WI 53719 USA

Dr Beverly TaylorTechnology and Scientific AffairsNovartisGaskill Road, SpekeLiverpool, L24 9GRUK

Dr Theodore TsaiTakeda Vaccines40 Landsdowne StCambridge, MA 02139USA

Dr John Martin WatsonDepartment of Health510, Wellington House133-144 Waterloo RoadSD1 8UG - LondonUK

2328

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Influenza Vaccine Response during the Start of a Pandemic – 2nd WHO Informal Consultation REPORT |

Dr Richard WebbyWHO Collaborating Centre for Studies on the Ecology of Influenza in AnimalsSt Jude Childrens Research HospitalDepartment Virology & Molecular Biology332 N. Lauderdale StMemphis TN 38105, USA

Dr Jerry WeirDivision of Viral ProductsCenter for Biologics Evaluation and ResearchFood and Drug Administration10903 New Hampshire AvenueSilver Spring, MD 20993USA

Dr John WoodDivision of VirologyNational Institute for Biological Standards and Control (NIBSC)Blanche Lane, South Mimms EN6 3QG - Potters Bar, HertsUK

Ms Margarita Xydia-CharmantaVaccines PolicyInternational Federation of Pharmaceutical Manufactures & AssociationsChemin des MinesP.O. Box 1951211 Geneva 20Switzerland

Dr Seyed Mohsen ZahraeiCentre for Disease Control Water & Food Borne Diseases DepartmentMinistry of Health and Medical EducationTehranIslamic Republic of Iran

WHO SECRETARIAT

Claudia Alfonso HQ/HIS/EMP/RHT/RSS

Hien Doan WHO/HQ/HSE/GIP

Martin Friede HQ/HIS/EMP/PHI

Gary Grohmann WHO/HQ/HSE/GIP

Joachim Hombach HQ/FWC/IVB/IVR

Marie-Paul Kieny HQ/HIS/HIA

Sasha Kontic HQ/HSE/PED/HIP

Philippe Lambach HQ/FWC/IVB/IVR

Justin Ortiz HQ/IVB

Laszlo Palkonyay HQ/HIS/EMP/RHT/PQT

Gina Samaan HQ/HIP

Guido Torelli HQ/HIS/EMP/PHI

Katelijn Vandemaele WHO/HQ/HSE/GIP

Wenqing Zhang WHO/HQ/HSE/GIP

Tiequn Zhou HQ/HIS/EMP/RHT/TSN

24 29