Pandemic Influenza Preparedness - Significant agreement on sharing of influenza viruses samples and benefit sharing at a global Open Ended Working Group (Geneva April 11th-16th)Archived

On 16 April 2011 and following four years of negotiations a formal Open-Ended Working Group of more than 90 countries finalized a detailed Pandemic Influenza Preparedness Framework for the World Health Organization’s Global Influenza Surveillance Network (GISN). The development was welcomed by WHO, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) and the Director of ECDC.

The framework deserves careful study (it runs to 45 pages with detailed Standard Material Transfer Agreements and Terms of Reference for laboratories) but three key elements that were agreed last week were:  1. Mandatory financial partnership contributions by the pharmaceutical industry to the WHO Network covering around 50 percent of the annual running costs and a series of options for donation of vaccines and antivirals in the event of a pandemic.  2. The above element including granting of developing country manufacturers licenses on mutually agreed terms, i.e., potential transfer of intellectual property rights. It was agreed that would be on a voluntary basis; 3. Electronic tracking of isolated viruses with pandemic potential, such as A(H5N1), so called PIP Biological Materials within the system and beyond.

The agreed document will now go to WHO’s governing body the World Health Assembly in May 2011 (16-24 May) with a report from the Group and a Resolution strongly recommending adoption. The agreement was discussed with industry representatives and their representative body (IFPMA) has expressed agreement in principle.  Details will need to be worked through and a remaining area of uncertainty is how the Framework relates to the United Nations Treaty the Convention on Biological Diversity and specifically its Nagoya Protocol on access and benefit sharing.

Background

Since 2007 there has been a significant threat to the long-established WHO global system of influenza virus sharing and surveillance (GISN) the details of which ECDC has previously summarised at intervals on its web-site (see the Time Line) (1-3). The GISN system is central to the global response to ever changing influenza viruses, especially the timely development of effective vaccines and diagnostics. A number of other mechanisms rely on it (see Table 1) and ECDC’s own systems the European Influenza Surveillance Network and its Community Network of Reference Laboratories feed into and support GISN. 

The essential value of the GISN system was demonstrated by the response to the 2009 pandemic virus when there was immediate sharing and analysis of the new viruses, the development and global distribution of diagnostic kits and the commencement of vaccine development. This was all in record time and only possible through the rapid but safe and proper international exchange of viruses and related reagents.(4) 

The threat to universal sharing came in early 2007 (see Time-line) when one country suspended sharing of avian influenza A(H5N1) viruses and timely reporting of data from human cases. This revealed long-standing underlying problems in a system which had expanded over five decades as an effective but essentially informal mechanism.  In particular some less-resourced countries did not feel they were receiving sufficient benefits in return for sharing what they considered ‘their’ viruses, so called ‘benefit-sharing’.(1)  However there were fundamental disagreements between countries over whether there should be formal (legally enforceable), informal or indeed any linkages between sharing of viruses and benefits. There was also the philosophical problem of who could own a pathogen coming from a patient or animal one country, detected in another and perhaps isolated in a third.

The crisis led to the appreciation that the influenza virus surveillance systems needed both reform and formalization.  At the direction of the World Health Assembly, WHO, Member States and partners made considerable progress between 2008 and 2010. Achievements included:

• convening working groups which reviewed and revised the terms of reference of the tiers of laboratories involved, practices for sharing viruses and sequence data for producing vaccines – this led to a detailed framework that was worked through over two years; 
• formulating mechanisms and guidelines for fairer distribution of pandemic influenza vaccines at affordable prices;
• moving towards establishing an international stockpile of human avian influenza vaccines for use by poorer countries; 
• mobilizing financial, technical and other support to implement mechanisms increasing equitable sharing of benefits from seasonal vaccines – the WHO Global Action Plan (5);
• establishing an electronic tracking system for viruses with pandemic potential.

A fundamental issue has been that use and production of seasonal influenza vaccines is skewed towards better resourced countries which have higher proportion of their populations at high risk from human seasonal influenza (older people and those with chronic illnesses). Under the Global Action Plan that situation is starting to change with manufacturing starting up in a number of moderate resource countries (Brazil, Mexico, Thailand, Viet Nam etc ).(5) European populations use more seasonal vaccines than most and European Union based producers account for nearly two thirds of all influenza vaccines worldwide. Hence this is an important issue for Europe, though the resolution of the issue had to be led by WHO.  At the final negotiations the EU was represented by the Hungarian Presidency, the European Commission and twenty other EU/EEA countries with ECDC chairing a group working on definitions. Precise definitions were important in restricting the virus materials that come under the framework, as including the many small bits of genetic material for example used in probes and primers would have made for an unworkable system1.

ECDC Comment: April 20th 2011 

There are many interesting points here. One of them is that this is the first time that it has been agreed that international pharmaceutical companies will formally make some investment in the systems of surveillance and virus handling. These are essential to the development of vaccines that takes place annually and there have been contributions in the past to individual laboratories but this change should now make for a more transparent and just system of support complementing the public investment in these systems. By analogy such arrangements could logically be extended to include support the essential systems that monitor vaccine effectiveness and safety. 

Once adopted, the PIP Framework will improve global health security.(4)  It puts WHO’s GISN Network on mutually agreed terms and at the same time improves pandemic preparedness of the world by asking industry to contribute to pandemic preparedness in a predictable and sustainable manner by paying a “partnership contribution” to WHO.

The Global Action Plan to increase influenza vaccine production and use is also key.(5) A fundamental mis-match can be seen from many less-resourced countries’ perspective that they share their viruses each year for vaccine manufacturers predominately in better resourced countries to vaccinate people in those countries.  That is changing as some of the biggest vaccine manufacturers in the world, like those in India, start influenza vaccine production. Influenza vaccination does not make cost effectiveness sense at present in the poorest countries but over the coming decades ‘at risk’ populations such as those with chronic conditions and older people will steadily increase in all countries including those with moderate and poor resources. Hence the benefits for all countries using seasonal vaccines will also rise.  Finally as was seen in the 2009 pandemic vaccine production cannot be increased quickly. Hence increasing the annual production capacity of seasonal vaccine is key to improving global preparedness.(4)

The final detail of the Convention on Biological Diversity and specifically its Nagoya Protocol on access and benefit sharing is not a trivial one, and not one for influenza alone.  Essentially Nagoya is about preserving biological diversity and ensuring benefit sharing. However it is based on a fundamental principle that countries ‘own’ their natural resources. That does not fit well with the way that micro-organisms behave. The same arguments apply to other pathogens (animal and human) not just influenza. Fortunately there is provision in the Nagoya Protocol for other special instruments to apply like the PIP Framework and the International Health Regulations (Article 4 of Nagoya) and it is hoped that is what will be agreed.

Table 1: Benefits of Influenza Virus Sharing

• surveillance for the seasonal human influenza A and B viruses including antigenic characterisation and genetic sequencing
• surveillance for novel emerging human and avian influenza A viruses and allowing immediate risk assessments and responses
• developing and improving diagnostic tests for influenza
• reviewing and revising the composition of seasonal human influenza vaccines 
• supporting complex trials of new vaccines
• supplying to manufacturers virus strains with the required growth and antigenic properties for vaccine production along with reagents to support that production
• supplying to manufacturers carefully prepared safe influenza candidate vaccine viruses for pandemic vaccine production (both pre-pandemic planning and responding to emergencies)2
• maintaining safety and standards in the handling of what are inherently dangerous pathogens.

1"PIP biological materials" for the purpose of this Framework (and its annexed SMTA and TORS) and the Influenza virus tracking mechanism (IVTM), includes human clinical specimens, virus isolates of wild type human H5N1 and other influenza viruses with human pandemic potential; and modified viruses prepared from H5N1 and/or other influenza viruses with human pandemic potential developed by WHO Network laboratories, these being candidate vaccine viruses generated by reverse genetics and/or high growth re-assortment.Also included in "PIP biological materials" are RNA extracted from wild-type H5N1 and other human influenza viruses with human pandemic potential and cDNA that encompass the entire coding region of one or more viral genes. There is also an operational exemption making it clear that materials shared within the WHO Network or with other laboratories specifically for non-commercial public health uses including  surveillance activities, diagnostic applications, and quality assurance, are not handled as PIP Biological Materials while their onward transfer for purposes other than specified in the Terms of Reference of National Influenza Centres, WHO Collaborating Centres, Essential Regulatory  Laboratories and H5 Reference Laboratories is not allowed.

2This is generally done by a sophisticated genetic engineering technique known as ‘reverse genetics’ – only three or four laboratories world-wide have the capability to do this.