Scientific advice and evidence in emergencies - Science and Technology Committee Contents

Memorandum submitted by the WHO Collaborating Centre for Reference and Research on Influenza, MRC National Institute for Medical Research (SAGE 07)

  This response comes from the WHO Collaborating Centre for Reference and Research on Influenza supported by the Medical Research Council and is based at the MRC National Institute for Medical Research at Mill Hill, London.

  The WHO Collaborating Centre has contributed to the reply submitted by the Medical Research Council on the questions about the H1N1 Influenza pandemic of 2009-10 but this reply provides further views from the international perspective and addresses the question: How important is international coordination and how could it be strengthened?


  International collaboration was essential to monitor the evolution of the pandemic H1N1 virus as it spread around the globe. The World Health Organisation coordinates a Global Influenza Surveillance Network (GISN) with virology laboratories in over 130 countries throughout the world; the activities of the laboratories in GISN are integrated by five WHO Collaborating Centres on Influenza (WHO CC), one of which is based at the Medical Research Council National Institute for Medical Research (NIMR). The WHO CCs provide advice, through WHO, on the most appropriate virus strain to be used in vaccines, about the emergence of variant viruses and on the prevalence of drug resistant viruses. It was critical that a soundly established surveillance network was in existence to identify rapidly the new pandemic and provide advice as the pandemic developed.

  The WHO CC at NIMR works closely with laboratories throughout Western and Eastern Europe, the Middle East, North Africa, West Africa and the Far East. Within the UK the WHO CC works closely with laboratories within the Health Protection Agency, notably the National Institute for Biological Standards and Control and the Centre for Infections in Colindale, as well as with the Wellcome Trust Sanger Institute. Being based at a medical research institute the WHO CC at NIMR is able to apply state-of-the-art research techniques to any new viruses resulting in an increased understanding of any changes to the virus that might be observed during the course of the pandemic. As part of the WHO network, these results can be rapidly shared with the international community.

  It is important to recognise that UK has played, and continues to play, a key role in the global efforts to counter influenza and in the preparedness for new pandemics and new epidemics of influenza. It is essential that UK retains its global role in influenza surveillance, research and development.


  Pandemic influenza is, by definition, an international problem, and international coordination and collaboration are essential for an appropriate response to the threat posed by an emerging influenza virus. The WHO coordinates a Global Influenza Surveillance Network (GISN) which was initially developed from an MRC project initiated in the late 1940's. The National Institute for Medical Research (NIMR) thus became the first WHO Collaborating Centre for Influenza when WHO formally set up GISN. GISN has laboratories designated as National Influenza Centres (NICs) throughout the world and is currently composed of 134 NICs in 104 countries and continues to expand. The activities of the NICs within GISN are integrated by the WHO Collaborating Centres (WHO CC) on Influenza which have now expanded in number to a total of five: in addition to the WHO CC at NIMR, there are collaborating centres based at Atlanta USA, Tokyo Japan, Melbourne Australia, and a WHO CC on the ecology of animal influenza viruses in Memphis USA. The role of the network is to identify newly emerging strains of influenza virus, to monitor human infections caused by animal influenza viruses (such as H5N1 viruses), to assess any emergence of new strains of human influenza viruses that necessitate a new vaccine, to monitor the emergence of drug resistant strains of virus and to survey the general threat of influenza to global public health. The WHO CCs recommend suitable strains for development into vaccines. In the context of the emergence of the H1N1 viruses international collaboration though GISN was critical to the response to the emerging pandemic.

  Funding for the network is complex. The NICs are funded through the Departments of Health of national governments; support for the WHO CCs is from a relevant supporting body. There are WHO NICs responsible for England and Wales, Scotland, and Northern Ireland and they are funded by the Department of Health. In UK the WHO CC is funded as a part of the Medical Research Council programme of research conducted at NIMR and is not funded by the Department of Health.


  The new H1N1 pandemic influenza virus was first recognised at the WHO CC in Atlanta, USA. Two cases of unusual influenza in California were investigated by the Atlanta scientists who identified the new virus. This information was made public and all the information at hand about the viruses was made freely available. There was immediate recognition that the virus was not confined to California but many cases of influenza in Mexico were likely to have been caused by this new virus.

  The first detection of the virus was carried out by the Atlanta WHO CC but all WHO CCs have the capacity and the expertise to carry out detailed analysis of any newly emerging influenza virus. It is the WHO CC that is most likely to carry out the initial characterisation of any new pandemic influenza virus. Each WHO CC will report any findings to the NIC of the country from which a virus has been submitted, as well as alerting WHO headquarters in Geneva of unusual viruses emerging. Thus WHO and the country are able to implement plans for the containment of, and response to, a new threat to health.


  Most current diagnostic methods for influenza viruses are based on the molecular characteristics of the virus genome and use the quantitative Polymerase Chain Reaction (qPCR) technique. These methods can be developed to give exquisite specificity but rely on knowledge of the nucleotide sequence of the genome of the virus. The scientists of the WHO CC in Atlanta shared their nucleotide sequence results freely through the public database dedicated to influenza viruses, GISAID.

  From these shared data from the WHO CC, National Laboratories were able to identify viruses emerging in the first few days of the pandemic directly from their nucleotide sequence identity with the California prototype H1N1 viruses. Subsequently the genome sequences were used to generate the reagents for the molecular diagnostic reagents. Many countries developed their own diagnostic reagents for validating their tests. The WHO CC laboratories also developed PCR protocols and reagents and these were shared freely through WHO.

  The key to the rapid detection of virus as it spread in the first few days of the pandemic and the speedy development of rapid and sensitive tests were both dependent on the timely sharing of results by the WHO CC who first identified the new virus.


  Many questions needed to be urgently answered through laboratory studies of the newly emerged H1N1 virus. These include how pathogenic the virus might be, whether the virus was susceptible to the available antiviral medicines, and whether those vaccinated against seasonal influenza viruses might be protected from infection by the newly emerged virus.

  The WHO CC network has the capability to try to answer all these questions. In the case of the H1N1 2009-10 pandemic virus the WHO CCs were all able to examine the prototype virus within a very short time and provide answers to the questions that were posed. The answers to these questions were freely shared with the relevant authorities to assist planning for the pandemic.

Vaccine development and monitoring antigenic drift

  International collaboration is essential to the development of influenza vaccine. The pandemic vaccine was produced to the anticipated time-lines through a highly effective international collaboration involving the WHO CCs alongside statutory National Control Laboratories in UK (National Institute for Biological Standards and Control), USA and Australia. All parties combined their information, viruses and reagents to enable vaccine production by the manufacturers to get underway as soon as possible.

  When the vaccine was under development and in use an important role of the WHO CCs within GISN was to monitor virus as it circulated all over the world for the emergence of antigenic variants against which vaccine might be less effective. This is a key activity for the WHO CCs for seasonal influenza vaccines and was enhanced for the emerging pandemic virus. To date, very little evidence of antigenic variation has been detected for within the H1N1 pandemic virus but antigenic analysis of all viruses provided by the National Influenza Centres is continuing within each WHO CC.

Monitoring antiviral resistance

  The 2009-10 influenza pandemic was the first in which antiviral medicines were widely available. Resistance to antiviral medicines is common amongst influenza viruses with the previously circulating seasonal H1N1 having acquired resistance to oseltamivir in recent years, and both the pandemic H1N1 virus and seasonal H3N2 viruses being resistant to another class of anti-influenza drugs, the adamantanes. It was therefore a priority to monitor on a global level antiviral resistance of the pandemic virus. The WHO CCs examined viruses shared by the NICs in GISN for resistance to both oseltamivir and zanamivir, the neuraminidase inhibitors. This international cooperation through the WHO CCs resulted in a comprehensive and up-to-date recognition of viruses resistant to the main drug of choice—oseltamivir. Throughout the pandemic resistance was only detected rarely and almost invariably was associated with use of oseltamivir.

  NICs with the appropriate expertise can carry out national surveillance for drug resistant strains of virus and the first virus that was suspected in Europe as being resistant to oseltamivir was thus detected at the NIC in Denmark. This virus was then shared with the WHO CC at NIMR to determine its precise antiviral profile and this information was immediately shared with the Danish authorities and WHO Headquarters. Subsequently the London WHO CC confirmed that resistant viruses emerged in Israel, France, Belgium, Portugal and Spain.

Monitoring changes in virulence and pathogenicity

  As the pandemic of 2009-10 emerged, it became apparent that the infection resulted, generally but not exclusively, in mild illness. Regardless, it was critical to determine whether virus from severe cases represented evolution of the virulence of the virus or was associated with other underlying causes. Many countries suffering severe infections were not able to carry out the detailed analysis required to analyse the viruses circulating in their country. Samples collected from patients with particularly severe illness were sent to WHO CCs for detailed analysis. This allowed the WHO CCs to assemble data on the virulence of viruses from all around the world and disseminate it freely. At the WHO CC at NIMR samples from cases with increased virulence were obtained from many countries but notably samples from Eastern Europe, the former Russian states and several countries in Africa made up the majority of the analyses of samples collected from patients with severe illness.

  The results of these analysis indicated that a possible hallmark of many variant viruses associated with increased virulence was detected but the circulation of these variants was not generally sustained.

  The WHO CC at NIMR has the ability to carry out such detailed analyses; within the research environment of NIMR the WHO CC is in a position to apply state-of-the-art research techniques in a timely fashion to any newly-emerging influenza virus. At NIMR expertise in physical biochemistry, molecular structure determination, mathematical biology, immunology as well as virology can be harnessed together and lead to in an increased understanding of the significance of changes that might be observed in the virus during the pandemic. As part of GISN, the WHO CC can therefore rapidly provide these results of thorough scientific research to the international community though communication with governments and with WHO.


  Whilst many NICs have sufficient expertise and capability to carry out detailed analysis of viruses in their countries (for example the HPA laboratories at Colindale) many had only limited capacity to handle samples and many did not have laboratories with sufficient containment propagate virus or to handle propagated virus. It is one of the roles of the WHO CCs to give as much assistance as possible to these laboratories. The WHO CC at NIMR received samples for analysis from many countries around the world to assist with the characterisation of the viruses in the samples. Examples included Ukraine, Moldova, Georgia, Romania, Kosovo, Ghana, Algeria, Morocco, Malta, Oman, Tajikistan, Nepal and many others. In addition a large number of countries shared their first samples taken during the pandemic for the WHO CC to confirm their first sets of results.

Enhanced training for National Influenza Centres

  In addition to acting as a WHO CC, the NIMR laboratory at Mill Hill, in partnership with the HPA Colindale and RIVM Netherlands, acts as part of the European Community Reference Laboratory for the European Centres for Disease Control. Both WHO and the ECDC have programmes for international training. These training programmes have been held as short courses, for example one held for ECDC in London for antigenic analysis; in addition specialist training for individuals or pairs of scientists has been provided at the WHO CC at NIMR for periods of two weeks to a month or longer for advanced training. These specialist training periods are focussed in improving molecular analysis or virological analysis of samples allowing the trainees to return to their NIC to enhance their national capability.

  At the WHO CC at NIMR we have hosted over the last 12 months visiting training fellows for advanced analysis of virus from Iraq, Senegal, Algeria, Georgia, Malaysia, Romania and Ghana; this training programme continues.


  Over the period of the 2009-10 pandemic the London WHO CC received clinical samples and virus isolates from over 50 countries including UK. As described above, the samples from some countries were either clinical samples for primary analysis or alternatively viruses already isolated in the country of origin. Over 2,000 samples were received during the 2009-10 pandemic. For all viruses that were propagated antigenic analysis was carried out and anti-neuraminidase drug sensitivity assays were carried out on all viruses that could be propagated to sufficient titre. A proportion of the samples were subjected to sequence analysis of the HA and NA genes (in the order of 20%) and a smaller set analysed by full genome analysis.

  MRC supported the WHO CC at NIMR during the pandemic, notably by supporting capital funding for replacing "at risk" high cost equipment and having supported expansion of its high containment laboratory facility. The expansion of this facility resulted in being ready and able within 72 hours of the first recognition of the new pandemic virus to handle and process any samples that might be received. Both the extended laboratory facility and new equipment were essential to fulfilling the international role of the WHO CC at NIMR. As expected staff resources were stretched to the limit throughout the period of the pandemic from April 2009 until June 2010.

  The UK has contributed to full genome analysis of a number of UK samples and samples from other countries. The ability to carry out this work had been markedly enhanced by previous funding from the Wellcome Trust to develop an influenza virus sequencing pipeline. This pipeline was further developed during the early stages of the pandemic and has made considerable progress. The first full genome sequence of a UK virus was determined jointly by the WHO CC at Mill Hill and the HPA in Colindale, and subsequently many of the analyses were carried out in collaboration with the newly established Virus Genomics group at the Sanger Institute and scientists from Universities of Oxford and Edinburgh.


  The international perspective of the pandemic was provided to UK Government in part by setting up a Scientific Advisory Group for Emergencies (SAGE) focussed on the emerging pandemic, It is striking that advice relating to the international activities was provided not by members of the WHO CC staff at NIMR but by the European Centre for Disease Control (ECDC) in Stockholm. ECDC is not involved directly in WHO GISN and the global surveillance of influenza; hence it was surprising that SAGE had not included a WHO CC representative to provide advice from the widest international viewpoint.


  GISN has been built up over more than 60 years and yet there remain some weaknesses. Some areas of the world have only a small number of National Influenza Centres, although the emergence of the influenza pandemic in 2009-10 has resulted in the WHO recognition of several new NICs. One region that still needs greater coverage is sub-Saharan Africa. International support for the laboratories in many of the countries without the capacity to carry out influenza surveillance would be highly beneficial and increased support for training of members of staff of the new laboratories is important. Currently WHO provide some funds for support, the USA Centers for Disease Control and Prevention also supports laboratory training but, on the whole, increased funding for training is needed.

  Recent advances in technology are likely to change the way in which influenza virus surveillance is carried out. Currently viruses are characterised after isolation but modern techniques make it possible to determine the full genome sequence of a virus without it being isolated. In the future it is likely that determination of the virus genome sequence directly on clinical samples will be the first level of virus characterisation, subsequently virus isolation will be carried out on a sub-set of samples that show significant genetic change. This will reverse the present situation with virus isolation preceding selection of strains for nucleotide sequencing. Whilst sequencing is becoming cheaper, it is still expensive to set up and sustain and it is still far from cost-effective to use sequencing as the primary screen. However, it is very likely that international hubs will be set up to carry out this work. The UK's expertise in sequencing should not be overlooked and the support of the Wellcome Trust Sanger Institute to the influenza work over the period of the pandemic needs to be sustained and expanded. A sustained international focus to sequence influenza virus samples from around the world needs to be encouraged. This focus would be developed hand-in-hand with experts in influenza virology as well as bio-informatics, to combine their expertise to chose and study samples for further analysis.

  The timely availability of the vaccine for the 2009 pandemic virus needs to be recognised but it also needs to be noted that this availability was not inevitable. Traditional influenza vaccines have a long history of success but the vaccine totally depends on our ability to culture the virus itself to high titre sufficient for effective vaccine production. Although the H1N1 2009 virus was not easily propagated, the manufacturers were able to adapt the virus adequately for vaccine production; next time we might be less fortunate. To circumvent this, vaccines that do not rely on the propagation of the virus per se might offer a feasible alternative. International co-operation should be set up to investigate a small number of new types of influenza vaccines that could be able to go into production over a five to 10 year period. These new vaccines would have to be chosen not only on their likely efficacy but also on their cost effectiveness, since if the vaccine is too expensive then it will not be widely used.

  The effectiveness of antiviral drugs in the control of the 2009-10 pandemic has yet to be fully evaluated. It is striking that during the pandemic treatment and prophylaxis was limited to one class of compounds the neuraminidase inhibitors, of which Oseltamivir was the most widely used. International collaborations need to be set up to promote companies to develop new influenza anti-viral compounds that can be used to supplement the neuraminidase inhibitors.


  UK played an important role during the 2009-10 H1N1 influenza pandemic. Within UK the response nationally was from led by the Health Protection Agency Centre for Infection. Internationally the Health Protection Agency National Institute for Biological Standards and Control played a critical role in the development and assessment of the pandemic vaccine. The WHO Collaborating Centre for Influenza at the Medical Research Council National Institute for Medical Research played an international role by integrating results from around the world with other WHO CCs, by assisting countries with less capability by carrying out virus isolation and characterization, sharing protocols and providing training, and by examining viruses from numerous countries in Europe, Africa, the Middle East and Asia for changes in antigenicity, virulence and drug resistance. It is important that UK continues to play an international role in the international response to influenza.

John W McCauley BSc PhD

Director, WHO Collaborating Centre

Division of Virology

6 September 2010

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