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?
SUMMARY
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.
THE GLOBAL
INFLUENZA SURVEILLANCE
NETWORK (GISN)
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 EMERGENCE
OF THE
H1N1 PANDEMIC
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.
INTERNATIONAL SHARING
OF GENETIC
DATA
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.
INTERNATIONAL SHARING
OF VIRUSES
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.
ENHANCING THE
CAPACITY OF
NATIONAL INFLUENZA
CENTRES
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.
EXTENT AND
SUPPORT OF
ACTIVITIES RELATED
TO THE
WHO COLLABORATING CENTRE
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.
INTERNATIONAL ADVICE
TO UK GOVERNMENT
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.
STRENGTHENING INTERNATIONAL
COLLABORATION
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.
CONCLUSION
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
| 
