APPENDIX 3: SUMMARY OF SEMINAR
4 February 2009
Members of the Select Committee present were Lord
Broers, Lord Colwyn, Lord Crickhowell, Baroness Finlay of Llandaff,
Lord Jenkin of Roding, Lord May of Oxford, Lord Methuen and Lord
Sutherland of Houndwood.
Participants were Dr Nimalan Arinaminpathy (Postdoctoral
research fellow (James Martin 21st Century School), Department
of Zoology, Oxford), Professor Neil Ferguson (Professor of
Mathematical Biology (Director, MRC Centre for Outbreak Analysis
and Modelling, Imperial College, London), Imperial College), Professor Nigel
Lightfoot (Chief Adviser to the CEO and Head of Influenza Programme,
Health Protection Agency), Dr Bruce Taylor (Consultant in
Intensive Care Medicine, Portsmouth Hospitals NHS Trust), Professor Alain
Townsend (Professor of Molecular Immunology, Oxford) and
Professor Jonathan Van Tam (Professor Health Protection,
University of Nottingham).
Overview of the current pandemic influenza issues
in the United Kingdom (Professor Nigel Lightfoot)
Professor Lightfoot explained that the Health
Protection Agency (HPA) was responsible for providing advice and
guidance to Government, professionals and the public about pandemic
influenza. Diagnosis, recognition, surveillance and monitoring
cases were important aspects of its function, alongside helping
the NHS.
The Government's pandemic influenza planning was
based on a maximum 50 per cent clinical attack rate (CAR)—higher
than other countries—giving rise to 750,000 excess deaths.
It was anticipated that there would be a marked difference between
the rate of increase in the number of cases locally and nationally,
with the number of cases locally rising sharply at an early stage
compared to national figures.
In terms of the World Health Organisation (WHO) classification
of the six phases towards a pandemic, the UK was currently at
Phase 3: the pre-pandemic phase. There had been 404 cases of human
H5N1 infection reported to the WHO, with 254 deaths. Most had
occurred in south east Asia. There had been no H5N1 avian outbreaks
in Europe since May 2008 although some had occurred in other parts
of the world. There had been seven avian influenza outbreaks in
the UK since 2003, two of which were H5N1, one H7N3 (including
one transmission to a worker) and another H7N2 (with four cases
of transmission to humans). Each had been contained effectively.
Planning for an influenza pandemic held a number
of challenges: avian influenza; recognising human transmission,
in the UK or elsewhere, at an early stage; recognising the first
cases to come into the UK; diagnosing and confirming those cases;
monitoring the first cases and contacts; preparing the surge capacity
of the NHS; developing a system of distribution for antivirals;
planning for public health interventions (particularly, hand-washing
and masks); managing social disruption and business continuity,
and planning for vaccine availability.
Avian influenza was a severe disease in chickens
and swans. It had been endemic in the far east for at least 10
years and had recently spread to Europe. Human transmission tended
to occur where humans had been in close contact with poultry.
There had been no reported cases of human-to-human transmission
save one or two cases in Indonesia.
Responsibility for addressing the challenges of a
pandemic influenza outbreak rested with the Department of Health
(DH) (government response, antivirals, vaccines, antibiotics,
the Scientific Advisory Group and communication with the public
through the Chief Medical Officer) and the HPA (maintaining global
awareness, providing systems for recognition of first cases, surveillance,
modelling and real time prediction, laboratory diagnosis and confirmation,
reference virology, vaccine strain development, advice and guidance
to the DH and NHS, communication with professionals and the public,
development programme of exercises, maintain a watch on the science
evidence base).
Turning to surveillance, Professor Lightfoot
said that UK cases were expected to be reported through contact
with "Flu Line". The Royal College of General Practitioners
also had an established surveillance system and Q Flu at Nottingham
University looked at every general practice and recorded diagnoses.
NHS Direct also provided a line for the public to call. Using
these systems, it was possible to monitor seasonal flu, the results
of which were published every week on the HPA website. Two exercises
had been conducted to enable this to progress to a daily reporting
system which would support the DH and COBR (Cabinet Office Briefing
Room). Importantly, monitoring information and the emerging picture
would be fed back to the local level.
Detailed knowledge about the first few hundred cases
was critical to understanding a new virus. A system for recording
had therefore been set up to enable modelling of the course of
an outbreak. Data collection for this exercise would be onerous—it
would take about an hour for each patient. The information would
be put into a database, which was near completion, and made available
to the modellers as quickly as possible. This would be done, with
NHS help, at local level through Health Protection Units. This
system was seen as an exemplar by the WHO and the European Communicable
Diseases Centre.
A system of diagnosis and laboratory confirmation
had been put in place using a network of 14 UK laboratories, each
using the same tests. We could therefore be confident that we
would be able to recognise the new viruses in whatever part of
the country they might occur in. The UK reference laboratory was
one of four WHO collaborating centres. It undertook confirmation,
typing and genetic analysis. Importantly, it also undertook antiviral
resistance monitoring and participated in vaccine research.
The HPA produced guidance documents on how to control
infection for a range of sectors, including hospitals, prisons
and funeral directors, and on clinical treatment guidelines. They
were all available on the HPA website.
Public health interventions were about understanding
the transmission characteristics of the virus. The essential message
was stay at home if you were ill but there were doubts about whether
people would follow that advice. Hand-washing and mask use had
to be considered, as did restricting unnecessary travel, school
and university closures and limiting large social gatherings.
The evidence suggested that the virus would be transmitted through
large droplet and contact routes. The virus would survive 24 to
48 hours on surfaces and 4 hours on skin. Therefore hygiene and
containing sneezes were critical.
It appears from the evidence to date that a pandemic
could not be stopped but only delayed by a short time—perhaps
two weeks. Border closures would have a wider impact on the continuous
supply of medicines and food into the country. Screening at borders
would be an alternative approach and perhaps a popular one but
screening would only detect cases in WHO Phases 4 and 5 and would
not detect incubating cases. Japan had already implemented screening
and the United States was committed to implementing screening
in Phase 5. The US had admitted that this would be very difficult,
that it would only detect 50 per cent of cases and that they would
do it only for two or three weeks. The UK had a policy of no border
closures and no screening.
In the past, closure of schools for the Christmas
break has halted the spread of a seasonal influenza outbreak.
So school closures could provide an effective measure but there
were other considerations: for example, would the children congregate
elsewhere? would there be an effect on health care workers who
might have to stay at home to look after their children? when
should the schools be re-opened?
Antivirals provided a strategy to reduce morbidity
and mortality. They were currently used as a post-exposure prophylaxis
for avian influenza. The UK stockpile was being built up and was
expected, by April 2009, to reach a level that would enable 50
per cent of the population to be treated.[16]
This was greater than the stockpile in France and Canada. An antiviral
had to be given within 48 hours—12 hours was the target.
Distribution presented a significant logistical problem. The DH
had considered various options when letting the "Flu line"
contract. Household prophylaxis was not current DH policy.
Vaccine procurement was difficult because of uncertainty
about the identity of the outbreak strain. H5N1 was a likely candidate
and 3.4 million H5N1 vaccine doses had been manufactured in the
UK, with a sleeping contract for 120 million doses. Research in
generic vaccines was essential, as was global co-operation.
Business continuity measures would have to be considered:
for example, more home-working, developing a culture of surface
cleaning and personal hygiene, and considering public or visitor
handling policy.
Conclusion
To sum up the achievements in UK preparedness, we
had in place global influenza intelligence monitoring and systems
of first cases recognition; there was a good network of laboratories
and an effective surveillance programme; guidance documents for
all sectors were available and a review of the science evidence
base was ongoing; exercises were being undertaken for the UK,
EC and WHO and real-time modelling was being developed by teams
in the Health Protection Agency, and in the MRC Centre directed
by Professor Ferguson at Imperial College.
Questions
In questions, Professor Lightfoot said that
the role of the Cabinet Office was to co-ordinate planning. At
the beginning of a pandemic, COBR meetings would be called on
a daily basis and those meetings would be informed by the data
gathered by the HPA. Professor Lightfoot was asked whether
tests had been carried out to determine how the frontline medical
services would cope in the face of staff being unavailable because
they or their families had fallen sick. He confirmed that tests
would be carried out—the contract had only just been put
in place. He agreed that they would need to be done and that they
should be full-blown practical tests.
Evolution and emergence of pandemic influenza (Dr Nimalan
Arinaminpathy)
Dr Arinaminpathy described work that he had
done with Professor Angela Mclean of the Department of Zoology,
Oxford. The focus of the work was to define the events which we
could expect to observe in the run up to a pandemic. A difficulty
was that the nature of the virus—its virulence and transmissibility—was
unknown. This made policy planning very difficult. So the strategy
adopted was to use simple mathematical models to demonstrate different
contingencies which may be faced in the run up to a pandemic and
to use the results from the modelling to give an indication of
the possible warning signs of a pandemic.
The H5N1 virus was the subtype of avian influenza
that was causing the greatest concern. H7N7 and H9N2 were also
pandemic candidates. There were many barriers to an avian influenza
virus becoming adapted to human transmissibility. The biology
of adaptation was complex and our understanding was partial at
best. There were two mechanisms by which a virus could overcome
species barriers: "viral adaptation" (an incremental
process driven by mutation and selection) and "viral reassortment"
(where an individual is infected with both a human virus and an
avian virus and the two viruses mix genetic material and potentially
produce a hybrid, novel virus).
Since 1997, we have been at Phase 3 of the WHO phases
of pandemic alert where we have no or very limited human-to-human
transmission. Increasing levels of alert correspond to increasing
levels of transmission. The WHO scheme was an intuitive picture
which suggested a gradual transition through the six phases. But
we had to ask ourselves under what circumstances we might jump,
say, from Phase 3 to a full-blown pandemic at Phase 6. Focusing
on "viral adaptation", Dr Arinaminpathy had applied
simple mathematical models to discover patterns of human cases
which we might expect to see before a pandemic.
In explaining the models, Dr Arinaminpathy referred
to the notation "R(zero)". It was the "average
number of secondary infections produced when one infected individual
is introduced into a host population where everyone is susceptible"
(Anderson and May, 1992). A human-adapted virus was where R(zero)
was greater than one. A poorly adapted virus had a R(zero) value
far less than one. By adaptation, a virus with an initially low
R(zero) could, by incremental mutations, achieve pandemic-capability.
Punctuated and gradual route to emergence
Dr Arinaminpathy explained two possible scenarios
for the development of a pandemic with a virus undergoing a series
of adaptations. First, there was the "punctuated" route
to emergence. This was characterised by R(zero) remaining well
below one through several adaptations and only the fully-adapted
virus having any appreciable increase in R(zero). By contrast,
the "gradual" route to emergence was characterised by
every successive adaptation conferring an increase in R(zero).
It was not possible to say which of these two scenarios was more
likely. They were equally plausible, as the genomics and microbiology
of the H5N1 virus were not sufficiently well-understood. The virus
that adapted gradually was the one which would be more likely
to afford warning of a pandemic in the form of large but self-limiting
outbreaks. The virus which adapted in a punctuated manner was
more likely to emerge without any prior warning. This distinction
was important to bear in mind in terms of pandemic preparedness
planning because each scenario would involve different degrees
of observable warning signs.
The different character of the punctuated and gradual
emergence routes was reflected in the numbers of "false alarms"
associated with each. The punctuated scenario tended to exhibit
fewer false alarms while the gradual scenario would present far
more. The gradual scenario therefore created the particular difficulty
of identifying when an outbreak was genuinely self-resolving (a
false alarm) or the start of a pandemic.
There were practical, resource consequences arising
from these different scenarios. Because of the relatively low
level of false alarms with the punctuated scenario, intervention
would be likely to be triggered in respect of a genuine pandemic
and therefore only the once. However, containment of a fully-adapted
virus would pose significant challenges. With the gradual scenario,
an outbreak may be sufficient to cause alarm and trigger an intervention
but may in fact be a false alarm. At each intervention, containment
would be comparatively easier than for the punctuated scenario.
However, the multiple interventions elicited by the gradual scenario
could drain valuable resources for when the pandemic eventually
took off.
Summary
In summary, Dr Arinaminpathy made the following
points: (1) pandemic preparedness plans should acknowledge that
although a pandemic might be heralded with repeated and large
outbreaks, it was also possible that it could happen without warning;
(2) each scenario posed unique challenges for preparedness and
for containment, and (3) in the absence of sufficiently detailed
knowledge of the steps an avian virus may take to adapt to humans,
early warning systems could benefit from analysis of past outbreaks.
Professor Townsend pointed out that the three
pandemics of the last century came without any warning. In addition
in the 1970s, when fear of swine flu re-emerged, it turned out
to be a false alarm but a huge effort was made to immunise in
the US with highly damaging results.
Recognising the warning signs of an influenza pandemic
(Professor Jonathan Van Tam)
Professor Van Tam said that he would describe
some of the practical issues relating to recognising the warnings
signs of a pandemic outbreak.
Pre-requisites for a pandemic
The pre-requisites for pandemic influenza were: that
the influenza virus was a novel influenza A subtype with an H
value unrelated to an immediate (pre-pandemic) predecessor; that
there was little or no pre-existing population immunity; that
the virus caused significant clinical illness, and that there
was efficient human-to-human transmission.
During the last century there had been three pandemics,
two originated in south east Asia and one may have originated
on the on the east coast of the US. In 2003, H5N1 re-emerged.
Although the human H5N1 "hotspots" were still concentrated
in south east and central Asia, there had been some incidents
closer to the UK. Outbreaks in Africa had a particular importance
because of the implications of its poor health infrastructure.
Historically, the only influenza A subtypes which had caused human
pandemics had been H1, H2 and H3. H5 was a leading candidate for
the next human pandemic, although many eminent biologists believed
that H2, for example, was a likely contender.
The sequence of detection
In trying to detect warning signs for a pandemic,
what would we be looking for in practical terms? The sequence
would begin with "recognition" of (unexplained) single
cases or clusters of moderate or severe acute respiratory infection.
For obvious reasons, disease severity and number of cases occurring
in an area were inversely related factors in triggering recognition
by healthcare workers—if the illness was mild, it was less
likely that a healthcare worker would recognise it as influenza
at an early stage. After the influenza virus had been recognised,
"diagnostics" would be applied to identify the novel
virus, followed by "epidemiological investigation" to
develop a pattern of human-to-human transmission. Finally, the
pandemic event would be "declared".
The WHO pandemic phases were under review and might
be changed in the next two to three months. The current scheme
was a rather stylised escalation to a pandemic outbreak. The phases
were theoretical and there was some doubt that the phases would,
in reality, translate into a smooth sequence of events.
Professor Van Tam summarised his views on the
likely origins of pandemic influenza: (1) the possibilities for
the site of emergence were far wider than south east Asia, especially
in relation to H5N1 disease activity in birds and humans; (2)
there was a very low possibility of emergence in the UK (but not
zero); (3) there should be an emphasis on the international collective
vulnerability: "we are as vulnerable as the weakest part",
and (4) there was no certainty that emergence would accord with
the ordered, escalating picture set out in the WHO plan.
Recognition
There were a number of practical difficulties in
recognising cases or clusters: there was huge international variability
in health systems and public health infrastructures; there was
often huge variability within countries, and Africa and central
Asia posed significant risks of delay. On the other hand, the
International Health Regulations were now in place, which would
increase the likelihood of effective monitoring. Also, once alerted,
we could be confident about the effectiveness of most parts of
the UK health system.
Diagnostics
After recognition, there was diagnosis. The first
stage was a rapid diagnostic test to determine whether the virus
was influenza and, if so, whether it was A or B. Then the specimen
would be interrogated to determine as rapidly as possible the
likely identity of the novel subtype—the "leading suspect".
Finally, platforms for diagnosis of other subtypes would be developed.
Clinical-epidemiological investigation
The next stage, clinical-epidemiological investigation,
was intended to provide an understanding of the syndromic picture
of the new virus. Mathematical modellers would attempt to quantify
the secondary spread of the infection—the patterns of transmission—and
this would inform the decisions of NHS managers about clinical
management pathways and the efficacy of treatments. All these
aspects of clinical-epidemiological investigation still required
testing and evaluation in the UK.
To assist in data collection in the event of a suspected
pandemic, the Health Protection Agency would enter information
about the first few hundred cases on the avian influenza database
and clinical information network—a web-based tool (FF100)—during
the early weeks of the pandemic. It would then be necessary to
switch over to a system that focused more centrally on clinical
information from the NHS to drive the treatment pathways. This
system was currently the subject of a tender. It would probably
take 12 to 18 months work-up time before we were in a position
to test it on normal, seasonal respiratory illness.
Questions
Professor Van Tam was asked about monitoring
from sentinel general practices and routine virology of those
who presented with symptoms, and whether anything had emerged
from such routine data collection. He said that there were two
big systems in the UK (Royal College of General Practitioners
(RCGP) Unit in Birmingham and Q Flu research system in Nottingham)
which recorded patients who present to GPs with a syndromic picture
of flu-like symptoms. Each system reported clinical evidence.
A subset of the RCGP network also took virology specimens. In
addition, another set of GPs sent specimens of flu-like illness
directly to the HPA.
Professor Ferguson commented that the sensitivity
of a sentinel system to pick up new viruses was very, very low.
In a severe pandemic, hospital-based surveillance was far more
likely to pick up abnormal, severe respiratory disease.
Pandemic containment and mitigation (Professor Neil
Ferguson)
Emergence
Professor Ferguson described a simulated emergence
in Anhui in China using mobility data collected for the purposes
of the model. The modelling indicated rapid spread within about
90 days, working on the assumption of a punctuated evolution of
the pandemic. It appeared that intervention could interrupt the
rate of transmission but action would have to be taken very, very
quickly. Action to block transmission would include treating isolated
cases with antivirals, public health measures such as school closures,
travel restrictions around the region, mass use of antivirals
prophylaxis in the population and possible use of vaccines (stockpiled
by the WHO).
Vaccination for containment
In recent years, work had been done with the WHO
to try to understand the role of a pre-pandemic H5N1 vaccine.
The political difficulty was that the WHO stockpile was only in
the region of 100 million courses. The initial plan had been to
give each country a small amount of vaccine for, say, critical
healthcare workers. But given the relative scarcity of vaccine,
researchers have considered whether it could be used more effectively.
One option would be to vaccinate at the source of an outbreak.
This would incentivise countries to report. On the other hand,
it was not an obvious policy to use because of the effect of the
time delay between vaccination and protection—in a fast-moving
outbreak, that delay could be critical to undermining the effectiveness
of the policy. Evidence suggested that mass vaccination would
make a very substantial difference if the vaccine were 60 per
cent efficacious after 7 days. The usefulness of mass vaccination
diminished as the period before reaching 60 per cent efficacy
lengthened—but even with the lengthening period, it remained
significant. Given this, the WHO had reserved half of its stockpile
of vaccine for use for containment operations.
Like Dr Arinaminpathy and Professor Van
Tam, Professor Ferguson had considered whether, once R(zero)
equalled one, the pandemic would go through WHO Phases 2 to 6
incrementally or whether there would be a sudden jump. For mutation
rates of only one per cent per infected individual per day—quite
a pessimistic assumption of how fast an influenza virus might
evolve—then the different scenarios about the percentage
transmissibility increase per mutation made relatively little
difference to the chances that containment would succeed. If containment
operations were going to succeed then it would be at the stage
where 100 or less cases of human influenza had accumulated. For
that reason it was pessimistically assumed that the virus would
take a punctuated path—the hardest situation to deal with
from a policy point of view.
Travel restrictions
There were doubts about the efficacy of travel restrictions
to slow spread. Ninety per cent travel restrictions would slow
the spread by about one to two weeks, and 99 per cent would slow
the spread by two to four weeks. According to the modelling, travel
restrictions would probably be useful only at a very early stage
when the cluster of cases was still very small. Border screening
was predicted to be almost completely ineffective. Some more nuanced
work had been done, looking at different types of traveller. Some
people—the "jet-set"—travelled a lot and
SARS had taught us that an infection would be transmitted more
quickly if it got into the "jet-set".
Spread of a pandemic without intervention
A pandemic which began in south east Asia is expected
to take one to four months to reach Europe, with the uncertainty
being due to the intrinsic variability in the early course of
epidemics and the unknown effect of seasonality in transmission.
With a value R(zero) (viral reproduction rate) of about two, the
epidemic would peak between eight and 12 weeks after the first
case in Europe. Based on data collected during past epidemics,
it was estimated that about one-third of people would fall sick,
with about 1,700 cases per 100,000 population during the worst
week. There would be significant local variation as to timing,
with up to a four to five week variation in the timing of the
peak of the epidemic between countries. There would also be timing
variations between regions within the same country and regional
variations in the peak daily case incidence, with local incidence
likely to be considerably higher at the district level (about
2,500 cases per 100,000 population in the worst week) compared
with the national average. This would have significant consequences,
in particular on local absenteeism which, in the worst week, could
be as high as 15 per cent (and even higher with the closure of
schools because of childcare ramifications).
Effectiveness of interventions
The results described above assumed no interventions.
The effectiveness of single interventions at reducing attach rates
was as follows:
(1) Treatment: if given within 24 hours of symptoms,
antivirals could lower transmission (as well as reducing severity
of disease) and thus reduce attack rates by about one eighth.
(2) Prophylaxis: household prophylaxis could
reduce attack rates by a third but this would need a larger stockpile
than a pure treatment strategy. The planned UK stockpile (50 per
cent of population size) was predicted by modelling to be enough
for household prophylaxis to be used, but prophylaxis was not
current UK policy.
(3) School closure: because of the social networks
associated with schools, school closure could reduce the peak
incidence by 40 per cent and it might also prevent about one seventh
of cases but it would have a significant impact on absenteeism.
(4) Vaccination: it was difficult to predict
its efficacy but 20 per cent coverage of low efficacy vaccine
might prevent one third of cases.
Combining interventions
There were benefits to combining interventions. The
results were not linear in that it was not just a matter of adding
together the various percentage reductions in rates of attack.
The total net benefit from multiple interventions could exceed
the sum of percentage reductions from individual interventions.
But this advantage depended on the multiple interventions not
"overlapping" (that is, not targeting the same location
or aspect of transmission). Interventions could be directed at
susceptibility (vaccines, prophylactics), infectiousness (antivirals)
and infectious contacts (social distance or public health measures—non-pharmaceutical
interventions). To get the maximum reduction in transmission,
it was necessary to combine interventions so that they would not
target the same place twice.
On the other hand, there was the secondary policy
demand of a "failsafe" approach. This also favoured
a policy of multiple layered interventions—even perhaps
including overlapping interventions with the same target. Failsafe
policies were needed because of the uncertainties associated with
pandemic influenza. For example, a high level antiviral-resistant
strain of H1N1 seasonal influenza had spread around the world
very rapidly in the last 18 months—hence the need for a
diversified antiviral stockpile. Another uncertainty was the identity
(and, critically, the lethality)[17]
of the specific strain which might cause the next pandemic. Finally,
we would be relying principally on public health measures and
the level of compliance was uncertain.
Questions
In discussion, Professor Ferguson was asked
why we did not have a policy of vaccination of frontline health
workers. He explained that there was currently an intense debate
going on about the ethical issues associated with advance use
of vaccines, in part because of adverse health effects of vaccines
and in part because of the cost-benefit analysis. A related issue
arose from the fact that a portion of the world stockpile was
about to expire—the question was being asked whether they
should be deployed rather than disposed of. Professor Van
Tam commented that it was DH's intention that if a H5N1 pandemic
were to breakout then the UK stockpile would be used to vaccinate
frontline health staff in a schedule of two doses 28 days apart.
There was strong immunological evidence to suggest that if individuals
were primed now by giving them one or possibly two doses of an
H5N1 vaccine, then if they were to encounter the same antigen
again, either through wild challenge or through booster dose,
their immune responses would be very dramatic. Evidence suggested
that the booster dose could be effective if given up to eight
years after the first two primer doses.
What is the prospect for a broadly cross-protective
vaccine for Influenza A viruses? (Professor Alain Townsend)
Professor Townsend said he would review a small
part of the biology of the virus and immunity reactions to it
with a view to describing how those reactions could be harnessed
to create vaccines.
The influenza virus
The virus was relatively simple, with eight genetic
segments and 10 proteins expressed in those segments. It had a
lipid envelop which had to fuse with the host cell in order for
that cell to become infected. The virus would be bound to the
host cell by the protein haemagglutinin, assisted by Ion channels—another
protein which maintained the acidity required for the fusion to
occur. The virus then infected the host cell. It uncoated and
replicated itself, and would then leave the cell. In order to
do that, it had to prevent the haemagglutinin remaining bound
to the cell—as a result, another protein, neuraminidase,
would cleave off the receptor to which the haemagglutinin was
bound. The drugs used at the moment to treat the virus had the
effect of rendering the neuraminidase ineffective so that the
virus was prevented from leaving the cell.
Immunity and cross-protection
To what extent would an infection with a type A strain
give rise to protective immunity? Humans who had recovered from
a particular strain of type A virus would be immune to that strain.
As for viruses which were of the same subtype (that is, the same
haemagglutinin value (say H1 or H5)) but had been subject to some
strain drift within the previous year or two, there was evidence
of some cross-protection. But the key question was whether, if
a person had been infected with a strain some years ago, that
person would be protected against all type A strains. The evidence
was very unclear save that it seemed to be the case that there
was no cross-protection in children. By contrast mice that have
recovered from infection by one A strain are protected from lethal
infection by any other A strain.
Professor Townsend then turned to the mechanisms
for Immune protection. Some were well understood, others less
so. "Antibodies" to haemagglutinin were well known.
They offered complete protection. They had the effect of preventing
the influenza virus binding and fusing with the host cell. "Cell
Mediated Immunity" was a mechanism which operated after the
host cell had been infected, whereby the conserved internal proteins
of the virus could be recognised by lymphocytes causing the infected
cells to be killed and growth of virus therby halted. It could,
in animals, be truly cross-protective against all A strains, but
was not proven in man. However In some circumstances where the
virus had infected a large area of lung before the lymphocytes
arrived, it could make matters worse since the effect of the mechanism
was to destroy infected tissue.
There were other immune mechanisms—for example,
"innate immunity" and antibody to the (M2) Ion channel
protein—about which less was known.
Current vaccines
Most current vaccines were based on inducing antibodies
to partially purified haemagglutinin and neuraminidase proteins.
This had been done for some years now, very successfully with
about a 25 per cent reduction in death rates. But, to be effective,
the haemagglutinin had to be well-matched to the infective strain
and, without using any other stimulus to make the immune response
stronger, the vaccines were very, very strain specific. The question
was whether it was possible to get antibodies which cross-reacted
across HA drift. Trials indicated that it was possible, particularly
with H5 haemagglutinin, when combined with an adjuvant. Another
problem was that it often took several months to develop the amount
of vaccine needed.
The second form used "live attenuated influenza
viruses" as vaccines. This has several significant advantages.
The vaccine is a live influenza virus that infects and replicates
in the lining of the nose but does not cause pneumonia. As a result
it can in principle stimulate all of the immune responses that
are induced by seasonal or pandemic influenza. Extensive trials
had taken place in Russia and the United States and there was
no doubt that live attenuated viruses were significantly better
than subunit vaccines in the context of strain specificity. They
definitely induced some immunity across HA drift in humans, even
in children. There had also been examples in mice and ferrets
where the vaccine cross-protected from seasonal influenza against
a challenge by an H5 virus. Live attenuated virus vaccines were
not yet available in Europe but were due to be licensed next year.
Experimental vaccines
There was a range of experimental vaccines, all of
which were years away in development but offered some hope. At
the moment, subunits were produced by growing them in chicken
eggs. It could also be done in live cultures of human cells although
there were worries that the cells would harbour unknown viruses.
However, the new technologies might eventually enable subunit
vaccines to be produced more quickly. Other developing areas included
genetically modified viruses (such as Smallpox vaccine or Adenovirus
engineered to make selected components of influenza) and DNA vaccines.
The engineered viruses can result in very powerful stimulation
of cell mediated immunity against the conserved internal proteins
of influenza. In animal experiments this can result in limitation
of virus replication in the lung with cross-protection between
all A strains. However, as discussed above, caution is required
as this mechanism if mis-timed has the potential to worsen tissue
damage rather than prevent it. The advantage of DNA vaccines was
that DNA was very quick to make and easy to transport—the
disadvantage was that it did not work in man efficiently enough
to be reliable—yet.
Conclusion
In conclusion, Professor Townsend said that
the best candidates for pre-pandemic immunisation were the live
attenuated vaccines and also subunit HA with adjuvant where there
was clinical evidence that they worked and would be likely to
afford some protection within an HA subtype. There was no universal
vaccine for human influenza at the moment.
How will NHS hospitals deal with the sickest of patients
during an influenza pandemic? (Dr Bruce Taylor)
Dr Taylor said that although his talk would
focus on intensive care, there were implications for the wider
NHS. He would be raising points for which he did not have answers.
He was concerned about how the NHS would cope in the event of
an influenza pandemic—the availability of intensive care
beds was a constant struggle even in normal circumstances.
Dr Taylor said that he first became involved
in the issue when he contributed to the development of a policy
on critical care contingency planning. He helped to produce a
report which focused on "planning for an emergency where
the number of patients substantially exceeds normal critical care
capacity", and the guidance had been accepted by and large
by the intensive care community.
Availability of healthcare workers (HCWs)
As a result of the SARS outbreak, studies had been
done in New York about the ability and willingness of HCWs to
report to duty during catastrophic disasters (Journal of Urban
health: Bulletin of the New York Academy of Medicine. Vol. 82,
No. 3). The results showed that 40 to 70 per cent of HCWs were
either unable or unwilling to report to duty. It was clear from
the SARS outbreak that staff morale and staff confidence were
absolutely critical. If staff believed that they would be protected
and looked after—and perhaps more importantly that the risk
to their families would not be increased, they were more likely
to come to work.
Triaging during a disaster
The most important effort should be in preventing
hospital referrals in the first place. But the likelihood was
that there would still be plenty of patients in any event. Patient
care depended on the ability to flow through the "primary
care—secondary care—complex care" pathway. But
even in normal NHS circumstances patient flows may be limited
by bed availability and so forth and, in the peak of a pandemic
pathways were likely to become blocked because of limited resources.
If there were a complete blockage, then patients who might normally
have had a reasonable chance of survival might not have access
to the treatment they required.
This then led to the difficult concept of triaging
patients in the face of limited bed capacity. Dr Taylor had
written a draft policy document on triaging suggesting that "increasing
age, chronic disease and co-morbidities may have to be accepted
as appropriate triage criteria". He argued that this was
not ageism but a realistic recognition that as we get older our
health deteriorate and intensive care unit beds may need to be
limited to patients more likely to have a good outcome. His proposal
had not been accepted.
The current guidance was that "the priority
is to reduce the impact on public health, ie to reduce illness
and save most lives in a way that is fair and in accordance with
the ethical framework". When Dr Taylor met the Committee
on Ethical Aspects of Pandemic Influenza (CEAPI), he had suggested
that, where there was only one intensive care unit (ICU) bed available,
the choice between a 90 year old and a 9 year old would not be
difficult. This was held to be "completely unacceptable"
by the CEAPI. But the difficulty for HCWs was that they had to
make these sorts of decisions on a daily basis in any event.
The Cabinet Office and DH had now published a document
entitled Responding to pandemic influenza: the ethical framework
for policy and planning. In a way it was perfect: everyone
mattered, everyone mattered equally—but this did not mean
that everyone would be treated the same way, and so forth. The
individual principles underlying the policy—respect, minimising
harm caused, fairness, working together, reciprocity, keeping
things in proportion, flexibility and good decision-making—were
all fine in normal circumstances. But they were not relevant to
dealing with a pandemic. A pandemic would require disaster-management,
as happened during the London bombings, and it would be unrealistic
to focus on ethical principles when overwhelmed with patients
and trying to identify those most likely to survive. There was
a gap between reality and expectations because resources were
limited.
Sequential organ failure assessment
To address the reality gap, the DH had produced a
document entitled Pandemic Influenza: surge capacity and prioritisation
in health services. It was based on "sequential organ
failure assessment" (SOFA), an approach advocated by a paper
from Canada. As demand for beds increased, then a patient's organ
failure would be assessed and the severity scored. If the SOFA
score totalled 11 or more, then the patient would not be accepted
for critical care.
There was a practical difficulty with this system.
If a patient was taken into an ICU because he was below 11 but
after 48 hours he was worse and exceeded 11 or if he remained
in the eight to 11 bracket after 48 hours, then he would be taken
out of the ICU and put back on to the ward where he would die.
However, under normal circumstances he might have been expected
to have survived. This action of having to remove critical care
from patients would cause emotional and ethical difficulties for
staff. Dr Taylor also provided anecdotal figures which confirmed
that the SOFA score approach would lead to patients, who in normal
circumstances would probably have survived, being left to die.
Deploying scare ICU resources in a pandemic and
the blame culture
So how should ICU referral decisions be made during
a pandemic? Perhaps a lottery system was the only realistic way
of meeting the ethical expectation of fairness. The fact was that,
at some point, ICU services may have to be closed because of lack
of resources. Dr Taylor's worry was that the implications
of the ethical guidance which clinicians were expected to meet
put them in an impossible position. They were required to apply
an ethical framework unsuited to times of disaster.
During what would effectively be a disaster scenario,
clinicians would have to make decisions based on current guidance
that would not be sufficient to meet the excess demand. This would
inevitably result in significant numbers of potentially preventable
deaths occurring. The NHS had a "blame culture". The
concern was that although it was hoped that people would want
to do their best to help others, this culture—in a period
of disaster—would discourage them from reporting to duty.
Without adequate staff attendance the plans to expand capacity
(or even just to maintain existing services) would not be successful.
HCWs needed formal assurance that they would not face professional
criticism or retrospective litigation for doing the best they
could under very difficult circumstances. It was also necessary
to address public expectations in an open and honest way. We had
to make it clear that the current standards of intensive care
which we currently expected would not be achievable during a pandemic.
Questions
It would be difficult to persuade staff to undertake
tasks which they deemed outside their competence. In times of
disaster, it would be necessary to develop a sense of immunity
from prosecution. The question was raised whether we should have
a concept of a state of emergency which would include strategies
for handling the consequences of the blame culture.
General discussion
A key theme was "complexity". One aspect
was the evident inability of the public services to handle complexity.
Another was that, as a result, it was essential that practical
solutions had to be developed which had been thoroughly road-tested.
There had to be confidence that the contingency planning worked.
More positively, there were clear indications of the routes that
had to be taken in order to develop an evidential base on which
to establish an effective contingency arrangement. Ministers should
ask themselves where and how they could make a difference.
The DH and its agencies had come a long way but tended
to focus on individuals. They found abstracts like "herd
immunity" difficult to deal with. They had had four years
but were still only thinking about targeted local prophylaxis.
If closing boundaries gained us one to two weeks,
why was it dismissed? Also, socially it would be difficult to
stop the public call for border closures. In answer, it was suggested
that whether border closure was a reasonable policy critically
depended on how long it would take to make vaccine. A cordon sanitaire
around a local cluster which was then treated robustly could be
highly effective. Screening, on the other hand, had very little
value, in any circumstances, since it would capture almost nobody.
Front line staff preparedness seemed to be poor.
16 Professor Ferguson suggested that this figure may
be further increased with stockpiles of both Tamiflu and Relenza
now being acquired. He said that the DH had not ruled out a household
prophylaxis strategy. Back
17
A matter which has concerned the Government Chief Scientist, John
Beddington, was the DH planning assumption of two per cent morality
as a reasonable risk scenario whereas that of H5N1 was more like
a 60 per cent case mortality rate. Back
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