APPENDIX 9
Memorandum submitted by Acambis Plc (April
2002)
EXECUTIVE SUMMARY
Acambis Plc has been asked by the Defence Select
Committee to submit evidence on the issue of public health defences
that can be put in place to protect against a bioterrorist attack
using smallpox. Acambis is well placed to provide information
on this subject as it has been selected by the US government to
provide the principal medical countermeasure that the United States
will use to protect its population against the threat posed by
smallpox.
However, Acambis is prevented from commenting
on the detail of the UK procurement of smallpox vaccine as it
is bound by confidentiality agreements with both the Ministry
of Defence and the Department of Health.
This submission makes several key assertions:
— The threat of a bioterrorist smallpox
attack is a low probability but high consequence event that is
considered credible and possible.
— Vaccine was proven effective to the
point of eradicating the (endemic) natural-disease from the planet.
Vaccination is the only medical countermeasure solution to smallpox.
There is no proven therapeutic agent. We therefore applaud the
UK government's decision to increase the UK's supply of smallpox
vaccine.
— Governments around the world, concerned
about the threat from smallpox, are considering following their
historical reliance on vaccination and the lead taken by US to
protect every one of their citizens.
— There is no difference in efficacy
in preventing smallpox between the two strains recommended by
the World Health Organisation (WHO) and most widely used to eradicate
endemic smallpox during the vaccination programmes (Lister and
NYCBH).
— We are not aware of any published
data questioning the efficacy of the NYCBH strain against any
of the smallpox strains. In fact, specific data indicate that
it was highly effective in all of the worldwide programs in which
it was actively used to control the disease.
— There is evidence that, because of
its lower pathogenicity, the NYCBH vaccine strain is less harmful
to recipients than Lister.
— It is critical that any new smallpox
vaccine be fully clinically tested to ensure that, in improving
the manufacturing process from an animal-based system to cell-culture,
it has retained its key properties relating to safety, efficacy
and consistency.
— Acambis' vaccine for the US government,
based on the NYCBH strain, is being fully tested in extensive
clinical trials, and will be submitted to the Food and Drug Administration
for registration.
THE THREAT
OF SMALLPOX
Smallpox is one of the most devastating of all
the infectious diseases. As it was finally eradicated as an endemic
disease over 20 years ago people are no longer vaccinated. The
WHO suggests that in most communities 90 per cent of the population
is fully susceptible to smallpox and experts believe the fatality
rate, which historically stood at 30 per cent, could well now
be higher.
Smallpox's potential for devastation is greater
than at any time before. Its high transmission rate of 1:15 heightens
its potential as a bio-weapon. After an incubation period of perhaps
14 days, infected individuals would begin to experience the symptoms
of smallpox. It is likely that a further two weeks may pass before
positive identification of smallpox because physicians lack familiarity
with the disease.
Following the success of the worldwide eradication
campaign against the disease the WHO determined that the only
remaining repository for live smallpox should be the facilities
under the direct control of the United States at Centers for Diseases
Control (CDC) and those of the former Soviet Union at Koltsovo.
All other stocks were supposedly destroyed and the determination
to destroy the remaining stocks made the responsibility of an
international commission.
However, according to many leading experts including,
Dr Anthony Fauci of the US National Institutes of Health, a bioterror
attack using smallpox is an "extremely realistic" possibility.
The stocks of the virus held in the Russian State Research Centre
of Virology and Biotechnology in Koltsovo, in the Novosibirsk
region of Russia, have not been secure and represent a source
of disseminated material.
The former director of the Russian bio-weapons
programme has confirmed that the Soviet Government embarked on
an ambitious programme to grow smallpox virus in large quantities
to use it for bombs and inter-continental ballistic missiles.
The USSR was capable of producing many tonnes of smallpox virus.
Many laboratories in Russia are now fiscally
constrained and there is extensive unemployment amongst skilled
scientists. The CIA estimates that there are around 11,000 former
Soviet biological warfare scientists looking for work.
Bio-weapon expertise, equipment and stocks could
have moved to other countries. Dr Ken Alibek, the former Head
Scientist of the Soviet Union's Biological Warfare Programme,
has stated that North Korea was experimenting with smallpox in
the late 1980s.
If, as indicated by expert testimony, there
is now a possibility that illegal stocks of smallpox may exist
outside the registered centres in Russia and America, it is likely
that it is the strain weaponised by the Russians, the so-called
India-battle strain (also known as "India-1" and "India-67").
This smallpox strain was obtained by the Soviets in 1967, and
identified as a particularly virulent form that was causing devastating
disease in the Indian subcontinent. It is worth noting in the
context of this submission that subsequent bilateral medical support
efforts in India by the Soviets, using a smallpox vaccine based
on the NYCBH strain (vaccine EM-63), proved spectacularly successful
in controlling the disease.
THE DEFENCE
AGAINST SMALLPOX
There is no therapeutic agent to treat smallpox.
The only medical countermeasure is vaccination.
The concern about the possible return of smallpox
requires prompt and extensive responses. In 1947, in response
to a single case of smallpox in New York City, six and a half
million people were immunised. And in Yugoslavia in 1972, faced
with 140 cases the government vaccinated 20 million people.
Around the world, governments have moved to
procure vaccines for each and every citizen. America recently
set contracts to procure a vaccine dose for every citizen.
The World Health Organisation's (WHO) eradication
programme began in 1958 and was intensified in 1967. Vaccination
was the key element of the programme'[1].[2].
Four Vaccinia (vaccine) strains were made available through commercial,
non-government, and government sources for manufacture of vaccines
around the world. In addition there were specific donations from
suppliers both to individual countries and through the WHO program
for human immunisation. Approximately one-third of the world's
population received one of these four strains. These strains were
found to have varying levels of pathogenicity and propensity to
cause adverse reactions.[3]
| Strain | Pathogenicity
|
| New York City Board of Health | Low
|
| Lister | Moderate |
| EM-63 | Low |
| Temple of Heaven | High |
The world expert on smallpox, Dr Donald Henderson, Director
of the US Office of Health Preparedness, has said "Most countries
have given little thought to the risk that's involved here and
not appreciated what the problem is, and therefore they've done
very little to prepare for it."[4]
TWO VACCINE
STRAINS DOMINATE
DEFENCES
No strain of vaccine is officially recommended by the WHO,
but in response to enquiries the Smallpox Eradication Unit advised
that either the Lister or New York City Board of Health strain
should be used.[5]
There are six pertinent points:
1. Dr Henderson has stated that "there is not a whit
of evidence" to support the Health Secretary's claim that
Lister is the only "appropriate strain".[6]
2. Professor Oxford of Bart's and the Royal London has
said that there is no medical reason to opt for the vaccine strain
chosen by the UK Government rather than the one chosen by the
US Government.
3. Dr Nedret Emiroglu, the WHO's regional adviser on communicable
disease control, prevention and eradication in Europe has said
"There is no difference; both are proven strains." The
WHO is engaged in research to review the situation "to make
doubly sure that the strains are still as effective—purely
because they were used so long ago. We believe they are still
valid and have no reason to think otherwise."[7]
4. The European Medicines Evaluation Agency (EMEA) recently
issued draft guidelines for development of new smallpox vaccines.
The recommendations state "that the vaccines should be derived
from a viral strain used in [the] eradication program in endemic
areas in order to obtain a vaccine, as close as possible to the
efficacious one used in [the] eradication programme." Being
based upon the NYCBH strain Acambis' vaccine fits within the EMEA
guidelines.
5. The most credible threat comes from the Russian weapons
strain of smallpox. The Soviets used EM-63 strain of vaccine which
is a variant of the NYCBH strain. Evidence from the eradication
campaign suggests that this strain of vaccine would be very effective
against the Russian weapons strain (India 1).
6. The NYCBH strain has had a lower pathogenicity, in
terms of the frequency of complications, than any other widely
used vaccinia strain. NYCBH is less pathogenic than the Lister
strain.[8] Henderson et
al concluded, "the frequency of complications associated
with the use of the New York City Board of Health strain is the
lowest for any established vaccinia virus strain.[9]
In the documentation concerning the use of these two vaccine
strains in the eradication programme, the emergence, and apparent
preponderance, of the Lister strain at the time of the intensified
programme (1967) can be confusing. The WHO advocated the Lister
strain at this time because of its relative ease in manufacture—not
because of any perceived performance advantage in the face of
the disease. In fact by the time that the Lister strain was being
distributed under WHO guidelines, smallpox was only occurring
in a few countries around the world. The eradication of smallpox
from Europe, the Americas and most of the rest of the world (excluding
Africa and India) having been achieved several decades before
the involvement of the WHO, and their intensified programme, which
targeted the last "pockets" of disease that might act
as reservoirs for future outbreaks. In these remaining areas of
endemic disease (and notably in Africa and India) the NYCBH strain,
together with Lister and other strains eventually succeeded in
the desired goal—defeat of smallpox.
It is worth noting that no formal clinical trials have ever
been performed. The effectiveness of different strains used for
manufacture has never been directly compared.
US PROCUREMENT OF
SMALLPOX VACCINE
The United States Government has run two competitions for
the procurement of smallpox. The first multi-company full and
open competition was held between January and September 2000,
during which a number of discussions, negotiations, and proposals
were undertaken. In September of that year Acambis was awarded
a contract to develop a new smallpox vaccine with provisions for
the US Government to order vaccine after licensure. The estimated
quantity of licensed vaccine that were expected to be ordered
was 40 million doses.
Demand increased following the events of 11 September 2001,
and Acambis was requested to scale-up its pre-licensure production
capacity to produce 54 million doses of vaccine under the September
2002 contract as investigational new drug (IND) material to be
held in reserve for emergency use, if needed. Following that decision,
the US Government solicited proposals for a selected number of
qualified firms to develop a second smallpox vaccine candidate
and to produce sufficient vaccine pre-licensure to supply every
US citizen with a smallpox vaccine dose.
The second US procurement process allowed interested companies
to supply details regarding their proposed product and probable
costs (Responses to a Request for Information and an oral presentation
were allowed). Four finalists were invited to submit a formal
proposal. Negotiations were carried out privately with each of
the four finalists, each was given the opportunity to submit its
best and final offer, and the company with the best proposal was
selected based upon evaluation criteria set forth in the Government
solicitation. The entire process took five weeks and work commenced
immediately. The sequence of events leading up to award of that
procurement are summarised below.
| Date | Activity
|
| 19 October 2001 | Request for information (RFI) sent to interested parties to assess their proposed approach and the company's ability to perform. The RFI provided a framework for responses to demonstrate capacity and capability.
|
| 22 October 2001 | Deadline for companies to ask questions of government.
|
| 24 October 2001 | US Government supplied answers to companies' questions.
|
| 25 October 2001 | Final RFI responses submitted.
|
| 30 October 2001 | Each interested party meets with CDC, deliver presentation and the opportunity to answer and ask questions.
|
| 1 November 2001 | Shortlist of four best-qualified companies decided by CDC (GSK, Wyeth, Merck, Acambis).
|
| 1 November 2001 | A 62 page Formal Request for Proposal was issued to the four companies selected to participate.
|
| 3 November 2001 | Technical and cost/price proposals were submitted to the US Government for evaluation.
|
| 28 November 2001 | Contract awarded following details negotiations, submission of revised proposals, and Government evaluation of final proposals under stated evaluation criteria for determining most advantageous proposal for award.
|
For reasons of confidentiality we are prevented from supplying
details of our involvement in the UK procurement process.
ABOUT ACAMBIS
Acambis is a British company and one of Europe's leading
biotechnology companies. In 2001 it was selected by the American
government to supply the Centers for Disease Control (CDC) with
a smallpox vaccine dose per citizen. Acambis was established in
1992 and employs 200 people. Its headquarters are in Cambridge,
UK. Research and development is carried out there and at its facilities
in Cambridge, Massachusetts. It also has a manufacturing facility
just outside Boston, Massachusetts.
1
World Health Organization. Methodology of freeze-dried smallpox
vaccines production. WHO, Geneva, SE/68.3 Rev.2) 1968. Back
2
Fenner F, Henderson DA, Arita A et al. Smallpox and its Eradication.
WHO, Geneva, 1988. Back
3
From 2 above: Back
4
Donald Henderson, Panorama, "Bin Laden's Biological Threat"
28 October 2001 Back
5
see 2 above Back
6
Sunday Telegraph, 22 April 2002. Back
7
Business Weekly, 22 April 2002. Back
8
Many reports document the frequencyof cases of postvaccinal encephalopathy
and encephalitis in Europe and the United States, but comparison
of rates is difficult because of differing criteria for diagnosis
and variability in the completeness of reporting. The usual levels
of incidence, such as those reported from the Netherlands, Germany,
and Austria, were initially higher than those reported in the
United Kingdom, and these rates in turn were higher than those
reported in the United State. (JM Lane, FL Ruben, JM Neff, and
JD Millar. Complications of smallpox vaccination, 1968. National
surveillance in the United States N Engl J Med 1969. 281: 1201-1208;
JM Lane, FL Ruben, JM Neff, and JD Millar. Complications of smallpox
vaccination, 1968: Results of ten statewide surveys J Infect Dis
1970. 122: 303-309; and JM Neff and JM Lane et al. Complications
of smallpox vaccination. I. National survey in the United States
1963 N Engl J Med 1967. 276: 125-132.) Whatever the criteria and
methods, differences between the rates appeared to be real, and
this fact caused a number of countries, during the 1960s, to begin
using the Lister strain, then in use in the United Kingdom and
supplied by the WHO refrence laboratory in Bilthoven, the Netherlands.
A dramatic reduction in the incidence of postvaccinal encephalitis
subsequently occurred (Polak MF. Complications of smallpox vaccination
in the Netherlands, 1959-1970. In International Symposium on Smallpox
Vaccine. Symposia Series in Immunobiological Standardization 19:
235-242, 1973 and Berger K, Heinrich W. Decrease in postvaccinal
deaths in Austria after introducing a less pathogenic virus strain.
In International Symposium on Smallpox Vaccine. Symposia Series
in Immunobiological Standardizaetion 19: 199-203, 1973). The incidence
in the Netherlands between 1964 and 1971 appeared to approach
that in the United States; 10 of 16 cases were fatal, however,
compared with only four of 16 cases reported in the United States
in 1968 (Henderson, DA, and Moss, B. Smallpox and Vaccinia. In:
Plotkin S A and Orenstein WA: Vaccines (3rd ed.) 1999: 74-97). Back
9
Henderson, DA, Inglesby, TV, Bartlett, JG et al. Smallpox as
a biological weapon: Medical and Public Health Management. JAMA
1999, 281 (2): 2127-2137. Back
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