BACKGROUND
Among the key issues that are
expected to be discussed at the World Health Assembly starting 14 May is the
stark inequity between developed and developing countries in their access to
vaccines in the event of a pandemic of avian influenza.
Many developed countries have
already placed orders and paid drug companies to stockpile pre-pandemic
vaccines and made advance purchase orders to have pandemic vaccines delivered
to them in the event of a pandemic. There is a rush to place the orders and
stockpile because vaccines are scarce and there is only a limited amount that
drug companies can produce in a year, which is far exceeded by demand if a
pandemic emerges.
According to a 2006 WHO report on
an action plan to increase vaccine supply, the global production capacity was
only 350 million doses, which could rise to 500 million doses at full capacity.
But as two doses may be needed a year per person, the global vaccine output
would not be enough for the world population in the event of an avian flu
pandemic. Even with technological advances, in 2008-9 flu vaccine production
would be at most 2.3 billion doses a year, "still several billion doses
short of the expected demand if there were to be a pandemic," said the
report.
As the vaccines are patented and
expensive, most developing countries cannot afford to order or buy them in the
amounts required. If a pandemic strikes, they fear their populations will be
unprotected, as much of the vaccine stocks will be located in and channeled to
people in the developed world.
Adding to this imbalance is the
fact that a crucial component - the avian flu viruses in the research and
development, and the manufacture, of the vaccines comes overwhelmingly from the
developing countries, where the human cases of avian influenza are located.
Under a WHO scheme countries
affected by avian flu send samples of the viruses to the WHO's collaborating
research centres and laboratories, all of which are national institutions
located in developed countries.
Under the WHO's 2005 and 2006
guidelines, these WHO-linked centres are not supposed to pass on the viruses to
third parties such as companies or to publish papers or make known the gene
sequences of the viruses without the prior permission of the countries
contributing the viruses.
However, officials of some
developing countries have discovered that their viruses have been made use of
in activities such as patenting, commercial development and production of
vaccines and publication of research materials, without their permission or
even their knowledge. The countries are being approached by drug companies to
make orders for vaccines that were developed or made with the use of the
viruses they supplied freely under the WHO scheme. The prices quoted by the companies are too
high for the countries to afford especially since they need vaccines in very
large quantities in the event of a pandemic.
World public attention was
focused on this issue when the Indonesian Health Ministry announced a few
months ago that it would no longer provide bird flu viruses to the WHO's
collaborating centres as it believed the centres and the system had betrayed
its trust.
Some viruses contributed by
Indonesia under the WHO system were being used not only for the research
activities that the centres were supposed to perform, but also passed on to
companies for commercial activities without Indonesia's knowledge or
permission, while there was no international system in place to ensure that
Indonesia or other developing countries would be supplied with sufficient
vaccines, and at affordable prices.
When announcing her country's
move to suspend the sharing of viruses, Indonesia's Minister of Health Siti
Fadilah Supari called the current system "unfair".
Indonesia, supported by other
developing countries, is expected to highlight this issue during the WHA
starting next Monday.
Indonesia, some other countries
and the WHO secretariat have been discussing how to ensure that the donated
viruses are not misused or misappropriated, and that a framework is established
to ensure benefits to developing countries.
Legal Basis for Rights of States over Genetic Resources: The Convention on Biological Diversity
Viruses are genetic materials and
their ownership is regulated by the Convention on Biological Diversity (CBD),
which recognizes the sovereign right of States over genetic resources. It is for the States to determine if there is
to be access to such resources by foreigners, and the conditions for such
access including prior informed consent and benefit sharing.
Preamble to CBD:
·
Reaffirming that States
have sovereign rights over their own biological resources
Article 15 of the Convention on Biological Diversity includes the
following:
·
Recognizing the sovereign
rights of States over their natural resources, the authority to determine
access to genetic resources rests with the national governments and is subject
to national legislation.
·
Access, where granted,
shall be on mutually agreed terms and subject to the provisions of this
Article.
·
Access to genetic resources
shall be subject to prior informed consent of the Contracting Party providing
such resources, unless otherwise determined by that Party.
·
Each Contracting Party
shall endeavour to develop and carry out scientific research based on genetic
resources provided by other Contracting Parties with the full participation of,
and where possible in, such Contracting Parties.
·
Each Contracting Party
shall take legislative, administrative or policy measures, as appropriate, and
in accordance with Articles 16 and 19 and, where necessary, through the
financial mechanism established by Articles 20 and 21 with the aim of sharing
in a fair and equitable way the results of research and development and the
benefits arising from the commercial and
other utilization of genetic resources with the Contracting Party providing
such resources. Such sharing shall be upon mutually agreed terms.
The scope of any benefit sharing
agreement/instrument should include all genetic resources (parts thereof, gene
sequences) and the information emanating from such genetic resources; and
derivatives.
Article 16(1) CBD:
“Parties recognising that both
access and transfer of technology (including biotechnology) “are essential
elements for the attainment of the objectives of [the] Convention, undertakes
... to provide and/or facilitate access to and transfer ... of technologies
...”
Information on Avian Influenza
Avian influenza is an infectious
disease of birds caused by type A strains of the influenza virus. Specifically
H5N1 viruses have caused widespread sickness and death in domestic and wild
bird populations globally in the last decade and as infection among birds increases,
so does the opportunity for H5N1 to be transmitted directly from birds to
humans, which in countries has already happened. If avian and human influenza
viruses were to simultaneously infect a person or animal, the two viruses might
swap genes. The result could be a new virus that is readily transmissible
between humans and against which humans would have no natural immunity, resulting
in a pandemic.
Between 2003 and 2007, (WHO’s
data as at 11 April 2007) 291 (including 172 deaths) confirmed human cases of
Avian Influenza A/ (H5N1) have been reported to the WHO.
To date Vietnam has been the most
affected country with 93 cases including 42 deaths between 2003 and 2005.
Indonesia is the second most affected with 81 confirmed human cases including
63 deaths between 2005-2007, followed by Egypt (34 cases including 14 deaths
between 2006-2007), Thailand, (25 cases including 17 deaths between 2004-2006),
China, (24 cases including 15 deaths between 2005-2007), Turkey, (12 cases
including 4 deaths in 2006), Azerbaijan, (8 cases including 5 deaths in 2006),
Cambodia, (7 deaths between 2005 and 2007), Iraq, (3 cases including 2 deaths
in 2006), Lao People’s Democratic Republic, (2 deaths in 2007), Nigeria, (1
death in 2007) and Djibouti, (1 case in 2006).
Several other countries including
Niger, Burkina Faso, Sudan, Ghana have reported bird flu cases in poultry. Altogether
more than half of the laboratory-confirmed cases have been fatal. Although the
number of H5N1 avian influenza in humans are still relatively few, it has to be
monitored closely as it could potentially evolve in ways that could start a
pandemic.
The main idea behind preparedness
is to avoid the kind of situation when the influenza pandemic of 1918-1919 broke
out and killed between 20 and 40 million people. It was cited as the most
devastating epidemic in recorded world history.
Noting the seriousness of the situation, it is in good faith that several of these affected developing countries have been contributing their viruses to the WHO Global Influenza Surveillance Network (GISN).
The WHO Global Influenza Surveillance Network (GISN)
The GISN is made up of the National
Influenza Centres (NICs) which sample patients with influenza-like-illness and
submit representative isolates to WHO Collaborating Centres (WHO CCs) for
analyses. NICs, WHO CCs and WHO form the WHO Global Influenza Surveillance
Network, with collaboration based on terms of reference. In 2004, WHO H5
Reference Laboratories were also established as an ad hoc component of the GISN.
Twice each year, the GISN
recommends the content of the influenza vaccine for the subsequent influenza
season. For this purpose it relies on NICs which annually submits around 2,000
viruses to the WHO CC.
There are four WHO Collaborating
Centres, all based in developed countries (i.e. in Australia, Japan, United
Kingdom, and United States) and three H5 Reference Laboratories (in Australia,
UK and US) that participate in the WHO GISN.
WHO procedures for Sharing Viruses
WHO's March 2005 "Guidance for the timely sharing of influenza viruses/specimens
with potential to cause human influenza pandemics" (See Annex 1)
states:
“The designated WHO Reference Laboratories will immediately report
results of analyses of viruses/specients to the originating laboratory and to
the WHO Global Influenza Programme.”
"There shall be no further distribution of viruses/specimens
outside the network of WHO Reference Laboratories without the permission from
the originating country/laboratory.”
“It also states that the "The designated WHO Reference
Laboratories will seek permission from the originating country/laboratory to
co-author and/or publish results obtained from the analyses of relevant
viruses/samples".
WHO August 2006 “Procedures for obtaining release of H5N1 sequences to
the public domain” (See Annex 2) states:
“WHO seeks permission from the country that provides the virus to place
sequence information in the public domain…WHO seeks to facilitate timely
release of sequence data to the public domain, such as the Los Alamos National
Lab flu sequence database and GenBank. Formal procedures exist by which the WHO
reference lab initially informs the originating lab of sequence results and
simultaneously requests permission to place these results in the public domain.
In the event of a negative or no reply,
WHO directly approaches the Health Ministry in the originating country,
requesting authorization to release sequence data.”
From these two documents the
following conclusions can be drawn:
(1) WHO recognizes that
permission of the originating country has to be sought to publish research
results and gene sequences in the public domain, thus implicitly also
recognizing the rights (of prior informed consent) that the country has over
the viruses and its parts, and the research derived.
(2) WHO recognizes that there is
to be no further distribution of viruses outside the WHO reference labs without
the permission of the originating country.
If these are followed, the country has the right to grant (or not grant)
permission and to have conditions for the access.
Have WHO procedures been
followed?
It is learnt that Indonesia's
response is partly due to its belief that the WHO and its collaborating centres
have been violating the WHO's own procedures on virus sharing.
Recently Indonesian health
officials asked a senior official from WHO Secretariat why the procedures were
not being adhered to, but no satisfactory response was given. Soon thereafter,
the WHO (March 2005) Guidance document appears to be removed from the WHO
website.
Various WHO notices reveal that
the WHO CC/H5 Reference Laboratories have been commonly passing seed viruses
developed from the viruses provided by affected countries to companies and
institutions outside the GISN. The WHO CC/H5 Reference Laboratories are even
signing "material transfer agreements" with these companies and
institutions.
For example, a WHO notification
dated March 2006 stated that "An
H5N1 recombinant vaccine strain developed from A/Indonesia/5/2005, by the WHO Collaborating
Centres for Disease Control and Prevention, Atlanta USA is available for
distribution under a Material Transfer Agreement".
The notice invites "Institutions, companies and others
interested in pandemic vaccine development, who wish to receive the prototype
strain" to "contact either the WHO Global Influenza Programme at
whoinfluenza@who.int or WHOCC CDC" in Atlanta, USA.
Similar WHO notifications are
also available in relation to recombinant H5N1 prototype vaccine strains
A/Vietnam/1194/04, A/Vietnam/1203/04, A/Hongkong/213/03,
A/turkey/Turkey/1/2005, A/Bar headed goose/Qinghai/1A/2005 and A/Whooping
swan/Mongolia/244/2005.
Some notifications also state
that several of the "H5N1 influenza
pandemic vaccine prototype strains have already been made available to a number
of institutions and companies and several different vaccines have been produced
for clinical testing".
The notices do not provide
information whether the consent of the countries contributing the viruses had
been obtained prior to providing the viruses to institutions outside the WHO
GISN, or whether there were benefit-sharing arrangements made with countries
contributing the viruses.
PATENTS INVOLVING VIRUSES
Applications for patents could
include patents for the gene sequence (or part of it) of the virus; patents of
a gene sequence of a virus that has been genetically-engineered, using part of
the sequence of the original virus; patenting of research or production
techniques that make use of the virus or its parts; patenting of the vaccine or
other products that make use of the virus and its genetic materials.
Patenting can have various
effects. For example, if the gene sequence (or parts of it) of the virus is
patented, this may create problems for others who want to research into or make
products containing the gene sequence or parts of it. The patenting of
techniques can hinder research or the development of the product.
One patent application in the US
was even filed by a WHO CC, to patent modified influenza virus that includes genes
from a Vietnam influenza virus. Other patent applications involving parts of
flu virus strains have been made by universities in the USA and by companies.
There are also patent applications on techniques used in research, development
and production of vaccines.
A search on patent applications
relevant to H5N1 influenza vaccines and which make use of parts of the avian
flu viruses found the following examples (see
Annex 3):
-- An application for a US Patent
by Hawaii Biotech Inc (USA) for a Influenza recombinant subunit vaccine. This
application, published in February 2007, claims a new type of influenza vaccine
and specific H5N1 vaccines made with the technology. It specifically makes
patent claims on genetic sequences from an influenza virus isolated in
Indonesia in 2005 (A/Indonesia/5/05) and another isolated in China in 1997
(A/Hong Kong/156/97).
-- An application for a US Patent
by St. Jude's Children's Hospital (USA), which is listed as a WHO Collaborating
Centre in one of WHO’s notifications[1],
for a Modified Influenza Virus for Monitoring and Improving Vaccine Efficiency.
This application, published in February 2007, makes claims on small changes to
influenza HA genes, intended to strengthen the immune system reaction to the
genetically engineered virus. It makes patent claims on any influenza HA gene
modified in a certain way and also specifically claims the modified HA gene
from an influenza virus isolated in Vietnam in 2004(A/Vietnam/1203/04).
-- An application for a US Patent
by University of Pittsburgh (USA), for Vaccines for the rapid response to
pandemic avian influenza. This application, published in January 2007, claims
new human and animal influenza vaccines based on
(theoretically) replication-deficient adenoviruses. These genetically engineered vaccines incorporate genetic sequences from H5N1 viruses. This application claims pieces of any influenza HA gene used in the adenovirus-based vaccine. It specifically makes claims on the HA gene from an influenza virus isolated in Vietnam in 2004 (A/Vietnam/1203/04).
(theoretically) replication-deficient adenoviruses. These genetically engineered vaccines incorporate genetic sequences from H5N1 viruses. This application claims pieces of any influenza HA gene used in the adenovirus-based vaccine. It specifically makes claims on the HA gene from an influenza virus isolated in Vietnam in 2004 (A/Vietnam/1203/04).
-- An application for a Patent in
the US, European Union, Australia, Canada, by Medimmune Vaccines Inc. (USA) and
the US government for Influenza hemagglutinin and neuraminidase variants. This
patent application claims any influenza HA and NA gene modified and used in
specific ways. The patent application specifically uses H5N1 types isolated in
Vietnam and China as examples (A/Vietnam/1203/2004, A/Hong Kong/491/97, and
A/Hong Kong/213/2003).
-- An application for a US Patent
by Novavax Inc. (USA) for Functional influenza virus-like particles (VLPs).
This patent covers methods of producing methods of producing VLPs from
influenza viruses. For the VLP to be useful as a vaccine, it must be derived
from a specific flu isolate, or a close relative, that it is intended to
protect against. The patent application claims any such VLP. According to
recent company statements, the patent application technology has been applied
to generate VLPs from recent Indonesian influenza isolates, most likely the
A/Indonesia/5/2005 strain recommended for vaccine development by WHO. The
company says its patent claims cover this Indonesia-derived candidate vaccine.
Patent applications in the above
cases were also filed with the Patent Cooperation Treaty (which is linked to
the World Intellectual Property Organisation), which helps facilitate
applications in many countries that are a party to the treaty.
COMMERCIALISATION INVOLVING AVIAN INFLUENZA VIRUSES & STOCKPILING OF VACCINES
Regarding commercially-related
activities, the international drug industry's federation (IFPMA) in 2006 listed
31 R&D projects for avian pandemic flu vaccines being undertaken by drug
companies, all of them from the USA, European countries and Japan. The projects
involve various avian flu virus strains, including H5N1 viruses from Vietnam, Hong
Kong, and other virus strains from China, Panama, and Singapore.
(See Annex 8)
Several developed countries have
been buying from drug companies and stockpiling large quantities of pre-pandemic
vaccines, and have placed orders in advance for large quantities of pandemic
vaccines in the event of a pandemic.
According to its November 2006
press release, Sanofi Pasteur (the vaccines business of the Sanofi-Aventis
Group) signed a $117.9 million contract with the US Health Department (HHS) for
the production of bulk concentrate of a new type of H5N1 pre-pandemic vaccines.
"This contract covers clade
2 of H5N1 virus (A/Indonesia) for use in the US government stockpile. Previous
stockpile contracts covered the clade 1 form of H5N1," said the release,
adding that the H5N1 clade 2 bulk material is being manufactured from a seed
virus provided by the US Centres for Disease Control and Prevention (a WHO
Collaborating Centre).
[The press release explained that
most of the viruses circulating during the past 4 years falls into two distinct
clades. Clade 1 viruses circulated in Cambodia, Thailand and Vietnam were
responsible for human infections in those countries in 2004 and 2005. Clade 2
viruses circulated in birds in China and Indonesia in 2003-04 and spread
westward to the Middle East, Europe and Africa.]
Sanofi also stated it was awarded
a contract by the French Ministry of Health to produce a 1.4 million dose
stockpile of the H5N1 candidate being studied by Sanofi. Under the agreement,
Sanofi could also be called upon to provide enough vaccine to protect up to 28
million people in France in the event of a pandemic being declared, once the
actual virus strain responsible is identified.
Sanofi has also entered into
agreements with Italy and Australia to supply vaccines in the event of a
pandemic influenza outbreak, and that it has other agreements with the US
government involving development of pandemic vaccine stockpiles, production of
investigational doses and the development of cell culture technology.
In September 2004, the company
signed a contract with HHS to produce two million doses of bulk vaccine derived
from the H5N1 viral strain. The H5N1 vaccine will be manufactured from a seed
virus provided by the National Institute of Allergy and Infectious Diseases
(NIAID), part of the US National Institutes of Health (NIH).
In September 2005, the HHS
awarded a $150 million contract to Sanofi Pasteur to produce a vaccine to for
the H5N1 influenza virus strain.
In April 2007, Sanofi Aventis
announced that the US Food and Drug Authority had approved for the first time
in the US of a vaccine against H5N1 avian influenza for use with humans. The
approval was based on a clinical trial by the NIAID, completed in 2005.
According to a February 2007
paper by NIAID, "The H5N1 reference virus (the strain used to produce the
H5N1 vaccines for NIAID's clinical trials) was developed by researchers at St.
Jude Children's Research Hospital" in the US. The seed virus for the
production of the vaccine was derived from the A/Vietnam/2004 and all other
genes were derived from the A/PR/8/34 virus, a laboratory strain.
Another company, GlaxoSmithKline
(GSK), entered into a supply contract with the Swiss Federal Office of Public
Health for 8 million doses of GSK's H5N1 antigen influenza vaccine and its
proprietary adjuvant for pre-pandemic use, according to a 23 October 2006
report in Medical News Today.
According to the report, the
order provides enough doses, one per head of the entire Swiss population, to
help prepare the immune system against the threat of a human influenza. The
contract also provides for an advance purchase agreement for 7.5 million doses
of a GSK pandemic vaccine which will be manufactured once a pandemic strain is
identified by the WHO.
On 12 March 2007, Medical News
Today reported on GSK's announcement that clinical trial data from two new
studies show that for the first time GSK's candidate pre-pandemic split antigen
H5N1 vaccine, formulated with GSK's proprietary adjuvant system, provides a
substantial level of cross-immunity against a 'drifted' (diverse) strain of
H5N1.
According to the report: "In
vivo data from the pre-clinical studies demonstrated that GSK's adjuvanted
vaccine, containing the Vietnam H5N1 strain, was not only able to protect
against challenge with the vaccine virus strain but it also provides 96%
(22/23) cross-protection against a lethal challenge with the drifted Indonesia
strain of H5N1, giving an additional boost to hopes that pre-pandemic
vaccination is a viable strategy for inclusion in pandemic preparedness
plans."
The report added that in May
2006, GSK received an HHS contract worth $274 million to develop cell-culture
technology to speed the development of new cell culture-based seasonal and
pandemic influenza vaccines, and to scale-up its cell culture manufacturing
capability; in November 2006 GSK received a $40 million initial order for bulk
H5N1 antigen from HHS while in January 2007 GSK received from the HHS a $63.3
million contract to develop antigen-sparing H5N1 pandemic influenza vaccines.
On 4 January 2007, GSK entered
into an Advance Purchase Agreement with the Danish government to supply its
split candidate pandemic antigen and proprietary adjuvant once a pandemic has
been declared.
Another company Novavax Inc. is
reported by Medical News Today (on 4 May 2007) as saying that it has received
positive study results from a live virus challenge to ferrets inoculated with
its pandemic influenza vaccine, paving the way for clinical trials this year.
The report adds that "In the
study, ferrets were inoculated with the company's virus-like particle (VLP)
vaccine made from an Indonesian strain of H5N1 avian influenza." The
ferrets were then challenged with live H5N1 virus, and all ferrets that
received the Novavax vaccine survived.
According to the study, ferrets
that received Novavax's H5N1 vaccine were protected not only against the
Indonesian strain of avian flu but also were cross-protected against a separate
strain originating in Vietnam.
WINNERS & LOSERS
One set of clear winners are the
vaccine manufacturers which have already obtained many hundreds of millions
worth of contracts to supply pre-pandemic and pandemic vaccines from the
developed countries.
These countries are also giving
several millions of dollars to the companies in grants and subsidies for
research and development activities.
The UPI agency on 8 February 2007
reported on a business analysis that the global vaccine market is expected to
top $10 billion dollars in 2007 and $ 23.8 billion dollars by 2012, with Flu
vaccines sales forecasted to grow to $14 billion by 2012.
Influenza, HIV and cancer will be
the biggest growth areas in the vaccine market, and "the biggest growth in
the flu-vaccine market will come in the area of vaccines for pandemics that
could be caused by the H5N1 strain of bird flu," added the report.
The developed countries are the
other set of winners as they are able to fork out the high cost of stockpiling
pre-pandemic vaccines and to make advance bookings for pandemic vaccines. The
scene is set for the rich to survive a global pandemic.
Moreover, under the present
WHO-organised scheme, the developing countries have become obliged to donate
their avian influenza viruses to WHO CC and H5 reference laboratories which are
located in the developed countries.
The CC and laboratories have been
passing on the viruses or the information contained in the viruses to other
institutions, including companies, even if this is not in line with the CBD or
the WHO Guidance. The companies and developed countries are making commercial
use of the viruses as they wish.
Meanwhile, the developing
countries have so far not benefited from this scheme. They face potential astronomical
bills, should they wish to purchase vaccines in sufficient quantities to
protect their populations.
An Influenza Bulletin published
by the US CDC provides a catalogue with prices for influenza vaccines licensed
for use in the US for the 2005-2006 flu season, which show that the prices
range from $10 to $25 per dose.
A Bloomberg news article of April
6 reported that "Indonesians spend an average of $30 annually on health
care, compared with $5,700 in the US, according to the World Health Report.
Glaxo's flu vaccine costs $6 to $11 a shot in markets around the world, and
receiving a flu shot from a doctor can cost as much as $59 in Jakarta."
With inadequate financial
resources to purchase vaccines, developing countries will suffer the most in the
event of a pandemic outbreak.
As it is, they already suffer
immense economic losses from having to cull poultry in areas of avian flu
outbreaks.
If a pandemic of the human
version of avian flu emerges, the cost to life, economy and society in these
countries could be of unimaginable proportions.
ANALYSIS OF WHO “BEST PRACTICE” Doc. on Sharing Influenza Viruses
It is also interesting to note
that the WHO document (A60/INF.DOC./1) on best practice for sharing influenza
viruses and sequence data (dated 22 March 2007) contains "best
practices" that conflict with the rights of countries of origin of genetic
resources, established by the CBD.
One of the "best
practices" is that no national influenza centre laboratory, WHO
Collaborating Centre or H5 Reference Laboratory should charge fees or sell
influenza viruses or strains or in any way seek to profit from participation in
the WHO GISN. They can only seek to recover the costs of shipping, handling,
storage or other direct administrative overheads.
Another "best practice"
states that no national influenza centre laboratory, WHO Collaborating Centre
or H5 Reference Laboratory should impose agreements or administrative
procedures that may inhibit the proper functioning of the WHO Global Influenza
Surveillance Network, including the timely sharing of material and information.
These "best practices"
prevent or hinder the countries contributing the viruses from seeking fair
benefit-sharing arrangements, in conflict with the CBD principles of access,
prior informed consent and benefit-sharing.
At the same time, another WHO
"best practice" states that the WHO CC/H5 Reference Laboratories
should provide candidate influenza vaccine strains to any requesting vaccine
producer to develop vaccines.
This "best practice"
conflicts with the provision in the March 2005 WHO Guidance that "There
shall be no further distribution of viruses/specimens outside the network of
WHO Reference Laboratories without the permission from the originating
country/laboratory."
It also contradicts the
"prior informed consent" right of countries contributing the virus
and makes it even more difficult for these countries to request a benefit
sharing arrangement with researchers and manufacturers undertaking commercial
activities.
It is obvious that the March 2007
WHO "best practices" are biased against the countries affected by
avian flu, which are strongly urged (and pressurised) to "share"
their viruses for the common good. They are required by the "Best
Practices" not to seek or obtain benefit-sharing. There is no mention that
their prior consent has to be sought for the subsequent use of their viruses.
Nor is there a mention of material transfer agreements.
On the other hand, the drug
companies obtain the most favourable treatment. The WHO CC/ Reference
laboratories are obliged to offer vaccine strains to these companies freely -
since neither the WHO-linked institutes nor the countries contributing the
viruses are allowed to impose any benefit-sharing conditions on the companies.
But there are no limitations or
obligations placed on the companies that receive the vaccine strains containing
parts of the viruses.
They are not obliged by the Best
Practices to ask for the consent of the countries of origin before obtaining
the viruses (and their parts and sequences), or before undertaking commercial
activities. They are free to obtain patents, and to sell their products without
price regulation.
These biases being shown by the
WHO and its "best practices" are a significant part of the reason why
several developing countries are unhappy with the present situation.
MATERIAL TRANSFER AGREEMENT
A MTA is a contractual instrument that defines the rights
and obligations of the provider and the recipient of genetic resources and
facilitates access and benefit sharing arrangements. It is often used in
intergovernmental fora (as well as by countries in their bilateral dealings
with companies or other entities) to facilitate the transfer of genetic
resources or materials, spelling out clearly issues involving proprietary
rights and benefit sharing arrangements.
For example, the Food and Agriculture Organisation (FAO) has
an international treaty on plant genetic resources and under this there is a
standard material transfer agreement that is to be used when a party wants to
access the materials.
Although the MTA is a regular feature in transfers of
materials, and MTAs are used by WHO collaborating centres when they transfer
vaccine strains containing parts of the donated viruses to companies, the WHO's
top bird flu official Dr. David Heymann is reported by Reuters as saying that
"An MTA is not a solution and a MTA will slow down the process of doing
assessment and also vaccine development".
It is interesting to note that while the WHO's centres are
themselves signing MTAs with companies, the countries contributing the viruses
are told by the WHO that they should not request for a MTA because this would
slow down assessment and vaccine development.
A WHO notification of March 2006 stated that "An H5N1 recombinant
vaccine strain developed from A/Indonesia/5/2005, by the WHOCC in Centres for
Disease
Control and Prevention, Atlanta USA, is available for
distribution, under a Material Transfer Agreement (MTA)" (See Annex 5)
A WHO notification in May 2006 stated that "Now, two
new H5N1 recombinant vaccine strains developed from A/Bar headed
goose/Qinghai/1A/2005 and A/Whooping swan/Mongolia/244/2005 selected from the
new genetic group, by the WHO Collaborating Centre at the St. Jude Children's
Research Hospital, Memphis USA, are available for distribution, under a
Material Transfer Agreement (MTA)." ( See Annex 6)
A June 2006 WHO notification stated that "A new H5N1
recombinant vaccine strain, NIBRG-23, has been developed by the National
Institute for Biological Standards and Control, England from
A/turkey/Turkey/1/2005, selected from a genetic group containing the majority
of A(H5N1) viruses since mid-2005. NIBRG-23 is available for distribution,
under a Material Transfer Agreement (MTA)." (See Annex 7)
From these WHO notices, it is obvious that the WHO
secretariat is fully aware of the transfer of virus strains to companies from
the WHO CC have been done with MTAs between the centres and the companies. Yet
a senior WHO official takes a position that it is undesirable for countries
contributing the viruses to require that a MTA accompanies the sharing of
virus.
A material transfer agreement usually implies sharing of
benefits between parties that have rights over the materials. A material
transfer document (a phrase that is recently being used in the context of
influenza virus sharing) may not imply the same. For example it could refer to information
relating to characteristics of the material being transferred and the
logistical aspects of its transfer, without expressing a relation of rights of
the parties involved in transferring and receiving the material
Various types of MTAs may be required: (1) between the country of origin and the WHO
and its centers and reference laboratories and other parties wishing to have
access (eg companies, universities, etc); (2) between the WHO and its
collaborating centers and reference labs; (3) between WHO, centers and labs on
one hand and those institutions (companies, universities etc) that wish to have
access to the viruses and to commercialise products involving the viruses.
MORE INFORMATION REQUIRED FROM WHO
The present system is for countries to send viruses to a WHO
CC. It is not clear what are the
proprietary rights of the countries of origin of the viruses, of WHO, of its
centres, and of researchers who make use of the viruses and the companies/other
organizations that may commercialise them, including patent part of the virus
and the vaccines that contain and make use of the virus or parts of the virus.
Further information is required from WHO on:
§ A list of the viruses that have been donated, by country, virus
strain and to which centres;
§ The research that has been conducted on each of the viruses, the
stage of research, results of the research at various stages, the institutions
that carry out the research, and the terms of reference and conditions within
which the research is being done.
§ Whether each of the centres have made available information and
data linked to the virus and if so how this information is made available (eg
to who, through which means) and the conditions, if any, attached.
§ Whether companies or researchers have entered material transfer
agreements with WHO or its centres, and for what and on what terms.
§ Whether countries of origin have been kept informed and their
permission sought at various stages of the research, the publication of
research results, the application for patents, and the commercialization of
products.
§ Whether there has been commercialization involving the virus,
e.g. patenting of the virus and parts thereof, development of vaccines
containing the virus and its parts, sale and contracts for “booking” of doses
of vaccines, the quantities sold or booked and the prices at which bookings or
sales have been made and to which countries.
ANNEX 1
Guidance for the timely sharing
of influenza viruses/specimens with potential to cause human influenza
pandemics
March 2005
ObjectiveThe objective of timely sharing of influenza viruses/specimens with potential for causing an influenza pandemic is to prepare for and respond to an influenza pandemic by:
- Monitoring and better understanding the evolution of influenza viruses and their public health significance, by advanced antigenic and genetic characterization performed by designated WHO Reference Laboratories;
- Selecting and developing prototype pandemic vaccine strains;
- Developing/updating WHO diagnostic reagents and adjusting WHO recommended diagnostic tests;
- Carrying out other investigations of public health importance linked to these viruses.
The viruses/specimens listed below should be shared with the WHO Global Influenza Programme:
- All viruses that could not be typed/subtyped by the most recently updated WHO diagnostic reagents;
- All viruses from human cases infected by animal influenza and selected viruses from animals in areas affected by animal influenza outbreaks; and
- Newly isolated animal influenza viruses with a record of causing human infection and disease.
Principles for sharing influenza viruses/specimens with the WHO Global Influenza Programme
- The designated WHO Reference Laboratories will immediately report results of analyses of viruses/specimens to the originating laboratory and to the WHO Global Influenza Programme.
- The WHO Global Influenza Programme will use the information from the analysis of viruses/specimens to select pandemic vaccine strains, to develop/update WHO diagnostic reagents and to address other global public health needs.
- The designated WHO Reference Laboratories will seek permission from the originating country/laboratory to co-author and/or publish results obtained from the analyses of relevant viruses/samples.
- There will be no further distribution of viruses/specimens outside the network of WHO Reference Laboratories without permission from the originating country/laboratory.
Available at: http://www.who.int/csr/disease/avian_influenza/guidelines/Guidance_sharing_viruses_specimens/en/index.html
ANNEX 2
WHO procedures for obtaining
release of H5N1 sequences to the public domain
23 August 2006
Information on the gene sequences of H5N1 viruses is
important for vaccine development, the preparation of reagents used for
diagnostic purposes, and monitoring for drug-resistant strains. Sequence
information on viruses collected over time and from different geographical
areas can help track evolutionary changes in the virus and identify mutations.
It is not, however, presently known which mutations affect the pathogenicity
and transmissibility of the virus in humans and thus might signal an altered
threat to human health. Epidemiological findings remain the most important
alert to changes in the virus that indicate improved transmissibility among
humans.
Currently, the genetic sequencing of H5N1 viruses is a
product of collaborative work between national or other laboratories receiving
specimens in countries with outbreaks and the international network of
specialized H5 reference laboratories coordinated by WHO. WHO seeks permission
from the country that provides the virus to place the sequence information in
the public domain.
WHO believes that timely sharing of H5 virus sequence
information is a critical step for improving the international response to the
avian and pandemic influenza threat. In its coordinating role, WHO seeks to
facilitate the timely release of sequence data to the public domain, such as
the Los Alamos National Laboratory (LANL) Influenza Sequence Database and
GenBank. Formal procedures exist by which the WHO reference laboratory
initially informs the originating laboratory of sequence results and
simultaneously requests permission to place these results in the public domain.
In the event of a negative reply or no reply, WHO directly approaches the
Ministry of Health in the originating country, requesting authorization to
release sequence data.
Available at: http://www.who.int/csr/disease/avian_influenza/guidelines/h5n1sequences2006_08_23/en/print.html
ANNEX 3
SOME PATENT
CLAIMS RELEVANT TO H5N1 INFLUENZA VACCINE
Notes about this summary:
1. This information only describes some claims related to H5N1
influenza. Notably, it does not include
the “reverse genetics” patents used to produce current seed strains. Nor does
this summary include patents on vaccine additives (adjuvants) and other
formulation technologies held by vaccine makers, which may have major
implications for access to vaccines. Nor does it include patents on
diagnostics.
2. There is a delay of six months or more between submission of
a patent application and its publication. Because of changes in the prevalent
form of circulating avian influenza virus (antigenic shift), the candidate
vaccine seed strains typically change yearly, causing researchers’ focus to
frequently move to from strain to (newly-isolated) strains. The combination of
the delay in patent publication, plus the moving target of antigenic shift,
plus the fluid state of vaccine technology development combine to mean that it
is reasonable to assume that significant additional patent claims exist but
have not yet been published, particularly on the most recent influenza virus
isolates identified for possible use in vaccines.
United States Patent Application
20070042002A1
PCT WO2007022425
Title: Influenza
recombinant subunit vaccine
Owner: Hawaii Biotech Inc. (US)
What is it? This patent application,
published on 22 February 2007, claims a new type of influenza vaccine and
specific H5N1 vaccines made with the technology.
Pertinent claims: This
patent application specifically claims genetic sequences from an influenza
virus isolated in Indonesia in 2005 (A/Indonesia/5/05) and another isolated in
China in 1997 (A/Hong Kong/156/97).
United States Patent Application
20070031453A1
PCT WO2007019094
Title: Modified Influenza Virus for Monitoring and
Improving Vaccine Efficiency
Owner: St. Jude’s Children’s Hospital
(US)
What is it? This patent application,
published on 8 February 2007, claims small changes to influenza HA genes. These
changes are intended to strengthen the immune system reaction (boost
immunogenicity) to the genetically engineered virus. This might improve
possible pandemic influenza vaccines because people vaccinated may exhibit a
stronger immune reaction against H5N1.
Pertinent claims: This
patent application claims any influenza HA gene modified in a certain way. It specifically
claims the modified HA gene from an influenza virus isolated in Vietnam in 2004
(A/Vietnam/1203/04).
United States Patent Application
20070003576A1
PCT WO2006063101
Title: Vaccines for the rapid response to pandemic
avian influenza
Owner: University of Pittsburgh (US)
What is it? This patent application,
published on 4 January 2007, claims new human and animal influenza vaccines
based on (theoretically) replication-deficient adenoviruses. These genetically
engineered vaccines incorporate genetic sequences from H5N1 viruses.
Pertinent claims: This
patent application claims pieces of any influenza HA gene used in the
adenovirus-based vaccine. It specifically claims the HA gene from an influenza
virus isolated in Vietnam in 2004 (A/Vietnam/1203/04).
United States Patent Application
20060008473A1
EU EP1766059, CA2568015,
AU2005248377, PCT WO2005116258
Title: Influenza hemagglutinin and neuraminidase
variants
Owner: Medimmune Vaccines Inc. (US) and
United States Government
What is it? This patent covers methods of
producing H5N1 vaccines wherein HA and NA genes are removed from circulating
wild human and or animal viruses, genetically-engineered, and placed into a
“backbone” of a laboratory-adapted influenza strain..
Pertinent claims: This
patent application claims any influenza HA and NA gene modified and used in
specific ways. The patent application specifically uses H5N1 types isolated in
Vietnam and China as examples (A/Vietnam/1203/2004, A/Hong Kong/491/97, and
A/Hong Kong/213/2003).
Unites States Patent Application 20060263804A1
PCT WO2007047831
Title: Functional influenza virus-like particles
(VLPs)
Owner: Novavax, Inc. (US)
What is it? This patent covers methods of
producing methods of producing virus-like particles from influenza
viruses. Virus-like particles (VLPs) are
proteins that replicate structures of actual viruses, prompting much the same
reaction in the human body as the virus itself. Thus, they may be used as
vaccines. VLPs lack actual genetic material; but their structure is determined
by genetic sequence data specific to particular flu isolates. In other words,
for the VLP to be useful as a vaccine, it must be derived from a the specific
flu isolate, or a close relative, that it is intended to protect against. The
patent application claims any such VLP.
Pertinent claims: According
to recent company statements, the patent application technology has been
applied to generate VLPs from recent Indonesian influenza isolates, most likely
the A/Indonesia/5/2005 strain recommended for vaccine development by WHO. The
company says its patent claims cover this Indonesia-derived candidate vaccine.
ANNEX 4
Availability of H5N1 prototype
strains for influenza pandemic vaccine development
February 2005
The WHO Influenza Surveillance Network has characterized
H5N1 influenza viruses isolated from humans and animals from several countries
affected by the 2004/2005 H5N1 outbreak in Asia. WHO has also made
recommendations on the antigenic and genetic characteristics of H5N1 viruses
which are suitable for vaccine production.
In addition, WHO collaborating centres and reference laboratories
have developed several recombinant H5N1 prototype vaccine strains, including
A/Vietnam/1194/04, A/Vietnam/1203/04 and A/Hongkong/213/03, according to the
requirements of several major national and international pharmaceutical
licensing agencies for influenza vaccine production. These H5N1 influenza
pandemic vaccine prototype strains have already been made available to a number
of institutions and companies and several different vaccines have been produced
for clinical testing.
It is understood that there are no intellectual property
issues restricting the use of reverse genetics for pandemic vaccine research.
However it is anticipated that licences must be negotiated before commercial
use of such vaccines.
In some countries, the reassortant may be viewed as a
genetically modified organism and approval will be needed for virus
cultivation. Also in some countries, although the reassortant is derived from a
human H5N1 virus, it may be subject to an import licence from veterinary
authorities.
Influenza vaccine manufacturers who wish to receive these
prototype strains should contact either the WHO Global Influenza Programme at
whoinfluenza@who.int or any of the institutions below:
- National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, England (fax: +44 1707 646730; e-mail: enquiries@nibsc.ac.uk)
- WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza, Centers for Disease Control and Prevention, 1600 Clifton Road, Mail stop G16, Atlanta, GA 30333, USA (fax: +1 404 639 23 34; e-mail: ncox@cdc.gov)
- WHO Collaborating Center for Studies on the Ecology of Influenza in Animals, St Jude Children's Research Hospital, 332 North Lauderdale St., Memphis, TN 38105-2794 USA (fax: +1 901 523 2622; e-mail: Robert.webster@stjude.org)
Questions or requests for additional information should be
addressed to WHO at whoinfluenza@who.int
Available at: http://www.who.int/csr/disease/avian_influenza/guidelines/avian_influenza_prototype_strains/en/print.html
Annex 5
Availability of new H5N1
prototype strain for influenza pandemic vaccine development
March 2006
The WHO
Global Influenza Programme has been closely monitoring the antigenic and
genetic evolution of circulating H5N1 viruses, especially human isolates. In
October 2005, an observation was noted that H5 haemagglutinin (HA) genes of
many newly isolated viruses from animals and humans were genetically
distinguishable from the H5N1
pandemic vaccine prototype strains selected in 2004 and there was also
evidence of antigenic variation among the HAs of recent viruses.
Since then, the WHO Collaborating Centres (WHOCCs) and
Reference Laboratories have started developing several new recombinant H5N1
prototype vaccine strains representative of different genetic sub-groups of
viruses. An H5N1 recombinant vaccine strain developed from A/Indonesia/5/2005,
by the WHOCC in Centres for Disease Control and Prevention, Atlanta USA, is
available for distribution, under a Material Transfer Agreement (MTA). As for
all other WHO selected and developed influenza prototype vaccine strains,
including seasonal and H5N1 influenza vaccines, the sequences
of HA and neuraminidase
(NA) of the new H5N1 recombinant stain can be found on the public Los Alamos National Laboratory database.
Institutions, companies and others interested in pandemic
vaccine development, who wish to receive the prototype strain should contact
either the WHO Global Influenza Programme at whoinfluenza@who.int or WHOCC CDC
at the address below:
WHO Collaborating Center for Surveillance, Epidemiology and
Control of Influenza, Centres for Disease Control and Prevention, 1600 Clifton
Road, Mail stop G16, Atlanta, GA 30333, USA (fax: +1 404 639 23 34; e-mail:
rdonis@cdc.gov).
The development of H5N1 prototype vaccine strains
representative of viruses recently circulating in Europe and Africa is ongoing
in other WHOCCs and Reference Laboratories.
At present, WHO does not recommend changing the selected
H5N1 prototype strains for ongoing pandemic vaccine development. However, for
vaccine research purposes, the WHO Global Influenza Programme will continue to
select, verify and develop new prototype vaccine strains from genetically
and/or antigenically different groups of circulating viruses, and will continue
to depend on close collaboration with affected countries as regards the rapid
sharing of A/H5N1 virus/specimens, both from humans and animals, and other
relevant information.
Available at http://www.who.int/csr/disease/avian_influenza/guidelines/avianinfluenzastrains2006/en/print.html
Annex 6
Availability of new H5N1
prototype strain for influenza pandemic vaccine development
May 2006
Since October 2005, it has been observed that H5 HA genes
of the majority of virus isolates from animals and humans received by the WHO
H5 Reference Laboratory Network are genetically distinguishable from the
earlier virus isolates from South- East Asia, which were represented by the 2
H5N1 prototype vaccine strains, A/Vietnam/1203/2004 and A/Vietnam/1194/2004, developed
by WHO in 2004-2005.
At the same time, along with the genetic differences,
antigenic variation has also been observed. The 3rd H5N1 prototype vaccine
strain, which is the 1st from the new genetic group, was developed from
A/Indonesia/5/2005 and made
available to the companies/institutions in March 2006 from the WHO
Collaborating Centre for Reference and Research on Influenza in CDC Atlanta.
Now, two new H5N1 recombinant vaccine strains developed
from A/Bar headed goose/Qinghai/1A/2005 and A/Whooping swan/Mongolia/244/2005
selected from the new genetic group, by the WHO Collaborating Centre at the St.
Jude Children's Research Hospital, Memphis USA, are available for distribution,
under a Material Transfer Agreement (MTA).
As is the case for all other WHO selected and developed influenza prototype
vaccine strains, including seasonal and A(H5N1) influenza vaccines, the
sequences of haemagglutinin (HA) and neuraminidase (NA) of these new H5N1
recombinant stains can be found on the public web site of Los Alamos National Laboratory database.
Institutions, companies and others interested in pandemic
vaccine development who wish to receive these two prototype strains should
contact either the WHO Global Influenza Programme at whoinfluenza@who.int or
WHO Collaborating Centre St Jude Hospital at the address below:
WHO Collaborating Centre for Studies on the Ecology of
Influenza in Animals, Department of Virology & Molecular Biology, St. Jude
Children's Research Hospital, University of Tennessee, 332 North Lauderdale,
P.O. Box 318, Memphis, TN 38105, USA (Fax: +1 901 523 2622; email:
robert.webster@stjude.org)
Another new H5N1 recombinant vaccine strain developed from
A/Turkey/Turkey/1/2005 is in the final stage of safety testing in the National
Institute for Biological Standards and Control, United Kingdom.
Studies on antigenic properties of these vaccine reference
strains and their relations with the emerging H5N1 viruses are ongoing in the
WHO H5 Reference Laboratory Network.
The
Global Influenza Programme has been closely monitoring the antigenic and
genetic evolution of the circulating viruses, especially human isolates.
Countries are encouraged to share with WHO their specimens/isolates, both from
humans and animals, in order to be included in WHO's H5N1 vaccine
selection/development and other activities of public health significance.
ANNEX 7
Availability of new H5N1 prototype strain for influenza
pandemic vaccine development
June 2006
A new H5N1 recombinant vaccine strain, NIBRG-23, has been
developed by the National Institute for Biological Standards and Control,
England from A/turkey/Turkey/1/2005, selected from a genetic group containing
the majority of A(H5N1) viruses since mid-2005. NIBRG-23 is available for
distribution, under a Material Transfer Agreement (MTA). As with all seasonal
and A(H5N1) influenza strains WHO has selected and used for vaccine
development, the sequences of haemagglutinin (HA) and neuraminidase (NA) of the
A/turkey/Turkey/1/2005 strain can be found on the public web site of Los Alamos National Laboratory database.
Institutions, companies and others interested in pandemic
vaccine development who wish to receive this prototype strain should contact
either the WHO Global Influenza Programme at whoinfluenza@who.int
or the National Institute for Biological Standards and Control at the address
below:
National Institute for Biological Standards and Control,
Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, England (fax:
+44 1707 646730; e-mail: enquiries@nibsc.ac.uk)
Studies on antigenic properties of A(H5N1) vaccine
reference strains and their relation to the emerging H5N1 viruses are ongoing
in the WHO H5 Reference Laboratory Network.
The
Global Influenza Programme has been closely monitoring the antigenic and
genetic evolution of the circulating viruses, especially human isolates.
Countries are encouraged to share with WHO their specimens/isolates, both from
humans and animals, in order to be included in WHO's H5N1 vaccine selection and
development and other activities of public health significance.
Available at: http://www.who.int/csr/disease/avian_influenza/guidelines/2strainsJune2006/en/print.html
[1] See WHO
Notification “Availability of
H5N1 prototype strains for influenza pandemic vaccine development” (February
2005) at
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