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Office of the Gene Technology Regulator
APPLICATION FOR LICENCE FOR INTENTIONAL RELEASE OF A GMO INTO THE
ENVIRONMENT: Application No. DIR 033/2002
SUMMARY INFORMATION
Project Title:
Recombinant live oral cholera vaccine (Orochol®
vaccine)
Applicant:
CSL Limited
45 Poplar Road
PARKVILLE VIC 3052
Common name of the parent organism:
Cholera
Scientific name of the parent organism:
Vibrio cholerae
Modified trait(s):
Attenuation by removal of cholera toxin subunit A and
inclusion of a mercury resistance marker
Identity of the gene(s) responsible for the
modified trait(s):
Deletion inactivation of the gene coding for the A
subunit of the cholera toxin (ctx)
Disruption of the hemolysin (hlyA) gene by insertion of
the mercury resistance locus (mer operon)
Proposed Date of Release:
Previously assessed under former (voluntary) system.
Supply commenced in Australia on 2 September 2000
and a licence issued under transitional arrangements.
This application is to continue supply of the vaccine.
Introduction
The Gene Technology Act 2000 (the Act) took effect on 21 June 2001. The Act, supported by the
Gene Technology Regulations 2001, an inter-governmental agreement and corresponding legislation
that is being enacted in each State and Territory, underpins Australia’s nationally consistent
regulatory system for gene technology. Its objective is to protect the health and safety of people and
the environment by identifying risks posed by or as a result of gene technology and managing those
risks by regulating certain dealings with genetically modified organisms (GMOs).
The Act establishes a statutory officer, the Gene Technology Regulator (the Regulator), to administer
the legislation and make decisions under the legislation. The Regulator is supported by the Office of
the Gene Technology Regulator (OGTR), a Commonwealth regulatory agency located within the
Health and Ageing portfolio.
The legislation sets out the requirements for considering applications for licences for dealings with
GMOs and the matters that the Regulator must take into account before deciding whether, or not, to
issue a licence.
The application and the proposed dealings
The OGTR has received an application from CSL Limited for a licence for release of live genetically
modified cholera vaccine (Orochol®). Orochol® is a self-administered prescription medicine to
immunise people against cholera. The vaccine was registered as a prescription medicine by the
Therapeutic Goods Administration under the Therapeutic Goods Act 1989 on 17 April 2000, after
undergoing extensive evaluation of its safety, quality and efficacy.
Cholera is a disease caused by the bacteria Vibrio cholerae. V. cholerae colonises the mucosal surface
of the human small intestine and secretes a toxin. The toxin stimulates secretion of water and
electrolytes by the cells of the small intestine, leading to the severe watery diarrhoea that is
characteristic of cholera.
Orochol® contains a live weakened (attenuated) strain of the bacteria Vibrio cholerae, which causes
the body to make antibodies against the bacteria and protects against the disease caused by the
bacteria. CSL Limited imports Orochol® from Berna Biotech Ltd in Switzerland, where it is
manufactured. It is distributed to specialist travel clinics, surgical/medical wholesalers and
pharmacies. It is sold through pharmacies to people who have been prescribed the vaccine by their
doctor and is taken as a liquid preparation.
CSL Limited proposes to sell 20-50,000 doses per year. Each dose consists of 200-1000 million
colony forming units of the attenuated bacteria.
Previous releases of the GMO
The vaccine has been sold in Australia since 2 September 2000, with over 60,000 doses distributed.
World wide, over 220,000 doses were sold in 1998 - 2000.
Parent organism
The parent organism is the cholera bacterium (Vibrio cholerae), which is found in estuarine waters,
where it is present in water, sediment and shellfish in low numbers. It has been isolated in several
continents, in tropical, semi-tropical and temperate climatic zones. It has been isolated in Australian
aquatic environments since 1977 and periodically cholera cases have followed exposure to these
environments. However, the disease cholera has an extremely low incidence in Australia. It has been
reported over the last ten years in all states of Australia except Tasmania, with an average of four
cases per year. Apart from one laboratory acquired case in 1996, all cases of cholera reported since
1991 were imported.
Genetic modification and its effect
Orochol® vaccine contains the live bacterium V. cholerae. Native cholera bacteria produce a toxin
containing 2 subunits, A and B. The vaccine strain has been produced by deleting most of the toxic
A-subunit gene (ctxA) and inserting a mercury resistance operon (mer) into the haemolysin gene
(hlyA). The non-active B-subunit of the cholera molecule is still synthesised but it does not cause
disease.
Method of gene transfer
Pieces of the V. cholera chromosome, one containing the ctxA gene and one containing the hlyA gene,
each were cloned into a plasmid vector. The restriction enzymes (enzymes that cut DNA at specific
sites) XbaI and ClaI were used to cut the cloned DNA and remove a 550 base pair length of DNA
from the ctxA gene. The cut ends were joined to create an inactive copy of the ctxA gene. The
restriction enzyme HpaI was used to cut a 400 base pair segment from the hlyA gene. This deleted
DNA was replaced with the mer operon. These two modified genes were then introduced into
V. cholera strain CVD103 by a targeted recombination (DNA exchange) technique that replaced the
functional ctxA and hlyA genes present in the host genome with the inactivated versions.
Consultation on risk assessment and risk management plan
As required by section 50 of the Act, the Regulator is preparing a risk assessment and risk
management plan in relation to the licence application and will seek input from a wide range of key
stakeholders and expert groups comprising State and Territory Governments, relevant Commonwealth
agencies, the Environment Minister, the Gene Technology Technical Advisory Committee and
appropriate local councils. Copies of the application are available on request from the OGTR. Please
quote application number DIR 033/2002.
As required by section 52 of the Act, the Regulator will again consult with these prescribed agencies
and authorities in finalising the risk assessment and risk management plan that is expected to be
issued in February 2003. The public will also be invited to provide comment on the risk assessment
and risk management plan over a six week consultation period, via advertisements in the media and
direct mail to anyone registered on the OGTR mailing list. Summaries and copies of the risk
assessment and risk management plan will be available from the OGTR or on the OGTR website.
Issues to be considered by the Regulator
In making a decision on whether to issue a licence for the proposed release, the Regulator is required
to consider applications and submissions within the context of the object of the Act, which focuses
upon protecting the health and safety of people and the environment. It is important to note that
this vaccine has already been evaluated by the Therapeutic Goods Administration in Australia and
similar regulatory agencies in other countries for safety, quality and efficacy.
If you have any questions about the application or the assessment process, please contact the OGTR
at:
The Office of the Gene Technology Regulator
MDP 54
PO Box 100
WODEN ACT 2606
Tel: 1800 181 030
Fax: 02 6271 4202
Email: [email protected]
Website www.ogtr.gov.au