November 2013

Introduction


An application has been made under the Gene Technology Act 2000 (the Act) for Dealings involving the Intentional Release (DIR) of genetically modified organisms (GMOs) into the Australian environment.

Application number:DIR 126
Applicant:PaxVax Australia Pty Ltd (PaxVax)
Project Title:Limited and controlled release of a genetically modified live bacterial vaccine against Cholera1.
Parent organism:Cholera bacterium (Vibrio cholera)
Introduced or modified genes and resulting modified traits:
  • insertion of mercury resistance operon (mer) from Shigella flexneri NR1 (selectable marker – mercury resistance)
  • deletion of Cholera toxin A subunit gene (ctxA) (loss of toxin expression - vaccine attenuation)
  • inactivation of haemolysin A gene (hlyA) (loss of toxin expression - vaccine attenuation)
Proposed release dates:12 months from date of approval
Proposed locations:Clinical sites in Queensland, South Australia, Victoria and Western Australia

The proposed dealings


PaxVax has proposed a clinical trial of a genetically modified (GM) live bacterial vaccine against Cholera

This proposed trial would form part of three international clinical trials covering different age groups. The trial would involve the inoculation of children and adults in Australia via oral ingestion of the GMOs. The purpose of the trial is to verify the effectiveness of the vaccine in producing an immune response against cholera. The trial is proposed to take place in clinical facilities in QLD, SA, VIC and WA. Once underway the trial is expected to be completed within one year.

The applicant has proposed a number of control measures to restrict the spread and persistence of the GMOs and their introduced genetic material that will be considered in the assessment of this application, including:
  • Inoculating a maximum of 1000 individuals in Australia with the GM vaccine
  • Requiring that inoculations be performed by trained nurses and/or physicians at health care facilities in accordance with standard universal precautions and ICH-GCP2
  • Storage and transport of all GM vaccines, including any waste or samples containing the GM vaccines, in accordance with relevant regulations
  • Monitoring vaccinated individuals for at least one hour after ingestion to ensure the vaccine solution is not expelled orally
  • Disposing of all waste in accordance with standard clinical waste disposal practices as required by the relevant local and state legislation

Confidential Commercial Information


Some details about the molecular characterisation and batch testing of the GMO are under consideration as Confidential Commercial Information under section 185 of the Act. Any confidential information will be made available to the prescribed experts and agencies that will be consulted on this application.

Parent organism


The parent organism Vibrio cholera is the causative agent of the gastroenteritis disease known as cholera, which is typically linked to the ingestion of contaminated water. Cholera is found in aquatic environments in tropical areas and has been isolated in some parts of Northern Australia.

The genetic modification and its effect


The GM vaccine contains live genetically modified bacteria V. cholerae. Unmodified cholera bacteria produce a toxin containing 2 subunits (A and B) and haemolysin (a protein which can break open blood cells). 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). As a result of the genetic modification the GMOs cannot produce the A-subunit of the cholera toxin molecule or haemolysin. The non-active B-subunit of the cholera toxin molecule is still synthesised but it does not cause disease or toxicity.

The mercury resistance operon contains seven genes and allows the bacteria to grow in the presence of mercury. This was used as a selective marker during the development and propagation of the GMOs and does not cause disease.

Method of genetic modification


Multiple steps were required to produce the genetic modifications found in the GMO. Fragments of the Cholera toxin A subunit and haemolysin A genes were cloned into separate plasmids. The gene fragments were then modified in vitro by the deletion of part of the toxin gene and by the insertion of the mer operon. The plasmids were transferred into the V. cholerae, one at a time, and the genetic modifications were incorporated into the bacterial genome by recombination.

Previous releases of the same or similar GMOs


Commercial release of this GMO as a human vaccine (formerly known as Orochol®) was previously approved by the Regulator under DIR 033. The licence for DIR 033 was issued to CSL Ltd on 20 June 2003 and was surrendered at the licence holder’s request on 14 September 2010. Prior to this, commercial release of the GMO was approved by the Genetic Manipulation Advisory Committee.

There have been no credible reports of adverse effects on human health and safety or the environment resulting from any of these releases.

Other regulatory approvals


PaxVax has indicated that a Clinical Trial Notification will be submitted to the Therapeutic Goods Administration and they will be applying to Department of Agriculture for a permit to import the vaccines.

Assessment and consultation process for this DIR application


The Act and the Gene Technology Regulations 2001 set out requirements for considering licence applications, including matters that the Gene Technology Regulator (the Regulator) must take into account before deciding whether or not to issue a licence.

The application qualifies as a limited and controlled release, under section 50A of the Act, as the principal purpose of the application is to enable the conduct of experiments, and the applicant has proposed limits on the size and duration of the release and controls to restrict the spread and persistence of the GMOs and their genetic material in the environment.

This means that the Regulator is not required to consult on the assessment of this application until after a risk assessment and risk management plan (RARMP) has been prepared in accordance with section 51 of the Act. In the interim, copies of the application are available on request from the OGTR. Please quote application number DIR 126.

The Regulator will seek comment on the consultation RARMP from the public as well as a wide range of experts, agencies and authorities including the Gene Technology Technical Advisory Committee, State and Territory Governments, Australian Government agencies and the Minister for the Environment. The RARMP will then be finalised, taking into account matters raised relating to risks to human health and safety and the environment, and form the basis of his decision whether or not to issue a licence.

At this stage, the RARMP is expected to be released for comment in late January 2014. The public will be invited to provide submissions on the RARMP via advertisements in the media and direct mail to anyone registered on the OGTR mailing list. The RARMP and other related documents will be available on the OGTR website, or in hard copy from the OGTR.

More information on Australia’s national scheme for regulation of gene technology and the assessment process can be found at the Office of The Gene Technology Regulator’s website.

If you have any questions about the application or the assessment process, or wish to register on the mailing list, please contact the OGTR at:
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Office of the Gene Technology Regulator, MDP 54, GPO BOX 9848 CANBERRA ACT 2601
Telephone: 1800 181 030 Facsimile: 02 6271 4202 E-mail: OGTR Website



1The title of the licence application submitted by PaxVax is “Clinical development of a recombinant live oral cholera vaccine (PXVX0200)”

2The international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, guidelines for good clinical practice

3The Regulator’s Guidelines for the Transport, Storage and Disposal of Genetically Modified Organisms, IATA Transportation Regulations