HSE - Scientific Advisory Committee on Genetically Modified Organisms (SACGM)

Minutes of the 5th meeting of the Scientific Advisory Committee on Genetic Modification (Contained Use).

This was an "Open meeting" and was held in public on 1st June 2005, at Rose Court, Southwark Bridge, London

Chair

Prof. Janet Bainbridge

Members

Prof David Baulcombe
Dr Gary Burns
Dr John Carr
Dr Martin Carrier
Dr Peter Coyle
Prof. Martin Gore (vice Chair)
Prof. Ernie Gould
Dr Penny Hirsch
Dr Keith Howard
Dr Sue Mayer
Mr Bob Osbourne
Dr Brian Robertson
Dr Peter Searle
Dr Michael Skinner
Secretariat
Dr Paul Logan
Dr Michael Paton
Mr Lee Wilson
Dr Matthew Penrose
Dr Jonathon Stoye - ACRE

Departmental Assessors

Dr Androulla Gilliland - DEFRA
Dr Paul Manser - DEFRA
Dr Liz Pollitt - MHRA
Ms Delyth Dyne - HSE
Ms Liz Sawyer - HSE
Dr Maggie Lacey HSENI

Guest Speakers

Dr George Kimble
Dr Jim Young
Apologies
Dr David Lewis
Dr Philip Minor
Prof. Peter Williams

Welcome & introductions

The meeting opened with the Chair welcoming everyone to the fifth meeting. There were apologies from Dr Peter Williams, Dr David Lewis and Dr Philip Minor. The Chair went on to welcome Dr Jonathon Stoye who is on the SACGM Clinical trials working group and ACRE, Dr Liz Pollitt from MHRA and the representatives from Defra, and HSE Northern Ireland.

The Chair asked all members to introduce themselves for the benefit of members of the public who were attending the meeting. The Chair then gave an introduction to the meeting - covering the work of SACGM, purpose of the open meeting, which was being conducted in as close a manner as possible to SACGM's normal business meeting. She then went on to inform the audience that the FMDV paper was going to be covered in a closed session, as there were national security issues involved.

Minutes of the fourth meeting - SACGM/06/05/P1

The minutes of the fourth meeting were agreed as a truerecord of proceedings.

Matters arising

The Secretariat informed members that the joint working group between SACGM & ACRE to look at the boundaries between deliberate release and contained use would convene as discussed and that the plan was to incorporate this into the Clinical trials working group.

The Secretariat also updated members on the FMDV replicon notification, adding that agreement had been reached by members of the Competent Authority on the conditions attached to the clearance letter. The work would go ahead at containment level 2 with additional security measures to ensure restricted access and safe storage of the replicon samples.

The Secretariat updated members on the Lentiviral vector safety alert, adding that until publication of the research findings, it would be difficult to issue further advice.

Secretariat report

The Secretariat informed members that:

• the revision of the Compendium of Guidance was due to commence, with particular attention being focused on the virology sections and clinical trials;
• the first draft of the SACGM annual report was ready for circulation and that it should be finalised by September 2005;
• the Schedule 5 biological agents list had been finalised, adding that the legislation had not made it through parliament in time, but would be published by the Home Office in the near future;
• the SACGM website was currently being updated and that all the relevant papers would be placed on it within the month. One member asked whether the public register would be available on the Web. The Secretariat said that it would and that HSEs IT department were currently looking into viable ways of doing this.

Regulatory issues relating to the application of reverse genetics - example of a live attenuated human influenza virus vaccine - SACGM/06/05P2

The Secretariat outlined the background to this paper, which was intended to bring to the attention of the Committee, developments in the field of influenza vaccine development. The secretariat also noted that potential anomalies may arise through the use of reverse genetics techniques and advice was being sought from members on whether in such cases, there are any supplementary risks to health and safety from reverse genetics techniques over and above those generated through the traditional process of forced reassortment.

The Chair then introduced Dr George Kemble and Dr Jim Young from MedImmune Corporation who gave a short presentation on the application of reverse genetics to the production of attenuated influenza viruses. They informed the committee that their vaccine was based on a cold adapted influenza virus, and was at present being marketed in the USA as a live vaccine. They explained to members that they wished to move to the use of reverse genetics to generate the vaccine, rather than the slower and less predictable, reassortment method that they currently used. They further informed members that the reverse genetics derived vaccine would be identical to the product currently being produced, but felt that if it was labelled as a GMO it would put regulatory hurdles in their way.

Members asked why they were so keen to avoid calling it a GMO? Dr Young said that this was down to public perception and also because it would require them to handle the manufacturing process differently, in terms of containment and waste disposal.

One member asked what containment measures were currently in place to protect the worker? Dr Young said that all open operations were carried out within biological safety cabinets, involving 10,000 to 12,000 eggs in trays of 800.

It was further asked whether there had been any studies carried out regarding person-to-person transmission? Dr Young said there had been a study carried out in Finland where children in a nursery were vaccinated intra-nasally, and allowed to mix and play with un-immunised children. He informed members that there had only one case of person-to-person transmission, and analysis showed that very little virus shed, even with innoculation of 3x107 viral particles. The vaccine was delivered nasally and only 20% of the children had shed the virus at low levels - at a maximum level of 103.

One member asked what the waste disposal implications were at the Merseyside production site if it was treated as a GMO? Dr Young said that they would need to bring in extra equipment for incineration. The Secretariat noted that assuming the vaccine was classified as class 1, waste inactivation would not be a difficult hurdle, and no additional measures should be required over and above those currently used. Similarly the controls within the plant that Dr Young had described would be sufficient even if the strain was GM derived.

The Chair summarised the discussions. She noted that although there was agreement that there were no intrinsic hazards arising from the use of reverse genetics, the committee needed to think of the precedents that would be set if this process was exempted from the regulations. The Chair added that it could made clear that the committee had looked at this application in great depth and was content that there would be no new hazards arising from the use of reverse genetics. Additionally the committee could issue a generic statement to cover all strains of influenza.

The Chair said that there should be a decision made that it was GM or the destinction between genetically modified/genetically derived could backfire for what was essentially a good, safe mechanism for producing vaccine. This was also a good opportunity to be open and say that this is a good use of GM. The Chair said that it would be useful to set up a working group from SACGM and ACRE members to look at the rationale/definition.

Action

The Secretariat to consider the best was of moving the issue forward.

First notification of a contained use Biopharming activity "Expression of human endostatin peptide in Nicotiana benthamiana and Nicotiana tabacum plants using potato virus X (PVX) and tobacco mosaic virus (TMV)". - SACGM/06/05/P5

The secretariat outlined the background to this paper, highlighting that this notification was intended to bring to the attention of members an emerging area of contained use research i.e. production of novel recombinant proteins in plants. The technology aims to exploit the controlled environment provided by the contained facilities to manufacture recombinant proteins 24 hours a day, all year round, in line with production in the pharmaceutical industry. The specific example discussed involved the use of modified plant viruses, Potato virus X (PVX) and Tobacco mosaic virus (TMV) to express pharmaceutical proteins.

Discussions centred primarily on the biological barriers associated with the virus vectors. One member stated that his experience with TMV vectors suggested that they were inherently highly attenuated: the host range appeared to be restricted to the experimental species Nicotiana benthamiana and that getting recombinant TMV to infect other species was difficult. This was supported by another member whose experience with working with PVX, TMV and Tobacco rattle virus (TRV) vectors over many years suggested that they were always disabled with inherent biological barriers. These include the fact that the GM viruses are genetically unstable, with the insert being lost over 1-2 passages as well as the difficulty in getting recombinant PVX to infect potatoes. However, it was confirmed that these disabling characteristics had not been systematically tested and reviewed, but were cited in a number of publications. For the specific notification, a number of members raised concerns about the lack of supporting data provided by the centre for their activity in relation to both the stability of the constructs and the potential harmful effects which may be associated with them and requested that HSE should ask the notifier to address some of the unknown scenarios thrown up should there be a breach in containment.

Action: The secretariat to request further information from the notifier to address the inadequacies in the risk assessment.

Class 4 activity notification "Genetic Manipulation of Foot & Mouth Disease Virus" - SACGM/06/05/P4: CLOSED SESSION

The secretariat outlined the background to the paper, which was aimed at assessing the adequacy of the risk assessment, the potential consequences of the proposed activities and the acceptability of the derogation requests.

It was also proposed that all Class 4 activities should be brought before the committee for information. The committee was in agreement that all Class 4 activiites should be brought to their attention, even where no further advice is being sought - in such cases for information. The Chair promised to review this if this presented an onerous workload on the committee.

The proposed study aims to investigate how FMDV a) binds to host cells; b) replicates; c) assembles & matures its capsid; d) how the latter packages the RNA genome and e) how antibodies recognise the virus. The work will involve mutating specific residues or short stretches of residues (including deletions), replacing or duplicating sequences with homologous sequences from other FMDV strains or members of the Picornaviridae and insertion of marker/reporter genes. Most of these modifications are expected to abrogate or remove gene function. In addition to modification of FMDV, the proposal included use of the replicon system (i.e. deletion of all or part of the coding sequence for viral capsid proteins), in the first instance to ascertain the properties of certain more hazardous mutations, prior to repeating the modifications in wild type virus. The modified virus may then be used for in vivo studies.

Whilst the committee agreed with the approach of using the replicon in the first instance, concern was raised in regard to its suitability for predicting effects on virus properties such as immune evasion and pathogenicity. However, this approach would provide information on the ability of the modified replicon to demonstrate replicative capacity in for example, primate cells. The committee raised concerns at the lack of detail in the assessments and related information i.e. waste inactivation, precise nature of the genetic modifications, the proposed animal work and requested that more information be sought.

The Defra assessor explained that validation of waste inactivation, standard operating procedures and emergency plans were in place as part of the requirements to obtain a Specified Animal Pathogen license. It was felt that these omissions as part of the GM notification were an oversight on behalf of the notifier.

The Committee's main concern with the work related less to the possibility of generating an FMDV construct with capability of causing disease in humans but rather modification/extension of the tropism such that the virus may be able to infect people sub-clinically. Such a scenario may lead to inadvertant release of the virus from containment the consequences of which for agriculture could be devastating. The notifiers have not considered this possibility. This has direct relevance to the derogation requests made for this activity. The committee felt more detailed information is required to adequately assess the likelihood of extending the tropism of FMDV.

Action: The secretariat to request further information from the notifier to address the inadequacies in the risk assessment.

Class 2 activity notification "siRNA" - SACGM/06/05/P5

The secretariat outlined the background to this paper, which is aimed at assessing the risks associated with the expanding technology of RNAi and whether the proposed guidance on interpretation of RNAi under GMO(CU) is sufficient to assist with the risk assessment requirements of those undertaking such activities.

The committee discussed the delivery of siRNA into cells, the possibility of spread to neighbouring cells - considered a unique feature of plants (e.g. spread in leaf) and the mechanism of action of siRNA (e.g. the degree of sequence similarity to achieve transcript down-regulation).

The committee's view was that the worse case scenario relating to siRNA mediated down-regulation, is the inactivation of a tumour-suppressor gene, culminating in the progression of the transformed cell, towards a tumorogenic state. This needs to be considered as part of each activity. The risk assessment also needs to consider the properties of the viral vectors used to deliver the siRNA, in determining routes of exposure, duration of transgene expression etc.

The committee felt that whilst the guidance is suitable and useful for interpretation purposes, it does not cover the risk assessment requirements. The guidance could be amended or updated to consider the risks associated with the work, or this could be included as part of the revised Compendium of Guidance.

Action: The secretariat to update and circulate the document to members for a quick response and subsequent placement on the web site.

AOB. There was no further business, so the Chair opened up the question and answer session, during which the audience would have an opportunity to ask the committee members questions.

Public feedback Session - Question & Answers on organisation/functioning of SACGM, Agenda items.

The Chair informed all that the Q&A session would be published on the web site along with the meeting papers and minutes.

Q: Were MedImmune more worried about the perceived control procedures for a GM than a non-GM?

A: The control procedures do not necessarily relate to the label of a particular product. This was a unique problem for MedImmune because the registration of a GM vaccine for marketing reasons was more difficult. A GMO medicine is covered by both EU directives (CU/DR). Public perception of GM also needs to be taken onto account, despite the fact that this was a good vaccine that would save many lives.

Q: Is the gene therapy horizon-scanning document available?

A: The document will be available and a review of the technology was to go before an internal HSE committee.

Q: Is there a GTAC link to the Clinical Trials working group?

A: Yes the Chair of the working group is also a member of GTAC. Furthermore there was a lot of dialogue between both secretariats.

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