Minutes of the thirteenth meeting of the Scientific Advisory Committee on Genetic Modification

Monday, 21 April 2008, The Rose Room, Rose Court, London

Welcome

1. The Chair welcomed everyone to the thirteenth meeting and thanked Dr Stoye and Prof Dunwell for agreeing to attend and provide input into the discussions, particularly on agenda item 5. The Chair informed the committee that representatives from the consortium involved in the development of a measles-HIV vaccine (agenda Item 5) will be joining the meeting to provide the Committee with relevant supporting information, to assist members in their deliberations.

2. Dr Cleland from the Office of the Gene Technology Regulator was also welcomed, to provide a short presentation on the regulation of genetic modification activities in Australia.

Minutes of the previous meeting

3. The minutes were accepted as a true and accurate record of proceedings.

Matters arising

4. The terms of reference of the Reverse Genetics Vaccine Working Group have not yet been established, due to other work commitments. It is proposed to address this at the next meeting.

5. Secretariat reported back on the 1st meeting of the Synthetic Biology Policy Coordination Group, under the auspices of the Royal Society. The Group membership includes representatives from academia (engineers, chemists, biologists and social scientists), Government (HSE, Department of Health), funding agencies (Environment Science Research Council, Wellcome Trust) amongst others. It is intended to expand the membership to encompass all interested parties. The first meeting aimed to set out the terms of reference of the group and identify the range of activities undertaken within, primarily, the UK. It is likely that SACGM will be asked to advise on the application of GMO(CU) regulations to this technology.

Secretariat report

6. Dr Logan informed the Chair that he would be stepping down as the Committee Secretary and colleague Dr Mike Paton would be assuming this role. The Chair thanked Dr Logan for the many years of service provided to the Committee; and also welcomed Dr Paton as the new Secretary.

7. The Secretariat updated the Committee on developments following Sir Bill Callaghan’s Review of the regulatory framework for animal pathogens, particularly the proposed establishment of a single regulatory framework for genetically modified microorganisms, human pathogens and animal pathogens.  The risk based model utilised in the GMO(CU) Regulations, which accommodates both human and animal pathogens, is viewed as a possible format to be adopted. HSE and defra solicitors are currently exploring the legal mechanism for implementing a single regulatory framework and are unlikely to report back on the way forward before the next meeting. A parallel work stream will involve the formulation of a common set of containment measures for human and animal pathogens. The Advisory Committee for Dangerous Pathogens (ACDP) will be invited to lead this work and will deliver it through a working group, to which members of SACGM will be co-opted. The working group is likely to be constituted by the next meeting.

8. Secretariat informed the Committee of the European Commission’s intention to form a Working Group to consider new and novel technologies and whether they fit with the definitions of genetic modification as specified in the GMO(CU) or GMO(DR) directives. The Working Group’s Terms of Reference are being formulated with the intention of the 1st meeting towards the end of 2008. The Secretariat will keep the Committee informed of progress in this area.

9. Secretariat outlined a clinical trial involving measles-HIV vaccine trial as the most substantive agenda item (item 5); the main issue being the regulatory status of the work.  Although the SACGM Compendium of Guidance provides some useful guidance on conducting clinical trials, the nature of the work borders on both the GMO(CU) and GMO(DR) regulations, hence the invitation for members of the Advisory Committee for Releases into the Environment (ACRE) to join the discussion.  Although Prof Lewis is a Consortium member, the Committee agreed that his contribution to the discussion would be invaluable hence should remain for the agenda item.

Classification of Lentiviral Vectors (SACGM/04/08/P4)

10. Secretariat introduced the agenda item stating that publication of the SACGM Compendium of Guidance, which is interpreted as steering users to classify pseudotyped retroviral/lentiviral vectors as Class 2, based on an inherent risk of insertional mutagenesis associated with retroviral and lentiviral vectors, has contributed to an increase in the number of activity notifications involving these expression systems. Furthermore, there is apparent disparity within the scientific community, in terms of interpretation of the guidance, resulting in differing approaches to classification of these viral vectors. Edinburgh University, specifically, approached HSE to ask that clarification be provided. Advice was therefore sought on whether: (a) the guidance should be reviewed; (b) the vectors should be ranked.

11. The Committee recognised the potential tumourgencity associated with retroviral vectors but questioned whether similar phenomenon had been seen in lentiviral vectors. The Secretariat reminded members of concerns raised in relation to the WPRE element of certain lentiviral vectors, which were linked to insertional mutagenesis in neonatal mice. These concerns had resulted in a precautionary recommendation that all work with these vectors be undertaken at containment level 2 (CL2). The revision of the Compendium of guidance had perhaps reiterated this precautionary approach. The Committee felt that ranking different vectors would be counterproductive particularly as new and modified versions were continually appearing; and classification is based on the vector and insert (rather than vector alone); and the activity being undertaken.

12. It was agreed that detailed scientific discussion of the insertional mutagenic potential of lentiviral (and retroviral) vectors could be addressed by the SACGM Virology Working Group and if necessary a revision of the Compendium drafted for approval by the Committee. Appropriate experts in the field should be recruited to the working group.

Action:  Secretariat to arrange SACGM Viruses Working Group meeting, including representatives from wider scientific community.

Classification of New Strains for Polio Virus Vaccine Production (SACGM/04/08/P3)

13. Dr Minor declared an interest in this work, however the Committee felt his participation in the discussions would be invaluable.  The Secretariat outlined the paper which asked for advice on the most appropriate classification of a genetically modified attenuated strain of polio virus, being developed for use in vaccine production. The application is particularly relevant to use in a post polio eradication era, when the only source of polio virus will be vaccine manufacturing facilities or laboratories.  Consequently, such facilities will need to operate at stringent levels of biocontainment to minimise the potential release of virus into the community. The proposed attenuated vaccine seed strain will be modified to minimise the potential for reversion or recombination that might result in a virulent strain of polio, and therefore provide a safer starting material and reduce the consequences of a release from containment. The World Health Organisation were reported as showing enthusiasm for the generation of genetically stable vaccine seed strains.

14. The Committee discussed the attenuating modifications and the potential for recombination with other enteroviruses, particularly in developing countries. The potential for a single recombination event restoring multiple attenuating mutations was sufficient to make recombination a concern. However, the application of Good Manufacturing Practice standards should minimise the potential for contamination of seed or production material with other enteroviruses thereby minimising the risk of heterologous recombination. The potential of co-infection of a worker in the production plant was also considered to be a possibility.

15.The reversion of the engineered attenuating mutations in the modified strains was discussed. Whilst it was acknowledged that the design of the mutations was such as to select against reversion, growth of the virus in large scale production needed to be assessed to accumulate data on reversion rates to support this assertion. Similarly growth of the attenuated virus in less permissive cells may select for compensatory mutations that facilitate virus growth. The Committee were of the view that although providing distinct advantage over other vaccine strains (e.g. Sabin), further data on reversion rates should be provided (e.g. growth of virus at pilot scale) before the work could be considered as Class 1.

Categorisation of non-circulating strains of influenza virus of known pandemic potential – update on ACDP deliberations (SACGM/04/08/P5)

16. The Secretariat informed the Committee that the Advisory Committee for Dangerous Pathogens (ACDP) had recently considered the categorisation of the re-constructed highly virulent 1918 pandemic influenza strain. Given the availability of prophylaxis and possible cross-reactivity of H1N1 vaccines, ACDP had been reluctant to assign the virus to Hazard Group 4.  ACDP have advised the use of ‘enhanced CL3’ as a minimum for work with this virus (i.e. CL3 with use of a closed fronted microbiological safety cabinet) and will provide an annex to their guidance on working with influenza, that incorporates risk-based approach to containment dependent on the activity being undertaken. As the reverse genetics was used to reconstruct the 1918 influenza virus, SACGM will be asked to provide input into this guidance.

17.  The Committee indicated that whilst the work was worthwhile, it was important to provide clear guidance on the containment measures necessary for this type of work. This will also set a benchmark for genetic modification activities involving influenza. Secretariat explained that the risk-based approach familiar to GMO(CU) would be applied to human and animal pathogens as part of a single regulatory framework, whereby containment measures will be selected from a clearly defined set of measures. The potential range of activities involving the 1918 influenza virus will be explored with the influenza research community.

Action:  Secretariat to liaise with ACDP work on how this work stream will be delivered and a stakeholder consultation set up.

Proposals to conduct clinical studies with a measles virus vaccine carrying an HIV derived insert (SACGM/04/08/P2)

18. The Chair thanked the two ACRE members for agreeing to attend and contribute to this agenda item. Dr Minor and Prof Lewis declared an interest as contributor to the development of the construct and a Consortium member respectively. The Chair invited both members to remain for the agenda item: Dr Minor for all aspects of the discussion; and Prof. Lewis to contribute points of clarity on this item, but not to discussions regarding the Committee’s decision. 

19. The Secretariat introduced the item and reminded the Committee that the work was first mentioned in January 2007.  The Secretariat highlighted a key issue as being the classification of the work as contained use or deliberate release activity, given that the vaccine, although clearly attenuated and biologically contained, would be given on an out-patient basis hence the issues of virus shedding is of major importance.

20. The Consortium provided: an overview of the construct; its use in pre-clinical studies; the measles vaccine’s history of safe use; properties of the measles Schwartz strain; the clinical trials procedures/protocols including the range of specimens to be taken, tests conducted and contingency arrangements for adverse reactions. The Committee posed several questions relating to: the immunomodulatory effects of the insert; the transmission characteristics of the Schwartz strain; the potential for virus shedding in the urine, faecal and oro-pharyngeal routes; and the testing regimen for patients. The areas that were focused on related to: the detection of virus components in urine and oro-pharyngeal specimens in pre-clinical trials; and the timescales for virus isolation and consequent change in proposed containment of patients.

21. Whilst the Committee were content (assuming the HIV components were non-biologically active) that given comparable properties displayed by the construct and Schwartz parental strain in pre-clinical trials, supported by an absence of documented person to person transmission of the vaccine strain, the construct presents negligible risk of harm and would be a Class 1 organism. However, the issue of whether the work was contained use or deliberate release remained unanswered. The Committee felt that as a labile virus, the detection in urine was most likely the result of virus breakdown products. However, it was agreed that evidence should be provided to this effect before the Committee could provide further advise on this issue. It was also suggested that a more timely indicator of virus shedding by the oro-pharyngeal route be used (e.g. PCR) and the protocol amended accordingly to ensure more timely containment of patients if necessary.

22. The Consortium reported that further pre-clinical studies are planned for later in 2008, which will provide the necessary data on virus shedding. The Secretariat emphasised the importance of this data, not only in the deliberations on Contained Use or Deliberate Release but in providing data to support the environmental risk assessment required for the marketing of medicinal products. The Chair invited the Consortium to return to SACGM when relevant data from further pre-clinical studies is available.

Action:  Secretariat to circulate draft letter to members and ACRE before responding to Consortium.

Overview of the Regulatory System in Australia

23. The Chair welcomed Dr Cleland who gave a short presentation describing the range of genetic modification activities undertaken in Australia; outline of the Australian GM regulatory structure; and the work of her Office which is responsible for regulating GM work in Australia.  A number of parallels and differences between the UK and Australian systems were highlighted and discussed.

Exemption of Safe Organisms

24. The Secretariat informed the Committee that this issue had been raised at the meeting of the European Competent Authorities (EC CA) for GM activities. The EC CA has published guidelines on criteria that need to be met in order to exempt an organism and the procedures for doing so. Although several Member States highlighted difficulties with the existing approach (considered overly bureaucratic, incurring significant costs in terms of time and effort), the EC CA pointed out that to date, no organisms have been registered or procedure utilised. Consequently there is a reluctance to change the system until it has been tried out.

25. EC CA has set up a working group to look at new and novel techniques. It is possible that this may extend to look at safe organisms. 

Action:  Secretariat to forward Commission guidance to members.

Any Other Business

26. On behalf of the Committee, the Chair thanked Dr Logan for his dedication and service to the Committee and wished him well for the future.

Close

27. The Chair thanked everyone for their attendance and contributions.

Date of next meeting: Thursday, 10 July 2008.