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

Minutes of the 6th meeting of the Scientific Advisory Committee on Genetic Modification (Contained Use) held on Monday, 10 October 2005, in the Globe Room at Rose Court, Southwark Bridge, London

Chair

Prof Janet Bainbridge

Members

Dr Gary Burns
Prof Ernie Gould
Dr Penny Hirsch
Dr Keith Howard
Dr David Lewis
Dr Sue Mayer
Dr Philip Minor
Mr Bob Osborne
Dr Peter Searle
Dr Michael Skinner
Prof Peter Williams

Secretariat

Dr Paul Logan
Mrs Diane Tsavalos

Departmental Assessors

Dr Androulla Gilliland (DEFRA)
Mr Paul Manser (DEFRA)
Mrs Susan Shearman (DEFRA)
Ms Liz Sawyer (HSE)
Dr Mike Paton (HSE)
Ms Lorraine Medcalf (HSE)
Dr Paul Heeney (HSE)

Apologies

Prof David Baulcombe
Dr John Carr
Dr Martin Carrier
Dr Peter Coyle
Prof Martin Gore (Vice Chair)
Dr Brian Robertson

Welcome and Introductions

1. The Chair welcomed everyone to the sixth meeting of the SACGM, and introduced Drs Gawn and Heeney and welcomed Mrs Tsavalos as the new Secretariat member.

2. Attention was drawn to the requirement that guest presenters should not be present during discussion of the substantive agenda items.

Minutes of the Fifth Meeting - SACGM/10/05/P1

3. Apart from two minor amendments, the minutes of the fifth meeting were agreed as a true record of proceedings.

Matters Arising

4. The Secretariat reported on the following action points:

1. The lentiviral vectors paper has been published and HSE will be unable to comment until data from further studies are provided.
2. Medimmune have notified their 'flu work as a Class 1 activity. There is now an urgent need to set up a Reverse Genetics Safety Working Group, as this technology is fast becoming mainstream. Working Group would take less than one day of members' time.
3. FMDV work will be carried out using the replicon system only and none of the modifications planned in the original notification will now take place; these will be notified as separate projects.
4. SiRNA guidance to be deferred to the updated Compendium of Guidance.

5. A question arose concerning how the UK and other European countries interpret reverse genetics under GM legislation. The European Commission has stated that individual CA has autonomy.

Secretariat Report

6. The Secretariat opened by introducing Mrs Medcalf and Dr Heeney and explained the purpose of their presence at the meeting.

7. Mrs Medcalf gave an update on the progress of the electronic public register, which is due to 'go live' within the next couple of weeks. A delay has been introduced by the failure to obtain final agreement of the content of the revised Schedule 5. The revised wording of the definition of GM means that many notifications that were previously withdrawn from the public register must now be reinstated.

8. One member drew attention to the fact that the withdrawal of animal pathogens needs to be pre-empted.

9. Dr Heeney was minded to seek the Committee's views and comments on the GM aspects only of his draft of ACDP's Containment Level 4 Guidance. He described the problems that had been encountered in making the guidance fit to the various regulatory frameworks involved. As copies weren't available for the meeting, the Secretariat agreed to comment on behalf of the Committee and copies would be circulated to members for information only.

10. The Secretariat reminded the committee that amendments had been made to the GM regulations on 1 October 2005.

11. The Chair requested and obtained agreement to rearrange the order of the papers to be presented.

Notification of a Class 4 activity: Pathogenicity testing of avian influenza viruses in animal models prior to vaccine manufacture

12. The Chair opened by commenting that given the current climate, it is inevitable that many CL4 notifications will be 'flu-related. One member declared a possible interest.

13. The Chair introduced Dr Paton of the Secretariat who went on to outline:

1. that the notification has been written so that it may cover additional pandemic 'flu strains
2. although the risk of a hazard to human health is low, there is concern about the scenario of its interaction with a wild type 'flu virus within the worker
3. in light of the practical problems encountered by workers, there is genuine scientific justification for decreasing the containment level.

14. The Secretariat distributed draft copies of the WHO guidance on vaccine manufacture, drawing the meeting's particular attention to the definition of 'enhanced level 3'.

15. The Chair welcomed and introduced the two guest speakers and reminded the meeting to bear in mind the issues at large. A short presentation was given outlining their plan of work and the pros and cons of current and proposed containment strategies. During the presentation, attention was drawn to the following:

1. Supply of viral seed stock has been outsourced.
2. The original notification proposed working with tissue culture - eggs will now be used.
3. The original notification involved mice - ferrets will now be used.

16. Questions: Ferrets:

1. Do staff have adequate handling training?
   Answer: Yes and there is a programme of exchange of staff between HPA and CEPR.
2. Where are they sourced?
   Answer: Pre-screened from CEPR and they have a period of acclimatisation after arrival at the facility.
3. What provisions have been made for the event of a bite to a worker?
   Answer: Following CEPR policy, i.e. antiviral therapy and monitoring.
4. How will they be calmed down?
   They are housed in specially designed cages. Anaesthetised intramuscularly; remote monitoring of temperature through intraperitoneal probe. Most work will be done remotely and analyses done terminally.
5. How many are to be used?
   Answer: 4

17. Question: Would the set-up be adequate for handling wild-type virus?
Answer: (provided by departmental assessor) The facilities must meet the relevant Defra containment requirements. From the information provided so far they appear to meet Defra CL4.

18. Question: What are the provisions for site-to-site virus transport?
Answer: The licence and consent allow for such transport without the need to inform the CA each time.
A discussion took place concerning the need for DEFRA's view that they may have a generic transport licence, but the meeting was reassured that packaging and transport guidelines are strictly adhered to and that DEFRA will be notified (including for wild-type virus). The Secretariat confirmed that there are no HSE transport notification requirements for this containment level

19. Question: Why are sharps included in the risk assessment, when the work will be administered intranasally?
Answer: Sharps will be used post-mortem, but not during the main work.

20. Question: Is this the first time that suits will have been used?
Answer: In this context, yes.

21. The plan is to run the ferret and chick projects concurrently and the Secretariat stated that, given the urgency of the work, the WHO were proposing that the recombinant virus may be released immediately to industry, so that process development work could be conducted in parallel to safety testing. This would only be allowed if the industrial facilities met enhanced containment level 3.

22. The meeting was informed that the long-term plan is to build in directional airflow within the cages. The Secretariat stressed to the committee that animal handling issues need to be studied in more detail.

23. A DEFRA assessor raised a concern that a licence application had not yet been completed. The meeting was assurance that it would be submitted within that week.

24. The Chair thanked the guests and asked them to leave the room before asking the meeting for their comments. All agreed with the Chair that satisfactory answers had been provided to all the questions posed. One member said that there was a need to have further clarification on the chick tests and that there may already be data available to illustrate the principles of the work. If this were to be the case, why is the committee considering it now? He conceded that the purpose of the committee is to consider the GM aspect, whereas most previous studies will have involved wild-type virus. The Secretariat drew attention again to the WHO paper and outlined what discussions took place to arrive at that final draft and the problems encountered translating it and putting it into practice in real life. Comment was made that it was unfortunate that the CEPR CL4 facility is being refurbished at this critical time. The Chair commented and all agreed that as wild-type and GM vaccine work is being done in tandem, there ought to be a mechanism in place to feed this information through to ACDP and such joined-up work needs to be expedited.

Action: HSE to write to HPA to confirm that the proposed amendments to the containment were acceptable, and the work could proceed as described.

Updated risk assessment and proposed amendments to a connected programme of work involving the construction and analysis of recombinant morbilliviruses: a class 4 activity - SACGM/10/05/P2

25. One member declared an interest, which was due to expire in 1 month's time. The Secretariat outlined the paper's background and informed the meeting of HSE's concerns of the potentially grave consequences were this work to create a novel virus. He went on to compare and contrast Pirbright and Compton's expertise and facilities. Attention was drawn to HSE's 1997 letter to the notifier and although the risk assessment has been updated, the original reservations still remain. The meeting was asked to consider:

1. The human health protection measures that were originally proposed have been downgraded.
2. Vaccination of workers is being used as a primary control measure.
3. The proposal is to run ferret and cattle studies concurrently.
4. Carrier status has not been considered.
5. Will levels of measles antibody be tested?
6. Does the Yoneida paper contradict the host specificity issue?

26. The Chair introduced the guest speaker, who went on to give a short presentation that included the phylogeny of the morbilliviruses and their known host ranges, his own definition of infection versus pathogenicity, the containment levels used at Pirbright (SAPO 4 for RPV) and Queen's, Belfast (GLP for CDV). He ended by outlining that the foundation for relying on vaccination to control the risk was due to the highly conservative nature of the viral fusion protein. He then went on to raise a number of key issues:

1. Growth in tissue culture doesn't correlate with virulence
2. Stress caused to ferrets in isolators, and manual difficulties of working in isolators due to cage size, and speed of movement of ferrets.
3. Rationale for ferret work to be carried out before cattle work unclear

27. There then followed an extensive question and answer session. Initially members focussed on whether measles vaccination would automatically protect against all morbilliviruses and in particular the chimaeras, for example does measles vaccination prevent CDV seroconversion in humans? It was stated that no studies have been done, but there is one paper with tenuous results. Vaccination does not induce sterilising immunity.

28. Regarding surrogate markers of antibody levels, one member asked could the immunological response of workers to vaccination be quantified? In answer it was stated that there is no way of telling. But everyone would be screened for the minimum required level. There is an absolute certainty that vaccination will protect against chimaeric viruses because it protects against RPV and CDV.

29. The questions moved on to containment. Containment relies on there being no export to the environment from the laboratory by workers, and this therefore implies that there is no human carrier. In response it was noted that this depends on what an individual's definition of carrier state is and as far as was known there is none. One member asked why, if that was the case, RPV hadn't been eradicated in Africa? In reply it was stated that this was due to the political instability of areas where the disease is endemic. The FAO is of the opinion that there is no wildlife reservoir - nomadic peoples' domesticated animals carry RPV.

30. Members then raised questions regarding culture in transformed cells; have there been studies in primary human cells to replicate the disease in humans? In reply it was stated that almost all work has been done in preactivated PBLs so this may be worth trying. Infection with MV of primary bovine cells has been achieved. SLAM expressing cells become infected, therefore primary cells may turn out to be resistant. Although cultured virus has adapted to infect cell lines with low SLAM levels.

31. One member noted that protection through vaccination will mask whether an infection has occurred. It may be possible to devise a subtle antibody screening, but this may not be worthwhile. In the future may need to consider doing primate work, but where possible, tissue culture systems are preferable.

32. It was noted that small numbers of staff and cattle would be used to carry out the study, so those potentially exposed would be limited. However, cattle with active viral infections shed copious quantities of virus in serious illness from mucous membranes and virus is present in faecal matter. In mild cases, shedding from eyes and saliva only. Similar profile for CDV. Animal handlers go through a thorough decontamination process.

33. One member asked whether host-restriction is dose dependent? It was noted that rabbits had become infected after exposure (experimentally) to high doses - 1x104. However, there were no reports of cattle to human RPV spread in Africa, and this may be the best evidence. Futhermore for the rabbit adapted RPV it has not been possible to publish the full sequence because the parental strain with Asian lineage is not known.

34. Members asked how the cattle are housed? All cattle kept in isolation with HEPA filtered air. It was noted that respiratory protection is not routinely used, although it has been used for allergy purposes in the past, it is possible and if the committee think it appropriate, airflow hoods could be used if it is deemed necessary (although this may be a stressor to the animals). The use of vaccination was considered as a belt and braces fallback measure.

35. Members noted that the worst-case scenario would be that a chimaera might enter a non-host species and then adapt to something different?
In reply it was stated that the RPV-PPR chimaera was put through without a query and that didn't culture very well.

36. The chair thanked the speaker for his presentation and a discussion took place around the following points.

37. The Chair reminded the meeting that the major issue of concern is the uncertainty of the behaviour of the chimaeric strains should they escape into the environment and is this possibility of genuine concern to the meeting. The fact that there has been no occurrence yet, does not preclude it from happening in the future. The work may alter the pathogenesis in humans and besides; other morbilliviruses may become a threat to human health if MV is eventually eradicated. The Chair also pointed out that the presentation gave evidence of how the science has moved on since 1997 and there is evidence that the family is not as host specific as was once thought, therefore there is an increased risk. Despite this, their proposed approach to containment remains the same.

38. One member stated that if the major claim for safety is immunity to MV then he would not be comfortable. The argument that that no-one in endemic RPV areas is vaccinated against measles is invalid because they're likely to have had immunity conferred by wild-type MV infection. Furthermore the legality of using MV vaccine for its unintended purpose is questionable. The consensus was that it was contradictory for the speaker to believe that the work posed no risk with an insistence on using vaccination as a primary control measure

39. The committee were also in agreement on the following points.

1. Their arguments against containment in the form of RPE are based purely on practicality and inconvenience.
2. If it is deemed necessary to do cabinet work with small animals, why then is the equivalent not used during the large animal part of the work?
3. If RPE can be worn to avoid allergic reactions, then why not for this work?
4. There would be merit in making a recommendation to carry out work in primary cell lines, as this has worked with the W138 and MRC5 lines.
5. The group should be asked to do some of the other constructs first before doing the P gene work.

Action: Secretariat to grant consent on condition that adequate RPE be worn.

Project Plan: Redrafting ACGM Compendium of Guidance - SACGM/10/05/P4

40. The Secretariat introduced Dr Gawn and discussed the shortcomings of the current Compendium of Guidance and the proposed amendments. The Chair outlined the importance of members' input to this guidance but this need not be too time consuming, but there is a tight deadline. With regard to the updated replicons guidance, the Secretariat is aware of a forthcoming notification on SARS, and to discuss the two at the same meeting would be beneficial, as would the formation of several small working groups consulting relevant community members with the responsibility for drafting remaining with HSE. It is envisaged the working groups will be combined with future committee meetings.

1. Genetically modified viruses and vectors: this will be the biggest area to be discussed, it is therefore proposed that this working group may meet up to three times. There will be a possible overlap with SAPO, therefore DEFRA input will be required. The Chair stated that it is the responsibility of the Secretariat to be aware of and to communicate with other regulatory bodies over the Compendium.
2. Genetically modified micro-organisms risk assessment: this is the most outdated part of the Compendium.
3. Genetically modified plant viruses: this will involve the least work and can incorporate work done recently by Dr Penrose of HSE.
4. Genetically modified animals
5. Replicons

Action: Secretariat to arrange series of working groups

SACGM Annual Report - SACGM/10/05/P5

41. The Secretariat informed the meeting that once finalised, this will be placed on the SACGM website and hard copies will be distributed to members, and requested that any issues should be raised now or sent via e-mail. The Chair stressed the importance of maintaining accurate biographical and interest information.

42. The Chair agreed with the author's view that rather than reproducing hard copies of minutes, reference should be made to their availability on the SACGM website. All agreed with one member's comment about the necessity to add a footnote to the report if something is not available on the Internet. The Secretariat said that there is a will to have everything published on the Internet, but the limiting factor here is HSE's electronic publishing infrastructure. The author accepted suggestions of a couple of changes of wording.

Action: Dr Paton to send out e-mail reminder to all for comments including nil responses.

AOB

43. The Secretariat informed the meeting of renewed discussions with Chiron regarding large scale 'flu vaccine manufacture and the associated waste disposal problems. Chiron and HSE are continuing to meet with the waste-handling contractor in order to arrive at the safest possible solution and agreement between all the CA will be required.

Next meeting dates

Thursday, 26 January 2006
Wednesday, 7 June 2006

Close

The Chair thanked everyone for their attendance and drew the meeting to a close.