Vaccine Development Process Maps

Genetically modified organisms (GMOs) are increasingly used as a vaccine platform for infectious and non-infectious diseases, especially in the area of outbreak pathogen vaccine development. 

The use of a GMO in this context, usually refers to a vaccine developed from a virus that has been genetically modified to elicit immunity against an antigen or suite of antigens not present on the original genome, and/or genetically modified from its ‘native’ form, in order to make the vaccine safer (for e.g. attenuating the virus so that it no longer replicates once it has ‘infected’ the host). 

A commonly used type of GMO vaccine is a recombinant viral vector, which exploits a virus’s natural capability to transport genes inside a cell that it infects.  A major driver for the development of viral-vectored vaccines and therapeutics is the long lasting immunogenicity they can induce, as well as being able to deliver an antigen or combination of recombinant antigens, safely. 

Currently licensed GMOs include vaccines against dengue and typhoid. 

Use of GMO vaccines in trial in the UK is regulated by separate legislation, driven originally by concerns about the risk of environmental contamination as much as by any risk to vaccines. Trials may be performed either under ‘contained use’ procedures or ‘deliberate release’ protocols. The former is generally the case, especially for widely used non-replicating vaccines, e.g. MVA (modified Vaccine Ankara) and adenoviral vectors.  ‘Contained use’ is defined as: “any activity in which micro-organisms are genetically modified or in which such GMMs are cultured, stored, transported, destroyed, disposed of or used in any other way, and for which specific containment measures are used to limit their contact with the general population and the environment”.

Separate approval is required for use of GMOs from the local genetic modification committee of the trial site.  Floor coverings of the clinic room may need alteration to minimise any persistence of GMOs and suitable procedures for sterilising residual vaccine or swabs will likely be required. The local pharmacy may require separate storage of GMP vaccine (potentially needing a new fridge or freezer) or may need special training of staff to handle GMOs.

Obtaining regulatory approval - local approvals must be obtained at any trial site the vaccine is to be tested.  This may cause delays either because a GM safety committee does not exist at a new site, has not been convened in recent years or because of unfamiliarity with the vaccine type to be used. An early application may be beneficial and is not contingent on other approvals.

• Check that a GM safety committee exists at the trial site.
• Identify the GM safety committee contact person
• Provide sufficient information on the vaccine to be used and site suitability for GMO use.
• Discuss early with pharmacy what procedures will be required by them.

• Repeal of outdated legislation would be the best solution in favour of a risk-based approach.  Establishing new guidelines and legislation may now be facilitated by avoidance of EU legislation
• National derogation to relax the use of common non-replication competent vaccine vectors (safer than the replication-competent counterpart) from the GMO legislation would enable more rapid progress
• Provision of a national GMO safety committee which could review vaccine GMOs for all UK locations could greatly reduce administration burden for multi-centre trials, particularly if the vector itself, rather than just its use in a single trial could be approved.
• Selection of trial sites familiar with GMOs

At some clinical sites it has apparently been difficult to convene a suitably qualified committee related to lack of expertise on GMO vectors and difficulties with remuneration of committee members.

Overall, this whole area would benefit a revision of regulations, and a new framework instated. Current legislation reflects the merging of regulation of gene therapy trials and trials using common vaccine vectors, however, derogating use of common viral vectors in a separate legislation from the currently applicable GMO regulations would have a substantial beneficial impact in speeding up approvals.

An additional potential approach would be to provide national review and potential approval of the use of specific GMO vaccines.