James RobertsonNIBSC

Member of t he Vaccine, Gene Ther apy and Biologics Wor king Par t ies at t he EMEA

To consider new types of genetic vaccines under development

- DNA vaccines

- Live r ecombinant vect or ed vaccines

To def ine t hem, t o consider t heir value and t heir impact on t he envir onment

To def ine how t hey will be r egulat ed.

Genetic VaccinesBenefits and Challenges

This t er m implies t he vaccine is modif ying or dir ect ly interacting with the genes of the recipient

They do not, and there is no intention of them doing so (although there are always exceptions)

The genetic in genetic vaccines refers to the genetic engineering events that are used to create the vaccine

This t er minology is poor PR; it is misr epr esent at ion and misinf or ms t he public who should be t he benef act or s of such developments but who may be concerned about vaccines that might modify their genes

Much more appropriate and more scientific to refer to them individually as:

DNA vaccines (vaccines that are composed of DNA).

t her e is not hing t o be af r aid of DNA we ingest DNA const ant ly in f oods, our cells br eakdown and DNA cir culat es t hr ough our blood st r eam, and occasionally DNA/ RNA is administ er ed parenterally via various bacterial or viral vaccines

Live recombinant vector vaccines (LRVV)

similar t o cur r ent highly accept able live at t enuat ed vaccines such as MMR, polio, et c. but wher e a vir us/ bact er ium (t he vect or ) has been genet ically engineer ed t o expr ess a f or eign ant igen (mor e lat er )

Management Forum, Oct 2007

Antigen encoding gene

CMV pr omot erCMV promoter terminatorterminator

selection markerselection marker bacterial bacterial origin of replicationorigin of replication

linear expr ession casset t es

Promoter antigen encoding gene terminator

DNA gener at ed by PCR

Vector (car r ier )Viral: pox viruses (MVA, avipox), adenovirus, yellow fever virus, measles virusBacterial: salmonella

Heterologous (foreign) antigenProtein antigen from an infectious agentHI V, malar ia, dengue, West Nile

Recombinant DNA t echnology is used t o inser t t he gene encoding the foreign antigen into the vector

genome

Potential for vaccines for diseases where vaccines don t exist, where there are difficulties in development, or where improvements arer equir ed, e.g. HI V, malar ia, Dengue, West Nile vir us, ebola, TB,pandemic inf luenza

DNA vaccinesThe potential of DNA remains to be proven in the development of human vaccines but from an immunological point of view, they have many of the positive features of a live attenuated vaccine but without any concerns of a live infectious agent

LRVVCurrent live (non-recombinant) vaccines e.g. MMR, polio, smallpox, varicella are highly efficaciousLRVV act in t he same way as live at t enuat ed vaccines and many vectors in use are live attenuated vaccines, e.g. MVA, yellow fever vaccine

DNA vaccinesWest Nile vir us (equine)I nf ect ious haemat opoiet ic necr osis vir us (salmon)

LRVVsPurevax FeLV (canarypox vector)Vaxxitek HVT+I BD (her pes vir us vect or )

Genetically Modified Organisms (GMO)The envir onment al r isk of a GMO is based on t he

likelihood of its unintended transfer or transmission to humans other than the intended person, to animals or to the environment at large, as well as the extent of its impact on the environment.

GMOs/ GMMs ar e r egulat ed by t wo EU dir ect ivesContained Use Dir ect ive 98/ 81/ EC (GMM s)Deliber at e Release Dir ect ive 2001/ 18 (GMO s)

Annex II principles for the environmental risk assessment (ERA)

DNA vaccinesThe act ive ingr edient (DNA) is not a Genet ically Modif ied Or ganism (GMO/ GMM) alt hough t he bact er ia in which t hey ar e pr oduced would qualif y as a GMO/ GMM; Cont ained Use Dir . Applies f or manuf act ur e.

LRVVThe active ingredient of a LRVV is a live, genetically modified infectious agent, typically a virus (most development in this area) or a bacteriumA live recombinant vector vaccine is a GMODeliber at e Release Dir . applies and an ERA is r equir edShedding and t he r isk t o non-vaccinees important

REGULATI ON (EC) No 726/ 2004...t he aut hor isat ion and super vision of

medicinal pr oduct s...

AnnexMedicinal pr oduct s t o be aut hor ised by t he communit y

1. Medicinal pr oduct s developed by means of one of t he f ollowing biot echnological pr ocesses:- r ecombinant DNA t echnology- ... ...

-> Cent r alised mar ket ing aut hor isat ion by emea

EMEAEst ablished 1995 / r e-est ablished 2004Regulat ion (EC) No 726/ 2004 (Tit le I V)Responsible f or t he pr ot ect ion and pr omot ion of public and animal healt h t hr ough t he evaluat ion and super vision of medicines f or human and vet er inar y useNet wor king agency

Commit t ee f or Human Medicinal Pr oduct s

Exper t advice is pr ovided by Wor king Par t ies

Vaccine (VWP)

Biologics (BWP)

Safety (SWP)

Gene Ther apy (GTWP)

And several others

EU Gene t r ansf er guideline (Q, S & E) (2001)

- But DNA needs updat ing- esp. nonclincial and clinical aspects

- New guidance being developed (Q, S & E) by VWP

- CONCEPT PAPER on guidance f or DNA vaccines CHMP/308136/07

FDA Consider at ions f or Plasmid DNA Vaccines f or I nf ect ious Disease I ndicat ions 10/ 29/ 2007 (Q & S)

WHO Guidelines f or assur ing t he qualit y and nonclinical saf et y evaluat ion of DNA vaccines (2007)

Qualit ymanufacture and control of bulk purified plasmid and final formulated vaccine

NonclinicalDNA insertionImmunopathological reactionsAutoimmune reactionsRisks of genes encoding cyt okines or co-stimulatory moleculesUnwant ed biological act ivit yExpr ession of ot her gene sequences

http://www.who.int/biologicals/publications/trs/areas/vaccines/dna/ Annex%201_DNA%20vaccines.pdf

EU concept paper on t he development of a guideline on live recombinant vector vaccines

EMEA/ CHMP/ 308139/ 2007

Quality, nonclinical, clinical sections

Guideline out f or consult at ion, ~ spr ing 2009

WHO inf or mal consult at ion, December 2003

Char act er isat ion and qualit y aspect of vaccines based on live vir al vect or s

pre-existing (if any) and post-vaccinat ion immune response to the vector, might conceivably interfere with the ability of the construct to elicit the desired protective response against the foreign protein expressed. on the other hand there could conceivably be a positive benefit if there was an immune response to the vector, which would need to be considered as a secondary consideration for the overall vaccine product.

Extent and duration of vaccine shedding; potential for transmission of the live vaccine to contacts

Potential for reversion of the viral vector to virulence

Pot ent ial f or r ecombinat ion or r eassor t ment wit h wild type agents that might co-incidentally occur in vaccinees around the time of dosing

Genetic stability

Change of tropism of vector vaccine

I ncidence of specif ic AEs t hat might r ef lect dist r ibut ion of t he vect or t o specif ic body sit es

Potential for integration of genes derived from the vector into the host genome

Public acceptance?

Can be and ar e being met :

wit h a clear ly def ined r egulat or y pat hway

by car ef ul and t hor ough scient if ic evaluat ion

and by pr ovision of guidance f r om t hose exper ienced in t he f ield, including t hose developing such vaccines and r egulat or s wit h exper ience in vaccine r egulat ion