Virus Shedding Dr David Eckland MB, PhD, FRCP Director of Research - - PowerPoint PPT Presentation

Virus Shedding

Dr David Eckland MB, PhD, FRCP Director of Research and Developm ent Ark Therapeutics Ltd

Excretion of virus from the infected host by any route W hat is shedding?

Medical Microbiology, S. Baron, U of Texas

• Do w e consider every conceivable route of

shedding?

• No, only those likely to result in potential

infection

• Are w e equally w orried about every

vector?

• No – Adenovirus vs Lentivirus vs AAV vs

Baculovirus

W hat are the m ajor factors that should inform how m uch shedding w ork w e undertake?

• W hat is the likelihood that it could be

transm itted to other people? I f im portant then,

• W hat is the likelihood that it constitutes a

hazard?

Factors to take into account

• Pathogenicity of virus
• Nature of virus ( integrating, replication

com petent)

• Nature of construct
• Mode of adm inistration
• Potential for, and consequence of

recom bination.

Mean DNA Vect or Measurement s in t he high Dose IV group

100000 200000 300000 400000 500000 600000 700000 800000 900000 Day 3 Day 30 Day 60 Day 90

Time (Days) Mean Vector DNA m easurem ents (copies/ ug DNA) Urine blood spleen liver kidneys Test is Ovaries heart lungs lymph node brain

Biodistribution of Cerepro after I V adm inistration

Mean Vect or DNA Measurement s in t he high dose IC group

500 1000 1500 2000 2500 3000 3500 4000 Day 3 Day 30 Day 60 Day 90

Time (days) Mean Vector DNA m easurem ents (copies/ ug DNA) Urine blood spleen liver kidneys Test is Ovaries heart lungs lymph node brain

Biodistribution of Cerepro after I C adm inistration

Hum an biodistribution after I C adm inistration Barely detected in blood or throat sw abs However, requirements for shedding information in clinical trials varies by country.

• Throat swabs/ no swabs
• Isolation of patient until shedding negative

Consistent approach across Europe w ould be beneficial

Translation of findings from anim al to m an

• Know ledge of the vector
• Potential toxicity of the construct
• Route of adm inistration
• Route of excretion/ shedding
• I m pact on the potentially exposed

Risk assessm ent is the appropriate approach to assessing shedding in m an

Analogy

• The vector is present to deliver a

therapeutic gene to a desired target

• I t encapsulates the relevant gene
• I n m any respects it is analogous to an
• ral capsule delivering a sm all m olecule
• At least adenoviral vectors could be

considered safe from a pharm acopoeia perspective, as long as the structural proteins are unchanged