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

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

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.

Biodistribution of Cerepro after I V adm inistration Mean DNA Vect or Measurement s in t he high Dose IV group 900000 Mean Vector DNA m easurem ents Urine 800000 blood 700000 spleen (copies/ ug DNA) liver 600000 kidneys 500000 Test is 400000 Ovaries 300000 heart lungs 200000 lymph node 100000 brain 0 Day 3 Day 30 Day 60 Day 90 Time (Days)

Biodistribution of Cerepro after I C adm inistration Mean Vect or DNA Measurement s in t he high dose IC group 4000 Mean Vector DNA m easurem ents Urine 3500 blood spleen 3000 (copies/ ug DNA) liver 2500 kidneys Test is 2000 Ovaries 1500 heart 1000 lungs lymph node 500 brain 0 Day 3 Day 30 Day 60 Day 90 Time (days)

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 • oral 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