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Assessment of Future Scientific Needs for Live Variola Virus (1999) / Chapter Skim
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6 Development of Antiviral Agents
Pages 47-52

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From page 47...
... Access to live variola virus would make it possible to test the activity of candidate antivirals in cell culture and could ultimately lead to the development of novel animal models systems for testing antivariola activity in vivo. It must be recognized however that neither of these preclinical approaches is able to substitute completely for trials conducted in infected patients.
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From page 48...
... Since single amino acid changes can have dramatic effects on the potency and specificity of antiviral agents, it is imperative that authentic target proteins be tested. Authentication of the target protein includes sequence analysis of the corresponding DNA from several clinical isolates.
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From page 49...
... In particular, such genetically engineered host cell lines are not necessarily representative of cells infected by the virus in viva. It is therefore essential that candidate agents be tested for activity and potency in a tissue culture assay employing clinical isolates of variola virus and recently isolated human cells to ascertain whether equivalent potency is obtained in the surrogate system.
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From page 50...
... Regimens of increasing single and multiple doses are used to determine drug absorption and duration, tolerance, and maximum tolerated dose. The ICY determined in vitro using live variola virus and cultured human host cells as described above would be used, along with observed blood and tissue levels of antiviral agent in test animals, to design a dose-ranging study aimed at determining safety and tolerability in humans under an approved investigational new drug (IND)
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From page 51...
... Food and Drug Administration should be active in the development of such drugs for use in emergencies. :~ ~ ~ :~:~:~ :~::: :~ B, ~ ~ ~ ~ :: : ~:~ :::: i :; -it I: ~:An~:lm:a: ~ vl-oc be so ~:~;:~;: :~:~::~:~: There:: have :~b~een seYera:l :atte~mpts::~:to develop suitable :animal~:~model~s~ fit ~ study variola~virus infedtion~.~:~Primates~ Used have included Cynomolg;us::~mon ;:~:~-keys~ ;~-(Macaca~:~:im¢)
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Key Terms

  • antiviral agents
  • cell culture
  • target protein
  • animal model
  • antiviral agent

  • culture assays
  • animal models
  • live variola
  • host cells
  • orthopoxvirus family

  • model studies
  • cultured cells
  • variola infection
  • virus infection
  • live virus

  • host cell
  • genetically engineered
  • human cells
  • preclinical opportunity
  • candidate antivirals

  • tissue culture
  • antivariola activity
  • study variola
  • assays provide
  • clinical isolates

  • inhibit replication
  • primary screening
  • complex setting
  • candidate agents
  • equivalent potency


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