title: Postchallenge administration of brincidofovir protects healthy and immune-deficient mice reconstituted with limited numbers of T cells from lethal challenge with IHD-J-Luc vaccinia virus.
abstract: Protection from lethality by postchallenge administration of brincidofovir (BCV, CMX001) was studied in normal and immune-deficient (nude, nu/nu) BALB/c mice infected with vaccinia virus (VACV). Whole-body bioluminescence imaging was used to record total fluxes in the nasal cavity, lungs, spleen, and liver and to enumerate pox lesions on tails of mice infected via the intranasal route with 10(5) PFU of recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve (AUCs) were calculated for individual mice to assess viral loads. A three-dose regimen of 20 mg/kg BCV administered every 48 h starting either on day 1 or day 2 postchallenge protected 100% of mice. Initiating BCV treatment earlier was more efficient in reducing viral loads and in providing protection from pox lesion development. All BCV-treated mice that survived challenge were also protected from rechallenge with IHD-J-Luc or WRvFire VACV without additional treatment. In immune-deficient mice, BCV protected animals from lethality and reduced viral loads while animals were on the drug. Viral recrudescence occurred within 4 to 9 days, and mice succumbed ∼10 to 20 days after treatment termination. Nude mice reconstituted with 10(5) T cells prior to challenge with 10(4) PFU of IHD-J-Luc and treated with BCV postchallenge survived the infection, cleared the virus from all organs, and survived rechallenge with 10(5) PFU of IHD-J-Luc VACV without additional BCV treatment. Together, these data suggest that BCV protects immunocompetent and partially T cell-reconstituted immune-deficient mice from lethality, reduces viral dissemination in organs, prevents pox lesion development, and permits generation of VACV-specific memory.
  
  
  OBJECTIVE
  Mass vaccination is the primary element of the public health response to a smallpox outbreak. In addition to vaccination, however, antiviral drugs are required for individuals with uncertain exposure status to smallpox or for whom vaccination is contraindicated. Whole-body bioluminescence imaging was used to study the effect of brincidofovir (BCV) in normal and immune-deficient (nu/nu) mice infected with vaccinia virus, a model of smallpox. Postchallenge administration of 20 mg/kg BCV rescued normal and immune-deficient mice partially reconstituted with T cells from lethality and significantly reduced viral loads in organs. All BCV-treated mice that survived infection were protected from rechallenge without additional treatment. In immune-deficient mice, BCV extended survival. The data show that BCV controls viral replication at the site of challenge and reduces viral dissemination to internal organs, thus providing a shield for the developing adaptive immunity that clears the host of virus and builds virus-specific immunological memory.
authors.affiliation: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA marina.zaitseva@fda.hhs.gov.
authors.forename: Marina
authors.initials: M
authors.lastname: Zaitseva
authors.affiliation: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Kevin Tyler
authors.initials: KT
authors.lastname: McCullough
authors.affiliation: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cruz
authors.affiliation: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Veterinary Services, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Diaz
authors.affiliation: Chimerix, Inc., Durham, North Carolina, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Keilholz
authors.affiliation: Chimerix, Inc., Durham, North Carolina, USA.
authors.forename: Irma M
authors.initials: IM
authors.lastname: Grossi
authors.affiliation: Chimerix, Inc., Durham, North Carolina, USA.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Trost
authors.affiliation: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Hana
authors.initials: H
authors.lastname: Golding
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D063065:Organophosphonates / Q000008:administration & dosage*; D020011:Protective Agents / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D014615:Vaccinia / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000821:virology; D014616:Vaccinia virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019562:Viral Load / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D020011:Protective Agents; C525733:brincidofovir; D003596:Cytosine; D008156:Luciferases