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J Virol 2015 Jan 14 [Epub ahead of print]

Post-challenge administration of Brincidofovir protects normal and immune-deficient mice reconstituted with limited numbers of T cells from lethal challenge with IHD-J-Luc vaccinia virus.

Zaitseva M, McCullough KT, Cruz S, Thomas A, Diaz CG, Keilholz L, Grossi IM, Trost LC, Golding H

Abstract

Protection from lethality by post-challenge administration of brincidofovir (BCV, CMX001) was studied in normal and immune-deficient (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 105 pfu of recombinant IHD-J-Luc VACV expressing luciferase. Areas Under the flux Curve (AUC) were calculated for individual mice to assess viral loads. A 3 dose regimen of 20 mg/kg BCV administered every 48 hours starting either on Day 1 or Day 2 post-challenge protected 100% of mice. Initiating BCV treatment earlier was more efficient in reducing viral loads and in protecting from pox lesion development. All BCV-treated mice that survived challenge were also protected from re-challenge with IHD-J-Luc or WRvFire VACV without additional treatment. In immune-deficient mice, BCV protected animals from lethality and reduced viral loads while on drug. Viral recrudescence occurred within 4-9 days and mice succumbed ~10-20 days after treatment termination. Nude mice reconstituted with 105 T cells prior to challenge with 104 pfu of IHD-J-Luc and treated with BCV post-challenge survived the infection, cleared the virus from all organs, and survived re-challenge with 105 pfu of IHD-J-Luc VACV without additional BCV treatment. Together, these data suggest that BCV protects immune competent 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. IMPORTANCE: 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. Post-challenge 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 re-challenge 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.


Category: Journal Article
PubMed ID: #25589648 DOI: 10.1128/JVI.03340-14
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2014-11-17 Entry Last Modified: 2015-01-16
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