Passive Immunotherapies Protect WRvFire and IHD-J-Luc Vaccinia Virus-Infected Mice from Lethality by Reducing Viral Loads in the Upper Respiratory Tract and Internal Organs

Abstract

Whole-body bioimaging was employed to study the effects of passive immunotherapies on lethality and viral dissemination in BALB/c mice challenged with recombinant vaccinia viruses expressing luciferase. WRvFire and IHD-J-Luc vaccinia viruses induced lethality with similar times to death following intranasal infection, but WRvFire replicated at higher levels than IHD-J-Luc in the upper and lower respiratory tracts. Three types of therapies were tested: licensed human anti-vaccinia virus immunoglobulin intravenous (VIGIV); recombinant anti-vaccinia virus immunoglobulin (rVIG; Symphogen, Denmark), an investigational product containing a mixture of 26 human monoclonal antibodies (HuMAbs) against mature virion (MV) and enveloped virion (EV); and HuMAb compositions targeting subsets of MV or EV proteins. Bioluminescence recorded daily showed that pretreatment with VIGIV (30 mg) or with rVIG (100 g) on day ؊2 protected mice from death but did not prevent viral replication at the site of inoculation and dissemination to internal organs. Compositions containing HuMAbs against MV or EV proteins were protective in both infection models at 100 g per animal, but at 30 g, only anti-EV antibodies conferred protection. Importantly, the t statistic of the mean total fluxes revealed that viral loads in surviving mice were significantly reduced in at least 3 sites for 3 consecutive days (days 3 to 5) postchallenge, while significant reduction for 1 or 2 days in any individual site did not confer protection. Our data suggest that reduction of viral replication at multiple sites, including respiratory tract, spleen, and liver, as monitored by whole-body bioluminescence can be used to predict the effectiveness of passive immunotherapies in mouse models.

Effects of Postchallenge Administration of ST-246 on Dissemination of IHD-J-Luc Vaccinia Virus in Normal Mice and in Immune-Deficient Mice Reconstituted with T Cells

“…The luciferase gene (under the control of the synthetic E/L promoter) was inserted at a truncated host range gene locus equivalent to the cowpox gene, CPX077. Details of the construction and characterization of sucrose gradient purified IHD-J-Luc were previously described (19,20; C. Meseda et al, unpublished data). BSC-1 cells were infected with IHDJLuc, and the titer of viral stock was determined using BSC-40 cells.…”

“…Previous publications and studies in our laboratory have shown that whole-body bioimaging provides an advantage over more traditional methods for assessing the effectiveness of vaccines and immunoglobulin-based treatments using mouse models of respiratory VACV infection (17)(18)(19)(20). In the present study, we used bioimaging and statistical analysis of viral loads calculated as the area under the flux curve (AUC) to further define mechanisms of protection from lethal challenge conferred by ST-246 in normal and in immune-deficient mice.…”

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

“…Previous publications including data from our laboratory have shown that whole-body bioluminescence imaging (BLI) provides an advantage over more traditional methods for assessing the effectiveness of vaccines and immunoglobulin-based treatments in mouse models of respiratory challenge with VACV (25)(26)(27)(28)(29). In the current study, we explored the effects of brincidofovir on protection of normal and immune-deficient mice from lethality following intranasal challenge with IHD-J-Luc VACV.…”

Application of Bioluminescence Imaging (BLI) to the Study of the Animal Models of Human Infectious Diseases

“…9.6a-e ) or with IHD-J-Luc VACV (Fig. 9.6f-j ) (Zaitseva et al 2011 ). All control mice died within 1 week (Fig.…”

“…It suggested that innate immune receptors play a major role in limiting in-host dissemination of VACV (Hutchens et al 2008 ). In our laboratory, BLI was extensively used to evaluate effects of anti-smallpox vaccine and antiviral treatments on dissemination of two strains of recombinant VACV expressing luciferase, WRvFire, and IHD-J-Luc, and the results of these studies are summarized at the end of this chapter (Zaitseva et al 2009(Zaitseva et al , 2011.…”