5 research outputs found
Use of Comprehensive Two-Dimensional Gas Chromatography with Time-of-Flight Mass Spectrometric Detection and Random Forest Pattern Recognition Techniques for Classifying Chemical Threat Agents and Detecting Chemical Attribution Signatures
In
this proof of concept study, chemical threat agent (CTA) samples
were classified to their sources with accuracies of 87–100%
by applying a random forest statistical pattern recognition technique
to analytical data acquired by comprehensive two-dimensional gas chromatography
with time-of-flight mass spectrometric detection (GC × GC-TOFMS).
Three organophosphate pesticides, chlorpyrifos, dichlorvos, and dicrotophos,
were used as the model CTAs, with data collected for 4–6 sources
per CTA and 7–10 replicate analyses per source. The analytical
data were also evaluated to determine tentatively identified chemical
attribution signatures for the CTAs by comparing samples from different
sources according to either the presence/absence of peaks or the relative
responses of peaks. These results demonstrate that GC × GC-TOFMS
analysis in combination with a random forest technique can be useful
in sample classification and signature identification for pesticides.
Furthermore, the results suggest that this combination of analytical
chemistry and statistical approaches can be applied to forensic analysis
of other chemicals for similar purposes
Immune Correlates of Protection from Filovirus Efficacy Studies in Non-Human Primates
Non-human primate (NHP) efficacy data for several Ebola virus (EBOV) vaccine candidates exist, but definitive correlates of protection (CoP) have not been demonstrated, although antibodies to the filovirus glycoprotein (GP) antigen and other immunological endpoints have been proposed as potential CoPs. Accordingly, studies that could elucidate biomarker(s) that statistically correlate, whether mechanistically or not, with protection are warranted. The primary objective of this study was to evaluate potential CoP for Novavax EBOV GP vaccine candidate administered at different doses to cynomolgus macaques using the combined data from two separate, related studies containing a total of 44 cynomolgus macaques. Neutralizing antibodies measured by pseudovirion neutralization assay (PsVNA) and anti-GP IgG binding antibodies were evaluated as potential CoP using logistic regression models. The predictive ability of these models was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). Fitted models indicated a statistically significant relationship between survival and log base 10 (log10) transformed anti-GP IgG antibodies, with good predictive ability of the model. Neither (log10 transformed) PsVNT50 nor PsVNT80 titers were statistically significant predictors of survival, though predictive ability of both models was good. Predictive ability was not statistically different between any pair of models. Models that included immunization dose in addition to anti-GP IgG antibodies failed to detect statistically significant effects of immunization dose. These results support anti-GP IgG antibodies as a correlate of protection. Total assay variabilities and geometric coefficients of variation (GCVs) based on the study data appeared to be greater for both PsVNA readouts, suggesting the increased assay variability may account for non-significant model results for PsVNA despite the good predictive ability of the models. The statistical approach to evaluating CoP for this EBOV vaccine may prove useful for advancing research for Sudan virus (SUDV) and Marburg virus (MARV) candidate vaccines
Ceftobiprole Medocaril Is an Effective Post-Exposure Treatment in the Fischer 344 Rat Model of Pneumonic Tularemia
Francisella tularensis subspecies tularensis is a category-A biothreat agent that can cause lethal tularemia. Ceftobiprole medocaril is being explored as a medical countermeasure for the treatment of pneumonic tularemia. The efficacy of ceftobiprole medocaril against inhalational tularemia was evaluated in the Fischer 344 rat model of infection. The dose was expected to be effective against F. tularensis isolates with ceftobiprole minimum inhibitory concentrations ≤0.5 µg/mL. Animals treated with ceftobiprole medocaril exhibited a 92% survival rate 31 days post-challenge, identical to the survival of levofloxacin-treated rats. By comparison, rats receiving placebo experienced 100% mortality. Terminally collected blood, liver, lung, and spleen samples confirmed disseminated F. tularensis infections in most animals that died prior to completing treatments (placebo animals and a rat treated with ceftobiprole medocaril), although levels of bacteria detected in the placebo samples were significantly elevated compared to the ceftobiprole-medocaril-treated group geometric mean. Furthermore, no evidence of infection was detected in any rat that completed ceftobiprole medocaril or levofloxacin treatment and survived to the end of the post-treatment observation period. Overall, survival rates, body weights, and bacterial burdens consistently demonstrated that treatment with ceftobiprole medocaril is efficacious against otherwise fatal cases of pneumonic tularemia in the rat model