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Ebola virus (EBOV) causes severe disease in humans, with mortality as high as 90%. The small-molecule antiviral drug remdesivir (RDV) has demonstrated a survival benefit in EBOV-exposed rhesus macaques. Here, we characterize the efficacy of multiple intravenous RDV dosing regimens on survival of rhesus macaques 42 days after intramuscular EBOV exposure. Thirty rhesus macaques underwent surgical implantation of telemetry devices for the fine-scale monitoring of body temperature and activity, as well as central venous catheters, to enable treatment administration and blood collection. Treatment, consisting of a loading dose of RDV followed by once-daily maintenance doses for 11 days, was initiated 4 days after virus exposure when all animals were exhibiting disease signs consistent with incipient EBOV disease as well as quantifiable levels of EBOV RNA in plasma. In the RDV treatment groups receiving loading/maintenance doses of 5/2.5 mg/kg, 10/5 mg/kg, and 20/10 mg/kg, a total of 6 of 8 (75%), 7 of 8 (87.5%), and 5 of 7 (71.4%) animals survived, respectively. In the vehicle control group, one of seven animals (14.3%) survived. The improved survival rate compared to the control group was statistically significant only for the 10/5 mg/kg RDV treatment group. This treatment regimen also resulted in a significantly lower systemic viral load compared to the vehicle control after a single RDV treatment. All three RDV regimens produced a significantly lower systemic viral load after two treatments. For most animals, RDV treatment, regardless of dose, resulted in the amelioration of many of the clinical–pathological changes associated with EBOV disease in this model. [ABSTRACT FROM AUTHOR]

Laboratory animals are commonly anesthetized to prevent pain and distress and to provide safe handling. Anesthesia procedures are well-developed for common laboratory mammals, but not as well established in reptiles. We assessed the performance of intramuscularly injected tiletamine (dissociative anesthetic) and zolazepam (benzodiazepine sedative) in fixed combination (2 mg/kg and 3 mg/kg) in comparison to 2 mg/kg of midazolam (benzodiazepine sedative) in ball pythons (Python regius). We measured heart and respiratory rates and quantified induction parameters (i.e., time to loss of righting reflex, time to loss of withdrawal reflex) and recovery parameters (i.e., time to regain righting reflex, withdrawal reflex, normal behavior). Mild decreases in heart and respiratory rates (median decrease of

Members of the family Filoviridae include Ebola virus (EBOV), Marburg virus (MARV), Ravn virus (RAVV), Sudan virus (SUDV) and Bundibugyo virus (BDBV), all of which cause severe viral haemorrhagic fevers [...], Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.

Ebola viruses and Marburg viruses are highly virulent emerging pathogens of the family Filoviridae and are causative agents of viral hemorrhagic fever (VHF). Nonhuman primate infection models closely reproduce the [...], Currently, no vaccines or therapeutics are licensed to counter Ebola or Marburg viruses, highly pathogenic filoviruses that are causative agents of viral hemorrhagic fever. Here we show that administration of positively charged phosphorodiamidate morpholino oligomers (PMOplus), delivered by various dosing strategies initiated 30-60 min after infection, protects >60% of rhesus monkeys against lethal Zaire Ebola virus (ZEBOV) and 100% of cynomolgus monkeys against Lake Victoria Marburg virus (MARV) infection. PMOplus may be useful for treating these and other highly pathogenic viruses in humans.

The recent outbreaks of Ebolavirus (EBOV) in West Africa underscore the urgent need to develop an effective EBOV vaccine. Here, we report the development of synthetic nanoparticles as a safe and highly immunogenic platform for vaccination against EBOV. We show that a large recombinant EBOV antigen (rGP) can be incorporated in a configurational manner into lipid-based nanoparticles, termed interbilayer-crosslinked multilamellar vesicles (ICMVs). The epitopes and quaternary structure of rGP were properly maintained on the surfaces of ICMVs formed either with or without nickel nitrilotriacetic acid (NTA)-functionalized lipids. When administered in mice, rGP-ICMVs without NTA-lipids efficiently generated germinal center B cells and polyfunctional T cells while eliciting robust neutralizing antibody responses. This study suggests the potential of vaccine nanoparticles as a delivery platform for configurational, multivalent display of large subunit antigens and induction of neutralizing antibody and T cell responses., (Copyright © 2018 Elsevier Inc. All rights reserved.)