The US Food and Drug Administration's Animal Rule was established to facilitate licensure of new products for life-threatening conditions when traditional efficacy trials in humans are unethical or ...impractical. In November, 2015 BioThrax became the first vaccine to receive approval for a new indication via this pathway. The basis for this approval and use of Animal Rule or other non-traditional approval pathways for licensure of vaccines for serious conditions are discussed.
The 2014 Ebolavirus outbreak in West Africa highlighted the need for vaccines and therapeutics to prevent and treat filovirus infections. A well-characterized small animal model that is susceptible ...to wild-type filoviruses would facilitate the screening of anti-filovirus agents. To that end, we characterized knockout mice lacking α/β and γ interferon receptors (IFNAGR KO) as a model for wild-type filovirus infection. Intraperitoneal challenge of IFNAGR KO mice with several known human pathogenic species from the genus Ebolavirus and Marburgvirus, except Bundibugyo ebolavirus and Taï Forest ebolavirus, caused variable mortality rate. Further characterization of the prototype Ebola virus Kikwit isolate infection in this KO mouse model showed 100% lethality down to a dilution equivalent to 1.0 × 10
pfu with all deaths occurring between 7 and 9 days post-challenge. Viral RNA was detectable in serum after challenge with 1.0 × 10² pfu as early as one day after infection. Changes in hematology and serum chemistry became pronounced as the disease progressed and mirrored the histological changes in the spleen and liver that were also consistent with those described for patients with Ebola virus disease. In a proof-of-principle study, treatment of Ebola virus infected IFNAGR KO mice with favipiravir resulted in 83% protection. Taken together, the data suggest that IFNAGR KO mice may be a useful model for early screening of anti-filovirus medical countermeasures.
Recent studies have shown the domestic ferret (
) to be a promising small animal model for the study of Ebola virus (EBOV) disease and medical countermeasure evaluation. To date, most studies have ...focused on traditional challenge routes, predominantly intramuscular and intranasal administration. Here, we present results from a non-clinical pathogenicity study examining oronasal, oral, and ocular mucosal challenge routes in ferrets. Animals were challenged with 1, 10, or 100 plaque forming units EBOV followed by monitoring of disease progression and biosampling. Ferrets administered virus via oronasal and oral routes met euthanasia criteria due to advanced disease 5-10 days post-challenge. Conversely, all ferrets dosed via the ocular route survived until the scheduled study termination 28-day post-challenge. In animals that succumbed to disease, a dose/route response was not observed; increases in disease severity, febrile responses, serum and tissue viral load, alterations in clinical pathology, and gross/histopathology findings were similar between subjects. Disease progression in ferrets challenged via ocular administration was unremarkable throughout the study period. Results from this study further support the ferret as a model for EBOV disease following oral and nasal mucosa exposure.
Immune response among patients exposed to molds Edmondson, David A; Barrios, Christy S; Brasel, Trevor L ...
International journal of molecular sciences,
12/2009, Volume:
10, Issue:
12
Journal Article
Peer reviewed
Open access
Macrocyclic trichothecenes, mycotoxins produced by Stachybotrys chartarum, have been implicated in adverse reactions in individuals exposed to mold-contaminated environments. Cellular and humoral ...immune responses and the presence of trichothecenes were evaluated in patients with mold-related health complaints. Patients underwent history, physical examination, skin prick/puncture tests with mold extracts, immunological evaluations and their sera were analyzed for trichothecenes. T-cell proliferation, macrocyclic trichothecenes, and mold specific IgG and IgA levels were not significantly different than controls; however 70% of the patients had positive skin tests to molds. Thus, IgE mediated or other non-immune mechanisms could be the cause of their symptoms.
(EBOV) causes Ebola virus disease (EVD), a devastating viral hemorrhagic fever in humans. Nonhuman primate (NHP) models of EVD traditionally use intramuscular infection with higher case fatality ...rates and reduced mean time-to-death compared to contact transmission typical of human cases of EVD. A cynomolgus macaque model of oral and conjunctival EBOV was used to further characterize the more clinically relevant contact transmission of EVD. NHPs challenged via the oral route had an overall 50% survival rate. NHPs challenged with a target dose of 1 × 10
PFU or 1 × 10
PFU of EBOV via the conjunctival route had 40% and 100% mortality, respectively. Classic signs of lethal EVD-like disease were observed in all NHPs that succumbed to EBOV infection including viremia, hematological abnormalities, clinical chemistries indicative of hepatic and renal disease, and histopathological findings. Evidence of EBOV viral persistence in the eye was observed in NHPs challenged via the conjunctival route.
This study is the first to examine the Kikwit strain of EBOV, the most commonly used strain, in the gold-standard macaque model of infection. Additionally, this is the first description of the detection of virus in the vitreous fluid, an immune privileged site that has been proposed as a viral reservoir, following conjunctival challenge. The oral and conjunctival macaque challenge model of EVD described here more faithfully recapitulates the prodrome that has been reported for human EVD. This work paves the way for more advanced studies to model contact transmission of EVD, including early events in mucosal infection and immunity, as well as the establishment of persistent viral infection and the emergence from these reservoirs.
Molnupiravir (EIDD-2801) is a prodrug of a ribonucleoside analogue that is currently being used under a US FDA emergency use authorization for the treatment of mild to moderate COVID-19. We evaluated ...molnupiravir for efficacy as an oral treatment in the rhesus macaque model of SARS-CoV-2 infection. Twenty non-human primates (NHPs) were challenged with SARS-CoV-2 and treated with 75 mg/kg (n = 8) or 250 mg/kg (n = 8) of molnupiravir twice daily by oral gavage for 7 days. The NHPs were observed for 14 days post-challenge and monitored for clinical signs of disease. After challenge, all groups showed a trend toward increased respiration rates. Treatment with molnupiravir significantly reduced viral RNA levels in bronchoalveolar lavage (BAL) samples at Days 7 and 10. Considering the mild to moderate nature of SARS-CoV-2 infection in the rhesus macaque model, this study highlights the importance of monitoring the viral load in the lung as an indicator of pharmaceutical efficacy for COVID-19 treatments. Additionally, this study provides evidence of the efficacy of molnupiravir which supplements the current ongoing clinical trials of this drug.
Although SARS-CoV-2-neutralizing antibodies are promising therapeutics against COVID-19, little is known about their mechanism(s) of action or effective dosing windows. We report the generation and ...development of SC31, a potent SARS-CoV-2 neutralizing antibody, isolated from a convalescent patient. Antibody-mediated neutralization occurs via an epitope within the receptor-binding domain of the SARS-CoV-2 Spike protein. SC31 exhibited potent anti-SARS-CoV-2 activities in multiple animal models. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, treatment with SC31 greatly reduced viral loads and attenuated pro-inflammatory responses linked to the severity of COVID-19. Importantly, a comparison of the efficacies of SC31 and its Fc-null LALA variant revealed that the optimal therapeutic efficacy of SC31 requires Fc-mediated effector functions that promote IFNγ-driven anti-viral immune responses, in addition to its neutralization ability. A dose-dependent efficacy of SC31 was observed down to 5mg/kg when administered before viral-induced lung inflammatory responses. In addition, antibody-dependent enhancement was not observed even when infected mice were treated with SC31 at sub-therapeutic doses. In SARS-CoV-2-infected hamsters, SC31 treatment significantly prevented weight loss, reduced viral loads, and attenuated the histopathology of the lungs. In rhesus macaques, the therapeutic potential of SC31 was evidenced through the reduction of viral loads in both upper and lower respiratory tracts to undetectable levels. Together, the results of our preclinical studies demonstrated the therapeutic efficacy of SC31 in three different models and its potential as a COVID-19 therapeutic candidate.
The unprecedented magnitude of the 2013–2016 Ebola virus (EBOV) epidemic in West Africa resulted in over 11 000 deaths and spurred an international public health emergency. A second outbreak in ...2018–2020 in DRC resulted in an additional >3400 cases and nearly 2300 deaths (WHO, 2020). These large outbreaks across geographically diverse regions highlight the need for the development of effective oral therapeutic agents that can be easily distributed for self-administration to populations with active disease or at risk of infection. Herein, we report the in vivo efficacy of N4-hydroxycytidine (EIDD-1931), a broadly active ribonucleoside analog and the active metabolite of the prodrug EIDD-2801 (molnupiravir), in murine models of lethal EBOV infection. Twice daily oral dosing with EIDD-1931 at 200 mg/kg for 7 days, initiated either with a prophylactic dose 2 h before infection, or as therapeutic treatment starting 6 h post-infection, resulted in 92–100% survival of mice challenged with lethal doses of EBOV, reduced clinical signs of Ebola virus disease (EVD), reduced serum virus titers, and facilitated weight loss recovery. These results support further investigation of molnupiravir as a potential therapeutic or prophylactic treatment for EVD.
•EIDD-1931 is a broadly active ribonucleoside analog and the active metabolite of the prodrug molnupiravir.•In vivo efficacy of EIDD-1931 was tested in a mouse model of lethal Ebola virus disease.•Twice daily oral dosing with EIDD-1931 protected mice challenged with 3000–7500 LD50 doses of EBOV.•The successful treatment initiated either prophylactically or therapeutically starting 6 h post-infection.
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