Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys.
BACKGROUND
Infection with the Ebola virus induces overexpression of the procoagulant tissue factor in primate monocytes and macrophages, suggesting that inhibition of the tissue-factor pathway could ameliorate the effects of Ebola haemorrhagic fever. Here, we tested the notion that blockade of fVIIa/tissue factor is beneficial after infection with Ebola virus.


METHODS
We used a rhesus macaque model of Ebola haemorrhagic fever, which produces near 100% mortality. We administered recombinant nematode anticoagulant protein c2 (rNAPc2), a potent inhibitor of tissue factor-initiated blood coagulation, to the macaques either 10 min (n=6) or 24 h (n=3) after a high-dose lethal injection of Ebola virus. Three animals served as untreated Ebola virus-positive controls. Historical controls were also used in some analyses.


RESULTS
Both treatment regimens prolonged survival time, with a 33% survival rate in each treatment group. Survivors are still alive and healthy after 9 months. All but one of the 17 controls died. The mean survival for the six rNAPc2-treated macaques that died was 11.7 days compared with 8.3 days for untreated controls (p=0.0184). rNAPc2 attenuated the coagulation response as evidenced by modulation of various important coagulation factors, including plasma D dimers, which were reduced in nearly all treated animals; less prominent fibrin deposits and intravascular thromboemboli were observed in tissues of some animals that succumbed to Ebola virus. Furthermore, rNAPc2 attenuated the proinflammatory response with lower plasma concentrations of interleukin 6 and monocyte chemoattractant protein-1 (MCP-1) noted in the treated than in the untreated macaques.


CONCLUSIONS
Post-exposure protection with rNAPc2 against Ebola virus in primates provides a new foundation for therapeutic regimens that target the disease process rather than viral replication.
Geisbert
Thomas W
TW
Virology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA. tom.geisbert@amedd.army.mil
Hensley
Lisa E
LE
Jahrling
Peter B
PB
Larsen
Tom
T
Geisbert
Joan B
JB
Paragas
Jason
J
Young
Howard A
HA
Fredeking
Terry M
TM
Rote
William E
WE
Vlasuk
George P
GP
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D029043:Ebolavirus / Q000187:drug effects / Q000276:immunology; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D015801:Helminth Proteins / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D008253:Macaca mulatta; D011994:Recombinant Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D015996:Survival Rate; D013925:Thromboplastin / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
D015801:Helminth Proteins; D011994:Recombinant Proteins; C400226:anti-coagulant protein C2, Ancylostoma caninum; D013925:Thromboplastin; D015942:Factor VIIa