Lack of Protection Against Ebola Virus from Chloroquine in Mice and Hamsters - Volume 21, Number 6—June 2015 - Emerging Infectious Disease journal - CDC
Volume 21, Number 6—June 2015
Lack of Protection Against Ebola Virus from Chloroquine in Mice and Hamsters
Chloroquine was first used as an antimalarial drug until widespread resistance in Plasmodium falciparum strains emerged. However, for >30 years this drug also has been recognized as having broad-spectrum antiviral properties (1), including activity against HIV-1 (2); the human coronaviruses, severe acute respiratory syndrome coronavirus (3) and OC43 (4); dengue virus (5); chikungunya virus (6); and influenza virus (7) in cell culture. Despite these data, chloroquine is not approved for use against any viral infections.
Previous in vitro data state a half maximal effective concentration (EC50) and EC90 of 16 and 25 mol/L for chloroquine against Ebola virus (EBOV), respectively (8). Twice daily dosing at 90 mg/kg intraperitoneally rapidly achieved a steady-state concentration of 2.5 μg/mL in the blood of mice. This dosing regimen resulted in survival of 85% of mice after infection with mouse-adapted (MA) EBOV (8). These data have led to the suggestion that chloroquine and its derivatives be used in persons with EBOV infection because this drug is approved for use in humans, has an extensive safety profile, and is inexpensive (1,9). To determine whether protection would extend to the EBOV hamster model, during 2013–2014 we investigated chloroquine treatment in this model and attempted to repeat previous in vitro findings and findings in the mouse model.
Dr. Falzarano, a research scientist at the University of Saskatchewan, performed this work while a visiting fellow at Rocky Mountain Laboratories. His research interests include determining posttranslational modifications on EBOV glycoproteins and antiviral strategies for severe virus infections.
We thank the animal care technicians for maintaining the animals used in this study.
This study was performed in accordance with the recommendations described in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, the Office of Animal Welfare, and the US Department of Agriculture. The Institutional Animal Care and Use Committee at Rocky Mountain Laboratories (RML) approved animal work. RML is an American Association for Accreditation of Laboratory Animal Care–approved facility. Trained personnel carried out all procedures with the animals under isoflurane anesthesia. The Institutional Biosafety Committee at RML approved all work with infectious EBOV under biosafety level 4 conditions.
This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
- De Clercq E. Ebola virus (EBOV) infection: therapeutic strategies. Biochem Pharmacol. 2015;93:1–10 .
- Savarino A, Gennero L, Sperber K, Boelaert JR. The anti-HIV-1 activity of chloroquine. J Clin Virol. 2001;20:131–5 .
- Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun. 2004;323:264–8.
- Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J, Van Ranst M, Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother. 2009;53:3416–21.
- Farias KJ, Machado PR, de Almeida Junior RF, de Aquino AA, da Fonseca BA. Chloroquine interferes with dengue-2 virus replication in U937 cells.Microbiol Immunol. 2014;58:318–26.
- Delogu I, de Lamballerie X. Chikungunya disease and chloroquine treatment. J Med Virol. 2011;83:1058–9.
- Paton NI, Lee L, Xu Y, Ooi EE, Cheung YB, Archuleta S, Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial.[Erratum in: Lancet Infect Dis. 2011;11:655.]. Lancet Infect Dis. 2011;11:677–83.
- Madrid PB, Chopra S, Manger ID, Gilfillan L, Keepers TR, Shurtleff AC, A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS ONE. 2013;8:e60579.
- Bishop BM. Potential and emerging treatment options for Ebola virus disease. Ann Pharmacother. 2015;49:196–206.
- Marzi A, Ebihara H, Callison J, Groseth A, Williams KJ, Geisbert TW, Vesicular stomatitis virus–based Ebola vaccines with improved cross-protective efficacy. J Infect Dis. 2011;204(Suppl 3):S1066–74.
- Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J. A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. J Infect Dis. 1998;178:651–61.
- Ebihara H, Zivcec M, Gardner D, Falzarano D, LaCasse R, Rosenke R, A Syrian golden hamster model recapitulating Ebola hemorrhagic fever. J Infect Dis. 2013;207:306–18.
- Ebola haemorrhagic fever in Zaire, 1976. Bull World Health Organ. 1978;56:271–93 .
- Ebola haemorrhagic fever in Sudan, 1976. Report of a WHO/International Study Team. Bull World Health Organ. 1978;56:247–70 .
- Tricou V, Minh NN, Van TP, Lee SJ, Farrar J, Wills B, A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults.PLoS Negl Trop Dis. 2010;4:e785.
Suggested citation for this article: Falzarano D, Safronetz D, Prescott J, Marzi A, Feldmann F, Feldmann H. Lack of protection against Ebola virus from chloroquine in mice and hamsters. Emerg Infect Dis. 2015 Jun [date cited]. http://dx.doi.org/10.3201/eid2106.150176
1Current affiliation: University of Saskatchewan, Saskatoon, Saskatchewan, Canada.