Ebola virus-induced eye sequelae: a murine model for evaluating glycoprotein-targeting therapeuticsResearch in context
Ha-Na Lee,
Biying Xu,
Aaron P. Lewkowicz,
Kaliroi Engel,
Logan Kelley-Baker,
Ian L. McWilliams,
Derek D.C. Ireland,
Jennifer L. Kielczewski,
Jinbo Li,
Robert N. Fariss,
Mercedes M. Campos,
Alina Baum,
Christos Kyratsous,
Kristen Pascal,
Chi-Chao Chan,
Rachel R. Caspi,
Mohanraj Manangeeswaran,
Daniela Verthelyi
Affiliations
Ha-Na Lee
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Biying Xu
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Aaron P. Lewkowicz
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Kaliroi Engel
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Logan Kelley-Baker
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Ian L. McWilliams
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Derek D.C. Ireland
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Jennifer L. Kielczewski
Biological Imaging Core, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Jinbo Li
Biological Imaging Core, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Robert N. Fariss
Biological Imaging Core, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Mercedes M. Campos
Biological Imaging Core, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Alina Baum
Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA
Christos Kyratsous
Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA
Kristen Pascal
Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA
Chi-Chao Chan
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Rachel R. Caspi
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Mohanraj Manangeeswaran
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Daniela Verthelyi
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA; Corresponding author.
Summary: Background: Ebola virus disease (EVD) survivors experience ocular sequelae including retinal lesions, cataracts, and vision loss. While monoclonal antibodies targeting the Ebola virus glycoprotein (EBOV-GP) have shown promise in improving prognosis, their effectiveness in mitigating ocular sequelae remains uncertain. Methods: We developed and characterized a BSL-2-compatible immunocompetent mouse model to evaluate therapeutics targeting EBOV-GP by inoculating neonatal mice with vesicular stomatitis virus expressing EBOV-GP (VSV-EBOV). To examine the impact of anti-EBOV-GP antibody treatment on acute retinitis and ocular sequelae, VSV-EBOV-infected mice were treated with polyclonal antibodies or monoclonal antibody preparations with antibody-dependent cellular cytotoxicity (ADCC-mAb) or neutralizing activity (NEUT-mAb). Findings: Treatment with all anti-EBOV-GP antibodies tested dramatically reduced viremia and improved survival. Further, all treatments reduced the incidence of cataracts. However, NEUT-mAb alone or in combination with ADCC-mAb reduced viral load in the eyes, downregulated the ocular immune and inflammatory responses, and minimized retinal damage more effectively. Interpretation: Anti-EBOV-GP antibodies can improve survival among EVD patients, but improved therapeutics are needed to reduce life altering sequelae. This animal model offers a new platform to examine the acute and long-term effect of the virus in the eye and the relative impact of therapeutic candidates targeting EBOV-GP. Results indicate that even antibodies that improve systemic viral clearance and survival can differ in their capacity to reduce acute ocular inflammation, and long-term retinal pathology and corneal degeneration. Funding: This study was partly supported by Postgraduate Research Fellowship Awards from ORISE through an interagency agreement between the US DOE and the US FDA.
