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Ebola virus-induced eye sequelae: a murine model for evaluating glycoprotein-targeting therapeutics
Ha-Na Lee1, Biying Xu2, Aaron P Lewkowicz1
1Division 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.
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.
Insights
Ebola virus disease (EVD) survivors may develop eye problems. Neutralizing antibodies targeting EBOV-GP show promise in reducing viral load and eye inflammation, but further therapeutics are needed for long-term ocular health.
Area of Science:
- Virology
- Immunology
- Ophthalmology
Background:
- Ebola virus disease (EVD) survivors often experience ocular complications, including vision loss and retinal damage.
- The efficacy of antibody therapies, such as monoclonal antibodies targeting the Ebola virus glycoprotein (EBOV-GP), in preventing these eye conditions is not fully understood.
Purpose of the Study:
- To evaluate the impact of anti-EBOV-GP antibody treatments on acute retinitis and ocular sequelae in a mouse model.
- To assess the effectiveness of different antibody types (polyclonal, neutralizing, ADCC-mediating) in mitigating EVD-related eye damage.
Main Methods:
- Developed a BSL-2 compatible mouse model using vesicular stomatitis virus expressing EBOV-GP (VSV-EBOV).
- Treated VSV-EBOV-infected mice with polyclonal antibodies, neutralizing monoclonal antibodies (NEUT-mAb), or antibody-dependent cellular cytotoxicity monoclonal antibodies (ADCC-mAb).
- Assessed viral load, survival rates, cataract incidence, ocular immune responses, and retinal damage.
Main Results:
- All antibody treatments significantly reduced viremia and improved survival rates.
- Cataract incidence was reduced across all treatment groups.
- NEUT-mAb, alone or combined with ADCC-mAb, was most effective in reducing ocular viral load, dampening inflammation, and minimizing retinal damage.
Conclusions:
- Anti-EBOV-GP antibodies improve survival in EVD but may not fully prevent ocular sequelae.
- The developed mouse model is a valuable tool for studying EVD's ocular effects and testing therapeutics.
- Different antibody types exhibit varying capacities to reduce ocular inflammation and long-term eye pathology, highlighting the need for targeted therapeutic strategies.
