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Published on: February 10, 2022
Potent neutralization of Marburg virus by a vaccine-elicited antibody
Amin Addetia1, Lisa Perruzza2, Kaitlin Sprouse1,3
1Department of Biochemistry, University of Washington, Seattle, WA, USA.
Abstract:
Marburg virus (MARV) is a filovirus that causes severe and often lethal haemorrhagic fever1,2. Despite the increasing frequency of MARV outbreaks, no vaccines or therapeutics are licensed for use in humans. Here we designed mutations that improve the expression, thermostability and immunogenicity of the prefusion MARV glycoprotein (GP) ectodomain trimer, which is the sole target of neutralizing antibodies and vaccines in development3-8. We discovered a fully human, pan-marburgvirus monoclonal antibody, MARV16, that broadly neutralizes all MARV isolates, Ravn virus and Dehong virus with 40-100-fold increased potency relative to previously described antibodies9. Moreover, MARV16 provided therapeutic protection in guinea pigs challenged with MARV. We determined a cryogenic electron microscopy structure of MARV16-bound MARV GP. The structure shows that MARV16 recognizes a prefusion-specific epitope spanning GP1 and GP2, which blocks receptor binding and prevents conformational changes required for viral entry. We further determined the architecture of the MARV GP glycan cap, which shields the receptor-binding site, and identified architectural similarities with distantly related filovirus GPs. MARV16 and previously identified antibodies directed against the receptor-binding site9-11 simultaneously bound MARV GP. These antibody cocktails required multiple mutations to escape neutralization by both antibodies, a result that paves the way for the development of MARV therapeutics resistant to viral evolution. MARV GP stabilization along with the discovery of MARV16 advance prevention and treatment options for MARV disease.
Insights
Researchers developed a stabilized Marburg virus glycoprotein (GP) and discovered MARV16, a potent antibody that neutralizes Marburg virus (MARV) and protects against lethal infection. This advances MARV disease prevention and treatment options.
Area of Science:
- Virology
- Immunology
- Structural Biology
Background:
- Marburg virus (MARV) causes severe hemorrhagic fever with no licensed vaccines or therapeutics.
- The MARV glycoprotein (GP) ectodomain trimer is a key target for vaccines and neutralizing antibodies.
- Current MARV treatments are limited, necessitating the development of new therapeutic strategies.
Purpose of the Study:
- To improve Marburg virus glycoprotein (GP) expression, stability, and immunogenicity.
- To discover novel monoclonal antibodies for broad MARV neutralization.
- To elucidate the structural basis of MARV neutralization for therapeutic development.
Main Methods:
- Protein engineering to stabilize the MARV prefusion GP ectodomain trimer.
- Discovery and characterization of a pan-marburgvirus monoclonal antibody (MARV16).
- Cryogenic electron microscopy (cryo-EM) to determine the structure of MARV16-bound MARV GP.
- In vivo efficacy studies in a MARV-challenged guinea pig model.
Main Results:
- Stabilized MARV GP trimers with enhanced expression and thermostability were designed.
- A potent human monoclonal antibody, MARV16, was discovered, broadly neutralizing MARV isolates, Ravn virus, and Dehong virus with high potency.
- MARV16 demonstrated therapeutic protection in MARV-infected guinea pigs.
- Cryo-EM revealed MARV16 binds a prefusion-specific epitope, blocking viral entry.
- MARV16 and existing antibodies can be used in combination, requiring multiple mutations for viral escape, suggesting resistance to viral evolution.
Conclusions:
- Stabilization of MARV GP and discovery of MARV16 represent significant advancements in MARV countermeasures.
- MARV16 offers a promising therapeutic candidate for Marburg virus disease.
- Combination antibody therapy strategies may overcome viral resistance, paving the way for robust MARV therapeutics.
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