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Published on: August 29, 2017
Generation and characterization of protective antibodies to Marburg virus
Jeffrey W Froude1, Thibaut Pelat2,3, Sebastian Miethe4,5
1a US Army Medical Research Institute for Infectious Disease (USAMRIID) , Fort Detrick , MD , USA.
Abstract:
Marburg virus (MARV) and Ebola virus (EBOV) have been a source of epidemics and outbreaks for several decades. We present here the generation and characterization of the first protective antibodies specific for wild-type MARV. Non-human primates (NHP), cynomolgus macaques, were immunized with viral-replicon particles expressing the glycoproteins (GP) of MARV (Ci67 isolate). An antibody fragment (single-chain variable fragment, scFv) phage display library was built after four immunogen injections, and screened against the GP1-649 of MARV. Sequencing of 192 selected clones identified 18 clones with distinct VH and VL sequences. Four of these recombinant antibodies (R4A1, R4B11, R4G2, and R3F6) were produced in the scFv-Fc format for in vivo studies. Mice that were challenged with wild-type Marburg virus (Ci67 isolate) receiving 100 µg of scFv-Fc on days -1, 1 and 3 demonstrated protective efficacies ranging from 75-100%. The amino-acid sequences of the scFv-Fcs are similar to those of their human germline counterparts, sharing an identity ranging between 68 and 100% to human germline immunoglobulin. These results demonstrate for the first time that recombinant antibodies offer protection against wild-type MARV, and suggest they may be promising candidates for further therapeutic development especially due to their human homology.
Insights
Researchers developed novel recombinant antibodies offering protection against wild Marburg virus (MARV). These antibodies, derived from immunized macaques, showed high efficacy in mice, paving the way for MARV therapeutics.
Area of Science:
- Virology
- Immunology
- Therapeutic Antibody Development
Background:
- Marburg virus (MARV) and Ebola virus (EBOV) pose significant public health threats due to recurrent epidemics.
- Effective treatments and preventative measures against MARV are critically needed.
Purpose of the Study:
- To generate and characterize the first protective antibodies against wild-type Marburg virus.
- To evaluate the in vivo efficacy of these novel recombinant antibodies.
Main Methods:
- Cynomolgus macaques were immunized with MARV glycoprotein (GP)-expressing viral-replicon particles.
- A single-chain variable fragment (scFv) phage display library was constructed and screened against MARV GP.
- Selected scFv clones were reformatted as scFv-Fc antibodies and tested in a MARV mouse challenge model.
Main Results:
- Eighteen distinct MARV GP-specific scFv clones were identified.
- Four recombinant antibodies (R4A1, R4B11, R4G2, R3F6) demonstrated 75-100% protective efficacy in mice challenged with wild-type MARV.
- The generated antibodies exhibit high homology to human germline immunoglobulins.
Conclusions:
- Recombinant antibodies can provide protection against wild-type Marburg virus infection.
- These human-homologous antibodies represent promising candidates for future MARV therapeutic development.
