Discovery of Marburg virus neutralizing antibodies from virus-naïve human antibody repertoires using large-scale structural predictions
[1];
[2];
[4];
[4];
[3];
[5]
- Vanderbilt Univ., Nashville, TN (United States)
- Vanderbilt Univ., Nashville, TN (United States); Vanderbilt Univ. Medical Center, Nashville, TN (United States)
- Vanderbilt Univ. Medical Center, Nashville, TN (United States)
- Univ. of Texas Medical Branch, Galveston, TX (United States)
- Vanderbilt Univ., Nashville, TN (United States); Leipzig Univ. Medical School (Germany)
Marburg virus (MARV) disease is lethal, with fatality rates up to 90%. Neutralizing antibodies (Abs) are promising drug candidates to prevent or treat the disease. Current efforts are focused in part on vaccine development to induce such MARV-neutralizing Abs. We analyzed the antibody repertoire from healthy unexposed and previously MARV-infected individuals to assess if naïve repertoires contain suitable precursor antibodies that could become neutralizing with a limited set of somatic mutations. Here, we computationally searched the human Ab variable gene repertoire for predicted structural homologs of the neutralizing Ab MR78 that is specific to the receptor binding site (RBS) of MARV glycoprotein (GP). Eight Ab heavy-chain complementarity determining region 3 (HCDR3) loops from MARV-naïve individuals and one from a previously MARV-infected individual were selected for testing as HCDR3 loop chimeras on the MR78 Ab framework. Three of these chimerized antibodies bound to MARV GP. We then tested a full-length native Ab heavy chain encoding the same 17-residue-long HCDR3 loop that bound to the MARV GP the best among the chimeric Abs tested. Despite only 57% amino acid sequence identity, the Ab from a MARV-naïve donor recognized MARV GP and possessed neutralizing activity against the virus. Crystallization of both chimeric and full-length native heavy chain-containing Abs provided structural insights into the mechanism of binding for these types of Abs. Our work suggests that the MARV GP RBS is a promising candidate for epitope-focused vaccine design to induce neutralizing Abs against MARV.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE Office of Science (SC); National Institutes of Health (NIH); National Center for Research Resources; Defense Threat Reduction Agency (DTRA)
- Grant/Contract Number:
- AC02-06CH11357; R1 AI141661; U19 AI117905; U19 AI109711; UL1 RR024975-01; UL1 TR000445-06; HDTRA1-13-1-0034; 5UC7AI094660-07; 085P1000817
- OSTI ID:
- 1734932
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Issue 49; ISSN 0027-8424
- Publisher:
- National Academy of SciencesCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
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