Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits.

Abstract

Lassa fever is a severe multisystem disease that often has haemorrhagic manifestations. The epitopes of the Lassa virus (LASV) surface glycoproteins recognized by naturally infected human hosts have not been identified or characterized. Here we have cloned 113 human monoclonal antibodies (mAbs) specific for LASV glycoproteins from memory B cells of Lassa fever survivors from West Africa. One-half bind the GP2 fusion subunit, one-fourth recognize the GP1 receptor-binding subunit and the remaining fourth are specific for the assembled glycoprotein complex, requiring both GP1 and GP2 subunits for recognition. Notably, of the 16 mAbs that neutralize LASV, 13 require the assembled glycoprotein complex for binding, while the remaining 3 require GP1 only. Compared with non-neutralizing mAbs, neutralizing mAbs have higher binding affinities and greater divergence from germline progenitors. Some mAbs potently neutralize all four LASV lineages. These insights from LASV human mAb characterization will guide strategies for immunotherapeutic development and vaccine design.

• Authors: James E Robinson, Kathryn M Hastie, Robert W Cross, Rachael E Yenni, Deborah H Elliott, Julie A Rouelle, Chandrika B Kannadka, Ashley A Smira, Courtney E Garry, Benjamin T Bradley, Haini Yu, Jeffrey G Shaffer, Matt L Boisen, Jessica N Hartnett, Michelle A Zandonatti, Megan M Rowland, Megan L Heinrich, Luis Martínez-Sobrido, Benson Cheng, Juan C de la Torre, Kristian G Andersen, Augustine Goba, Mambu Momoh, Mohamed Fullah, Michael Gbakie, Lansana Kanneh, Veronica J Koroma, Richard Fonnie, Simbirie C Jalloh, Brima Kargbo, Mohamed A Vandi, Momoh Gbetuwa, Odia Ikponmwosa, Danny A Asogun, Peter O Okokhere, Onikepe A Follarin, John S Schieffelin, Kelly R Pitts, Joan B Geisbert, Peter C Kulakoski, Russell B Wilson, Christian T Happi, Pardis C Sabeti, Sahr M Gevao, S Humarr Khan, Donald S Grant, Thomas W Geisbert, Erica Ollmann Saphire, Luis M Branco, Robert F Garry
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 11544 (05 10 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27161536 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neutralizing
• Antibodies, Viral
• Antigens, Viral
• Epitopes
• Viral Envelope Proteins
• glycoprotein gp1, lassa virus
• glycoprotein gp2, lassa virus

Topics

• Antibodies, Monoclonal (immunology)
• Antibodies, Neutralizing (immunology)
• Antibodies, Viral (immunology)
• Antibody Specificity
• Antigens, Viral (chemistry, genetics, immunology)
• Arenavirus (immunology)
• Cross Reactions
• Epitope Mapping
• Epitopes (chemistry, genetics, immunology)
• Humans
• Lassa Fever (immunology, prevention & control)
• Lassa virus (genetics, immunology)
• Models, Molecular
• Mutagenesis, Site-Directed
• Sequence Deletion
• Viral Envelope Proteins (chemistry, genetics, immunology)