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

James E Robinson,John S Schieffelin,Megan M Rowland,Onikepe A Follarin,Pardis C Sabeti,Erica Ollmann Saphire,Jeffrey G Shaffer,Chandrika B Kannadka,Augustine Goba,Kathryn M Hastie,Peter C Kulakoski,Donald S Grant,Luis Martínez-Sobrido,Sahr M Gevao,Deborah H Elliott,Benjamin T Bradley,Robert F Garry,Julie A Rouelle,Momoh Gbetuwa,Brima Kargbo,Kristian G Andersen,Joan B Geisbert,Jessica N Hartnett,Odia Ikponmwosa,Russell B Wilson,Robert W Cross,Lansana Kanneh,Kelly R Pitts,Mohamed Fullah,Michael Gbakie,Richard Fonnie,Megan L Heinrich,Luis M Branco,Veronica J Koroma,Christian T Happi,Rachael E Yenni,Mambu Momoh,Matthew L Boisen ,Juan Carlos De La Torre ,Peter O Okokhere ,Benson Yee Hin Cheng ,Danny Asogun ,Mohamed Vandi ,Michelle Zandonatti ,Ashley R Smira ,Simbirie Jalloh ,Sheik Humarr Khan ,Haixia Yu ,Courtney E Garry

doi:10.1038/ncomms11544

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.

Highlights

Lassa fever is a severe multisystem disease that often has haemorrhagic manifestations
All but one of the monoclonal antibodies (mAbs) were first detected by enzyme-linked immunosorbent assay (ELISA) reactivity with an unprocessed insect cell-produced recombinant glycoprotein complex (GPC) (Josiah strain lineage IV) lacking the transmembrane and intracytoplasmic domains as the capture antigen
The exception was 8.9F, which did not bind to rGPe in ELISA, but was detected by its ability to neutralize a pseudovirus expressing Lassa virus (LASV) GPC

Summary

Introduction

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. We have cloned 113 human monoclonal antibodies (mAbs) specific for LASV glycoproteins from memory B cells of Lassa fever survivors from West Africa. Some mAbs potently neutralize all four LASV lineages These insights from LASV human mAb characterization will guide strategies for immunotherapeutic development and vaccine design. To date the epitopes of LASV glycoproteins that elicit protective antibody responses in naturally infected human hosts have not been identified or characterized. To elucidate the antigenic structure of LASV glycoproteins, we isolated and characterized mAbs derived from West African patients who had survived Lassa fever and who had developed sustained antibody titres to LASV antigens months or years into convalescence. The elucidation of the antigenic structure of the surface glycoproteins of LASV can guide future efforts to derive immunotherapeutics and vaccines

Methods

Results

Conclusion