title: 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.affiliation: Section of Infectious Disease, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.affiliation: Department of Immunology and Microbial Science, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Hastie
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, Texas 77555, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Cross
authors.affiliation: Department of Microbiology and Immunology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors.forename: Rachael E
authors.initials: RE
authors.lastname: Yenni
authors.affiliation: Section of Infectious Disease, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Elliott
authors.affiliation: Section of Infectious Disease, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Rouelle
authors.affiliation: Section of Infectious Disease, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors.forename: Chandrika B
authors.initials: CB
authors.lastname: Kannadka
authors.affiliation: Section of Infectious Disease, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Smira
authors.affiliation: Section of Infectious Disease, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.|Autoimmune Technologies, LLC, 1010 Common St #1705, New Orleans, Louisiana 70112, USA.
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Garry
authors.affiliation: Section of Infectious Disease, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors.forename: Benjamin T
authors.identifier: 0000-0002-8064-9314
authors.initials: BT
authors.lastname: Bradley
authors.affiliation: Section of Infectious Disease, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors.forename: Haini
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane School of Public Health and Tropical Medicine, New Orleans, Louisiana 70112, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Shaffer
authors.affiliation: Corgenix, Inc., 11575 Main Street #400, Broomfield, Colorado 80020, USA.
authors.forename: Matt L
authors.initials: ML
authors.lastname: Boisen
authors.affiliation: Department of Microbiology and Immunology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Hartnett
authors.affiliation: Department of Immunology and Microbial Science, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Zandonatti
authors.affiliation: Zalgen Labs, LLC, 20271 Goldenrod Lane, Suite 2083, Germantown, Maryland 20876, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Rowland
authors.affiliation: Zalgen Labs, LLC, 20271 Goldenrod Lane, Suite 2083, Germantown, Maryland 20876, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Heinrich
authors.affiliation: Department of Microbiology and Immunology, University of Rochester, 601 Elmwood Avenue, Rochester, New York 14642, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Sobrido
authors.affiliation: Department of Microbiology and Immunology, University of Rochester, 601 Elmwood Avenue, Rochester, New York 14642, USA.
authors.forename: Benson
authors.initials: B
authors.lastname: Cheng
authors.affiliation: Department of Immunology and Microbial Science, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: de la Torre
authors.affiliation: Department of Immunology and Microbial Science, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Kristian G
authors.initials: KG
authors.lastname: Andersen
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.
authors.forename: Augustine
authors.initials: A
authors.lastname: Goba
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.|Department of Laboratory Sciences Polytechnic College, 2 Combema Road, Kenema, Sierra Leone.
authors.forename: Mambu
authors.initials: M
authors.lastname: Momoh
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.|Department of Laboratory Sciences Polytechnic College, 2 Combema Road, Kenema, Sierra Leone.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Fullah
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.
authors.forename: Michael
authors.initials: M
authors.lastname: Gbakie
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.
authors.forename: Lansana
authors.initials: L
authors.lastname: Kanneh
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Koroma
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.
authors.forename: Richard
authors.initials: R
authors.lastname: Fonnie
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.
authors.forename: Simbirie C
authors.initials: SC
authors.lastname: Jalloh
authors.affiliation: Ministry of Health and Sanitation, 4th Floor Youyi Building, Freetown, Sierra Leone.
authors.forename: Brima
authors.initials: B
authors.lastname: Kargbo
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.|Ministry of Health and Sanitation, 4th Floor Youyi Building, Freetown, Sierra Leone.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Vandi
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.|Ministry of Health and Sanitation, 4th Floor Youyi Building, Freetown, Sierra Leone.
authors.forename: Momoh
authors.initials: M
authors.lastname: Gbetuwa
authors.affiliation: Department of Medicine, Institute of Lassa Fever Research and Control, Irrua Specialist Teaching Hospital, Km. 87, Benin/Auchi Road, Irrua, Nigeria.
authors.forename: Odia
authors.initials: O
authors.lastname: Ikponmwosa
authors.affiliation: Department of Medicine, Institute of Lassa Fever Research and Control, Irrua Specialist Teaching Hospital, Km. 87, Benin/Auchi Road, Irrua, Nigeria.
authors.forename: Danny A
authors.initials: DA
authors.lastname: Asogun
authors.affiliation: Department of Medicine, Institute of Lassa Fever Research and Control, Irrua Specialist Teaching Hospital, Km. 87, Benin/Auchi Road, Irrua, Nigeria.
authors.forename: Peter O
authors.initials: PO
authors.lastname: Okokhere
authors.affiliation: Department of Medicine, Institute of Lassa Fever Research and Control, Irrua Specialist Teaching Hospital, Km. 87, Benin/Auchi Road, Irrua, Nigeria.|Department of Biological Sciences, College of Natural Sciences, Redeemer's University, Off Gbongan-Oshogbo Road, Ede, Nigeria.|African Center of Excellence for Genomics of Infectious Disease (ACEGID), Redeemer's University, Off Gbongan-Oshogbo Road, Ede, Nigeria.
authors.forename: Onikepe A
authors.initials: OA
authors.lastname: Follarin
authors.affiliation: Section of Infectious Disease, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.|Section of Infectious Disease, Department of Internal Medicine, Tulane University School of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Schieffelin
authors.affiliation: Corgenix, Inc., 11575 Main Street #400, Broomfield, Colorado 80020, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Pitts
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, Texas 77555, USA.
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authors.initials: JB
authors.lastname: Geisbert
authors.affiliation: Autoimmune Technologies, LLC, 1010 Common St #1705, New Orleans, Louisiana 70112, USA.
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authors.initials: PC
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authors.affiliation: Autoimmune Technologies, LLC, 1010 Common St #1705, New Orleans, Louisiana 70112, USA.
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authors.initials: RB
authors.lastname: Wilson
authors.affiliation: Department of Medicine, Institute of Lassa Fever Research and Control, Irrua Specialist Teaching Hospital, Km. 87, Benin/Auchi Road, Irrua, Nigeria.|Department of Biological Sciences, College of Natural Sciences, Redeemer's University, Off Gbongan-Oshogbo Road, Ede, Nigeria.|African Center of Excellence for Genomics of Infectious Disease (ACEGID), Redeemer's University, Off Gbongan-Oshogbo Road, Ede, Nigeria.
authors.forename: Christian T
authors.initials: CT
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authors.affiliation: Department of Organismic and Evolutionary Biology, Center for Systems Biology, Harvard University, 1350 Massachusetts Avenue, Cambridge, Massachusetts 02138, USA.|Center for Systems Biology, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Immunology and Infectious Disease, Harvard School of Public Health, 677 Huntington Avenue, Boston, Massachusetts 02115, USA.
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authors.initials: PC
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authors.affiliation: Department of Medicine, University of Sierra Leone, Freetown, Sierra Leone.
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authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.|Ministry of Health and Sanitation, 4th Floor Youyi Building, Freetown, Sierra Leone.
authors.forename: S Humarr
authors.initials: SH
authors.lastname: Khan
authors.affiliation: Viral Hemorrhagic Fever Program, Kenema Government Hospital, 1 Combema Road, Kenema, Sierra Leone.|Ministry of Health and Sanitation, 4th Floor Youyi Building, Freetown, Sierra Leone.
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authors.initials: DS
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authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, Texas 77555, USA.
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authors.initials: TW
authors.lastname: Geisbert
authors.affiliation: Department of Immunology and Microbial Science, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.|The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Erica Ollmann
authors.initials: EO
authors.lastname: Saphire
authors.affiliation: Zalgen Labs, LLC, 20271 Goldenrod Lane, Suite 2083, Germantown, Maryland 20876, USA.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Branco
authors.affiliation: Department of Microbiology and Immunology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.|Zalgen Labs, LLC, 20271 Goldenrod Lane, Suite 2083, Germantown, Maryland 20876, USA.
authors.forename: Robert F
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mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D000918:Antibody Specificity; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D018050:Arenavirus / Q000276:immunology; D003429:Cross Reactions; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D007835:Lassa Fever / Q000276:immunology / Q000517:prevention & control; D007836:Lassa virus / Q000235:genetics / Q000276:immunology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017384:Sequence Deletion; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D000939:Epitopes; D014759:Viral Envelope Proteins; C066508:glycoprotein gp1, lassa virus; C077198:glycoprotein gp2, lassa virus