Neutralizing Antibodies against Lassa Virus Lineage I

Buck, Tierra; Enriquez, Adrian; Schendel, Sharon L.; Zandonatti, Michelle; Harkins, Stephanie; Li, Haoyang; Moon-Walker, Alex; Robinson, James E.; Branco, Luis M.; Garry, Robert F.; Saphire, Erica Ollmann; Hastie, Kathryn M.

doi:10.1128/mbio.01278-22

Cited by 19 publications

(21 citation statements)

References 50 publications

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“…S3A), indicating that, in the absence of the antibody, loop 3 is flexible and might partially occlude the GPC-B epitope. This mechanism of GPC-B antibody evasion could explain the lack of neutralization by 37.7H, as observed with Lassa Lineage I 43 . Furthermore, to improve neutralizing responses and to elicit neutralizing antibodies targeting the GPC-B epitope, partial or complete removal of loop 3 might be necessary .…”

Section: Resultsmentioning

confidence: 79%

“…The N termini of the fusion peptides of Lassa GP trimers solved to date are each situated at the trimeric interface and are in a near-identical location regardless of whether or not an antibody is bound (Fig. 2A) 39, 40, 43, 44, 46 . Modeling of one protomer of uncleaved LCMV GP onto the Lassa GP trimer predicted the GP1 C-terminal transposition, but did not necessarily suggest that any more than local repositioning of the GP2 N-terminus occurred.…”

Section: Resultsmentioning

confidence: 99%

“…1C). We previously identified this region as modulating access by GPC-B antibodies to Lassa Lineage I GP 43 . LCMV, along with its close relatives Lunk virus 53 and Dandenong virus 54 , have the longest loop 3 amongst arenaviruses.…”

Section: Structural Organization Of the Lcmv Gp Trimer And Its Recogn...mentioning

confidence: 99%

“…Studies of the immune response against Lassa virus (LASV), a close relative of LCMV and etiological agent of Lassa hemorrhagic fever, revealed that most neutralizing antibodies elicited during Lassa virus infection target the pre-fusion conformation of GP [38][39][40][41][42] . These antibodies bind to four discrete epitopes on the surface of GP [38][39][40]43,44 , although the majority target the epitope termed GPC-B. GPC-B antibodies bind LASV GP at the base of the trimer and lock GP in the pre-fusion conformation by engaging adjacent GP monomers 40 .…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for antibody-mediated neutralization of Lymphocytic choriomeningitis virus

Moon-Walker

Zhang

Zyla

et al. 2022

Preprint

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The mammarenavirus Lymphocytic choriomeningitis virus (LCMV) is a globally distributed zoonotic pathogen that can be lethal in immunocompromised patients and cause severe birth defects if acquired during pregnancy. Despite the fundamental importance of LCMV for studying immunobiology, the structure of the trimeric surface glycoprotein, essential for entry, vaccine design and antibody neutralization, remains unknown. In this study, we present the cryoEM structure of the LCMV surface glycoprotein (GP) in its trimeric prefusion assembly both alone and in complex with a rationally engineered monoclonal neutralizing antibody termed 18.5C-M28 (M28). Additionally, we show that passive administration of M28 protects mice from LCMV clone 13 challenge when administered as either a prophylactic or therapeutic. Our study illuminates not only the overall structural organization of LCMV GP and the mechanism for its inhibition by M28, but also presents a promising therapeutic candidate to prevent severe or fatal disease in individuals who are at risk of infection by a virus that poses a threat worldwide.

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Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Structural Organization Of the Lcmv Gp Trimer And Its Recogn...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural basis for antibody-mediated neutralization of Lymphocytic choriomeningitis virus

Moon-Walker

Zhang

Zyla

et al. 2022

Preprint

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“…The high genetic diversity of LASV may be problematic for creating a broadly reactive immunotherapeutic. Antibodies that are highly potent against LASV of lineage IV were ineffective against the divergent lineage I 115 . Synergistic drug combinations may be needed to achieve therapeutic levels 116 .…”

Section: Lassa Fever Medical Countermeasuresmentioning

confidence: 99%

Lassa fever — the road ahead

Garry

2022

Nat Rev Microbiol

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Lassa virus (LASV) is endemic in the rodent populations of Sierra Leone, Nigeria and other countries in West Africa. Spillover to humans occurs frequently and results in Lassa fever, a viral haemorrhagic fever (VHF) associated with a high case fatality rate. Despite advances, fundamental gaps in knowledge of the immunology, epidemiology, ecology and pathogenesis of Lassa fever persist. More frequent outbreaks, the potential for further geographic expansion of Mastomys natalensis and other rodent reservoirs, the ease of procurement and possible use and weaponization of LASV, the frequent importation of LASV to North America and Europe, and the emergence of novel LASV strains in densely populated West Africa have driven new initiatives to develop countermeasures for LASV. Although promising candidates are being evaluated, as yet there are no approved vaccines or therapeutics for human use. This Review discusses the virology of LASV, the clinical course of Lassa fever and the progress towards developing medical countermeasures.

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Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies

et al. 2023

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Neutralizing Antibodies against Lassa Virus Lineage I

Abstract: No vaccine or therapeutics are approved to prevent LASV infection or treat LF. All vaccine platforms currently under development present only the LIV GP sequence.

Cited by 19 publications

References 50 publications

Structural basis for antibody-mediated neutralization of Lymphocytic choriomeningitis virus

Structural basis for antibody-mediated neutralization of Lymphocytic choriomeningitis virus

Lassa fever — the road ahead

Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies

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