A Human Monoclonal Antibody Combination Rescues Nonhuman Primates from Advanced Disease Caused by the Major Lineages of Lassa Virus

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2023 Aug 17

PMID 37590417

Authors

Robert W Cross

Megan L Heinrich

Karla A Fenton

Viktoriya Borisevich

Krystle N Agans

Abhishek N Prasad

Courtney Woolsey

Daniel J Deer

Natalie S Dobias

Megan M Rowland

Raju Lathigra

Rodrigo Borrega

Joan B Geisbert

Robert F Garry

Luis M Branco

Thomas W Geisbert

Affiliations

Soon will be listed here.

Abstract

There are no approved treatments for Lassa fever (LF), which is responsible for thousands of deaths each year in West Africa. A major challenge in developing effective medical countermeasures against LF is the high diversity of circulating Lassa virus (LASV) strains with four recognized lineages and four proposed lineages. The recent resurgence of LASV in Nigeria caused by genetically distinct strains underscores this concern. Two LASV lineages (II and III) are dominant in Nigeria. Here, we show that combinations of two or three pan-lineage neutralizing human monoclonal antibodies (8.9F, 12.1F, 37.D) known as Arevirumab-2 or Arevirumab-3 can protect up to 100% of cynomolgus macaques against challenge with both lineage II and III LASV isolates when treatment is initiated at advanced stages of disease on day 8 after LASV exposure. This work demonstrates that it may be possible to develop postexposure interventions that can broadly protect against most strains of LASV.

Citing Articles

Lassa virus protein-protein interactions as mediators of Lassa fever pathogenesis.

Jan S, Phadke K, Lam V, Branda S, Johnson D Virol J. 2025; 22(1):52.

PMID: 40022100 PMC: 11869472. DOI: 10.1186/s12985-025-02669-y.

Structure-guided design of a prefusion GPC trimer induces neutralizing responses against LASV.

Wang S, Li R, Pan X, Wang M, Wu Y, Li Y NPJ Vaccines. 2025; 10(1):37.

PMID: 39987102 PMC: 11847010. DOI: 10.1038/s41541-025-01090-4.

Oral obeldesivir provides postexposure protection against Marburg virus in nonhuman primates.

Cross R, Woolsey C, Prasad A, Borisevich V, Agans K, Deer D Nat Med. 2025; .

PMID: 39805309 DOI: 10.1038/s41591-025-03496-y.

Current perspectives on vaccines and therapeutics for Lassa Fever.

Warner B, Safronetz D, Stein D Virol J. 2024; 21(1):320.

PMID: 39702419 PMC: 11657583. DOI: 10.1186/s12985-024-02585-7.

Conformational ensemble-based framework enables rapid development of Lassa virus vaccine candidates.

Mishra N, Avillion G, Callaghan S, DiBiase C, Hurtado J, Liendo N bioRxiv. 2024; .

PMID: 39605488 PMC: 11601624. DOI: 10.1101/2024.11.21.624760.

References

Chika-Igwenyi N, Harrison R, Psarra C, Gil-Cuesta J, Gulamhusein M, Onwe E . Early onset of neurological features differentiates two outbreaks of Lassa fever in Ebonyi state, Nigeria during 2017-2018. PLoS Negl Trop Dis. 2021; 15(3):e0009169. PMC: 7984835. DOI: 10.1371/journal.pntd.0009169. View

Thielebein A, Ighodalo Y, Taju A, Olokor T, Omiunu R, Esumeh R . Virus persistence after recovery from acute Lassa fever in Nigeria: a 2-year interim analysis of a prospective longitudinal cohort study. Lancet Microbe. 2022; 3(1):e32-e40. DOI: 10.1016/S2666-5247(21)00178-6. View

Keeffe J, Van Rompay K, Olsen P, Wang Q, Gazumyan A, Azzopardi S . A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. Cell Rep. 2018; 25(6):1385-1394.e7. PMC: 6268006. DOI: 10.1016/j.celrep.2018.10.031. View

Yadouleton A, Picard C, Rieger T, Loko F, Cadar D, Kouthon E . Lassa fever in Benin: description of the 2014 and 2016 epidemics and genetic characterization of a new Lassa virus. Emerg Microbes Infect. 2020; 9(1):1761-1770. PMC: 7473144. DOI: 10.1080/22221751.2020.1796528. View

Frame J . Clinical features of Lassa fever in Liberia. Rev Infect Dis. 1989; 11 Suppl 4:S783-9. DOI: 10.1093/clinids/11.supplement_4.s783. View

Bloch A . A serological survey of Lassa fever in Liberia. Bull World Health Organ. 1978; 56(5):811-3. PMC: 2395672. View

Bell-Kareem A, Smither A . Epidemiology of Lassa Fever. Curr Top Microbiol Immunol. 2021; 440:87-109. DOI: 10.1007/82_2021_234. View

Ibukun F . Inter-Lineage Variation of Lassa Virus Glycoprotein Epitopes: A Challenge to Lassa Virus Vaccine Development. Viruses. 2020; 12(4). PMC: 7232328. DOI: 10.3390/v12040386. View

Jahrling P, Peters C . Passive antibody therapy of Lassa fever in cynomolgus monkeys: importance of neutralizing antibody and Lassa virus strain. Infect Immun. 1984; 44(2):528-33. PMC: 263556. DOI: 10.1128/iai.44.2.528-533.1984. View

10.

Safronetz D, Strong J, Feldmann F, Haddock E, Sogoba N, Brining D . A recently isolated Lassa virus from Mali demonstrates atypical clinical disease manifestations and decreased virulence in cynomolgus macaques. J Infect Dis. 2013; 207(8):1316-27. PMC: 3603532. DOI: 10.1093/infdis/jit004. View

11.

Mire C, Cross R, Geisbert J, Borisevich V, Agans K, Deer D . Human-monoclonal-antibody therapy protects nonhuman primates against advanced Lassa fever. Nat Med. 2017; 23(10):1146-1149. PMC: 5719877. DOI: 10.1038/nm.4396. View

12.

Markham A . REGN-EB3: First Approval. Drugs. 2021; 81(1):175-178. PMC: 7799152. DOI: 10.1007/s40265-020-01452-3. View

13.

Cross R, Woolsey C, Prasad A, Borisevich V, Agans K, Deer D . A recombinant VSV-vectored vaccine rapidly protects nonhuman primates against heterologous lethal Lassa fever. Cell Rep. 2022; 40(3):111094. DOI: 10.1016/j.celrep.2022.111094. View

14.

Robinson J, Hastie K, Cross R, Yenni R, Elliott D, Rouelle J . Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits. Nat Commun. 2016; 7:11544. PMC: 4866400. DOI: 10.1038/ncomms11544. View

15.

Cummins D, Bennett D, Fisher-Hoch S, FARRAR B, Machin S, McCormick J . Lassa fever encephalopathy: clinical and laboratory findings. J Trop Med Hyg. 1992; 95(3):197-201. View

16.

Pallotta A, Kim C, Gordon S, Kim A . Monoclonal antibodies for treating COVID-19. Cleve Clin J Med. 2021; . DOI: 10.3949/ccjm.88a.ccc074. View

17.

Akpede G, Asogun D, Okogbenin S, Dawodu S, Momoh M, Dongo A . Caseload and Case Fatality of Lassa Fever in Nigeria, 2001-2018: A Specialist Center's Experience and Its Implications. Front Public Health. 2019; 7:170. PMC: 6603170. DOI: 10.3389/fpubh.2019.00170. View

18.

EMOND R, Bannister B, Lloyd G, Southee T, BOWEN E . A case of Lassa fever: clinical and virological findings. Br Med J (Clin Res Ed). 1982; 285(6347):1001-2. PMC: 1500383. DOI: 10.1136/bmj.285.6347.1001. View

19.

Rosenke K, Feldmann H, Westover J, Hanley P, Martellaro C, Feldmann F . Use of Favipiravir to Treat Lassa Virus Infection in Macaques. Emerg Infect Dis. 2018; 24(9):1696-1699. PMC: 6106425. DOI: 10.3201/eid2409.180233. View

20.

Cashman K, Smith M, Twenhafel N, Larson R, Jones K, Allen 3rd R . Evaluation of Lassa antiviral compound ST-193 in a guinea pig model. Antiviral Res. 2011; 90(1):70-9. PMC: 3319460. DOI: 10.1016/j.antiviral.2011.02.012. View