A human monoclonal antibody combination rescues nonhuman primates from advanced disease caused by the major lineages of Lassa virus

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Significance

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 therapies against LF is that there are several different genetically distinct lineages of Lassa virus. Here, we show that combinations of two or three broadly neutralizing human monoclonal antibodies known as Arevirumab-2 or Arevirumab-3 can protect up to 100% of cynomolgus monkeys against challenge with two of the major lineages of Lassa virus when treatment is initiated at advanced stages of disease on day 8 after Lassa virus exposure. This work demonstrates that it may be possible to develop postexposure interventions that can broadly protect against most of the different lineages of Lassa virus.

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.

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Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies

Alina Baum, Benjamin Fulton, Elzbieta Wloga … (2020)

Antibodies targeting the spike protein of SARS-CoV-2 present a promising approach to combat the COVID19 pandemic; however, concerns remain that mutations can yield antibody resistance. We investigate the development of resistance against four antibodies to the spike protein that potently neutralize SARS-CoV-2, individually as well as when combined into cocktails. These antibodies remain effective against spike variants that have arisen in the human population. However, novel spike mutants rapidly appeared following in vitro passaging in the presence of individual antibodies, resulting in loss of neutralization; such escape also occurred with combinations of antibodies binding diverse but overlapping regions of the spike protein. Importantly, escape mutants were not generated following treatment with a non-competing antibody cocktail.

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Treatment of Argentine hemorrhagic fever

Delia A. Enría, Ana M. Briggiler, Zaida Sánchez (2007)

Argentine hemorrhagic fever (AHF) is a rodent-borne illness caused by the arenavirus Junin that is endemic to the humid pampas of Argentina. AHF has had significant morbidity since its emergence in the 1950s, with a case-fatality rate of the illness without treatment between 15% and 30%. The use of a live attenuated vaccine has markedly reduced the incidence of AHF. Present specific therapy involves the transfusion of immune plasma in defined doses of neutralizing antibodies during the prodromal phase of illness. However, alternative forms of treatment are called for due to current difficulties in early detection of AHF, related to its decrease in incidence, troubles in maintaining adequate stocks of immune plasma, and the absence of effective therapies for severely ill patients that progress to a neurologic–hemorrhagic phase. Ribavirin might be a substitute for immune plasma, provided that the supply is guaranteed. Immune immunoglobulin or monoclonal antibodies should also be considered. New therapeutic options such as those being developed for systemic inflammatory syndromes should also be valuated in severe forms of AHF.

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Ranking the risk of animal-to-human spillover for newly discovered viruses

Zoe L. Grange, Tracey Goldstein, Christine Johnson … (2021)

The recent emergence and spread of zoonotic viruses, including Ebola virus and severe acute respiratory syndrome coronavirus 2, demonstrate that animal-sourced viruses are a very real threat to global public health. Virus discovery efforts have detected hundreds of new animal viruses with unknown zoonotic risk. We developed an open-source risk assessment to systematically evaluate novel wildlife-origin viruses in terms of their zoonotic spillover and spread potential. Our tool will help scientists and governments assess and communicate risk, informing national disease prioritization, prevention, and control actions. The resulting watchlist of potential pathogens will identify targets for new virus countermeasure initiatives, which can reduce the economic and health impacts of emerging diseases. The death toll and economic loss resulting from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are stark reminders that we are vulnerable to zoonotic viral threats. Strategies are needed to identify and characterize animal viruses that pose the greatest risk of spillover and spread in humans and inform public health interventions. Using expert opinion and scientific evidence, we identified host, viral, and environmental risk factors contributing to zoonotic virus spillover and spread in humans. We then developed a risk ranking framework and interactive web tool, SpillOver, that estimates a risk score for wildlife-origin viruses, creating a comparative risk assessment of viruses with uncharacterized zoonotic spillover potential alongside those already known to be zoonotic. Using data from testing 509,721 samples from 74,635 animals as part of a virus discovery project and public records of virus detections around the world, we ranked the spillover potential of 887 wildlife viruses. Validating the risk assessment, the top 12 were known zoonotic viruses, including SARS-CoV-2. Several newly detected wildlife viruses ranked higher than known zoonotic viruses. Using a scientifically informed process, we capitalized on the recent wealth of virus discovery data to systematically identify and prioritize targets for investigation. The publicly accessible SpillOver platform can be used by policy makers and health scientists to inform research and public health interventions for prevention and rapid control of disease outbreaks. SpillOver is a living, interactive database that can be refined over time to continue to improve the quality and public availability of information on viral threats to human health.

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Author and article information

Contributors

Luis M. Branco

Thomas W. Geisbert:

ORCID: https://orcid.org/0000-0003-0858-1877

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Electronic, pub): 17 August 2023

Publication date (Print, pub): 22 August 2023

Publication date PMC-release: 17 August 2023

Volume: 120

Issue: 34

Electronic Location Identifier: e2304876120

Affiliations

[1] ^aGalveston National Laboratory, University of Texas Medical Branch , Galveston, TX 77555

[2] ^bDepartment of Microbiology and Immunology, University of Texas Medical Branch , Galveston, TX 77555

[3] ^cZalgen Labs, Limited Liability Company , Frederick, MD 21703

[4] ^dDepartment of Microbiology and Immunology, Tulane University School of Medicine , New Orleans, LA 70112

Author notes

²To whom correspondence may be addressed. Email: lbranco@ 123456zalgenlabs.com or twgeisbe@ 123456utmb.edu .

Edited by Stephan Becker, Philipps-University Marburg, Marburg, State of Hesse, Germany; received March 27, 2023; accepted July 13, 2023 by Editorial Board Member Diane E. Griffin

¹R.W.C., M.L.H., and K.A.F. contributed equally to this work.