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Virulence Differences of Monkeypox Virus Clades 1, 2a and 2b.1 in a Small Animal Model

Jeffrey L. Americo, Patricia L. Earl, View ORCID ProfileBernard Moss
doi: https://doi.org/10.1101/2022.12.01.518711
Jeffrey L. Americo
1Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814 USA
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Patricia L. Earl
1Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814 USA
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Bernard Moss
1Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814 USA
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  • ORCID record for Bernard Moss
  • For correspondence: bmoss@nih.gov
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ABSTRACT

Human monkeypox, a disease with similarities to smallpox, is endemic in Africa where it has persisted as a zoonosis with limited human-to-human spread. Unexpectedly, the disease expanded globally in 2022 driven by human-to-human transmission outside of Africa. It is not yet known whether the latter is due solely to behavioral and environmental factors or whether the monkeypox virus is adapting to a new host. Genome sequencing has revealed differences between the current outbreak strains, classified as clade 2b, and the prior clade 2a and clade 1 viruses but whether these differences contribute to virulence or transmission has not been determined. We demonstrate that the wild-derived inbred CAST/EiJ mouse provides an exceptional animal model for investigating clade differences in monkeypox virus virulence and show that the order is clade 1 > clade 2a > clade 2b.1. The greatly reduced replication of the clade 2b.1 major outbreak strain in mice and absence of lethality at 100-times the lethal dose of a closely related clade 2a virus, despite similar multiplication in cell culture, suggest that clade 2b is evolving diminished virulence or adapting to other species.

SIGNIFICANCE Three clades of monkeypox virus are recognized: clade 1 is present in the Congo Basin, causes 10% human mortality and is transmitted by rodents with little human-to-human spread; clade 2a exists in West Africa, has a low mortality and is also a zoonosis; clade 2b is currently spreading globally by human transmission. The genetic basis for differences in virulence and transmission have not been determined. A major roadblock is the need for a small animal model that can be studied under the stringent safety conditions required. Here we demonstrate that the three clades exhibit highly significant differences in CAST/EiJ mice in the order clade 1 > clade 2a > clade 2b, similar to the severity of clinical disease.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 01, 2022.
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Virulence Differences of Monkeypox Virus Clades 1, 2a and 2b.1 in a Small Animal Model
Jeffrey L. Americo, Patricia L. Earl, Bernard Moss
bioRxiv 2022.12.01.518711; doi: https://doi.org/10.1101/2022.12.01.518711
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Virulence Differences of Monkeypox Virus Clades 1, 2a and 2b.1 in a Small Animal Model
Jeffrey L. Americo, Patricia L. Earl, Bernard Moss
bioRxiv 2022.12.01.518711; doi: https://doi.org/10.1101/2022.12.01.518711

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