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Tecovirimat is effective against human monkeypox virus in vitro at nanomolar concentrations

Nature Microbiology volume 7, pages 1951–1955 (2022)Cite this article

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Abstract

The ongoing monkeypox virus (MPXV) outbreak is the largest ever recorded outside of Africa. We isolated and sequenced a virus from the first clinical MPXV case diagnosed in France (May 2022). We report that tecovirimat (ST-246), a US Food and Drug Administration approved drug, is efficacious against this isolate in vitro at nanomolar concentrations, whereas cidofovir is only effective at micromolar concentrations. Our results support the use of tecovirimat in ongoing human clinical trials.

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Fig. 1: MPXV/France/IRBA2211/2022 imaging and phylogeny.
Fig. 2: Tecorivimat and cidofovir potency against MPXV/France/IRBA2211i/2022 in vitro.

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Data availability

All data supporting the findings of this study are available in the manuscript. The MPXV genomic data analysed here are deposited in GenBank (https://www.ncbi.nlm.nih.gov/genbank/, ON755039). The raw sequencing data of isolate MPXV/France/IRBA2211i/2022 have been deposited in the sequence read archive (https://www.ncbi.nlm.nih.gov/sra) under Accession PRJNA864836. The isolate MPXV/France/IRBA2211i/2022 is available upon request, as it may be useful for evaluating diagnostic tools, antivirals or vaccines (contact: irba-cnropv.accueil.fct@def.gouv.fr). Source data are provided with this paper.

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Acknowledgements

We thank all the healthcare workers, public health employees and scientists involved in the MPX outbreak response; the technical skills of C. Castellarin for preparing the samples for transmission electron microscopy; and the authors, and originating and submitting laboratories of the Orthopoxvirus sequences deposited in GenBank. This work used the computational and storage services provided by the IT department at Institut Pasteur, Paris.

The E.S.-L. laboratory acknowledges funding from the INCEPTION programme (Investissements d’Avenir grant ANR-16-CONV-0005), the NIH PICREID programme (Award Number U01AI151758) and the Labex IBEID (ANR-10-LABX-62-IBEID). O.F., A.F. and J.-N.T. acknowledge the support from Santé Publique France for the CNR-LE Orthopoxvirus. F.I. acknowledges funding from the Direction Générale de l’Armement (DGA) (Biomedef PDH-2-NBC-5-B-4120). F.G. acknowledges funding from the Agence Innovation Défense (AID) (RAPID DENALPOVIR 192906106).

Author information

Author notes

  1. These authors jointly supervised this work: Frédéric Iseni, Etienne Simon-Loriere, Jean-Nicolas Tournier.

Authors and Affiliations

  1. Virology Unit, Microbiology and Infectious Diseases Department, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France

    Gaëlle Frenois-Veyrat, Olivier Ferraris, Audrey Ferrier, Frédéric Iseni & Jean-Nicolas Tournier

  2. Institut de Recherche Biomédicale des Armées, National Reference Center for Orthopoxviruses (CNR-LE Orthopoxvirus), Brétigny-sur-Orge, France

    Gaëlle Frenois-Veyrat, Olivier Ferraris & Audrey Ferrier

  3. NeoVirTech, SAS, Toulouse, France

    Franck Gallardo & Elie Marcheteau

  4. Bacteriology Unit, Microbiology and Infectious Diseases Department, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France

    Olivier Gorgé & Flora Nolent

  5. G5 Evolutionary Genomics of RNA Viruses, Institut Pasteur, Université Paris Cité, Paris, France

    Artem Baidaliuk & Etienne Simon-Loriere

  6. Imagery Unit, Platform and Technological Research Department, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France

    Anne-Laure Favier, Cécile Enfroy & Xavier Holy

  7. Maison Médicale Chemin Vert, Paris, France

    Jérémy Lourenco

  8. Cerballiance, Paris, France

    Rhéa Khoury

  9. SIGA Technologies, Inc., Corvallis, OR, USA

    Douglas W. Grosenbach & Dennis E. Hruby

  10. Ecole du Val-de-Grâce, Paris, France

    Jean-Nicolas Tournier

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  1. Gaëlle Frenois-Veyrat
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Contributions

F.I., J.-N.T. and E.S.-L. conceived and designed the experiments; J.L. and R.K. provided patient care; O.F., A.F. and G.F.-V. conducted virus isolation, production and titration; A.-L.F., C.E. and X.H. conducted electron microscopy; O.G. and F.N. performed sequencing; F.I. and G.F.-V. performed MPXV antiviral assay; F.G. and E.M. conducted VACV antiviral assay; D.W.G. and D.E.H. provided antiviral material; A.B. and E.S.-L. performed phylogenetic analysis; J.-N.T. and E.S.-L. wrote the original draft, and reviewed and edited the manuscript with inputs from all authors.

Corresponding authors

Correspondence to Frédéric Iseni, Etienne Simon-Loriere or Jean-Nicolas Tournier.

Ethics declarations

Competing interests

F.G. and E.M. are employed by NeoVirTech SAS. F.G. is a shareholder of NeoVirTech SAS. Tecovirimat is manufactured by SIGA Technologies. D.E.H. and D.W.G. are employees of SIGA Technologies and hold shares of SIGA stock. The remaining authors declare no competing interests.

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Nature Microbiology thanks the anonymous reviewers for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 ST-246 inhibits VACV ANCHORTM-GFP propagation at nM concentration.

a, Reconstruction of 12 imaging fields captured on a CX7 CellInsight HCS microscope 48 h post infection with indicated concentration of ST-246. Blue: nuclei, green VACV ANCHORTM. (b,c) Quantification of the impact of ST-246 on the number of infected cells at 48 h (b) and 72 h (c) post-infection. IC50 and R2 are indicated. Data are presented as mean values +/- SD. Experiments were performed once in triplicate.

Source data

Extended Data Fig. 2 VP37 (F13L homologs) amino acid analysis.

VP37 (F13L homologs) amino acid alignment to MPVX clade IIb shows multiple differences, marked with black vertical bars, with other orthopoxviruses susceptible to tecovirimat. The E353K mutation in VP37 is a signature substitution of MPXV lineage B.1 (2022). Experimentally generated and verified mutations associated with resistance to ST-246 are marked in red below the alignment as well as in the corresponding OPV species in which they have been experimentally tested (vertical red bars). Importantly, these mutations (in red) are annotated in the alignment in the corresponding positions, while they do not exist in the original sequences.

Extended Data Fig. 3 Cytopathic effect on Vero cell line of MPXV/France/IRBA2211i/2022 strain (optical microscopy 20x).

Experiments were performed twice.

Supplementary information

Source data

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Frenois-Veyrat, G., Gallardo, F., Gorgé, O. et al. Tecovirimat is effective against human monkeypox virus in vitro at nanomolar concentrations. Nat Microbiol 7, 1951–1955 (2022). https://doi.org/10.1038/s41564-022-01269-8

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