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Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection

Abstract

There is concern that variola virus, the aetiological agent of smallpox, may be used as a biological weapon. For this reason several countries are now stockpiling (vaccinia virus-based) smallpox vaccine. Although the preventive use of smallpox vaccination has been well documented, little is known about its efficacy when used after exposure to the virus. Here we compare the effectiveness of (1) post-exposure smallpox vaccination and (2) antiviral treatment with either cidofovir (also called HPMPC or Vistide) or with a related acyclic nucleoside phosphonate analogue (HPMPO–DAPy) after lethal intratracheal infection of cynomolgus monkeys (Macaca fascicularis) with monkeypox virus (MPXV). MPXV causes a disease similar to human smallpox1 and this animal model can be used to measure differences in the protective efficacies of classical and new-generation candidate smallpox vaccines2. We show that initiation of antiviral treatment 24 h after lethal intratracheal MPXV infection, using either of the antiviral agents and applying various systemic treatment regimens, resulted in significantly reduced mortality and reduced numbers of cutaneous monkeypox lesions. In contrast, when monkeys were vaccinated 24 h after MPXV infection, using a standard human dose of a currently recommended smallpox vaccine (Elstree-RIVM), no significant reduction in mortality was observed. When antiviral therapy was terminated 13 days after infection, all surviving animals had virus-specific serum antibodies and antiviral T lymphocytes. These data show that adequate preparedness for a biological threat involving smallpox should include the possibility of treating exposed individuals with antiviral compounds such as cidofovir or other selective anti-poxvirus drugs.

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Figure 1: Kaplan–Meier plot showing the effect of different post-exposure treatments on the survival of monkeys.
Figure 2: Blood O 2 saturation profiles.
Figure 3: Viral load profiles after infection with MPXV.

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Acknowledgements

We are grateful to F. Pistoor, J. Rimmelzwaan-Offutt, S. Slabbekoorn-Romijn, R. D. d'Ullois and J. Guldemeester for assistance and to R. Gruters for comments. This work in Leuven and Prague was supported by an NIAID/NIH grant to J.N. and A.H.. This study is a part of an IOCB (Prague) research programme and project.

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Correspondence to Albert D. M. E. Osterhaus.

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Competing interests

The Department of Virology and ViroClinics BV are involved in performing monkeypox virus challenge experiments for Bavarian Nordic GmbH (Martinsried, Germany), supported by the National Institutes of Health (NIH).

Supplementary information

Supplementary Notes

This file contains Supplementary Methods, the Supplementary Figure Legend and additional references. (DOC 38 kb)

Supplementary Figure 1

Development of poxvirus-specific IgG antibodies in 1/100-diluted plasma samples of all the monkeys treated as described for Fig.1 (main text). (PDF 16 kb)

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Stittelaar, K., Neyts, J., Naesens, L. et al. Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection. Nature 439, 745–748 (2006). https://doi.org/10.1038/nature04295

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