Cowpox virus: Infectious substances pathogen safety data sheet

Section I – Infectious agent

Name

Cowpox virus

Agent type

Virus

Taxonomy

Family

Poxviridae

Genus

Orthopoxvirus

Species

Orthopoxvirus cowpox

Synonym or cross-reference

Cowpox virus (CPXV) is the etiological agent of cowpox, also known as catpoxFootnote 1. Prior to the 1930s, the terms cowpox, smallpox vaccine, and vaccinia were synonymousFootnote 2.

Characteristics

Brief description

CPXV is an enveloped, brick-shaped virus measuring 220-450 nm by 140-260 nmFootnote 3 Footnote 4. CPXV has a linear double-stranded DNA genome that ranges in size from 205 to 229 kbpFootnote 3. CPXV has the largest genome among orthopoxvirusesFootnote 3. The genome has a G+C content of 33.5%Footnote 5.

DNA sequencing studies have shown that isolates of CPXV do not share a most recent common ancestor, and the species can be divided into a minimum of 5 distinct monophyletic clades that represent different viral species with species-level genomic distinctionsFootnote 6 Footnote 7. The number of clades has been consistent over the years since the first publication in 2011Footnote 8, however, there has been varying consensus among researchers on how to merge or split the cladesFootnote 6. In the most recent publication, the 5 clades can be characterized as 3 CPXV-like clades, 1 variola-like clade, and 1 vaccinia-like clade.

Properties

CPXV replicates in the cytoplasm of host cellsFootnote 4. CPXV produces cytoplasmic A-type inclusion bodies and forms characteristic large red hemorrhagic pocks on the chorioallantoic membraneFootnote 3 Footnote 9. CPXV strains isolated from different geographic regions, passages, or species may vary significantly in pathogenicity, genome size, and/or reactogenicityFootnote 3 Footnote 10. Pathogenicity ranges from 0 to 100% for variant strains using miceFootnote 11. CPXV infects the widest range of host species among orthopoxvirusesFootnote 12. CPXV encodes immunomodulatory proteins that suppress activity of host cell pro-inflammatory cytokines, which reduces antiviral activity and inhibits antigen presentation on cell surface, thereby preventing activation of T-cells.

Section II – Hazard identification

Pathogenicity and toxicity

Cowpox is largely self-limiting in immunocompetent individualsFootnote 3. Symptoms include fatigue, headache, regional lymphadenopathy, and myalgiaFootnote 13 Footnote 14 Footnote 15. Lesions most commonly appear on the hands, trunk, and/or face, or occasionally on the eyelidFootnote 14 Footnote 15. Approximately 72% of patients develop only one lesionFootnote 14. Lesions progress through papular and vesicular stages (day 7-12) and then form black eschars (2-3 weeks), which are approximately 1-3 cm in diameterFootnote 14. Bacterial superinfections and involvement of the eyes and oral mucosa can developFootnote 15. Most patients recover by 6 to 8 weeks, although some take longer than 12 weeksFootnote 14. Fatal cases are rare, and mostly occurs in immunocompromised patients or those with severe eczemaFootnote 3 Footnote 14 Footnote 16 Footnote 17 Footnote 18 Footnote 19. Ocular forms of disease may lead to serious complications, such as necrosis, keratitis, and blindnessFootnote 20.

Clinical presentation is similar in other animal hosts. CPXV has been associated with disease in domestic animals, including cats, dogs, horses, and cattle, and in a wide range of non-domestic speciesFootnote 15. Clinical manifestations of disease vary between species; some animals develop a cutaneous syndrome with lesions varying in severity, whereas a severe systemic form with fulminant viremia associated with high morbidity and a fatal outcome has been reported in other species. Systemic disease can lead to lesions forming in the digestive and respiratory tractsFootnote 21. Cats usually develop fever and lymphadenopathy, with primary skin lesions followed by a rash distributed over the body, and secondary rash 4-16 days post-exposureFootnote 3 Footnote 22 Footnote 23. An atypical pulmonary form of cowpox is occasionally observedFootnote 3 Footnote 24. Most cats recover, although some conditions that compromise the immune system, such as co-infection or feline immunodeficiency virus, may increase the severity of diseaseFootnote 3 Footnote 22.

CPXV infection has caused fatalities in many different species, including alpacasFootnote 25, non-human primatesFootnote 26 Footnote 27 Footnote 28, feline predatorsFootnote 29 Footnote 30, mongoosesFootnote 29, and elephantsFootnote 3 Footnote 31.

Epidemiology

CPXV is maintained in small rodent populations in Europe and AsiaFootnote 32. Human CPXV infection is relatively rare; an estimated 2 to 4 human cases per year are reported in Britain, and between 1969-1994, only 54 human cases were reportedFootnote 14. Two outbreaks of human cowpox were traced back to the purchase of cowpox-infected rats from pet stores in Germany and France between 2008-2011, comprising about 40 casesFootnote 33. Other more recent human cases of CPXV include a potential case of fomite-transmitted CPXV, where a 45-year old male electrician was cut by a guardrail's sharp end that developed into an eschar, and a fatal case of fetal infection from an unknown etiology infecting a pregnant motherFootnote 6. Human and feline cases follow a seasonal distribution pattern, with the majority of cases occurring between July and OctoberFootnote 14. Although cowpox was traditionally a bovine disease, CPXV rarely affects cattle and is most prevalent in cats, with up to 16% of domestic felines showing antibodies against CPXV in England, Norway, Austria, Germany, and FinlandFootnote 3 Footnote 13 Footnote 19 Footnote 22 Footnote 34. Outbreaks of CPXV infection in various animal species have been reported, particularly in zoos and circuses where high mortality rates were observedFootnote 3 Footnote 26 Footnote 28 Footnote 29 Footnote 35.

Individuals with conditions that affect the integrity of the skin barrier (e.g., eczema, Darier disease) and those with atopic and immunosuppressive conditions are more susceptible to CPXV infectionFootnote 3 Footnote 11 Footnote 16 Footnote 17 Footnote 18. These infections are often systemic and more severe compared to otherwise healthy individualsFootnote 14 Footnote 18 Footnote 36, however, there has been a reported case of a healthy patient without medical conditions that had a severe clinical presentationFootnote 37. Evidence indicates that certain substances that suppress the immune response (e.g., diazepam, alcohol) may also increase the severity of infectionFootnote 17 Footnote 19 Footnote 38. Given that immunity to orthopoxviruses is cross-reactive, smallpox vaccination is suspected to have suppressed CPXV infection in human populationsFootnote 39. A seroprevalence study conducted in veterinarians in Finland showed that each individual over 50 years of age had orthopoxvirus antibodies, with decreasing seroprevalence in younger age groups, reflecting the gradual cessation of smallpox vaccination. As such, younger age groups may be more susceptible to infection with CPXV and other orthopoxviruses.

Host range

Natural host(s)

Humans, cattle, cats and feline predators, dogs, mice, lemmings, horses, llamas, alpacas, red pandas, beavers, elephants, rhinoceroses, okapi, anteaters, mongoose, and non-human primatesFootnote 7 Footnote 10 Footnote 29 Footnote 32 Footnote 40 Footnote 41 Footnote 42.

Other host(s)

Rabbits, rats, voles, and non-human primates have been experimentally infected with CPXVFootnote 3 Footnote 43 Footnote 44 Footnote 45. In captivity, small deer, aardvarks, and tapirs have been infected with CPXVFootnote 6 Footnote 21.

Infectious dose

In a pregnant woman diagnosed with cowpox, viral titers at 31 days post-infection were 1.86 × 10 TCID50/mL in a cutaneous biopsy, 2.32 × 107 TCID50/mL in the fetus, and 9.74 × 107 TCID50/mL in the placenta; at 44 days post-infection, viral titers were 1.95 × 108 TCID50/mL in a vaginal swabFootnote 46.

Incubation period

Approximately 8 to 12 daysFootnote 15. CPXV excretion in urine and feces of rats varies from 11 to 35 days post-infectionFootnote 3.

Communicability

CPXV is most commonly transmitted to humans via direct contact with infected animals, particularly domestic cats, which are responsible for 50% of human cases, and pet ratsFootnote 3 Footnote 9 Footnote 14 Footnote 47. CPXV enters through scratches/abrasions in skin or through contact with mucous membranesFootnote 14 Footnote 46 Footnote 48. Transmission by indirect contact via fomites is atypical for CPXV, but is possible as it is a common route for other orthopoxvirusesFootnote 49. Vertical transmission through the placenta to a fetus is also possibleFootnote 46.

In animals, CPXV transmission occurs via ingestion of rodents carrying CPXV and through direct contact with infected animalsFootnote 29. CPXV has been experimentally introduced in various host species via injection and intranasal routeFootnote 3.

Section III – Dissemination

Reservoir

Bank vole, short-tailed field vole, mice, gerbilsFootnote 9 Footnote 32.

Zoonosis

Infected animals can transmit cowpox to humans (e.g., from cat to human)Footnote 6.

Vectors

None.

Section IV – Stability and viability

Drug susceptibility/resistance

Cidofovir, brincidofovir (CMX001), ST-246®, and 4'-thioidoxuridine efficacy against CPXV has been demonstrated in animal modelsFootnote 50 Footnote 51 Footnote 52 Footnote 53 Footnote 54. Terameprocol, trifluridine, adefovir, and pro-nucleotide derivatives of acyclovir, penciclovir, and brivudine inhibited CPXV growth in vitroFootnote 55 Footnote 56 Footnote 57.

CPXV resistance to cidofovir has been observed in vitroFootnote 58.

Susceptibility to disinfectants

Cowpox virus is sensitive to formalin (0.5%), sodium hydroxide (0.1%), hypochlorous acid (0.2%), iodine (1%), sodium hypochlorite (1%), chloramine T (0.2%), iodine and phenolic compounds (3%), and other detergentsFootnote 59 Footnote 60. Susceptibility to Sanytex, sodium hypochlorite, quarterary ammonium combined with chlorhexidine, and quaternary ammonium with glutaraldehyde has been demonstrated for other members of the Orthopoxvirus genusFootnote 61 Footnote 62.

Physical inactivation

Exposure to moist heat at 56-60°C for 15 minutes has resulted in at least 4-log reduction of infective orthopoxvirusFootnote 59 Footnote 63. Dry heat at 95°C for 2 hours resulted in a 4-log reduction of orthopoxvirusFootnote 64. Exposure to UV irradiation for 2 minutes resulted in a 5-log reduction of infective CPXVFootnote 59. Exposure to Roche MagNA Pure lysis/binding buffer and high-speed centrifugation also inactivates orthopoxvirusesFootnote 65 .

Survival outside host

Poxviruses are highly resistant to dryingFootnote 66. Vaccinia virus (Orthopoxvirus genus) dried on glass slides at ambient temperature was found to persist for more than 5 weeksFootnote 67; vaccinia virus is also highly stable in food and water matricesFootnote 68.

Section V – First aid/medical

Surveillance

Diagnosis is accomplished through the monitoring of clinical symptoms. CPXV can be detected using viral culture, electron microscopy, orthopoxvirus-specific immunohistochemical and serological tests, and PCRFootnote 69. Swabs of skin lesions or biopsy samples can be analysed using PCR assays targeting specific genes (e.g., hemagglutinin gene, ATI gene, crmB gene)Footnote 9 Footnote 29. CPXV can be identified by PCR amplicon sequencing.

Note: The specific recommendations for surveillance in the laboratory should come from the medical surveillance program, which is based on a local risk assessment of the pathogens and activities being undertaken, as well as an overarching risk assessment of the biosafety program as a whole. More information on medical surveillance is available in the Canadian Biosafety Handbook (CBH).

First aid/treatment

Treatment is supportive and focused on containmentFootnote 69. There is no approved antiviral therapy for CPXV infection. Antibiotics can be given to treat secondary bacterial infections or to prevent superinfectionsFootnote 20. Cidofovir, a nucleotide analog that is licensed for treatment of other conditions, has serious side effects and is only used when CPXV infection is severeFootnote 13. Vaccinia Immune Globulin (VIGIV), or CNJ-016™, is licenced for treatment of complications of vaccinia vaccination, and may be used to treat severe CPXV infectionsFootnote 19.

Note: The specific recommendations for first aid/treatment in the laboratory should come from the post-exposure response plan, which is developed as part of the medical surveillance program. More information on the post-exposure response plan can be found in the CBH.

Immunization

Imvanex/Imvamune, a third-generation vaccine, and ACAM2000, a vaccinia live virus vaccine, are indicated for active immunization against smallpox, which is closely related to cowpox, and have been approved for use in CanadaFootnote 70 Footnote 71. These vaccines may be indicated for certain workers at high risk of exposure, such as laboratory workers who handle vaccinia or other replicating orthopoxviruses such as CPXV in specialized reference or research facilitiesFootnote 71. In the United States, vaccination every ten years is recommended for laboratory personnel working with CPXVFootnote 72 . Modified Vaccinia Virus Ankara (MVA) has been used to immunize zoo and circus animals in Europe against cowpoxFootnote 9 Footnote 29.

Note: More information on the medical surveillance program can be found in the CBH, and by consulting the Canadian Immunization Guide.

Prophylaxis

None recommended.

Note: More information on prophylaxis as part of the medical surveillance program can be found in the CBH.

Section VI – Laboratory hazard

Laboratory-acquired infections

Three laboratory-acquired cases of CPXV infection have been reported post-1970: one case in 1988 involving inoculation by an infected rodentFootnote 73, one case in 2010 likely transmitted via contact with contaminated surfaces or from handling contaminated reagentsFootnote 74, and one case in 2011 involving accidental self-inoculationFootnote 75.

Note: Please consult the Canadian Biosafety Standard (CBS) and CBH for additional details on requirements for reporting exposure incidents.

Sources/specimens

Urine, feces, blood, biopsy specimens, pus, and contents of pustules and lesionsFootnote 3 Footnote 29.

Primary hazards

Exposure of skin to infectious material and bites/scratches of an infected animal are the primary hazards associated with exposure to CPXVFootnote 2 Footnote 4 Footnote 8 Footnote 27.

Special hazards

None.

Section VII – Exposure controls/personal protection

Risk group classification

CPXV is a Risk Group 2 Human Pathogen and Risk Group 2 Animal PathogenFootnote 76 Footnote 77.

Containment requirements

Containment Level 2 facilities, equipment, and operational practices outlined in the CBS for work involving infectious or potentially infectious materials, animals, or cultures.

Protective clothing

The applicable Containment Level 2 requirements for personal protective equipment and clothing outlined in the CBS are to be followed. The personal protective equipment could include the use of a lab coat and dedicated footwear (e.g., boots, shoes) or additional protective footwear (e.g., boot or shoe covers) where floors may be contaminated (e.g., animal cubicles, PM rooms), gloves when direct skin contact with infected materials or animals is unavoidable, and eye protection where there is a known or potential risk of exposure to splashes.

Note: A local risk assessment will identify the appropriate hand, foot, head, body, eye/face, and respiratory protection, and the personal protective equipment requirements for the containment zone and work activities must be documented.

Other precautions

A biological safety cabinet (BSC) or other primary containment devices to be used for activities with open vessels, based on the risks associated with the inherent characteristics of the regulated material, the potential to produce infectious aerosols or aerosolized toxins, the handling of high concentrations of regulated materials, or the handling of large volumes of regulated materials.

Use of needles and syringes are to be strictly limited. Bending, shearing, re-capping, or removing needles from syringes are to be avoided, and if necessary, performed only as specified in standard operating procedures (SOPs). Additional precautions are required with work involving animals or large-scale activities.

For diagnostic laboratories handling primary specimens that may contain Cowpox virus, the following resources may be consulted:

Section VIII – Handling and storage

Spills

Allow aerosols to settle. Wearing personal protective equipment, gently cover the spill with absorbent paper towel and apply suitable disinfectant, starting at the perimeter and working towards the centre. Allow sufficient contact time with disinfectant before clean up (CBH).

Disposal

All materials/substances that have come in contact with the regulated materials to be completely decontaminated before they are removed from the containment zone or standard operating procedures (SOPs) to be in place to safely and securely move or transport waste out of the containment zone to a designated decontamination area / third party. This can be achieved by using decontamination technologies and processes that have been demonstrated to be effective against the regulated material, such as chemical disinfectants, autoclaving, irradiation, incineration, an effluent treatment system, or gaseous decontamination (CBH).

Storage

The applicable Containment Level 2 requirements for storage outlined in the CBS are to be followed. Primary containers of regulated materials removed from the containment zone to be labelled, leakproof, impact resistant, and kept either in locked storage equipment or within an area with limited access.

Section IX – Regulatory and other information

Canadian regulatory information

Controlled activities with CPXV require a Pathogen and Toxin licence issued by the Public Health Agency of Canada. CPXV is a terrestrial animal pathogen in Canada; therefore, importation of CPXV requires an import permit under the authority of the Health of Animals Regulations (HAR). The PHAC issues a Pathogen and Toxin licence which includes a Human Pathogen and Toxin licence and an HAR importation permit.

The following is a non-exhaustive list of applicable designations, regulations, or legislations:

Last file update

November 2023

Prepared by

Centre for Biosecurity, Public Health Agency of Canada.

Disclaimer

The scientific information, opinions, and recommendations contained in this Pathogen Safety Data Sheet have been developed based on or compiled from trusted sources available at the time of publication. Newly discovered hazards are frequent and this information may not be completely up to date. The Government of Canada accepts no responsibility for the accuracy, sufficiency, or reliability or for any loss or injury resulting from the use of the information.

Persons in Canada are responsible for complying with the relevant laws, including regulations, guidelines and standards applicable to the import, transport, and use of pathogens in Canada set by relevant regulatory authorities, including the Public Health Agency of Canada, Health Canada, Canadian Food Inspection Agency, Environment and Climate Change Canada, and Transport Canada. The risk classification and related regulatory requirements referenced in this Pathogen Safety Data Sheet, such as those found in the Canadian Biosafety Standard, may be incomplete and are specific to the Canadian context. Other jurisdictions will have their own requirements.

Copyright © Public Health Agency of Canada, 2024, Canada

References

Footnote 1

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Footnote 2

Baxby, D. 1982. The natural history of cowpox. Bristol Med. Chir. J. 97:12-16.

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Footnote 3

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Footnote 4

Peterson, B. W., and I. K. Damon. 2015. Orthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox, p. 1694. J. E. Bennett, R. Dolin, and M. J. Blaser (eds.), Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Elsevier/Saunders, Philadelphia, PA.

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Footnote 5

Li, Y., H. Meyer, H. Zhao, and I. K. Damon. 2010. GC content-based pan-pox universal PCR assays for poxvirus detection. J Clin Microbiol 48:268-76.

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Footnote 6

Bruneau, R. C., L. Tazi, and S. Rothenburg. 2023. Cowpox Viruses: A Zoo Full of Viral Diversity and Lurking Threats. Biomolecules 13.

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Footnote 7

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Footnote 8

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Footnote 9

Essbauer, S., and H. Meyer. 2007. Genus OrthopoxvirusCowpox virus, p. 75. A. A. Mercer, A. Schmidt, and O. Weber (eds.), Poxviruses. Birkhäuser Basel, Boston.

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Footnote 10

Bennett, M., and D. Baxby. 1996. Cowpox. J. Med. Microbiol. 45:157-158.

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Footnote 11

Duraffour, S., B. Mertens, H. Meyer, J. J. van den Oord, T. Mitera, P. Matthys, R. Snoeck, and G. Andrei. 2013. Emergence of cowpox: study of the virulence of clinical strains and evaluation of antivirals. PLoS One. 8:e55808.

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Footnote 12

Alzhanova, D., and K. Früh. 2010. Modulation of the host immune response by cowpox virus. Microbes Infect 12:900-9.

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Footnote 13

Nitsche, A., and G. Pauli. 2007. Sporadic human cases of cowpox in Germany. Euro Surveill. 12:E070419.3.

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Footnote 14

Baxby, D., M. Bennett, and B. Getty. 1994. Human cowpox 1969-93: a review based on 54 cases. Br. J. Dermatol. 131:598-607.

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Footnote 15

Becker, C., A. Kurth, F. Hessler, H. Kramp, M. Gokel, R. Hoffmann, A. Kuczka, and A. Nitsche. 2009. Cowpox virus infection in pet rat owners: not always immediately recognized. Dtsch Arztebl Int 106:329-34.

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Footnote 16

Fassbender, P., S. Zange, S. Ibrahim, G. Zoeller, F. Herbstreit, and H. Meyer. 2016. Generalized Cowpox Virus Infection in a Patient with HIV, Germany, 2012. Emerg Infect Dis 22:553-5.

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Footnote 17

Czerny, C.-P., A. M. Eis-Hübinger, A. Mayr, K. E. Schneweis, and B. Pfeiff. 1991. Animal poxviruses transmitted from cat to man: current event with lethal end. J Vet Med B 38:421-431.

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Footnote 18

Haase, O., A. Moser, C. Rose, A. Kurth, D. Zillikens, and E. Schmidt. 2011. Generalized cowpox infection in a patient with Darier disease. Brit J Dermatol 164:1116-1118.

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Footnote 19

Kak, V. 2003. Cowpox--not cows but cats. Arch. Intern. Med. 163:249.

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Footnote 20

Krankowska, D. C., P. A. Woźniak, A. Cybula, J. Izdebska, M. Suchacz, K. Samelska, A. Wiercińska-Drapało, and J. P. Szaflik. 2021. Cowpox: How dangerous could it be for humans? Case report. International Journal of Infectious Diseases 104:239-241.

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Footnote 21

Costa, T., M. F. Stidworthy, R. Ehmann, D. Denk, I. Ashpole, G. Drake, I. Maciuca, G. Zoeller, H. Meyer, and J. Chantrey. 2023. Cowpox in zoo and wild animals in the United Kingdom. J Comp Pathol 204:39-46.

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Footnote 22

Bennett, M., C. J. Gaskell, D. Baxby, R. M. Gaskell, D. F. Kelly, and J. Naidoo. 1990. Feline cowpox virus infection. J Small Anim Pract. 31:167.

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Footnote 23

Jungwirth, N., C. Puff, K. Köster, R. Mischke, H. Meyer, A. Stark, B. Thoma, G. Zöller, F. Seehusen, M. Hewicker-Trautwein, A. Beineke, W. Baumgärtner, and P. Wohlsein. 2018. Atypical Cowpox Virus Infection in a Series of Cats. J Comp Pathol 158:71-76.

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Footnote 24

McInerney, J., K. Papasouliotis, K. Simpson, K. English, S. Cook, E. Milne, and D. A. Gunn-Moore. 2016. Pulmonary cowpox in cats: five cases. J. Feline Med. Surg. 18:518-525.

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Footnote 25

Prkno, A., D. Hoffmann, D. Goerigk, M. Kaiser, A. C. F. van Maanen, K. Jeske, M. Jenckel, F. Pfaff, T. W. Vahlenkamp, M. Beer, R. G. Ulrich, A. Starke, and M. Pfeffer. 2017. Epidemiological Investigations of Four Cowpox Virus Outbreaks in Alpaca Herds, Germany. Viruses. 9:344. doi: 10.3390/v9110344. eCollection 2017 Nov.

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Footnote 26

Cardeti, G., C. E. M. Gruber, C. Eleni, F. Carletti, C. Castilletti, G. Manna, F. Rosone, E. Giombini, M. Selleri, D. Lapa, V. Puro, A. Di Caro, R. Lorenzetti, M. T. Scicluna, G. Grifoni, A. Rizzoli, V. Tagliapietra, L. De Marco, M. R. Capobianchi, and G. L. Autorino. 2017. Fatal Outbreak in Tonkean Macaques Caused by Possibly Novel Orthopoxvirus, Italy. Emerg. Infect. Dis. 23:1941-1949.

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Footnote 27

Girling, S. J., R. Pizzi, A. Cox, and P. M. Beard. 2011. Fatal cowpox virus infection in two squirrel monkeys (Saimiri sciureus). Vet. Rec. 169:156.

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Footnote 28

Matz-Rensing, K., H. Ellerbrok, B. Ehlers, G. Pauli, A. Floto, M. Alex, C. P. Czerny, and F. J. Kaup. 2006. Fatal poxvirus outbreak in a colony of New World monkeys. Vet. Pathol. 43:212-218.

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Footnote 29

Kurth, A., M. Straube, A. Kuczka, A. J. Dunsche, H. Meyer, and A. Nitsche. 2009. Cowpox virus outbreak in banded mongooses (Mungos mungo) and jaguarundis (Herpailurus yagouaroundi) with a time-delayed infection to humans. PLoS One. 4:e6883.

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Footnote 30

Baxby, D., D. G. Ashton, D. M. Jones, and L. R. Thomsett. 1982. An outbreak of cowpox in captive cheetahs: virological and epidemiological studies. J. Hyg. (Lond). 89:365-372.

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Footnote 31

Kurth, A., G. Wibbelt, H. P. Gerber, A. Petschaelis, G. Pauli, and A. Nitsche. 2008. Rat-to-elephant-to-human transmission of cowpox virus. Emerg. Infect. Dis. 14:670-671.

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Footnote 32

Chantrey, J., H. Meyer, D. Baxby, M. Begon, K. J. Bown, S. M. Hazel, T. Jones, W. I. Montgomery, and M. Bennett. 1999. Cowpox: reservoir hosts and geographic range. Epidemiol. Infect. 122:455-460.

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Footnote 33

Antwerpen, M. H., E. Georgi, A. Nikolic, G. Zoeller, P. Wohlsein, W. Baumgärtner, C. Peyrefitte, R. Charrel, and H. Meyer. 2019. Use of Next Generation Sequencing to study two cowpox virus outbreaks. PeerJ 7:e6561.

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Footnote 34

Chomel, B. B. 2014. Emerging and Re-Emerging Zoonoses of Dogs and Cats. Animals (Basel). 4:434-445.

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Footnote 35

Stagegaard, J., A. Kurth, D. Stern, P. W. Dabrowski, A. Pocknell, A. Nitsche, and L. Schrick. 2017. Seasonal recurrence of cowpox virus outbreaks in captive cheetahs (Acinonyx jubatus). PLoS One. 12:e0187089.

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Footnote 36

Blackford, S., D. L. Roberts, and P. D. Thomas. 1993. Cowpox infection causing a generalized eruption in a patient with atopic dermatitis. Br. J. Dermatol. 129:628-629.

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Footnote 37

Elsendoorn, A., G. Agius, G. Le Moal, F. Aajaji, A. L. Favier, E. Wierzbicka-Hainault, G. Béraud, O. Flusin, J. M. Crance, and F. Roblot. 2011. Severe ear chondritis due to cowpox virus transmitted by a pet rat. J Infect 63:391-3.

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Footnote 38

Huemer, H. P., C. Lassnig, N. Nowotny, E. U. Irschick, M. Kitchen, and M. Pavlic. 2010. Diazepam leads to enhanced severity of orthopoxvirus infection and immune suppression. Vaccine. 28:6152-6158.

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Footnote 39

Pelkonen, P. M., K. Tarvainen, A. Hynninen, E. R. Kallio, K. Henttonen, A. Palva, A. Vaheri, and O. Vapalahti. 2003. Cowpox with severe generalized eruption, Finland. Emerg Infect Dis 9:1458-61.

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Footnote 40

von Bomhard, W., E. A. Mauldin, W. Breuer, S. Pfleghaar, and A. Nitsche. 2011. Localized cowpox infection in a 5-month-old Rottweiler. Vet. Dermatol. 22:111-114.

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Footnote 41

Franke, A., F. Pfaff, M. Jenckel, B. Hoffmann, D. Hoper, M. Antwerpen, H. Meyer, M. Beer, and D. Hoffmann. 2017. Classification of Cowpox Viruses into Several Distinct Clades and Identification of a Novel Lineage. Viruses. 9:10.3390/v9060142.

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Footnote 42

Vorou, R. M., V. G. Papavassiliou, and I. N. Pierroutsakos. 2008. Cowpox virus infection: an emerging health threat. Curr Opin Infect Dis 21:153-6.

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Footnote 43

Kalthoff, D., P. König, H. Meyer, M. Beer, and B. Hoffmann. 2011. Experimental cowpox virus infection in rats. Vet Microbiol 153:382-6.

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Footnote 44

Franke, A., R. G. Ulrich, S. Weber, N. Osterrieder, M. Keller, D. Hoffmann, and M. Beer. 2017. Experimental Cowpox Virus (CPXV) Infections of Bank Voles: Exceptional Clinical Resistance and Variable Reservoir Competence. Viruses 9.

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Footnote 45

Johnson, R. F., S. Yellayi, J. A. Cann, A. Johnson, A. L. Smith, J. Paragas, P. B. Jahrling, and J. E. Blaney. 2011. Cowpox virus infection of cynomolgus macaques as a model of hemorrhagic smallpox. Virology 418:102-12.

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Footnote 46

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