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 catpox^{Footnote 1}. Prior to the 1930s, the terms cowpox, smallpox vaccine, and vaccinia were synonymous^{Footnote 2}.

Characteristics

Brief description

CPXV is an enveloped, brick-shaped virus measuring 220-450 nm by 140-260 nm^{Footnote 3 Footnote 4}. CPXV has a linear double-stranded DNA genome that ranges in size from 205 to 229 kbp^{Footnote 3}. CPXV has the largest genome among orthopoxviruses^{Footnote 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 distinctions^{Footnote 6 Footnote 7}. The number of clades has been consistent over the years since the first publication in 2011^{Footnote 8}, however, there has been varying consensus among researchers on how to merge or split the clades^{Footnote 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 cells^{Footnote 4}. CPXV produces cytoplasmic A-type inclusion bodies and forms characteristic large red hemorrhagic pocks on the chorioallantoic membrane^{Footnote 3 Footnote 9}. CPXV strains isolated from different geographic regions, passages, or species may vary significantly in pathogenicity, genome size, and/or reactogenicity^{Footnote 3 Footnote 10}. Pathogenicity ranges from 0 to 100% for variant strains using mice^{Footnote 11}. CPXV infects the widest range of host species among orthopoxviruses^{Footnote 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 individuals^{Footnote 3}. Symptoms include fatigue, headache, regional lymphadenopathy, and myalgia^{Footnote 13 Footnote 14 Footnote 15}. Lesions most commonly appear on the hands, trunk, and/or face, or occasionally on the eyelid^{Footnote 14 Footnote 15}. Approximately 72% of patients develop only one lesion^{Footnote 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 diameter^{Footnote 14}. Bacterial superinfections and involvement of the eyes and oral mucosa can develop^{Footnote 15}. Most patients recover by 6 to 8 weeks, although some take longer than 12 weeks^{Footnote 14}. Fatal cases are rare, and mostly occurs in immunocompromised patients or those with severe eczema^{Footnote 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 blindness^{Footnote 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 species^{Footnote 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 tracts^{Footnote 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-exposure^{Footnote 3 Footnote 22 Footnote 23}. An atypical pulmonary form of cowpox is occasionally observed^{Footnote 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 disease^{Footnote 3 Footnote 22}.

CPXV infection has caused fatalities in many different species, including alpacas^{Footnote 25}, non-human primates^{Footnote 26 Footnote 27 Footnote 28}, feline predators^{Footnote 29 Footnote 30}, mongooses^{Footnote 29}, and elephants^{Footnote 3 Footnote 31}.

Epidemiology

CPXV is maintained in small rodent populations in Europe and Asia^{Footnote 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 reported^{Footnote 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 cases^{Footnote 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 mother^{Footnote 6}. Human and feline cases follow a seasonal distribution pattern, with the majority of cases occurring between July and October^{Footnote 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 Finland^{Footnote 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 observed^{Footnote 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 infection^{Footnote 3 Footnote 11 Footnote 16 Footnote 17 Footnote 18}. These infections are often systemic and more severe compared to otherwise healthy individuals^{Footnote 14 Footnote 18 Footnote 36}, however, there has been a reported case of a healthy patient without medical conditions that had a severe clinical presentation^{Footnote 37}. Evidence indicates that certain substances that suppress the immune response (e.g., diazepam, alcohol) may also increase the severity of infection^{Footnote 17 Footnote 19 Footnote 38}. Given that immunity to orthopoxviruses is cross-reactive, smallpox vaccination is suspected to have suppressed CPXV infection in human populations^{Footnote 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 primates^{Footnote 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 CPXV^{Footnote 3 Footnote 43 Footnote 44 Footnote 45}. In captivity, small deer, aardvarks, and tapirs have been infected with CPXV^{Footnote 6 Footnote 21}.

Infectious dose

In a pregnant woman diagnosed with cowpox, viral titers at 31 days post-infection were 1.86 × 10^7­ 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 swab^{Footnote 46}.

Incubation period

Approximately 8 to 12 days^{Footnote 15}. CPXV excretion in urine and feces of rats varies from 11 to 35 days post-infection^{Footnote 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 rats^{Footnote 3 Footnote 9 Footnote 14 Footnote 47}. CPXV enters through scratches/abrasions in skin or through contact with mucous membranes^{Footnote 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 orthopoxviruses^{Footnote 49}. Vertical transmission through the placenta to a fetus is also possible^{Footnote 46}.

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

Section III – Dissemination

Reservoir

Bank vole, short-tailed field vole, mice, gerbils^{Footnote 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 models^{Footnote 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 vitro^{Footnote 55 Footnote 56 Footnote 57}.

CPXV resistance to cidofovir has been observed in vitro^{Footnote 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 detergents^{Footnote 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 genus^{Footnote 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 orthopoxvirus^{Footnote 59 Footnote 63}. Dry heat at 95°C for 2 hours resulted in a 4-log reduction of orthopoxvirus^{Footnote 64}. Exposure to UV irradiation for 2 minutes resulted in a 5-log reduction of infective CPXV^{Footnote 59}. Exposure to Roche MagNA Pure lysis/binding buffer and high-speed centrifugation also inactivates orthopoxviruses^{Footnote 65} .

Survival outside host

Poxviruses are highly resistant to drying^{Footnote 66}. Vaccinia virus (Orthopoxvirus genus) dried on glass slides at ambient temperature was found to persist for more than 5 weeks^{Footnote 67}; vaccinia virus is also highly stable in food and water matrices^{Footnote 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 PCR^{Footnote 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 containment^{Footnote 69}. There is no approved antiviral therapy for CPXV infection. Antibiotics can be given to treat secondary bacterial infections or to prevent superinfections^{Footnote 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 severe^{Footnote 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 infections^{Footnote 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 Canada^{Footnote 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 facilities^{Footnote 71}. In the United States, vaccination every ten years is recommended for laboratory personnel working with CPXV^{Footnote 72} . Modified Vaccinia Virus Ankara (MVA) has been used to immunize zoo and circus animals in Europe against cowpox^{Footnote 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 rodent^{Footnote 73}, one case in 2010 likely transmitted via contact with contaminated surfaces or from handling contaminated reagents^{Footnote 74}, and one case in 2011 involving accidental self-inoculation^{Footnote 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 lesions^{Footnote 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 CPXV^{Footnote 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 Pathogen^{Footnote 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:

• Human Diagnostic Activities Biosafety Guideline
• Local Risk Assessment Biosafety Guideline

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:

• Human Pathogens and Toxins Act and Human Pathogens and Toxins Regulations
• Health of Animals Act and Health of Animals Regulations
• Transportation of Dangerous Goods Act and Transportation of Dangerous Goods Regulations

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.

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