Control Tools

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  For most zoonotic poxviruses there are no universal diagnostic tests in use. When available, diagnosis is mainly performed at academic institutions or in public health reference laboratories.

  The main exception is for zoonotic orthopoxviruses, in particular MPV diagnosis. Following the 2022 pandemic, MPV has attracted increased interest from researchers and companies, leading to the release of various diagnostic solutions on the market.

  GAPS

  Rapid (validated), point-of-care tests are not available, except in the case of some zoonotic orthopoxviruses, mainly MPV.

• Diagnostic kits validated by International, European or National Standards

  None, except for a limited range of OPV diagnostics. According to FINDDX, there are a number (289) of MPV assays available for antibody detection (IgG and IgM), antigen detection and MPV DNA detection in the format of lab based, near point of care and real point of care for humans. One such is the isothermal amplification near point of care kit (Xenturion srl, Italy) for the identification of CoPV, VV, and MPV in several pathological matrices.

  GAPS

  Less than 50% of the assays available (111) reached regulatory status “achieved” for use in humans.

• Diagnostic method(s) described by International, European or National standards

  For PPVs, ELISAs and IFAs and PCRs are available. Several laboratories in the EU, including national public health (and defense) laboratories in the UK, Germany, Spain, France and Italy, and Brazil have the capacity to perform nucleic acid-based testing for the presence of orthopox virus signatures in clinical specimens. Several LAMP techniques, a new mini array method able to simultaneously detect OPV and PPV and an OPV ELISA detection have been recently published.

  GAPS

  Missed or mistaken diagnosis constitutes a ground for reflection on the sometimes incapacitating consequences of the disease on certain categories of patients such as children and immunocompromised individuals and on public health in case of poxvirus zoonoses and other life-threatening cutaneous agents.Lack of translation of research results into commercial products for these neglected diseases.Point of care diagnostic test for antigen detection is required, PCR could be used in animal diagnosis.

• Commercial potential for diagnostic kits worldwide

  Recently, possibly due to the increase in severe outbreaks of the disease, labs across Europe, the US, Japan, India and South Africa have shown an interest in the parapox viruses. In most instances this has been to confirm diagnosis of disease outbreaks, thereby reducing the incidence of misdiagnosis.

  A standard diagnostic test should be established to assess PPV associated disease across Europe. Developing a test(s) capable of distinguishing between the parapox-viruses and other agents causing vesicular disease in ruminants. Pen-side devices allowing veterinarians and physicians to rapidly distinguish PPV from other agents causing vesicular diseases in animals and life-threatening cutaneous zoonoses.

  As with PPVs, OPV point-of-care diagnostic assays would be of considerable value for routine screening of animals (and people) having vesicular-pustular lesions to quickly determine an appropriate level of suspicion for orthopox-virus infection. This would encourage rapid implementation of sanitary measures to prevent ongoing transmission of virus. This type of intervention is particularly important as vaccines and therapies are not readily available. An ability to eliminate from the diagnosis other lesion causing agents (anthrax, foot-and-mouth disease) is also of great importance.

  GAPS

  No robust or commercial antibody test.Species specific immunological detection reagents are not available – pre-existing smallpox vaccination, for instance, can obscure diagnosis for OPVs.

  These zoonotic infections share clinical manifestations and exposure risks with other, potentially life-threatening zoonoses (e.g., cutaneous anthrax) and are likely under-recognized because of a lack of clinical suspicion and widely available diagnostics.

  Better knowledge about PPV epidemiology will open the market for commercial diagnostics because negative testing for PPV infection will become a quality standard.

  Specificity and sensitivity need to be maximised against the library of virus strains from across Europe.An assessment of worldwide PPV strain variability will be important to developing accurate diagnostics test that can differentiate between endemic and imported isolates. This may also allow for regional differentiation and will enhance epidemiological efforts.Differential diagnosis will also require an understanding of variation present among other agents causing vesicular disease and how they differ genetically and biologically.

• DIVA tests required and/or available

  None available and a low requirement as routine vaccine use in endemic areas is not frequent.

• Vaccines availability

• Commercial vaccines availability (globally)

  Limited licenced vaccines available for PPVs. Commercial vaccines are available in several countries and are primarily based on live attenuated or scab-derived Orf virus preparations. Current commercial vaccines are mostly live attenuated vaccines and provide partial, short-term protection; therefore, revaccination is often required. Research is ongoing to develop safer and more effective recombinant parapoxvirus vaccines for veterinary use. Comercially available vaccines are used to reduce the severity and spread of disease in livestock populations. Examples of commercially available parapoxvirus-related veterinary vaccines include:

  • Scabivax manufactured by MSD Animal Health for the prevention of contagious pustular dermatitis (Orf) in sheep.

  • Ovine Ecthyma Vaccine, Live Virus produced by Bimeda Biologicals for vaccination against Orf disease in sheep.

  • Ovine Ecthyma vaccine marketed by Colorado Serum Company for sheep and goats.

  • Rapidoll, an inactivated Parapoxvirus ovis immunostimulant manufactured by Dollvet Veterinary Vaccines, used to enhance nonspecific immunity in several animal species. Commercially available vaccines against orthopoxviruses are primarily developed for protection against smallpox and mpox (monkeypox). These vaccines are based on vaccinia virus strains that provide cross-protective immunity against several orthopoxviruses. The two main licensed vaccines currently in use are JYNNEOS and ACAM2000.Vaccine Manufacturer Type Indication JYNNEOS- Bavarian NordicLive, non-replicating Modified Vaccinia Ankara (MVA-BN) vaccine Prevention of smallpox and mpox

  ACAM2000-Emergent Product Development Gaithersburg Inc.

  Live, replication-competent vaccinia virus vaccine Prevention of smallpox and mpox in high-risk individuals

  JYNNEOS (also known as Imvamune or Imvanex) is considered a third-generation orthopoxvirus vaccine and contains a weakened, non-replicating vaccinia strain known as Modified Vaccinia Ankara (MVA). It is administered as a two-dose vaccine and has a better safety profile, especially in immunocompromised individuals.

  ACAM2000 is a second-generation live vaccinia vaccine administered using a bifurcated needle by skin scarification. Because the virus can replicate, vaccinated individuals may transmit vaccinia virus from the inoculation site, therefore, the vaccination site requires special care to prevent the virus from spreading and adverse reactions such as myocarditis have been reported.

  Other stockpiled or regionally used orthopoxvirus vaccines include:

  • Imvanex / Imvamune — European and Canadian trade names for JYNNEOS manufactured by Bavarian Nordic.

  • LC16m8 — an attenuated vaccinia vaccine licensed in Japan for smallpox preparedness.

  • Aventis Pasteur Smallpox Vaccine (APSV) —is an investigational vaccine that may be used in a smallpox emergency under the appropriate regulatory mechanism (i.e., Investigational New Drug application or Emergency Use Authorization [EUA]).

  GAPS

  Initial work on recombinant Orf vaccines needs to be completed.

  There is no published information available on the level of usage of Orf vaccines.

  Vaccines for prevention of OPV infection in animals are currently unavailable, and none are under development apart from Camelpox

• Marker vaccines available worldwide

  None

• Effectiveness of vaccines / Main shortcomings of current vaccines

  Orf: Live, fully virulent virus that causes disease and if used off-label can result in disease outbreaks in flocks.

  Current vaccines against orf are successful in reducing the severity of the disease but can disseminate the vaccine strain of the virus which can cause disease. Live virus vaccines can spread to uninfected animals or humans (zoonotic risk)

  No sterile immunity is induced. Vaccination considered to be effective for 6 -12 months.

  Regarding Orthopoxviruses, modern vaccines such as JYNNEOS and ACAM2000 are highly effective due to strong cross-protection among orthopoxviruses inducing robust humoral and cellular immunity. JYNNEOS provides safer protection, especially in immunocompromised individuals while ACAM2000 can cause serious adverse effects (e.g., myocarditis). Other shorcomings include:

  • Limited supply and accessduring outbreaks
  • Two-dose schedule (JYNNEOS)→ slower population-level protection
  • Waning immunity over time
  • Not specifically tailored to all emerging orthopoxviruses
  • Cold-chain and stockpiling challenges

  Mpox vaccines can help prevent infection and slow the spread of mpox. Vaccination also helps to protect people from severe symptoms. According to WHO, Mpox vaccination is recommended for people at risk of contracting mpox, especially during an outbreak. Whether or not vaccination is advised depends on an individual’s personal risk level and national and local health policies. It is important to use the available stocks to protect the people who are most at risk.

  GAPS

  It is undetermined if vaccination against smallpox extends protection from infection with CoPV.

  The duration of immunity conferred by smallpox vaccination is unknown and highly debated.

  Improved vaccines that offer sterile immunity.

• Commercial potential for vaccines

  There is considerable scope for improving the currently available vaccines against Orf given its economic impact.

  Mass vaccination against zoonotic poxviruses (i.e. vaccination of a large number of people in a country or a region regardless of their level of risk) is not currently recommended. For this, vaccines are produced mainly for strategic reserves, not routine use. During mpox outbreaks, unequal distribution was evidenced and Regulatory approvals may differ across regions with possible delayed access in low-income countries. Vaccines such as JYNNEOS (from Bavarian Nordic) may be deployed under Emergency Use Authorization (EUA) and Stockpile-based distribution. Governments and manufacturers should estimate how much to stockpile including Shelf-life management and replacement cycles and balance high cost with uncertain demand.

  GAPS

  Moderate if safety issues are dealt with.

• Regulatory and/or policy challenges to approval

  There are concerns related to current PPV vaccines using live virulent virus (scab-based) with the Risk of virus spread within flocks and zoonotic transmission to humans while Regulatory agencies impose strict containment and labelling requirements. Orf is not a notifiable or high-priority transboundary disease receiving less public funding and regulatory fast-tracking. Efficacy of trials are limited since Natural infection is widespread making it difficult to design controlled field trials. Parapoxvirus vaccines face challenges mainly due to low economic priority, weak efficacy data, and safety concerns with traditional live vaccines.

  Orthopoxvirus vaccines face challenges rooted in biodefense policy, including ethical constraints on trials, reliance on animal models, and balancing safety with emergency preparedness.

  Second and third generation vaccines currently licensed or in clinical trial have improved safety profiles and are likely to be of greater acceptability than vaccines used during smallpox eradication.

• Commercial feasibility (e.g manufacturing)

  Parapoxvirus vaccines are generally considered low–moderate commercial feasibility products but they have several manufacturing advantages such as technically simple production as vaccines can be produced in existing facilities for livestock vaccines. However, the market is considered small and seasonal linked to sheep/goat farming cycles with low willingness to pay per dose. Orthopoxvirus vaccines are moderate–high complexity but commercially viable under government contracts

• Opportunity for barrier protection

  OPV: Barrier protection would be advocated.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  There are no approved veterinary treatments for poxvirus-related infections.Parapoxvirus infections have no specific curative therapy exists; management is mainly supportive. There are records of traditional or alternative remedies used for the treatment and prevention of OV infections in sheep and goats. Application of different oils (sesame and castor), the juice of Acra (Calotropis procera) and that of Thor (Euphorbia spp) have been used in India and in several African countries while Ilex aquifolium has been employed to cure and prevent ecthyma in the Netherlands and in France. The anti-orf virus activity of Cidofovir (HPMPC, CDV, Vistide®) was demonstrated in studies in vitro and ex vivo. In vivo, in experimentally infected lambs, it was shown that the topical application of cidofovir cream resulted in milder lesions that resolved more quickly than untreated lesions. Cidofovir also reduces the amount of viable virus found in the lesions and thus could be critical to reducing the incidence of disease on farms that have a persistent problem with orf. Orthopoxvirus infections have structured antiviral treatment options and effective vaccines, making both curative and preventive strategies significantly stronger, especially for outbreak control and biodefense preparedness. First-line antivirals include Tecovirimat (TPOXX) considered the main therapeutic option for severe orthopoxvirus infection. It is FDA-approved for smallpox and used for mpox under expanded access. Cidofovir (VISTIDE®) has shown a significant level of anti-orthopoxvirus activity in cell-based in vitro and animal model studies and may be used— along with Probenecid— in ‘off-label’ treatment of humans orthopoxvirus infections or, where possible, as an investigational therapy. VISTIDE® has been licensed for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS and may be available in hospital pharmacies, however, due to significant toxicity, this drug must be administered along with Probenecid to protect against renal damage.

  GAPS

  A pan-poxvirus therapeutic.

• Future therapy

  Several promising compounds, developed under the auspices of bioterrorism preparedness, are currently under investigation. There has been little consideration thus far of their potential application to the prevention and treatment of neglected poxvirus-associated zoonoses.

• Commercial potential for pharmaceuticals

  Pharmaceuticals would be of greatest value in the event of an outbreak and/or following an introduction event,primarily for Orf or MPV in humans outbreaks.

• Regulatory and/or policy challenges to approval

  The use of some key antivirals in food animals is prohibited under EC Directive 2022/1255, but use of these and other compounds for humans, companion and other high value animals (zoo animals) could be explored.

  GAPS

  Cost:benefit assessment of treatment protocols.

• Commercial feasibility (e.g manufacturing)

  Needs to be cost:benefit positive.

• New developments for diagnostic tests

• Requirements for diagnostics development

  Diagnostic tests for poxvirus-associated zoonoses should be developed such that rapid screening can be performed in the field by clinicians (veterinarians and physicians) to readily distinguish poxvirus-associated illnesses from other sources of infection.

  GAPS

  PPVs: Specificity and sensitivity need to be maximised against the library of virus strains from across Europe and worldwideIt will be important to developing accurate diagnostics test that can differentiate between endemic and imported isolates.

  OPVs: Antigen or nucleic acid-based rapid detection assays would likely be preferable and of greater utility than screening tests designed to detect orthopoxvirus antibodies in serum. The former could be run using lesion material as clinical diagnostic specimens. Confirmatory testing could be performed at designated reference facilities having appropriate bio-containment capacity. Ideally, reference laboratories would include facilities specializing in human and in veterinary medical diagnosis. Confirmatory testing should encompass identification of the viral agent to species level (e.g. vaccinia virus vs. monkeypox virus) which is typically accomplished through nucleic acid-based analysis (i.e., PCR, DNA sequencing).

• Time to develop new or improved diagnostics

  Short term.

  For PPVs assay validation will likely require collaboration with reference laboratories and research groups.

  For OPVs molecular assays developed for human patients should be validated also for domestic and wildlife animals.

• Cost of developing new or improved diagnostics and their validation

  Limited.

• Research requirements for new or improved diagnostics

  Limited.

  GAPS

  PPVs:

  • An assessment of worldwide strain variability will be important to developing accurate diagnostics test that can differentiate between endemic and imported isolates. This may also allow for regional differentiation and will enhance epidemiological efforts.

  • Differential diagnosis will also require an understanding of variation present among other agents causing vesicular disease and how they differ genetically and biologically.

  • Sourcing negative sheep / cattle may prove difficult for validation purposes.

  OPVs:

  • A better understanding should be obtained with respect to the identity and distribution of zoonotic reservoirs for OPV-associated zoonotic agents; this will enhance understanding of the genetic variability of species of concern;

  • In keeping with point 2 above, a better understanding of protein and nucleic acid level differences between OP viruses and within OPV species will allow for the development of rapid diagnostic tests that can distinguish between agents and identify viruses to strain type; understanding the precise clinical profiles of the different infections along with risk factors for human and animal infection would support development of clinical algorithms to identify suspected cases and to guide appropriate application of any diagnostic testing.

• Technology to determine virus freedom in animals

  This technology does not exist and would be difficult to develop.

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  PPVs: Requirement for a vaccine that does not cause disease in its own right. Multiple different approaches to vaccine development could be considered including, live-attenuated virus vaccines, DNA vaccines, live recombinant vaccines.

  There is a need to improve vaccines against OV since current vaccines are fully virulent live viruses.

  It is most likely that protective immunity to OV requires the stimulation of a cellular response. It cannot be predicted if this will be achieved most efficiently by a non-infectious subunit vaccine, an engineered attenuated OV, or some other means such as a vector containing the appropriate OV genes. For this reason, it is important to pursue each of these lines of investigation.

  Deliver viral antigens in such a way as to stimulate a cell mediated Th 1 response, including the presentation of peptides on class 1 MHC.

  Most promising candidate is DNA vaccination.

  Alternative approach is generating neutralising antibody response directed against secreted PPV proteins that are unlike any host protein.

  GAPS

  • Determine how the virus avoids the immune response

  • Determine how an effective vaccine can be achieved:

  -Identification of virulence genes to facilitate the selection of virus components that can induce immune reactions without being blocked by counteracting viral proteins

  -Determine which genes encode produce protective antigens able to stimulate protective immune responses. best at stimulating immune activities

  • Continued studies on the use of poxviruses as expression vectors to improve vaccine development and possibly gene therapy by exploiting their potential as immunomodulators.

  -The lack of commercially available products for prevention and control of Orthopox-virus infections suggests that highly-targeted opportunities exist in this arena, particular for overseas markets in highly affected regions.

  -Vaccines against orthopox-virus-associated zoonoses should provide durable cross-protection against infection with multiple species of orthopoxvirus and should pose little to no risk of transmission between humans (giving special consideration to persons with immune-compromising conditions).

• Time to develop new or improved vaccines

  Long term (5 years with full market authorization).

• Cost of developing new or improved vaccines and their validation

  Unknown/ variable. Will depend on the approach selected.

• Research requirements for new or improved vaccines

  See Section “Requirements or opportunities for vaccines development/ main characteristics for improved vaccines” above.

• New developments for pharmaceuticals

• Requirements for pharmaceuticals development

  Testing of anti-virals / excipients / delivery mechanisms.

  GAPS

  • efficacy after development of symptoms,
  • low toxicity,
  • low potential for development of resistance.

• Time to develop new or improved pharmaceuticals

  2-3 years.

• Cost of developing new or improved pharmaceuticals and their validation

  Unknown.

• Research requirements for new or improved pharmaceuticals

  Robust animal infection model, validated and consistent.

Disease details

• Description and characteristics

• Pathogen

  Poxviridae is a family of enveloped, generally oval or brick-shaped viruses, 220–450 nm long, 140–260 nm wide and 140–260 nm thick with a genome comprising a single linear molecule of dsDNA of 128–375 kbp with covalently-closed ends.The family includes two subfamilies:• Members of the Chordopoxvirinae infect vertebrates• While members of the Entomopoxvirinae infect insects

  Generally, gene content and synteny vary between the subfamilies, with only 49 gene products conserved between the two subfamilies.

  Family Poxviridae, subfamily Chordopoxvirinae. The genus Parapoxvirus (PPV) includes five members: 1. Bovine papular stomatitis virus (BPSV) 2. Pseudocowpox virus (PCPV) 3. Orf virus (ORFV)4. Parapoxvirus of red deer in New Zealand (PVNZ)5. Sealpox virus (SPV)

  The genus Orthopoxvirus (OPV) includes six members: 1. Mpox virus (MPV)2. Vaccinia virus (VV)3. Cowpox virus (CoPV)4. Buffalopox virus (BPV)5. Camelpox virus (CaPV)Variola virus [smallpox - eradicated]

  GAPS

  • Little is known about prevalence
  • Inadequate disease recognition
  • Outmoded countermeasures
  • Few barriers to importation
  • More sequencing needs to be conducted to identify novel variants

• Variability of the disease

  Routine PPV diseases are normally self-limiting with low impact on individual animals, although lack of thrift is common leading to delayed finishing times. Occasional severe outbreaks occur leading to loss of teats or to fatalities.

  There are multiple zoonotic pathogens within the genus Orthopoxvirus. These engender a high degree of serologic cross reactivity and may confer some degree of immunologic protection following infection. Within certain “species”, most notably cowpox, there is a significant amount of diversity which may contribute to different disease severity/disease manifestations depending upon the host species.

  Studies conducted in Brazil demonstrate that VV infection can present subclinically in cattle. Furthermore, the country reports co-circulation of VV and PPV in rural areas.

  GAPS

  Little is known about prevalence of severe disease due to. PPV.

  Nothing is known about risk factors associated with severe disease.

  Missing knowledge about the clinical and sub-clinical prevalence of PPV infections in cattle and small ruminants in EU member states.

  For OPV:

  1. Virus reservoirs (particularly rodent)
  2. Range of permissive hosts
  3. Genetic variation within “species” and effect on disease presentation
  4. Interpretation of genetic variation

• Stability of the agent/pathogen in the environment

  Scabs contain millions of virus particles which, when they dry up and drop off the animal, will contaminate the environment for years. Very stable in dry and frozen environments.

  GAP

  Stability of live virus under ambient conditions in nature is largely unknown.

• Species involved

• Animal infected/carrier/disease

  Zoonotic PPVs are:Orf (OV)– sheep/goats/reindeer/muskox/humanBPSV – cattle/camel/humanPCPV– cattle/reindeer/dromedary/human A new GC rich Poxvirus resembling PPV was isolated from a human case possibly linked to a contact with horses.All of these viruses cause contagious skin infections.

  Zoonotic OPVs are:VV/BPVs scabby lesions and ulcers - bovids/ sylvan and peri-domestic rodents, and rodents/humans. More than one outbreak of VV was recently described in horses in Brazil. Cowpox (CoPV) - Pustular rash and fever - historically associated with dairy cattle, but occurs naturally in sylvan rodents (voles, wood mice, gerbils) with some spill-over into in peri-domestic pests (rats). Occasionally observed in housecats, exotic felids, elephants, rhinoceros, horses and okapis. Foxes are also suspected to be susceptible. Cattle (now rare), humans, domestic felines /zoo animals/rodents. Monkeypox (MPV) - smallpox-like illness with disseminated pustular rash and fever. -primates/ rodents, squirrels and marsupials.

  GAPS

  Range of permissive hosts for interspecies recombination

  For OPV:

  1. Virus reservoirs (particularly rodent)
  2. Sylvatic transmission cycles and principal opportunities/risks for spill-over

• Human infected/disease

  General from benign and self-limiting to severe (hospitalisation).

  Reports exist of atypical proliferating forms of giant OV in immunosuppressed and several reports of complicated forms also in immunocompetent individuals. The number of reported complicated cases in immune-suppressed patients is increasing as well as cases linked to religious slaughtering and cases of human to human transmission.

  VV, BPV & CoPV infections can be life-threatening in people who are immune-compromised. A fatal case of CoPV occurred in Germany in 1990.

  MPV infections in people result in the development of a smallpox-like illness with fever, prostration and disseminated pustular rash. Human infections with Congo Basin variants of MPV are fatal up to 15% of the time. Clades 1 and 2 of MPV differ in clinical presentation and severity.

  CaPV - although rare, the infection may spread to the hands of those that work closely with camels.

  GAPS

  Nothing is known about risk factors associated with severe disease.

  The number of reports on complicated OV infections, after religious slaughtering, seems to suggest that predisposing factors related to the ethnic background may contribute to the condition.

  Under-reported because it is seen as occupational hazard that normally is self-limiting

  Proportion of population at risk for sever adverse consequences from Orthopoxvirus infection, owing to immune compromise, exfoliative skin conditions, pregnancy, etc.

  Increasing understanding of natural (clinical) history of MPV infection of humans but little known about prevalence of asymptomatic infections from MPV and other poxvirus infections in humans.

• Vector cyclical/non-cyclical

  None identified.

• Reservoir (animal, environment)

  PPVs infect domestic and wild ruminants as well as wildlife species (e.g seal).

  VV are known to be capable of infecting several species of sylvan and peri-domestic rodents, which are thought to be important for maintaining local foci of infection. In South America, outbreaks of vaccinia virus infection have been described in Brazil and Colombia, affecting cattle and humans. Outbreaks in equines have been described in Brazil. Furthermore, numerous studies have demonstrated exposure in a wide range of domestic and wild mammals, including dogs, cats, marsupials, primates, rodents, etc.

  Eurasian CoPVs have historically been associated with dairy cattle, but occur naturally in sylvan rodents (voles, wood mice, gerbils) with some spill-over into in peri-domestic pests (rats). CoPV infections have occasionally also been observed in housecats, exotic felids, elephants, rhinoceros, horses and okapis. Foxes are also suspected to be susceptible. Similarly, MPV is thought to be maintained naturally in one or more species of African rodent (possibly pouched rats or African dormice), but has the capacity to infect and cause illness in a broad range of taxa including primates, squirrels and marsupials.

  GAPS

  A better understanding of the identity and distribution of reservoirs for poxvirus associated zoonotic agents.

  A better understanding of the identity and distribution of reservoirs for poxvirus associated zoonotic agents.

  Sylvatic transmission cycles and principal opportunities/risks for spill-over.

  Subclinical infections either caused by OPV or PPVs have been recently reported in cattle, horse and red deer. Subclinically infected animals may play the role of reservoirs.

  For OPVs specifically:

  1. Virus reservoirs (particularly rodents)
  2. Range of permissive hosts/transmitting hosts

• Description of infection & disease in natural hosts

• Transmissibility

  Highly transmissible (almost 100% morbidity on affected farms). PPVs infect via broken, scarified or otherwise damaged skin and replicates in epidermal cells following direct contact with infected animals or with contaminated fomites. PPV, VV, BPV and CoPVs are transmissible by direct contact with infectious material, either cutaneous lesions or fomites contaminated with scab material or lesion exudate. The viruses establish infections in new hosts through breaks in the skin or across mucous membranes (particularly of the eye). In certain cases, respiratory transmission is also likely. In Brazil, several studies demonstrate the excretion of VV in milk and the presence of viral DNA in cheeses made with raw milk. Furthermore, serological studies show that unvaccinated individuals present anti-OPV antibodies in municipalities within dairy farming regions. Studies in murine models demonstrate that cheeses contaminated with VV lead to animal infection. There is evidence of VV excretion in faeces of contaminated cattle and of experimental contamination of rodents that came into contact with cattle feces containing viral particles.MPV can be transmitted via direct physical contact (as above) but also via inhalation of infectious materials or respiratory droplets. Infectious respiratory droplets are a particular concern in that person-to-person transmission of virus can occur if hygienic measures are not enacted, especially during the first three days after symptom onset, when ill persons are febrile but lacking in evident signs of rash. Viable virus has also been recovered from the urine and faeces of animals infected with MPV in laboratory settings. Infectious MPV virions are shed from excretions and secretions of infected animals. In humans MPV is infectious in any specimen matrix except serum.CaPV can be spread by indirect contact infection. A camel becomes infected after contact with an infected environment. The virus is spread through milk, saliva, ocular secretions, and nasal secretions, and has been shown to remain virulent outside of a host for four months. CaPV has been isolated from camel ticks (Hyalomma dromedarii) removed from infected animals. It is believed that the ticks can transmit the disease from camel to camel. This theory is supported by increases in Camelpox infections immediately following heavy rains, during which the camel tick population increases greatly.

  GAPS

  Circumstances surrounding interspecies transmission of Orthopoxviruses remain largely unknown.

  Orthopoxviruses are not thought to be transmissible through contaminated milk products, but definitive evidence is lacking.

• Pathogenic life cycle stages

  PPVs, VV/BPV and CoPV are epitheliotropic, infecting damaged skin and replicating in regenerating epidermal keratinocytes., Lesions are localised and progress from erythema to pustule and scab causing painful oral sores in nursing young or cutaneous infections in dairy workers (typically on the hands or arms). Lesions on individual animals can persist for several weeks; animal mortality is rare, but has been reported. In other cases, such as taterapox, no visible lesions were observed in the species attributed as the host. Rodents and primates experimentally infected with MPV typically demonstrate fever, weight loss, diminished activity and disseminated rash, often with signs of pneumonia, blepharoconjunctivitis, and/or anal sores. Manifestation of illness and mortality proportion are dependent on virus dose, route of infection, age and size of the animal etc. Infectious MPV virions are shed from excretions and secretions of infected animals.

  GAPS

  Several aspects of virus genotype-associated pathology remain undefined and are currently understudied.

• Signs/Morbidity

  PPV progress from erythema to macule/papule/vesicle to pustule then scab usually around the mouth or nares of lambs, but also occasionally on the teats of nursing ewes or around the coronets. Potential for misdiagnosis with other pathogens causing vesicular disease in ruminants. Primary lesions can be severe and proliferative, but generally resolve within 6 weeks. Reinfections are less severe and resolve more rapidly than primary ones, usually within 2 weeks. Virus is shed with scab material, and there is no evidence of systemic spread generally, with a suggestion of this in elephants observed. Severe outbreaks of orf can occur where lesions are extensive and proliferative and do not spontaneously regress. Clinically, VV/BPV and CoPV infections of domestic bovines manifest similarly, causing lesions and nodules on the teats of milk-producing animals which release infectious virions. Domestic and exotic cats can die from cowpox.Rodents and primates experimentally infected with MPV typically demonstrate fever, weight loss, diminished activity and disseminated rash, often with signs of pneumonia, blepharoconjunctivitis, and/or anal sores. Manifestation of illness and mortality proportion are dependent on virus dose, route of infection, age and size of the animal etc. Camelpox (CaPV) - skin lesions and a generalized infection. Approximately 25% of young camels that become infected will die from the disease, while infection in older camels is generally more mild.

  GAPS

  Prevalence not known in EU member states

  Possibility of mis-diagnosis with other pathogens causing vesicular disease in ruminants.

  The sub-clinical occurrence of PPV is largely however in context with diagnostic surveillance of notifiable diseases such as FMD, Bluetongue, BVD-Mucosal Disease and BHV-1 parapoxviruses (PPV) have been frequently detected in skin biopsies and swabs.

• Incubation period

  PPVs: 3-4 days;

  VV/CoPV: 5-8 days;

  MPV: 6-10 days, or possibly shorter;

  CaPV: 3-15 days

  GAPS

  Possibility for PPVs subclinical infections in animals

  The influence of virus strain, host type and condition and mode of infection on incubation is under study for OPXV.

• Mortality

  The mortality rate of PPVs is usually less than 1% but secondary complications OV can increase this rate to around 20 to 50%.

  The mortality rate in humans for MPV (Clade 1 genetic type) can be as high as 15% in humans under 16 years-old, and the virus is highly lethal in many animal species. Mortality varies by clade, with lower Case Fatality Rates for clade 2. Clinical outcomes appear to be more serious in immunosuppressed persons.

  GAPS

  The influence of virus strain, host type and condition and mode of infection on morbidity/mortality is under study for OPV.

  Natural history of infection in HIV immunosuppressed persons needs to be better understood and quantified

• Shedding kinetic patterns

  Virus is principally shed during the symptomatic phases of illness. All scab that is shed into the environment is loaded with fully infectious virus. Viral DNA can be recovered weeks after symptom defervescence in animals experimentally infected in the laboratory and in rare instances live virus has been recovered from animals > 1 month after initial infection.

  ORFV virus in wool remains infectious for at least one month.

  GAPS

  OPVs: Shedding patterns have not been defined for all of the permissive hosts for these promiscuous viruses.

  The shedding caused by subclinically infected animals acting as reservoirs need to be further investigated.

• Mechanism of pathogenicity

  The OPV that causes camelpox behaves very similarly to the virus that causes smallpox. After the virus attaches to a host cell, it injects its viral core (the shell containing its DNA) into the cell's cytoplasm. The virus carries DNA polymerase which is used to transcribe its genes. Eventually, the viral core dissolves, and the genetic material is bare within the cytoplasm. When all of the structural proteins have been produced, viral assembly takes place. The newly formed virus particles can be released during cell lysis, or they can derive a host cell produced membrane and be released via budding.

  GAP

  Much is inferred from studies of vaccinia virus or ectromelia, but actual studies in reservoir, transmitting or “end” hosts have been limited.

• Zoonotic potential

• Reported incidence in humans

  Human infections with orf, reindeerpox, sealpox and pseudocowpox have been recorded in recent years across Europe. In the UK, orf virus infections are the most common viral zoonotic reported to the public health laboratory. One study conducted in New Zealand found a 4% annual OV incidence amongst workers directly involved in slaughtering sheep. Multiple reports by CDC for OV, VACV, MPV. In late 2008-early 2009 an outbreak of pet-associated CoPV occurred in the EU resulting in >30 human cases in France, Germany and the Netherlands (ECDC report 11/02/2009). In South America, VV outbreaks have been described in Colombia and Brazil. Brazil is highly endemic for VV, and human infections have been reported in many states. PPV infections have also been described in animals throughout Brazil; however, due to the lack of laboratory diagnostics for human samples, human infections are underreported.Monkeypox virus is communicable in humans.An increasing number of complicated cases after religious slaughtering is being reported.Outbreak associated with imported guinea rats as exotic pets, contaminated co-housed prairie dogs that caused Mpox (Clade 2) outbreak of 71 children in the USA.

  GAPS

  Lack of epidemiological investigations.

  The incidence in humans is frequently unknown because the diseases are not notifiable.

• Risk of occurence in humans, populations at risk, specific risk factors

  The majority of PPVs are transmissible to man with disease considered an occupational hazard to farmers, shepherds, veterinarians, animal handlers, meat and wool processors and also associated with religious slaughter of animals. Increasing number of cases in children exposed to infected animals in an occupational setting or during recreation (source CDC). There is a high risk of contracting orf infection from handling pelts and wool, and that direct contact with current lesions was not required.Recent human Orthopoxvirus infections in the EU have been in pet owners, zoo workers and veterinarians. Infections have either direct contact with infected rats, or contact with other animals (elephant, cat) that had presumably became infected following contact with a rat or other small rodent harbouring CoPV. As OPVs gains further inroads into the peridomestic rat population, the range of people at risk for infection is likely to increase.

  Those currently most at risk for infection with VV/BPVs are individuals engaged in traditional, non-mechanized, dairy production in Brazil and south Asia. Milkers contract infection from manual contact with affected animals and often play a role in transmitting the virus to other animals in the herd.Decreasing cross-protection achieved by VV vaccinationIncreasing number of immune-compromised individuals increase the number of cases. Smallpox vaccine prevents human infection, although replicating smallpox vaccines are dangerous in HIV patients.Transmission of camelpox to humans was confirmed in 2009 when camel herders in India presented with infections of the hands and fingers. Although other cases of human infection have been reported, no other cases have been verified. Due to the close contact between camels and their human handlers in much of the world, it is believed that camelpox is transmitted to humans via direct contact.

  GAPS

  OPV are not thought to be transmissible through contaminated milk products, but definitive evidence is lacking.

  Many risk factors are unknown. It might be reasonable to investigate population specific contribution of the HLA haplotype leading to complications after infection with zoonotic poxviruses.

• Symptoms described in humans

  PPVs cause painful lesions on the hands, fingers and face that respond poorly to treatment. The viruses can cause a systemic reaction sufficiently severe to require hospitalisation. Reports exist of atypical proliferating forms of giant orf in immunosuppressed and reports exist also for immunocompetent individuals. Further complications such as erythema multiform, bullous pemphigoid, swan-neck deformity and paresthesia and autoimmune blistering disorders have also been reported following OV infection.

  OPVs cause painful lesions, typically on the hands and forearms of people at occupational risk; systemic flu-like symptoms (fever, myalgia, fatigue) also occur. People with compromised immune systems or with concurrent exfoliative skin conditions such as eczema are at risk for severe complications from infection, including death.

  A fatal human case of CoPV occurred in Germany in 1990.

  MPV infections in people result in the development of a smallpox-like illness with fever, prostration and disseminated pustular rash. Human infections with Clade 1 viruses of MPV are fatal up to 15% of the time in humans under 16 years-old.

  Camelpox infections in humans result in mild skin lesions on the hands and fingers. Reports have been made that the lesions can be found on the mouth and lips if the patient drank milk from an infected camel, but these symptoms have not been confirmed.

  GAPS

  These zoonotic infections share clinical manifestations and exposure risks with other, potentially life-threatening zoonoses (e.g., tularaemia, cutaneous anthrax) and are likely under-recognized because of a lack of clinical suspicion and widely available diagnostics.

  Specific treatments for individuals experiencing complications do exist, but availability of those biologicals and compounds that have been approved as therapies is limited.

  Natural history of infection in humans and clinical outcome by clade need further study. Protocols must be ready to roll out at the time of outbreaks and funding needed to ongoing studies in sub-Saharan Africa.

• Likelihood of spread in humans

  PPV’s human to human transmission is possible but usually limited to direct contacts.

  Orthopoxviruses are potentially transmissible between persons (CDC). Recent MPV outbreaks have demonstrated the ability of direct human transmission.

  GAPS

  Not known what promotes spread in humans, recent MPV outbreaks need to be further investigated.

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  OPV and PPV: Isolation and quarantine of new animals are useful prevention tactics.

  OPV: Rodent exclusion and contact precautions (use of gloves, eye protection when manipulating symptomatic animals), and environmental remediation as well as vaccination may be useful for control. In Brazil, educational materials on OPV are available for healthcare professionals, veterinarians, and rural producers, but they are still under-disseminated nationwide. Healthcare administrators make little use of them.

  CaPV outbreaks often lead to the loss of young camels, and render older camels useless in terms of milk and meat production, and transportation.

  GAPS

  Efficient and safe vaccines providing long lasting immunity are missing

  Large scale prevention and control programs in animals have not been systematically evaluated for efficacy or acceptability.

  Is vaccination feasible in domestic animals that are at risk

• Endangered wild species affected or not (estimation for Europe / worldwide)

  Orf has a severe effect (high mortality) in semi-domesticated reindeer and in muskox.

  OPV infections cause a high degree of mortality and morbidity in a broad range of taxa, affecting animals as diverse as elephants, dormice, alpacas and ant-eaters. Outbreaks of MPV and CoPV have repeatedly occurred in captive animal populations, often in such instances human illnesses occur. The growing number of anecdotal reports of CoPV in peri-domestic rats raises concern for increased transmission to domestic species, particularly cats and cattle.

  GAPS

  Prevalence in wildlife ruminants is unknown.

  The impact of CoPXV transmission to threatened or endangered native mammals has not yet been thoroughly explored.

• Slaughter necessity according to EU rules or other regions

  Ewes and cows, which suffer loss of mammary function due to PPVs, VV and BPV, may have to be culled. Cohorting, isolation and quarantine may be effective mitigation strategies.

• Geographical distribution and spread

• Current occurence/distribution

  PPV-associated infectious diseases are found throughout the world. Recently it was reported that 40% of the flocks in the USA have been infected with orf virus (source CDC). VV/BPVs are found currently in several Brazilian States (Minas Gerais, Rio de Janeiro, São Paulo, Espírito Santo, Bahia, Ceará, Pará, Maranhão, Rio Grande do Sul, Goiás, etc) and also in Colombia, and throughout South Asia (India, Pakistan). The range of CoPV extends throughout much of Eurasia (excluding Ireland). MPV is naturally occurring in heavily forested regions of West Africa and the Congo Basin.

  GAPS

  The current prevalence of CoPV in rats in the EU is undefined.

  Wild animal studies in sub-Saharan Africa where Mpox occurring in humans, especially Nigeria for Clade 2 and DRC for Clade 1.

• Epizootic/endemic- if epidemic frequency of outbreaks

  Frequency of outbreaks is currently undefined. In clinically affected herds up to 80% morbidity.

  PPV infections are endemic wherever sheep / goats / cattle are farmed. VV/BPV and CoPV infections rarely occur as individual sporadic cases but rather emerge as focal outbreaks.

  Appears to be endemic with year round transmission among animal reservoir, and then seasonal infection in humans for MPV – drought may force rodents closer to humans for food.

  GAPS

  Frequency of outbreaks /affected herds is not known in EU member states and worldwide.

  Currently undefined due to under-reporting.

  No information about subclinical infection.

• Seasonality

  Undefined.

• Speed of spatial spread during an outbreak

  PPVs: Appears to be very fast within a flock / herd.

  OPVs: Currently undefined, situationally dependent.

  GAPS

  Undefined nature.

• Transboundary potential of the disease

  Only with animal movements.

  CoPV: High, based on outbreak in the EU (2008/2009).

  MPV is high risk based upon recent human outbreaks.

• Route of Transmission

• Usual mode of transmission (introduction, means of spread)

  Direct contact / infectious fomites. Always through broken skin.

  PPVs and OPVs are not transmissible via respiratory routes.

  MPV, on the other hand, can be transmitted via direct physical contact (as above) but also via inhalation of infectious materials or respiratory droplets, especially during the first three days after symptom onset, when ill persons are febrile but lacking in evident signs of rash.

  GAP

  Need to understand whether scabs of animal lesions are infectious, as was the case with smallpox virus.

• Occasional mode of transmission

  OPV(VV): was anthropozoonotic, from recently smallpox-vaccinated humans

• Conditions that favour spread

  Previous outbreaks / Rough pasture / Housing / Over-crowding / intensive farming practises.

  GAPS

  Conditions favouring virus transmission from one species to another remain poorly defined.

  Many risk factors remain unknown.

  Seasonality of transmission must be understood

• Detection and Immune response to infection

• Mechanism of host response

  PPVs: Vigorous humoral and cell-mediated response to infection. Neutralising antibodies not normally found. Colostrum from vaccinated / previously exposed ewes has no protective effect.

  OPV: animals, including humans, mount a specific cellular and humoral immune response after infection. The duration of the immunity is varied and repeated infections can occur for VV/BPV (after an interval of years) and potentially for CoPV, but the symptoms of infection are generally mitigated with subsequent infections.

  GAP

  Mechanism of protection not fully understood.

• Immunological basis of diagnosis

  Detection of IgG response to whole virus.

  Antibody responses to old world Orthopox-viruses are broadly cross reactive. A new multiplex assay is able to to differentiate MPV from VV infections

  GAPS

  No robust or commercial antibody test

  Species specific immunological detection reagents are not available – pre-existing smallpox vaccination, for instance, can obscure diagnosis for OPVs.

• Main means of prevention, detection and control

• Sanitary measures

  Disinfection / steam cleaning required for food troughs, buildings etc. used with known affected animals. Appears to be effective.

  Although seldom practised, safe storage of grains away from rodents is key in prevention of transmission to humans.

• Mechanical and biological control

  Scabs contain millions of virus particles which, when they dry up and drop off the animal, will contaminate the environment. Distribution of fomites contaminated with variola virus scabs (the agent of smallpox, a non-zoonotic orthopox virus) was a means of intentional and unintentional disease propagation during the smallpox era. Hygienic measures such as quarantine or isolation of symptomatic animals and use of personal protective equipment or restriction from work of symptomatic persons can be instituted to diminish the potential for continuing spread of orthopox viruses.

• Diagnostic tools

  For PPVs ELISAs and IFAs and PCRs are available. Several laboratories in the EU including national public health (and defense) laboratories in the UK, Germany, Spain, France and Italy have the capacity to perform nucleic acid-based testing for the presence of orthopox virus signatures in clinical specimens.

  Several LAMP techniques, a new mini array method able to simultaneously detect OPV and PPV and an OPV ELISA detection have been recently published.

  GAPS

  Missed or mistaken diagnosis constitutes a ground for reflection on the sometimes-incapacitating consequences of the disease on certain categories of patients such as children and immunocompromised individuals and on public health in case of poxvirus zoonoses and other life-threatening cutaneous agents.

  Lack of translation of research results into commercial products for these neglected diseases.

  Point of care diagnostic test for antigen detection required, PCR could be used in animal diagnosis.

• Vaccines

  Limited licenced vaccines available for PPVs. All vaccines are fully virulent live viruses that can themselves cause outbreaks of disease.

  Human smallpox vaccines are based on VVs. Use of smallpox vaccine in persons at occupational risk for exposure to VV/BPV or MPV may be considered. Only one such vaccine, MVA (modified vaccinia Ankara) is currently licensed for use in the United States for persons with immune-compromise or other conditions for which use of non-highly attenuated vaccines is contra-indicated.

  Two vaccines, known as MVA-BN and LC16m8, can help prevent Mpox.MVA-BN protects animals from lethal doses of Mpox and similar viruses.

  An attenuated vaccine is currently available that provides long term protection against camelpox if administered when the camel is at least 9 months old. An inactivated vaccine is also available, but must be administered yearly to maintain protection.

  GAP

  Few vaccines are under development for specific use in animals.

  Initial work on recombinant Orf vaccines needs to be completed.

• Therapeutics

  Non available commercially, but anti-virals have been tested successfully in the laboratory.

  When the camelpox virus is identified as the causative agent, the disease can be treated with anti-viral medications. The most common medication used to treat camelpox is Cidofovir, a broad spectrum anti-viral that acts by inhibiting the viral DNA polymerase. Cidofovir has proven to be 100% effective at preventing death in infected camels.

  Cidofovir and its prodrug brincidofovir are antiviral medications that inhibit DNA polymerase activity and, thus, DNA replication. Although no randomized efficacy data exist in humans, animal models suggest that brincidofovir may be effective against orthopoxviruses, including Mpox. Data for cidofovir use are extrapolated from the data for brincidofovir.

  GAP

  No therapies are under development for specific use in animals and humans.

• Biosecurity measures effective as a preventive measure

  Recommendation not to use the vaccine on premises where there is no history of OV infection.

  Persons receiving smallpox vaccination should refrain from contact with domestic livestock or zoo animals for a defined period.

  Monkeypox is a select agent in the U.S.

  Segregation of animals in co-housing facilities, with emphasis on quarantine areas for imported animals from high risk geographies, Africa for example.

• Border/trade/movement control sufficient for control

  Not normally practised, but imports/exports are occasionally affected.

• Prevention tools

  Prophylactic vaccination and sanitary / bio-security measures.

• Surveillance

  No routine surveillance programmes in place.

  GAPS

  Humans often act a sentinel population for infections in animals. Routine surveillance programmes in humans could identify sites for animal study/control.

• Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

  No country has eradicated the diseases. Prevention and control is normally a combination of vaccination and sanitary / bio-security measures. Recent gains in diagnostic and treatment capacity for orthopoxvirus infections engendered through bio-terror preparedness activities could be leveraged to combat the negative health, welfare and economic impacts of zoonotic orthopoxviruses including VV/BPV, CoPV and MPV.

  The camelpox virus is sensitive to a number of common disinfectants. It can also be destroyed by autoclaving, short term exposure to UV light, and boiling for at least 10 minutes. These methods may be used by camel herders to minimize risk of environmental contamination.

  GAP

  Controlled field studies to investigate optimal methods for Orf control and/or elimination.

• Costs of above measures

  Costs of surveillance are relatively low (c.€5/sample), but significant in terms of low farm gate prices and in LMICs.

  GAP

  Modelling of cost benefit of vaccination programmes including oral baited vaccine should one be feasible.

• Disease information from the WOAH

• Disease notifiable to the WOAH

  Apart from camelpox, PPV and OPV infections of domestic animals are not reportable to WOAH. Outbreaks of VV occur in several states of Brazil, primarily as annual events during the summer months, causing substantial economic losses and stigma to be affected farms. Reporting of BPV outbreaks in south Asia is variable, but nosocomial human infections (19 probable cases over a 5-month period) were observed in a burn ward in Karachi in 2004-5. Instances of CoPV infection in domestic animals do occur in the EU. In 2008-09, at least 30 cases of pet-associated human CoPV infections were reported from France, Germany and the Netherlands.

  GAPS

  In general, there is likely to be under-reporting of the occurrence of zoonotic poxvirus infections worldwide as appropriate diagnostic assays are not readily available, and the stigma attached to producers and hunters due to contact with these agents is considerable.

• WOAH disease card available

  Direct links to the WOAH.

• WOAH Terrestrial Animal Health Code

  Direct links to the WOAH.

• WOAH Terrestrial Manual

  Direct links to the WOAH.

• Socio-economic impact

• Zoonosis: impact on affected individuals and/or aggregated DALY figures

  Worldwide – more significant in farming communities and in the rural poor in developing countries. Camelpox virus infections in camel herders in the Middle East for example.

  Persons can become infected with Orthopoxviruses through contact with domestic bovine (Brazil, South Asia), peri-domestic or exotic species or pets (EU) or sylvatic species (Congo basin).

  Numbers seldom reflect the real importance of the disease in the communities in which they occur. Poxvirus zoonoses fall into the category of neglected zoonoses with considerable potential to cause significant, even life-threatening, disease in humans and animals as well as profound negative impacts on agricultural productivity.

  GAPS

  Current economic losses in human and animal productivity due to Orthopoxvirus infection in Brazil and South Asia are unknown.

  The incidence is often unknown or greatly underestimated. Under-reporting leads to underestimating the true number of DALYs which can be averted by effective control.

• Zoonosis: cost of treatment and control of the disease in humans

  Unknown

  GAP

  Case studies and modelling required to establish typical outbreak costs.

• Direct impact (a) on production

  Parapoxvirus infections and in particular orf have a great economic impact to those rural communities that are predominantly reliant on livestock farming for their livelihood. OV is in the top twenty most important viral diseases of sheep and goats globally in terms of impact on the poor. Growth may be retarded in lambs affected with the mouth form of orf or with strawberry footrot. There may be a reduction in the reproductive performance of a flock if rams affected with the venereal form of orf become reluctant to mate. Lambing percentages may be reduced and/or the breeding season and lambing may be extended. Bottle feeding and the isolation of infected animals may also add to operating costs, reduction in milk production, extra veterinary costs are due to the usual occurrence of secondary infections on teats leading to mastitis. The reduction in milk production and the spread of these viruses could severely impact the economy. Reindeer infections cause important economic losses to indigenous people (Saami) in Northern Europe. All these factors can result in increased prices of milk, cheese, meat, hides and other products.

  BPV/VV is known to cause substantial economic losses in several regions (Brazil, India, Saudi Arabia, etc.). VV/BPV primarily affects traditional dairy producers whose facilities are generally smaller and have fewer animals than those using automated machinery. Consequently, the spread of VV/BPV may have a devastating impact on rural, artisanal dairies where production depends on a small number of cows or buffaloes.

  Approximately 25% of young camels that become infected will die from the disease, while infection in older camels is generally more mild.

  GAP

  There are no published studies on the costs of OPXV diseases in the EU and worldwide.

• Direct impact (b) cost of private and public control measures

  Unknown. Initial impact likely to be high due to scientific uncertainty and public perception (fear) of poxviruses.

  GAP

  No cost benefit analysis available.

• Indirect impact

  Significant losses in productivity occur when the ability of young animals to feed is negatively impacted either due to the development of mastitis in the adult (often following secondary infection) or oral pain or obstruction in the juvenile. Infections rarely occur as individual sporadic cases, but rather emerge as focal outbreaks, often affecting the majority of animals within a given herd resulting in significant curtailment of dairy production for an affected producer.

  GAP

  No structured analysis available.

• Trade implications

• Impact on international trade/exports from the EU

  Initial impact likely to be high due to scientific uncertainty and public perception (fear) of poxviruses.

  Australia exports large numbers of live sheep (several million each year) to Middle Eastern markets. In the past the presence of orf virus infected sheep has been a problem and has resulted in shipments being not accepted. In light of this potential trade barrier, all sheep for live export must be vaccinated against orf virus prior to export.

  GAPS

  Unknown.

  Surveys are necessary.

• Impact on EU intra-community trade

  Occasional. DG SANCO communication 12/02/2009 to CVOs: CoPV in humans associated with contact with pet rats from Czech Republic.

  GAP

  Unknown.

  Questionnaires necessary.

• Impact on national trade

  Occasional.

• Links to climate

  Seasonal cycle linked to climate

  Dry season - it is believed that the presence of thistles in areas where the animals are grazing favours outbreak and spread – basically things that can break the skin.

  GAP

  Undefined under study

• Distribution of disease or vector linked to climate

  No arthropod vectors mostly.The camelpox virus has been isolated from camel ticks (Hyalomma dromedarii) removed from infected animals. It is believed that the ticks can transmit the disease from camel to camel. This theory is supported by increases in Camelpox infections immediately following heavy rains, during which the camel tick population increases greatly.

• Outbreaks linked to extreme weather

  Virus more stable in dry conditions.

  GAP

  No information from countries with extreme climate differences.

• Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

  No arthropod vector.

  GAP

  Not known if climate change may affect the distribution of disease via impact on reservoir or transmitting host habitats.

• Main perceived obstacles for effective prevention and control

  No vaccine capable of providing sterile immunity for PPVs.

  Obstacles for prevention and control of zoonotic poxviruses include, an absence of readily available diagnostic assays, lack of familiarity with human and animal clinical disease (among veterinarians and physicians), lack of vaccines and therapeutics to prevent virus acquisition/transmission, current incomplete understanding of the burden and distribution of zoonotic poxviruses globally.

  GAP

  Rodent reservoirs for CoPV (and VV) are undefined on the European continent impeding fundamental control measures.

• Main perceived facilitators for effective prevention and control

  For PPVs: Vaccination / biosecurity / sanitary measures.Recent gains in diagnostic and treatment capacity for orthopoxvirus infections engendered through bio-terror preparedness activities could be leveraged to combat the negative health, welfare and economic impacts of zoonotic orthopoxviruses including VV/BPV, CoPV and MPV.

Global challenges

• Antimicrobial resistance (AMR)

• Mechanism of action

  Through misdiagnosis, infection with zoonotic poxviruses can lead to the incorrect use of antibiotics, thereby increasing the risk of AMR.

• Conditions that reduce need for antimicrobials

  Effective diagnosis and prevention of infection and disease associated with zoonotic poxviruses can reduce the incidence of clinical disease that precipitates the use of antimicrobials.

• Alternatives to antimicrobials

  See above Section « Conditions that reduce need for antimicrobials”

• Impact of AMR on disease control

  No direct effect.

• Established links with AMR in humans

  No direct link.

• Digital health

• Precision technologies available/needed

  N/A

• Data requirements

  N/A

• Data availability

  N/A

• Data standardisation

  N/A

• Climate change

• Role of disease control for climate adaptation

  N/A

• Effect of disease (control) on resource use

  N/A

• Effect of disease (control) on emissions and pollution (greenhouse gases, phosphate, nitrate, …)

  N/A

• Preparedness

• Syndromic surveillance

  It is crucial to emphasize the importance of identifying reservoir animal species of zoonotic orthopoxviruses in endemic areas, accurately determining the viral species involved and supporting risk exposure assessment for local communities.

  In Brazil the Federal Laboratories for Agricultural Defense (LFDA) are the official laboratories of the Ministry of Agriculture, Livestock and Supply and are linked to the Secretariat of Agricultural Defense, through the General Coordination of Agricultural Laboratories – CGAL/DTEC/SDA. They act as an authority on various laboratory matters relevant to federal agricultural defense.

  The Network of Federal Laboratories for Agricultural Defense (Rede LFDA) is responsible for providing technical data and results of laboratory analyses, which contribute to decision-making in the field of agricultural defense.

  Based on quality and management tools, it seeks to meet the needs of agricultural inspection in its particularities, guaranteeing the reliability of its test results.

  Brazil has one of the LFDA laboratories dedicated to the diagnosis of vesicular diseases, especially in cattle. This is the laboratory responsible for diagnosing foot-and-mouth disease in Brazil, and because it is a disease often confused with other viral diseases, the laboratory tests a panel of viruses associated with vesicular and exanthematous diseases in animals, including OPV and PPV.

  GAPS

  Parapoxvirus infections are likely under-recognized due to limited clinical suspicion and the lack of widely available diagnostic tools.These infections share clinical features and exposure risks with other potentially life-threatening zoonoses (such as cutaneous anthrax) and highly contagious, high-impact diseases (such as foot-and-mouth disease). Diagnostic assays must achieve optimal sensitivity and specificity against a comprehensive panel of viral strains circulating across Europe. An evaluation of global parapoxvirus strain diversity will be essential for developing accurate diagnostic tests capable of distinguishing between endemic and imported isolates. This could also support regional differentiation and strengthen epidemiological surveillance efforts.Effective differential diagnosis will further require a detailed understanding of the genetic and biological variability among other vesicular disease agents and how they differ from parapoxviruses.Regarding zoonotic orthopoxviruses, the diagnostic tools available for human cases remain far less comprehensive than those developed for animals, including reservoir species and other susceptible animal hosts. While many molecular assays used in human diagnostics could, in principle, be applied to animals, their use would require appropriate adaptation and formal validation.

• Diagnostic platforms

  There are numerous diagnostic protocols published in the scientific literature for the identification of zoonotic poxviruses. For parapoxviruses, these continue to be studied by research groups and a few reference laboratories. Few of these protocols have been developed into commercial kits—one example is https://www.biopremier.com/en/real-time-pcr-detection-kit-orf-virus-parapoxvirusThe situation is different for zoonotic orthopoxviruses. Following the 2022 pandemic, interest in diagnostics has increased worldwide, with kits capable of identifying all zoonotic viruses of the Orthopoxvirus genus and others capable of differentiating between the various species (CoPV, VV, MPV) in humans and in animals. For MPV, a limited number of tests can differentiate between clades I and II and their subclades; these tests are currently available for laboratories and not for point-of-care use.

  In Brazil, molecular diagnosis of orthopoxviruses and parapoxviruses is carried out by research institutions as well as by reference laboratories of both the Ministry of Health and the Ministry of Agriculture and Livestock. Since the introduction of MPV in Brazilian territory, FIOCRUZ, the largest public health agency in Brazil, has developed a molecular diagnostic kit that allows differentiation between VV, MPV, and VZV.

  GAPS

  Missed or incorrect diagnoses underscore the need to consider the sometimes debilitating impact of these diseases, particularly among vulnerable groups such as children and immunocompromised individuals, as well as their broader implications for public health in the context of poxvirus zoonoses and other life-threatening cutaneous pathogens.There remains a significant gap in translating research findings into commercially available products for these neglected diseases.Point-of-care diagnostic tests for antigen detection are needed. PCR can be used for animal diagnosis, and reservoir identification this applies particularly to zoonotic parapoxviruses. For zoonotic orthopoxviruses, the availability of diagnostic kits has increased following the 2022 pandemic; however, with the exception of West Asia and Southeast Asia, achieving regulatory approval is very difficult and requires a significant effort—particularly in financial terms—for companies seeking it; for this reason, many of the available tests are for Research Use Only (RUO).

• Mathematical modelling

  N/A

• Intervention platforms

  N/A

• Communication strategies

  N/A

Risk

• Risks for outbreaks of VV/BPXV are greatest where traditional, non-mechanized diary production occurs, but instances of CPXV (which is endemic through much of Eurasia) have also been observed even on mechanized farms. The experience in the United States with zoonotic transmission of MPXV, which entered the country via imported exotic animals, underscores the importance of being prepared to manage a potentially catastrophic situation.

Main critical gaps

• 1. Diagnostics and surveillance

  • Need for rapid, validated point-of-care tests, especially for field diagnosis and animal hosts.
  • Limited commercial availability and regulatory approval of diagnostic kits.
  • Need for better differential diagnosis and integrated syndromic surveillance.

  2. Viral diversity, epidemiology, and reservoirs

  • Insufficient data on strain variability, endemic versus imported isolates, and reservoir species.
  • Incomplete understanding of burden, distribution, exposure routes, and clinical profiles.

  3. Vaccines

  • Need for safer, more effective parapoxvirus vaccines with longer protection and no disease risk.
  • Lack of animal orthopoxvirus vaccines, marker vaccines, and clear DIVA strategies.
  • Uncertainty about breadth and duration of cross-protection from existing orthopoxvirus vaccines.

  4. Immunology and pathogenesis

  • Need to clarify immune evasion, protective antigens, virulence genes, and correlates of protection.
  • Limited understanding of host–pathogen interactions driving severity, transmission, and immunity.

  5. Pharmaceuticals and therapeutics

  • No approved veterinary treatments and need for a broad pan-poxvirus therapeutic.
  • Need to assess efficacy after symptoms, toxicity, resistance risk, delivery, regulation, and cost–benefit.

  6. Animal models and validation platforms

  • Need for robust animal models and well-characterised samples to validate diagnostics, vaccines, and treatments.

  7. Commercialisation, regulation, and implementation

  • Limited translation of research outputs into approved, commercially available diagnostics, vaccines, and therapeutics.
  • Uncertain markets, costly regulation, stockpiling needs, and access challenges limit product development.

  8. Preparedness, policy, and One Health coordination

  Need for clinician awareness, rapid diagnostic capacity, outbreak response tools, and integrated human–animal–wildlife survelliance.

Conclusion

• Research in this field may lead to a reduction in the incidence, and therefore in the impact, of parapoxvirus-associated disease. This will not only have benefits for the health and welfare of affected animals but should also reduce the zoonotic impact on human health. The substantial research gaps indicate a need for Zoonotic Poxviruses to be prioritised through the Animal health law and One Health regulations.

  There is a high and promising potential for improvement and standardization of PPV-infection diagnostics. Especially rapid and reliable diagnostic differentiation of PPV from high priority notifiable virus infections in cattle and small ruminants is urgently needed.

  Orthopoxvirus-associated infections have had significant negative impacts on local production and have generated public health concerns for people who interact with the infected animals. Preparation includes having (1) trained clinicians who can identify suspected cases of orthopoxvirus-associated illnesses in humans and animals, (2) diagnostic testing capacity to rapidly identify a poxvirus-associated ethiology and identify the species of virus involved, (3) implementation capacity for appropriate sanitary measures, which may include quarantine and vaccination, and (4) therapeutic treatments available for persons experiencing severe illness due to infection with any one of these agents.

  Thoughtful and efficient use of resources may be necessary to ensure that issues related to the availability and development of safe vaccines and effective drugs are addressed.

Sources of information

• Expert group composition

  Jeremy Salt, The Vaccine Group Ltd., UK – [Leader]

  Alessandra Scagliarini, University of Bologna, Italy

  Giliane de Souza Trindade, Federal University of Minas Gerais, Brazil

  Jacqueline Weyer, National Institute for Communicable Diseases, South Africa

  David Hayman, London School of Hygiene & Tropical Medicine, UK

  Tanja Opriessnig, Iowa State University, USA & The Moredun Research Institute, UK

  Martin Ludlow, University of Veterinary Medicine Hannover, Germany

  Andreas Nitsche, Robert Koch Institute, Germany

  Jonas Albarnaz, The Pirbright Institute, UK

• Reviewed by

  Project Management Board.

• Date of submission by expert group

  2nd July 2026

• References

  N/A