The contagious ecthyma (CE) is a disease caused by the Orf virus (ORFV) that primarily affects small ruminants (Gómez et al., 2024).
The high prevalence of CE worldwide and the severe economic losses it causes in affected farms make it one of the most important small ruminant diseases today (Lovatt et al., 2012; Windsor et al., 2017).
CONTAGIOUS ECTHYMA: CHALLENGES IN ITS PREVENTION AND CONTROL
EC is characterized by the presence of papules, vesicles, and pustules on the muzzle, lip, and base of the ears that can lead to proliferative crusty dermatitis, currently defined as pseudotumoral lesions (Pintus et al., 2024).
Less frequently, these dermal lesions can also be observed in other anatomical regions, such as the teats. Likewise, this disease causes erosions and ulcers in the oral and gastrointestinal mucosa (Lacasta et al., 2024).
Lesions caused by ORFV promote the occurrence of secondary bacterial infections that increase the severity of the clinical condition (Haig & Fleming, 1999).
EC is not a notifiable disease and countries lack specific control and prevention programs.
Currently, no commercial diagnostic tools are available and, therefore, epidemiological studies are limited to reporting new cases.
EC does not have a specific treatment, although some antiseptic-analgesic formulas have managed to reduce the severity of lesions in natural infections (Gómez et al., 2024).
Most affected farms tend to treat animals with different antibiotics due to concomitant secondary infections, potentially generating resistances due to prolonged treatments (Kumar et al., 2015).
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In some countries like Australia or France, vaccination is used as the main control measure in endemic areas. However, in Spain there is no registered vaccine against ORFV. Currently, there is no universal effective and safe vaccine against EC as ORFV is able to evade the immune system through different mechanisms (Bukar et al., 2021; Fleming et al., 2015):
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The accessory genes, located at the ends of the ORFV genome, encode immunomodulatory proteins such as OVIFNR (interferon resistance protein), vVEGF (viral vascular endothelial growth factor), GM-CSF (granulocyte-macrophage colony-stimulating factor), and vCBP (viral chemokine binding protein) that inhibit antigen presentation and the recruitment of leukocytes to the affected epidermis and mucosae.The infection localized in epithelial cells of the skin and oral-gastrointestinal mucosa are difficult to access for antibodies and immune cells such as T lymphocytes, which favors the persistence of the virus (Bukar et al., 2021; Fleming et al., 2015).
The different strains of ORFV can present mutations leading to changes in virulence and pathogenicity that complicate immunization strategies (Fleming et al., 2015; Hosamani et al., 2009).
The widespread distribution of this disease, its impact on the viability of farms, and its zoonotic potential make the development of safe and effective vaccines of special interest.
So far, different types of vaccines against ORFV have been generated:
Crust-based vaccines
Live attenuated vaccines
Subunit vaccines
DNA vaccines
Viral vector-based vaccines
Currently, live attenuated vaccines in cell culture are the only ones registered in some countries.
 The aim of this work is to present the advantages and disadvantages of each type of vaccine against EC. |
IMMUNOLOGICAL PARAMETERS RESPONSIBLE FOR PROTECTION AGAINST ORFV
An essential step in the development of vaccination strategies is knowing what type of immune response is intended to be prioritized to confer the highest possible degree of protection.
Natural infection induces a humoral response mediated by antibodies that are not capable of inducing protection against infection, nor elimination of the virus (Buddle & Pulford, 1984; Mercer et al., 1997).
In general, ORFV infection does not induce high titers of neutralizing antibodies. However, some studies show that animals with a high antibody titer are able to recover better after reinfection (McKeever et al., 1988; Yirrell et al., 1991).
Therefore, the role of antibodies in the control of this disease is not fully known.
T lymphocytes, both CD4+ and CD8+, play a very important role in the elimination of the virus (Anderson et al., 2001; Haig, 2006; Haig & McInnes, 2002), with the Th1/cellular response being the most important for the control of this disease.
Additionally, multiple studies have suggested that the stimulation of the innate immune response in the first hours of ORFV infection is key in its immunological control (Friebe et al., 2004; Haig, 2006).
VACCINES AGAINST ORFV: PAST, PRESENT AND FUTURE
Crust-based vaccines
Crust-based vaccines require the isolation and purification of ORFV strains obtained from proliferative crusty lesions of affected lambs or goat kids.
These vaccines were used in 1930 with some success (Bala et al., 2018; Musser et al., 2008, 2012), but fell into disuse due to their serious safety issues such as the high incidence of lesions in immunized animals, even transmissible to non-vaccinated animals.
Moreover, this type of vaccine did not induce cross-protection against other viral strains and posed a risk of viral recombination and generation of new strains.
Live attenuated vaccines in cell cultures
Later, live attenuated vaccines were developed in cell cultures based on pathogenic viruses attenuated after numerous infection passages in different cell lines.
After a certain number of passages, the viruses begin to undergo mutations, some of which may affect the virulence genes, preventing them from inducing pathology in vivo after inoculation.
Although they are safer than the previous ones, they induce a partial, short protection (3-6 months) and not transmissible to the offspring through colostrum (Bath et al., 2005; Bhanuprakash et al., 2012; Friebe et al., 2004; Musser et al., 2008; Onyango et al., 2014; Tan et al., 2009).
These vaccines are currently registered in some countries such as France and Australia and are only recommended in enzootic areas.
Live attenuated vaccines through targeted deletion
Currently, live attenuated vaccines are being investigated through targeted deletion, using different genetic editing techniques, of some of the pathogenic genes of ORFV (Shen et al., 2023; Zhu et al., 2022).
So far, two recombinant ORFVs with deletions in two (vCBP and GM-CSF) and three (vCBP, GM-CSF, and ORFV 121) genes have been generated, achieving complete protection in goat kids against ORFV infection.
However, this type of vaccine has not been tested in sheep and its protection against other viral strains requires further studies.
Additionally, this type of attenuated virus can revert its virulence, recombine with field viruses generating new strains, or become contaminated during laboratory production (Asín et al., 2021; Buddle & Pulford, 1984).
Subunit and DNA vaccines
A safer option consists of non-replicative vaccines of antigenic subunits or DNA vaccines, based on immunogenic proteins or highly conserved genes such as ORFV B2L (ORFV 011 gene) and ORFV F1L (ORFV 059 gene) (Wang et al., 2023; Wassie et al., 2019; Zhao et al., 2011).
Both subunit vaccines and heterologous regimens with subunit and DNA vaccines based on these proteins have induced a robust specific humoral and cellular immune response against ORFV in mouse models.
Recently, a subunit vaccine against ORFV containing multiple epitopes derived from ORFV B2L, F1L, and 080 proteins (Pang et al., 2024).
This vaccine has shown that it is capable of inducing a robust specific immune response in different cell cultures. Therefore, the next step is to determine if this type of vaccine induces protection against ORFV in small ruminants.
Vaccines based on viral vectors
Vaccines based on viral vectors are currently being widely studied against different pathogenic agents. So far, Vaccinia and Adenovirus viruses have been used as viral vectors for the development of vaccines against ORFV.
The generation of a recombinant Vaccinia virus expressing multiple fragments of ORFV DNA has shown marked protection in lambs against ORFV infection (Mercer et al., 1997). However, the immunogenic proteins responsible for this are unknown.
The recombinant Adenovirus expressing ORFV proteins B2L and F1L (Wang et al., 2023) has lower immunogenicity than heterologous regimens based on DNA and subunit vaccines.
The vectors based on the murine Sendai virus (SeV) are known as inducers of pro-inflammatory, antiviral responses and have a high capacity for transgenic expression (Griesenbach et al., 2010).
Recently, the authors of this work generated two recombinant SeVs expressing the B2L (rSeV-GFP-B2L) and F1L (rSeV-GFP-059) proteins.
The rSeV-GFP-B2L vector exacerbates ORFV infection.
Sheep immunized with the rSeV-GFP-059 vector showed complete protection against ORFV infection (Gómez et al., 2023).
 Viral vector-based vaccines can be considered a promising option for the control of ORFV. |
CONCLUSIONS
In conclusion, vaccination is the best, if not the only effective measure to control EC.
The available live attenuated vaccines are not effective and may present safety issues.
The immune-evasive strategies of ORFV complicate vaccine design, requiring a deep understanding of the genome and the immunogenic properties of its proteins.
New strategies based on molecular biology offer the possibility of generating safer recombinant vaccines with a targeted immunological spectrum.
Subunit vaccines, heterologous regimens of subunit and DNA vaccines, and those based on viral vectors constitute a safer and more effective option for the future control of this disease.
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