**9. Vaccines against BPV**

**Figure 6.** A diagram of the genomic organisation of BPV13. The three main regions characteristic of PV genomes are shown as grey rectangles above the ruler. The viral genome is represented as linear, and ORFs are shown as white rectangles. The numbers below each ORF indicate the nt positions of the start to stop codons and the corresponding

In Brazil, the association between BPV infection and the occurrence of cutaneous papilloma‐ tosis, enzootic hematuria, and upper gastrointestinal neoplasias has been confirmed in cattle [46,48,57-59]. Previous studies have found BPV in tissues other than the skin epithelium. Thus, BPV1, 2, and 4 have been identified in the embryos and female reproductive tissues of infected cows [60-63]. Similarly, BPV DNA has been detected in samples of blood, milk, urine, seminal fluid, and spermatozoa from infected cattle. These findings point to the possible participation

In addition, other studies have shown the occurrence of multiple infections in cattle exhibiting several cutaneous papillomas that are caused by different BPV types and the possibility of viral co-infections in single lesions [65-68]. Additionally, the presence of several BPV types in single lesions is similar to the situation in human skin, where co-infection by more than 10

Each papillomavirus is known to exhibit specificity for a single animal host species in which it replicates productively. However, only a few viral types are also able to infect a second animal species. In such cases, non-productive infections, that is, infections without the production of infective virions, are the result [1]. This type of infection is the case for the equine sarcoid, which can be defined as a fibroblastic locally invasive skin tumor. Sarcoid is the most frequent neoplasia affecting equine species, and it represents the best-known example of heterologous PV infection because it is caused by BPV1 and 2 [70]. In addition to horses, donkeys, and mules, skin lesions caused by these viral types have also been described in zebras and buffaloes [71,72]. Another example of heterologous PV infection is provided by the detection of DNA from FeSarPV (feline sarcoid-associated papillomavirus), a putative new PV type that was initially identified in feline sarcoids with non-productive infections, in fibropa‐ pillomas and skin samples from cattle with dermatitis [73-75]. The recent detection of FeSarPV in biological samples from cattle strengthens the hypothesis that cattle might be the natural

molecular mass (in parentheses) for each putative viral protein. Source: [55].

126 Current Issues in Molecular Virology - Viral Genetics and Biotechnological Applications

**8. Co-infections and heterologous infections**

of these fluids and cell types in BPV transmission [64].

viral types is frequently detected [69].

host of this virus [73].

Immunity against BPV is considered to be type-specific, and the immune status of the in‐ fected animals is considered to be the crucial factor for clinical progression. Whereas hu‐ moral immunity prevents new infections, cellular immunity (possibly mediated by T lymphocytes) is associated with the spontaneous and immune-mediated regression of es‐ tablished lesions [76].

The finding that epitopes that induce the production of neutralizing antibodies are present in the structural proteins L1 and L2 explains the success of the use of these proteins in the production of vaccines [34].

The recent availability of VLP-based immunogens against HPV that are able to protect mainly against infection by HPV16 and 18 has allowed the development of the first vaccine against one of the main human neoplasias, *i.e.,* cervical cancer [77]. The data that have been collected since the implementation of the HPV vaccine are quite encouraging, and these vaccines seem to be highly efficient [78,79].

In addition, preventive vaccines have been developed for cattle that are mainly against BPV2 and 4. These viral types were selected because they represent the cutaneous and mucous BPVs, respectively, and are associated with the development of cancer in cattle [80]. A vaccine prepared with the BPV2 L1 capsid protein produced as a beta-galactosidase fusion protein in Escherichia coli induced the production of neutralizing antibodies and was able to prevent infection [81]. A similar effect was achieved using an E. coli derived BVP1 L1 protein, which protected calves against post-vaccine challenge with a homologous virus [82].

VLPs produced from the L1 or L1 and L2 genes from BPV4 have also proven to be highly immunogenic and produce powerful prophylactic vaccines. The prevention of infection during challenge with BPV4 through vaccination with L1 VLPs has shown that L1 promotes the production of neutralizing antibodies [34]. Vaccination with VLPs produced from BPV4 L1 and L2 proteins in insect cells also efficiently prevented the development of experimentally induced papillomas [83].

Because BPV does not grow in conventional cell cultures for the production of killed or attenuated live vaccines, protein expression systems, such as yeast and insect cells, have been used to produce VLP vaccines. However, the use of these systems is expensive. Recently, as has been described for other papillomaviruses (e.g., HPV16), a candidate vaccine against BPV1 consisting of L1 VLPs produced *in planta* elicited a strong and specific immune response, which demonstrated its potential as a future vaccine that could be produced at a lower cost [84].

Because the viral life cycle and the progression from benign to malignant lesion are similar in humans and animals, animal PVs and their natural hosts have represented good models for the study of HPV [30,85]. In addition, animal PVs, particularly BPV1 and 4, SfPV1, and CPV1, have also served as models for vaccines against PVs, and observation of the induction of protective immunity through the use of VLP-based vaccines in their corresponding host species has opened the way for the implementation of VLPs in HPV vaccines [86,87].

Currently, immunization through the use of L2 protein peptides has been suggested as an alternative to the use of VLP-based HPV vaccines. Curiously, residues at the N terminus of the L2 viral protein appear to represent a cross-neutralizing epitope capable of eliciting a broad-spectrum protection against many different viral types [87]. Once more, vaccination of both cattle and rabbits with L2-based vaccines has been highly protective against challenge with infectious virus [88,89], which confirms the great potential of L2 vaccines in preventing HPV infections.

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