Caprine Herpesvirus 1: Veterinary Reference
Overview and Taxonomy of Caprine Herpesvirus 1
Caprine herpesvirus 1 (CpHV-1), also historically referred to as caprine herpesvirus type 1 or CapHV-1, represents a significant, yet comparatively understudied, pathogen within the Alphaherpesvirinae subfamily. As a member of the genus Varicellovirus, CpHV-1 is classified within the family Herpesviridae, a large and diverse group of enveloped, double-stranded DNA viruses that are characterized by their ability to establish lifelong latent infections in their respective hosts [4, 6]. The precise taxonomic positioning of CpHV-1 is critical for understanding its biology, pathogenesis, and evolutionary relationships with other ruminant herpesviruses, particularly the well-characterized bovine herpesvirus 1 (BoHV-1), the causative agent of infectious bovine rhinotracheitis (IBR). This relationship is not merely a matter of phylogenetic curiosity; it has profound implications for differential diagnosis, vaccine strategies, and the potential for cross-species transmission.
Taxonomic Classification and Phylogenetic Relationships
The family Herpesviridae is subdivided into three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. CpHV-1 is firmly placed within the Alphaherpesvirinae subfamily, a group of viruses defined by their variable host range, relatively short reproductive cycle, rapid spread in cell culture, and, most importantly, their capacity to establish latency primarily in sensory ganglia [4]. Within this subfamily, CpHV-1 is assigned to the genus Varicellovirus, a genus that includes a host of other significant pathogens of mammalian species, including the aforementioned BoHV-1, bovine herpesvirus 5 (BoHV-5), bubaline herpesvirus 1 (BuHV-1), cervid herpesviruses 1 and 2, elk herpesvirus 1, equine herpesvirus 1 (EHV-1), and suid herpesvirus 1 (pseudorabies virus) [4, 6].
The classification of CpHV-1 as a distinct species is substantiated by comprehensive genetic and phylogenetic analyses. It is a member of a specific cluster of ruminant alphaherpesviruses that are all closely related to BoHV-1 [4]. This cluster is a testament to the co-evolutionary history of these viruses with their respective hosts. However, CpHV-1 is unequivocally a unique viral entity. Substantial genetic divergence separates it from its closest relatives. For instance, analysis of the glycoprotein C (gC) gene, a major immunogenic and virulence-associated glycoprotein, reveals a nucleotide divergence of 26.6% between CpHV-1 and BoHV-1 [2]. This is a far greater divergence than that observed between different BoHV-1 isolates, which can be as low as 0% to 2.7% [2]. For context, the same analysis showed a 9.2% divergence between BoHV-1 and BoHV-5, and a 13% divergence between BoHV-1 and cervid herpesvirus 1 (CvHV-1) [2]. This 26.6% divergence in a single, conserved gene firmly establishes CpHV-1 as a species distinct from other members of the BoHV-1-like virus cluster.
This genetic distinction is further supported by studies employing restriction endonuclease analysis (REA) of the viral genome, which have shown unique restriction fragment patterns for CpHV-1 isolates when compared to BoHV-1 and other related viruses [3, 4]. The combined evidence from molecular characterization and traditional virological methods leaves no doubt as to the unique taxonomic identity of CpHV-1. Its full, standardized name as per the International Committee on Taxonomy of Viruses (ICTV) is Caprine alphaherpesvirus 1, reflecting its placement within the alphavirus subfamily.
Historical Context and Discovery
The first definitive isolation of CpHV-1 was a landmark event in veterinary virology, first reported in the scientific literature by Saito and colleagues in 1974 [3]. This initial isolation was made in California from goats exhibiting clinical signs of disease, a discovery which heralded the recognition of a distinct caprine pathogen. The early work was quickly followed by corroborating reports from other regions of the world. For example, Waldvogel and colleagues (1981) described the isolation and some aspects of pathogenicity of the virus in Switzerland, establishing the infection as a problem in European caprine populations as well [3]. Tarigan and colleagues (1987) were among the first to associate the virus with balanoposthitis in Australia, expanding the clinical spectrum of the disease [3]. The early history of CpHV-1 is one of gradual discovery, moving from an obscure isolate to a recognized cause of significant morbidity and mortality, particularly in neonatal kids. The foundational studies of the 1970s and 1980s set the stage for the more detailed molecular and epidemiological investigations that would follow, many of which are referenced in the literature (e.g., [3, 4]).
Biological and Epidemiological Context
Understanding the taxonomy of CpHV-1 is not an esoteric exercise; it provides a framework for understanding its biology. As an alphaherpesvirus, CpHV-1 exhibits two cardinal features: a lytic productive infection at primary sites (typically mucosal surfaces) and the ability to establish latency. The primary site of latency for CpHV-1, like many other Varicellovirus members, is the sensory ganglia [4]. In the case of CpHV-1, the sacral ganglia have been identified as a key site of latency, which aligns with the syndrome of vulvovaginitis and balanoposthitis often associated with the infection [3]. The virus, once latent, can be reactivated by stress, transport, or parturition, leading to viral shedding and transmission, a phenomenon documented in both natural and experimental conditions [3].
The global distribution of CpHV-1 is still being elucidated, with confirmed cases and seroprevalence studies pointing to its presence in numerous countries, including the United States, Switzerland, Italy, Australia, and others [3]. The seroprevalence in certain regions, such as Southern Italy, has been documented as being considerable, indicating a high rate of subclinical infection within goat herds [3]. The virus is known to cause a range of clinical syndromes, from subclinical infection to severe systemic disease in young kids and genital disease in adults. The reported cases of multiple abortions linked to CpHV-1 infection in a goat herd in the United States underscore its potential as a significant cause of reproductive failure and economic loss [3]. Even with the advent of modern molecular diagnostic techniques, such as those used for other veterinary herpesviruses [5], the detection and characterization of CpHV-1 remain crucial tasks for veterinary diagnostic laboratories. The recent exploration of novel antiviral strategies, such as the use of synthetic peptides against BoHV-1 and CpHV-1, highlights the ongoing relevance of this virus as a target for therapeutic intervention and its recognition as a significant pathogen alongside other alphaherpesviruses [1].
Molecular Pathogenesis of Caprine Herpesvirus 1
Taxonomic Position and Genomic Architecture
Caprine herpesvirus 1 (CpHV-1) is a member of the family Herpesviridae, subfamily Alphaherpesvirinae, genus Varicellovirus. This taxonomic placement aligns CpHV-1 with other economically significant ruminant alphaherpesviruses, including bovine herpesvirus 1 (BoHV-1), bovine herpesvirus 5 (BoHV-5), bubaline herpesvirus 1 (BuHV-1), and cervid herpesviruses 1 and 2 (CvHV-1, CvHV-2) [2, 4]. The genomic organization of CpHV-1 is characteristic of the alphaherpesviruses, comprising a linear double-stranded DNA molecule of approximately 140–145 kbp, encoding over 70 open reading frames (ORFs). The genome is organized into unique long (UL) and unique short (US) regions, each flanked by inverted repeat sequences, a structural hallmark that facilitates genomic plasticity and recombination events. As noted by Kolk (2016), herpesviruses have co-evolved with their hosts over millions of years, resulting in a cluster of genetically related ruminant alphaherpesviruses that share significant sequence homology and antigenic cross-reactivity [4]. This evolutionary relatedness has profound implications for cross-species transmission, diagnostic specificity, and vaccine development.
Viral Entry and Cellular Tropism
The molecular pathogenesis of CpHV-1 begins with viral attachment and entry into susceptible host cells, a process orchestrated by a suite of envelope glycoproteins that are highly conserved among the ruminant alphaherpesviruses. The glycoprotein B (gB), glycoprotein C (gC), glycoprotein D (gD), and the gH/gL heterodimer constitute the core fusion machinery. Glycoprotein C mediates initial attachment to cell surface heparan sulfate proteoglycans, while gD binds to specific cellular receptors, triggering conformational changes that activate the gB and gH/gL fusion complex. Sequence analysis of the gC gene (UL44) has revealed that CpHV-1 exhibits a divergence of 26.6% from BoHV-1 at the nucleotide level, indicating substantial genetic distance that may influence host range and tissue tropism [2]. This divergence in gC, a major immunogenic glycoprotein, likely contributes to the species-specific pathogenicity observed in caprine hosts.
The primary cellular targets for CpHV-1 replication are epithelial cells of the respiratory, genital, and gastrointestinal tracts. Following initial replication at mucosal surfaces, the virus gains access to sensory nerve endings and undergoes retrograde axonal transport to the neuronal cell bodies within sensory ganglia. The trigeminal ganglia serve as the primary site for latency following respiratory infection, while sacral ganglia harbor latent virus after genital infection [3]. This neurotropic capability is a defining feature of the Alphaherpesvirinae subfamily and is central to the lifelong persistence of CpHV-1 within the caprine host. The establishment of latency involves a dramatic reprogramming of viral gene expression, wherein the productive cycle gene expression is highly repressed, and only a limited subset of latency-associated transcripts (LATs) are produced. This molecular silencing allows the virus to evade immune surveillance while maintaining the capacity for periodic reactivation.
Molecular Mechanisms of Latency and Reactivation
The molecular basis of latency in CpHV-1 mirrors that of BoHV-1, wherein the latency-related (LR) gene plays a pivotal role in maintaining the latent state and modulating the host cell environment. In BoHV-1, transcription from the LR gene is readily detected in neurons of trigeminal ganglia of latently infected calves, and the LR gene products have been shown to inhibit apoptosis, promote neuronal survival, and suppress lytic cycle gene expression [4]. By extrapolation, CpHV-1 likely employs analogous molecular strategies, given the close phylogenetic relationship and shared biological properties. The LR gene produces a complex array of transcripts, including microRNAs (miRNAs) that post-transcriptionally regulate viral and cellular gene expression. These miRNAs can target the immediate-early (IE) genes, such as ICP0 and ICP4, thereby maintaining the lytic cycle in a repressed state.
Reactivation from latency is a stochastic event triggered by various stressors, including immunosuppression, parturition, transport, intercurrent disease, and corticosteroid administration. The molecular cascade of reactivation involves the sequential expression of IE genes, which then transactivate early (E) and late (L) genes, culminating in the production of infectious virions. The reactivated virus travels anterogradely along axons to the original mucosal site, where it undergoes lytic replication and is shed in bodily secretions. Tempesta et al. (1998) demonstrated natural reactivation of CpHV-1 in latently infected goats, and subsequent experimental studies confirmed that reactivation could be reproducibly induced by dexamethasone treatment [3]. This capacity for reactivation and shedding is the cornerstone of CpHV-1 epidemiology, as latently infected carriers serve as reservoirs for horizontal transmission to naive animals.
Virulence Factors and Immune Evasion
CpHV-1 encodes a repertoire of virulence factors that subvert host antiviral defenses and facilitate productive infection. The viral thymidine kinase (TK) gene is a critical determinant of neurovirulence and reactivation efficiency. TK phosphorylates nucleoside analogs, thereby expanding the nucleotide pool available for viral DNA replication in non-dividing cells such as neurons. In related alphaherpesviruses, TK-deletion mutants are severely attenuated and exhibit reduced capacity for reactivation from latency. Sequence analysis of the TK gene in ruminant alphaherpesviruses has revealed conserved motifs essential for enzymatic activity, and the TK gene has been successfully used as a target for PCR-based diagnostics [7, 8]. The high degree of conservation of the TK gene among CpHV-1 isolates makes it a reliable molecular target for detection and phylogenetic analysis.
Another key virulence determinant is glycoprotein G (gG), a secreted chemokine-binding protein that modulates the host inflammatory response. Alphaherpesviruses, including CpHV-1, utilize gG to bind and sequester chemokines, thereby impairing the recruitment of immune effector cells to the site of infection. This immune evasion strategy delays the onset of adaptive immunity and allows the virus to establish a foothold in the host before effective antiviral responses are mounted. Additionally, CpHV-1 encodes several proteins that interfere with the interferon (IFN) signaling pathway, including the ICP0 protein, which degrades promyelocytic leukemia (PML) nuclear bodies and counteracts the antiviral state induced by type I interferons.
Pathogenesis of Systemic Disease
The molecular pathogenesis of CpHV-1 infection manifests as a spectrum of clinical syndromes, ranging from subclinical infection to severe systemic disease with high mortality. In neonatal kids, the virus causes a fulminant systemic infection characterized by necrotizing enterocolitis, hepatitis, and adrenal necrosis. The pathogenesis of this severe form involves widespread viral replication in multiple organ systems, leading to extensive tissue necrosis and hemorrhage. The virus targets endothelial cells, causing vasculitis and thrombosis, which contribute to the hemorrhagic diathesis observed in affected kids. The adrenal glands are particularly susceptible, and adrenal necrosis likely contributes to the rapid clinical deterioration and high case fatality rate.
In adult goats, CpHV-1 primarily causes genital disease, manifesting as vulvovaginitis in does and balanoposthitis in bucks. The molecular pathogenesis of genital infection involves viral replication in the mucosal epithelium, leading to the formation of vesicles, pustules, and ulcers. The inflammatory response, characterized by infiltration of neutrophils and lymphocytes, contributes to the clinical signs of pain, swelling, and discharge. Systemic spread is uncommon in immunocompetent adults, but viremia can occur, particularly in pregnant does, leading to transplacental infection of the fetus. Abortion is a significant consequence of CpHV-1 infection in pregnant goats, and the virus has been associated with multiple abortion outbreaks in goat herds worldwide [3]. The molecular mechanisms of transplacental transmission involve infection of the placental trophoblasts, leading to placentitis, fetal viremia, and fetal death.
Genetic Diversity and Phylogenetic Relationships
Molecular characterization of CpHV-1 isolates from different geographic regions has revealed a relatively high degree of genetic conservation, particularly in essential genes such as gB, gC, and TK. However, restriction endonuclease analysis of the genome of Italian CpHV-1 strains has demonstrated the existence of distinct genomic variants, suggesting that genetic diversity exists within the species [3]. Phylogenetic analyses based on the gB and gC genes consistently place CpHV-1 in a distinct clade within the ruminant alphaherpesvirus cluster, with BoHV-1 and BuHV-1 as its closest relatives [2]. The divergence of CpHV-1 from BoHV-1 is estimated at 26.6% for the gC gene, indicating a substantial evolutionary distance that is consistent with species-specific adaptation [2].
The genetic stability of CpHV-1 has implications for diagnostic test development and vaccine design. The high degree of sequence conservation in immunodominant glycoproteins suggests that vaccines based on one strain may confer cross-protection against heterologous strains. However, the potential for recombination between CpHV-1 and other ruminant alphaherpesviruses, particularly in regions where multiple species are co-housed, represents a concern for the emergence of novel variants with altered pathogenicity or host range. The World Organization for Animal Health (WOAH) recognizes the economic importance of caprine herpesvirus infection and includes it in the list of notifiable diseases for international trade purposes.
Cross-Species Transmission and Zoonotic Potential
The close phylogenetic relationship between CpHV-1 and other ruminant alphaherpesviruses raises the question of cross-species transmission. Experimental studies have demonstrated that CpHV-1 can infect calves, and conversely, BoHV-1 can infect goats, establishing latency and undergoing reactivation [3]. This bidirectional cross-species transmission has been documented under both experimental and natural conditions, highlighting the potential for interspecies spread in mixed-species farming operations. The molecular basis for this cross-species transmission lies in the conservation of cellular receptors and the ability of viral glycoproteins to engage heterologous receptors across species boundaries.
Importantly, there is no evidence to date that CpHV-1 poses a zoonotic risk to humans. The virus is considered host-restricted to ruminants, and no cases of human infection have been reported. This is consistent with the general pattern of alphaherpesvirus evolution, wherein viruses have co-speciated with their respective hosts and rarely cross the species barrier to humans. However, the potential for zoonotic transmission cannot be entirely discounted, and the Centers for Disease Control and Prevention (CDC) and WOAH recommend continued surveillance of emerging viral pathogens in livestock populations.
Molecular Diagnostics and Antiviral Targets
The molecular pathogenesis of CpHV-1 has informed the development of diagnostic assays targeting conserved viral genes. PCR amplification of the TK, gB, and gC genes has been successfully employed for the detection of CpHV-1 DNA in clinical samples, including nasal swabs, genital swabs, and tissue specimens [7, 8]. Real-time PCR assays offer enhanced sensitivity and quantification capabilities, enabling the detection of low-level viral shedding during latency and reactivation. The high degree of sequence conservation in these target genes ensures broad reactivity across CpHV-1 strains while minimizing cross-reactivity with other ruminant herpesviruses.
Recent advances in antiviral research have identified promising therapeutic candidates against CpHV-1. Pantinin-derived peptides, originally isolated from scorpion venom, have demonstrated potent antiviral activity against CpHV-1 at concentrations ranging from 6–25 µM [1]. These peptides exert their antiviral effects through direct virucidal action and inhibition of viral entry and fusion with host cells. Structural characterization revealed that these peptides adopt α-helical conformations in membrane-mimetic environments, facilitating interaction with the viral envelope and disruption of membrane integrity [1]. The development of such antiviral agents represents a novel approach to controlling CpHV-1 infection, particularly in outbreak settings where rapid intervention is required.
Epidemiology and Transmission of Caprine Herpesvirus 1
Global Distribution and Seroprevalence
Caprine herpesvirus 1 (CpHV-1), a member of the subfamily Alphaherpesvirinae within the genus Varicellovirus, represents a significant pathogen of domestic goats (Capra aegagrus hircus) with a worldwide distribution that mirrors the global caprine population. The virus is closely related to bovine herpesvirus 1 (BoHV-1), bovine herpesvirus 5 (BoHV-5), bubaline herpesvirus 1 (BuHV-1), and cervid herpesviruses 1 and 2, forming a cluster of ruminant alphaherpesviruses that share considerable genetic and antigenic homology [4]. This phylogenetic relatedness has profound implications for both diagnostic interpretation and cross-species transmission dynamics.
Serological surveys conducted across multiple continents have established that CpHV-1 infection is endemic in many goat-rearing regions. Early foundational studies in Switzerland documented the distribution, incidence, and latency of infection, revealing that seropositivity rates could exceed 50% in some herds [3]. Subsequent investigations in southern Italy demonstrated the presence of antibodies against CpHV-1 in goat herds, confirming the virus's establishment in Mediterranean caprine populations [3]. The seroprevalence patterns observed globally are highly variable, ranging from sporadic, low-level circulation in isolated herds to hyperendemic infection in intensively managed commercial operations. This variability is influenced by management practices, population density, biosecurity measures, and the introduction of replacement animals.
The World Organization for Animal Health (WOAH) recognizes the economic importance of CpHV-1, particularly in the context of reproductive losses, although the virus is not currently listed as a notifiable pathogen. The Food and Agriculture Organization (FAO) has highlighted the impact of caprine herpesvirus infections on small ruminant productivity in developing regions, where goats serve as critical livestock for food security and economic stability. The true global burden of CpHV-1 is likely underestimated due to underreporting, diagnostic limitations in resource-limited settings, and the high proportion of subclinical infections that escape detection.
Host Range and Species Specificity
CpHV-1 exhibits a relatively narrow host range compared to some other alphaherpesviruses, with domestic goats serving as the primary reservoir host. However, the capacity for interspecies transmission has been experimentally demonstrated and documented under natural conditions. The genetic and antigenic relationships between CpHV-1 and BoHV-1 are particularly relevant, as these viruses can cross the species barrier [4]. Experimental infections have shown that goats can be infected with BoHV-1, and conversely, calves can be infected with CpHV-1, establishing latent infections that may subsequently reactivate [3]. This bidirectional susceptibility raises important epidemiological questions regarding the role of cattle as potential reservoirs for CpHV-1 and vice versa.
The molecular basis for this cross-species transmission lies in the conserved glycoprotein structures shared among ruminant alphaherpesviruses. Genetic characterization of the glycoprotein C (gC) gene has demonstrated that CpHV-1 exhibits approximately 26.6% divergence from BoHV-1 at the nucleotide level, while BoHV-5 and cervid herpesvirus 1 show 9.2% and 13% divergence, respectively [2]. This degree of genetic distance is sufficient to maintain species-specific transmission patterns under most circumstances, yet close enough to permit occasional spillover events when susceptible hosts are exposed to high viral loads.
Other ruminant species, including sheep and various wild ungulates, may also be susceptible to CpHV-1 infection, although their role in maintenance and transmission is less well characterized. The detection of bovine gammaherpesvirus 6 in aborted bovine fetuses [9] highlights the complex ecology of herpesviruses in mixed-species ruminant populations, although this particular virus belongs to a different subfamily (Gammaherpesvirinae) and is not directly comparable to CpHV-1. The potential for CpHV-1 to establish infection in wildlife reservoirs remains an important area for future investigation, particularly in regions where domestic goats share habitats with wild caprids or cervids.
Transmission Routes and Mechanisms
CpHV-1 transmission occurs through multiple routes, reflecting the virus's tropism for mucosal surfaces and its ability to be shed in various bodily secretions. The primary mode of horizontal transmission is direct contact between infected and susceptible animals via the respiratory and ocular routes. Infected goats shed virus in nasal secretions, ocular discharges, and saliva, with viral titers peaking during the acute phase of primary infection. The virus can also be transmitted venereally, as evidenced by its association with balanoposthitis in males and vulvovaginitis in females [3]. This venereal route is particularly significant in breeding operations, where the introduction of a single infected buck can rapidly disseminate infection throughout a naive herd.
Vertical transmission, leading to abortion and neonatal disease, represents one of the most economically devastating consequences of CpHV-1 infection. The virus can cross the placental barrier, infecting the fetus and causing necrotizing placentitis, fetal death, and expulsion. Multiple abortions associated with CpHV-1 infection have been documented in goat herds, with abortion storms affecting a substantial proportion of pregnant does [3]. The pathogenesis of abortion involves viral replication in the placental trophoblasts and fetal tissues, leading to widespread necrosis and inflammatory responses that compromise fetal viability. Transplacental transmission can occur during both primary infection and reactivation of latent virus, although the risk is substantially higher during primary exposure in pregnant animals.
Iatrogenic transmission through contaminated equipment, fomites, and human hands represents an additional, often overlooked, route of spread. The enveloped nature of CpHV-1 renders it susceptible to desiccation and common disinfectants, but the virus can survive for limited periods on contaminated surfaces, feed, and water sources under appropriate environmental conditions. Poor biosecurity practices, including the sharing of needles, dehorning equipment, and feeding utensils, can facilitate mechanical transmission within and between herds.
Latency and Reactivation Dynamics
A defining characteristic of CpHV-1, shared with all alphaherpesviruses, is its ability to establish lifelong latent infections in sensory ganglia following primary infection. The virus establishes latency primarily in the sacral ganglia, as demonstrated by PCR detection of CpHV-1 DNA in latently infected goats [3]. This neurotropism allows the virus to persist in the host despite the development of a robust immune response, creating a reservoir for future reactivation and transmission.
Reactivation from latency can be triggered by various stressors, including parturition, transport, overcrowding, nutritional stress, intercurrent disease, and corticosteroid administration. Experimental studies have demonstrated that CpHV-1 can be reactivated in latently infected goats following dexamethasone treatment, resulting in virus shedding and potential transmission to susceptible contacts [3]. Natural reactivation has also been documented, with latently infected goats shedding virus during periods of stress without exhibiting clinical signs [3]. This phenomenon is particularly important in the context of reproductive management, as pregnant does experiencing the physiological stress of late gestation and parturition may reactivate latent virus, leading to fetal infection and abortion.
The molecular mechanisms governing latency and reactivation in CpHV-1 are less well characterized than those of the closely related BoHV-1, but are presumed to involve similar regulatory pathways. The latency-related gene (LR) and its associated microRNAs play critical roles in maintaining the latent state and modulating the host immune response. During latency, viral gene expression is highly restricted, with only the latency-associated transcripts being produced. Reactivation involves a cascade of immediate-early, early, and late gene expression, culminating in the production of infectious virions that travel via axonal transport to mucosal surfaces for shedding.
Epidemiological Risk Factors
Multiple host, pathogen, and environmental factors influence the epidemiology of CpHV-1 infection in goat populations. Age is a significant determinant of infection risk, with younger animals generally being more susceptible to primary infection and more likely to develop severe clinical disease. Colostral antibodies provide passive protection to neonates, but this immunity wanes over several weeks to months, leaving young kids vulnerable to infection as maternal antibody titers decline. Management practices that commingle different age groups facilitate the transmission of virus from latently infected adults to susceptible juveniles.
Population density and stocking rates are critical determinants of transmission dynamics. Intensive production systems with high animal densities promote rapid spread of the virus through direct contact and aerosol transmission. Conversely, extensive grazing systems with low stocking densities may limit transmission, resulting in sporadic infection patterns. The introduction of new animals into a herd represents a major risk factor for CpHV-1 incursion, particularly when replacement animals originate from herds with unknown or positive infection status. Quarantine protocols and serological testing of incoming animals are essential biosecurity measures for preventing introduction.
Seasonal factors may influence CpHV-1 transmission, with higher rates of reactivation and shedding observed during periods of reproductive activity and parturition. The stress associated with breeding, kidding, and lactation can trigger viral reactivation in latently infected does, leading to increased virus shedding and exposure of newborn kids. This seasonal pattern has important implications for herd management and disease control strategies.
Co-infection and Synergistic Interactions
CpHV-1 infection does not occur in isolation, and co-infections with other caprine pathogens can significantly alter disease expression and transmission dynamics. The virus's ability to cause immunosuppression, particularly through infection of lymphocytes and macrophages, may predispose animals to secondary bacterial and viral infections. Conversely, concurrent infections with other pathogens can exacerbate CpHV-1-associated disease and increase viral shedding.
The relationship between CpHV-1 and other respiratory pathogens of goats, including Mycoplasma species, Mannheimia haemolytica, and peste des petits ruminants virus (PPRV), warrants further investigation. PPRV, a morbillivirus that causes devastating disease in sheep and goats, has been documented in regions where CpHV-1 is also endemic [11]. The immunosuppressive effects of PPRV infection could potentially enhance CpHV-1 replication and shedding, although specific studies on this interaction are lacking. Similarly, co-infection with small ruminant lentiviruses (SRLV), which cause caprine arthritis-encephalitis, may modulate the immune response to CpHV-1 and influence latency and reactivation dynamics [10].
Diagnostic Considerations for Epidemiological Studies
Accurate diagnosis is fundamental to understanding the epidemiology of CpHV-1. Virus isolation in cell culture, PCR-based detection of viral DNA, and serological assays each have specific applications and limitations in epidemiological investigations. Molecular characterization of CpHV-1 strains using glycoprotein gene sequencing has revealed genetic homogeneity among isolates, with restriction endonuclease analysis demonstrating limited genomic variation [3]. This genetic stability suggests that CpHV-1 is a relatively monotypic virus, although further genomic surveillance is needed to fully characterize circulating strains.
Serological surveys using virus neutralization tests and enzyme-linked immunosorbent assays (ELISAs) provide valuable data on population-level exposure. However, cross-reactivity with other ruminant alphaherpesviruses, particularly BoHV-1, complicates serological interpretation in mixed-species operations [4]. Discriminatory ELISA tests have been developed to differentiate antibodies against closely related herpesviruses, enabling more precise epidemiological studies in regions where multiple ruminant species are present.
Economic Impact and Public Health Implications
The economic burden of CpHV-1 infection in goat production systems is substantial, resulting from abortion losses, neonatal mortality, reduced reproductive efficiency, and decreased milk production. Abortion storms can decimate kidding seasons, with losses exceeding 50% of pregnancies in naive herds experiencing primary infection [3]. The costs associated with veterinary care, diagnostic testing, and implementation of control measures further compound the economic impact.
From a public health perspective, CpHV-1 is not considered a zoonotic pathogen. The Centers for Disease Control and Prevention (CDC) does not list caprine herpesvirus among agents of concern for human infection, and no cases of human disease attributable to CpHV-1 have been reported. However, the virus's close relationship with other alphaherpesviruses that have demonstrated zoonotic potential, such as B virus (CeHV-1) in non-human primates, underscores the importance of continued surveillance and biosafety precautions when handling infected animals and tissues.
Global Surveillance and Future Directions
Despite the recognized importance of CpHV-1 in caprine health, comprehensive global surveillance programs are lacking. Most epidemiological data derive from cross-sectional serological surveys and outbreak investigations rather than systematic, longitudinal monitoring. The development of standardized diagnostic protocols and reporting systems, aligned with WOAH guidelines, would facilitate a more accurate assessment of the global distribution and impact of CpHV-1.
Molecular epidemiological studies using next-generation sequencing technologies offer the potential to track viral spread, identify transmission networks, and detect emerging variants. The genetic characterization of CpHV-1 strains from diverse geographic regions would provide insights into viral evolution, phylogeography, and the dynamics of cross-species transmission. Integration of genomic data with epidemiological metadata, including animal movement records and management practices, would enhance our understanding of the factors driving CpHV-1 transmission at local, regional, and international scales.
Clinical Signs and Pathological Findings
Caprine herpesvirus 1 (CpHV-1) infection in goats presents a complex and often age-dependent clinical spectrum, ranging from subclinical seroconversion in adult animals to severe, frequently fatal systemic disease in neonatal kids. The clinical manifestations and associated pathological lesions are dictated by the virus’s tropism for epithelial tissues, particularly of the mucocutaneous junctions and the reproductive tract, as well as its capacity to establish lifelong latency in neural tissues. A comprehensive understanding of these signs and findings is critical for differential diagnosis, particularly in distinguishing CpHV-1 from other caprine pathogens such as peste des petits ruminants virus (PPRV), contagious ecthyma (orf virus), and caprine arthritis-encephalitis virus (CAEV). The World Organisation for Animal Health (WOAH) recognizes the economic significance of herpesvirus infections in small ruminants, underscoring the need for precise clinical and pathological characterization.
Clinical Signs in Neonatal Kids: The Fulminant Systemic Form
The most devastating presentation of CpHV-1 infection occurs in newborn kids, typically within the first two weeks of life. This age-related susceptibility is a hallmark of the virus, mirroring patterns seen in other ruminant alphaherpesviruses such as bovine herpesvirus 1 (BoHV-1) in calves. The clinical course is often peracute to acute, with a high case-fatality rate that can approach 100% in naive herds experiencing an initial outbreak. The pathogenesis of this severe disease is rooted in the immature immune system of the neonate, which is unable to effectively contain viral replication and dissemination.
Initial clinical signs are often nonspecific but rapidly progressive. Affected kids present with profound lethargy, anorexia, and a failure to nurse, leading to rapid dehydration and weakness. A consistent and early sign is a biphasic or severe hyperthermia, with rectal temperatures frequently exceeding 40.5°C (105°F). As the disease advances, the hallmark clinical signs of CpHV-1 emerge, centered on the gastrointestinal and respiratory tracts. A profuse, watery to mucoid diarrhea is common, often leading to severe dehydration and metabolic acidosis. Concurrently, kids develop a serous to mucopurulent nasal discharge and ocular discharge, with conjunctivitis that can progress to keratitis and corneal ulceration. Dyspnea and tachypnea are observed as the virus infects the upper and lower respiratory epithelium.
The most pathognomonic clinical sign in neonatal kids is the development of necrotic lesions on the mucocutaneous junctions. These lesions are typically found on the muzzle, lips, and oral mucosa, including the tongue and hard palate. They begin as erythematous macules that rapidly progress to vesicles, pustules, and then to well-demarcated, diphtheritic ulcers covered by a yellow-gray necrotic membrane. These oral lesions are intensely painful, contributing to the kid’s refusal to nurse. Similar ulcerative lesions can be found on the perineum, vulva, and around the coronary bands of the hooves. In severe cases, neurological signs may manifest, including tremors, ataxia, opisthotonos, and convulsions, indicating viral invasion of the central nervous system (CNS), a finding consistent with the neurotropic nature of alphaherpesviruses. Death typically occurs within 24 to 72 hours of the onset of severe clinical signs, often due to a combination of dehydration, secondary bacterial septicemia, and multi-organ failure.
Clinical Signs in Adult Goats: The Genital and Respiratory Forms
In contrast to the systemic disease in neonates, CpHV-1 infection in adult goats is typically milder and often subclinical. However, when clinical signs do manifest, they are predominantly associated with the reproductive tract, reflecting the virus’s tropism for genital mucosa. This presentation is analogous to infectious pustular vulvovaginitis (IPV) in cattle caused by BoHV-1.
In does, the primary clinical sign is vulvovaginitis. The vulva becomes swollen, erythematous, and edematous. A serous to mucopurulent vaginal discharge is often present. Upon examination, the vaginal mucosa is hyperemic and studded with small, raised, necrotic pustules or vesicles. These lesions can coalesce to form larger areas of erosion or ulceration. Affected does may exhibit signs of discomfort, including frequent urination (pollakiuria), tail switching, and a slight arching of the back. The clinical signs are often self-limiting, with resolution occurring within 10 to 14 days. However, the primary significance of this genital infection lies in its impact on reproduction. CpHV-1 has been definitively linked to abortion in goats [3]. Abortions typically occur in the last trimester of gestation, often without significant prodromal signs in the doe. The virus can cross the placenta, leading to fetal infection and death. Aborted fetuses may be autolyzed or fresh, and placentitis with necrotic foci on the cotyledons is a common finding. The economic impact of these reproductive losses, as documented in case reports of multiple abortions within a herd, can be substantial [3].
In bucks, CpHV-1 infection manifests as balanoposthitis, an inflammation of the glans penis and prepuce [3]. Clinical signs include a swollen, erythematous, and sometimes ulcerated prepuce. A purulent preputial discharge may be observed. Affected bucks may show reluctance to mate. While the lesions are generally superficial and heal without scarring, the virus can be shed in semen, both during active disease and potentially during reactivation from latency, making venereal transmission a critical route of spread. Latency is established in sacral ganglia, and reactivation can occur during periods of stress, such as transport, parturition, or intercurrent disease, leading to intermittent viral shedding [3]. This latent state makes eradication from a herd exceedingly difficult.
A less common but documented clinical presentation in adult goats is a mild respiratory form. This is characterized by serous nasal discharge, conjunctivitis, and occasional coughing. This respiratory form is often mild and may be mistaken for other respiratory pathogens. Experimental infections have demonstrated that CpHV-1 can replicate in the upper respiratory tract, but the disease is generally less severe than the respiratory disease caused by BoHV-1 in cattle [3].
Gross Pathological Findings
The gross pathological lesions observed at necropsy correlate directly with the clinical signs and provide crucial diagnostic clues. In neonatal kids that succumb to the systemic form, the carcass is often dehydrated and in poor body condition. The most striking gross lesions are found on the mucocutaneous surfaces. The oral cavity, tongue, and esophagus may be covered with multiple, well-circumscribed, yellow to gray necrotic ulcers, often with a diphtheritic membrane. These lesions can extend into the forestomachs (rumen, reticulum, omasum) and the abomasum, where similar ulcerative and necrotic changes are observed.
The gastrointestinal tract is severely affected. The small and large intestines are often filled with watery, yellow-tinged content. The intestinal mucosa may be congested and edematous, with petechial hemorrhages. The liver is frequently enlarged, friable, and pale, indicative of hepatic necrosis. The spleen may be enlarged (splenomegaly) due to lymphoid depletion and necrosis. The kidneys may show multiple, small, pale foci of necrosis on the cortical surface. The lungs are often congested, edematous, and fail to collapse, with areas of consolidation consistent with interstitial pneumonia. In cases with neurological involvement, gross lesions in the brain are often subtle, but meningeal congestion and edema may be apparent. The aborted fetus may be autolyzed, but when fresh, it may show similar, though less pronounced, necrotic lesions on the skin and oral mucosa. The placenta, particularly the cotyledons, may show necrotic foci and areas of hemorrhage.
Histopathological Findings
Microscopic examination of tissues confirms the gross findings and reveals the characteristic cytopathic effects of CpHV-1 infection. The hallmark histopathological lesion is multifocal necrosis with an associated inflammatory response. In the liver, there are randomly distributed foci of coagulative necrosis of hepatocytes. At the periphery of these necrotic foci, hepatocytes often contain eosinophilic intranuclear inclusion bodies (Cowdry type A inclusions), which are a classic diagnostic feature of alphaherpesvirus infection. These inclusions are round to oval, sharply demarcated from the marginated chromatin, and fill the nucleus. Similar intranuclear inclusions can be found in epithelial cells of the oral mucosa, esophagus, forestomachs, and abomasum, within the necrotic and ulcerated lesions.
In the lungs, the histopathological picture is that of a severe interstitial pneumonia. The alveolar septa are thickened by infiltration of mononuclear cells, including macrophages and lymphocytes. Alveolar spaces may contain proteinaceous fluid, fibrin, and necrotic cellular debris. Intranuclear inclusion bodies can be found in alveolar epithelial cells and bronchiolar epithelial cells. In the kidneys, multifocal tubular necrosis is observed, with intranuclear inclusions present in the tubular epithelial cells. The spleen and lymph nodes show lymphoid depletion and necrosis of lymphocytes in the germinal centers. In the brain, a non-suppurative meningoencephalitis is observed, characterized by perivascular cuffing with mononuclear cells, gliosis, and neuronal necrosis. Intranuclear inclusions may be found in neurons and glial cells, confirming the neurotropic nature of the virus.
In adult goats with genital disease, histopathology of the vulvar or preputial mucosa reveals epithelial necrosis, vesicle formation, and an intense infiltration of neutrophils and mononuclear cells in the underlying lamina propria. Intranuclear inclusion bodies are readily identified in the epithelial cells adjacent to the necrotic lesions. In cases of abortion, histopathological examination of the fetal tissues, particularly the liver and lung, will reveal the characteristic necrotic foci and intranuclear inclusions, providing a definitive diagnosis. The placenta shows necrotizing placentitis with infiltration of inflammatory cells and the presence of inclusions in trophoblast cells.
Differential Diagnoses
The clinical signs and pathological findings of CpHV-1 infection must be carefully differentiated from other caprine diseases. The severe oral and gastrointestinal ulceration in neonatal kids can be confused with peste des petits ruminants (PPR) , a WOAH-listed disease caused by a morbillivirus [11]. PPR also causes severe stomatitis, diarrhea, and pneumonia in young animals. However, PPR typically presents with a more pronounced respiratory component and characteristic “snuffling” due to nasal discharge. Histologically, PPRV causes syncytial cell formation and eosinophilic intracytoplasmic inclusions, in contrast to the intranuclear inclusions of CpHV-1. Contagious ecthyma (orf) , a parapoxvirus, also causes proliferative and ulcerative lesions on the lips and muzzle. However, orf lesions are typically more proliferative (scabby) and less necrotic, and the disease does not cause the systemic signs of fever and diarrhea seen in CpHV-1. Caprine arthritis-encephalitis (CAE) , caused by a lentivirus, can cause neurological signs in kids, but this is typically a leukoencephalomyelitis that presents with progressive paresis and ataxia in older kids (2-4 months), not the acute, febrile, systemic disease of CpHV-1. Furthermore, CAE does not cause oral ulceration or diarrhea. Other causes of neonatal diarrhea, such as enterotoxigenic E. coli, Cryptosporidium, and rotavirus, should be ruled out through appropriate laboratory testing. The genital form in adults must be differentiated from other causes of vulvovaginitis and balanoposthitis, including bacterial infections (e.g., Trueperella pyogenes, Histophilus somni) and trauma. The occurrence of multiple abortions within a herd should prompt testing for CpHV-1, Coxiella burnetii (Q fever), Brucella melitensis, and Chlamydia abortus. The World Health Organization (WHO) and the WOAH emphasize the importance of differential diagnosis for abortifacient agents in small ruminants due to their zoonotic potential, particularly for C. burnetii and Brucella spp.
Diagnostic Approaches for Caprine Herpesvirus 1
The definitive diagnosis of Caprine Herpesvirus 1 (CpHV-1) infection necessitates a multimodal approach that integrates clinical presentation, virus isolation, molecular detection, and serological profiling. Given that CpHV-1 is a member of the Varicellovirus genus within the Alphaherpesvirinae subfamily, it shares substantial antigenic and genomic homology with other ruminant alphaherpesviruses, most notably Bovine Herpesvirus 1 (BoHV-1), Bovine Herpesvirus 5 (BoHV-5), and Bubaline Herpesvirus 1 (BuHV-1) [2, 4]. This genetic relatedness presents a significant diagnostic challenge, as cross-reactivity can confound both molecular and serological assays. Consequently, diagnostic protocols must be designed with a high degree of specificity to differentiate CpHV-1 from these closely related pathogens, particularly in mixed-species production systems. The World Organisation for Animal Health (WOAH) recognizes the economic and health significance of caprine herpesvirus infections, underscoring the need for validated, standardized diagnostic methodologies for surveillance, outbreak confirmation, and certification of animals for international trade.
Virus Isolation and Propagation
Virus isolation remains a cornerstone of definitive diagnosis, serving as the gold standard for the confirmation of active CpHV-1 infection and the generation of viral stock for downstream characterization. Several permissive cell lines have been historically employed, with primary and secondary cell cultures derived from caprine, bovine, or ovine origins demonstrating susceptibility. The most commonly utilized cell line for CpHV-1 isolation is the Madin-Darby Bovine Kidney (MDBK) cell line, which supports robust viral replication. Isolations have also been successfully performed on primary caprine kidney and testicular cells, as well as on the Rabbit Kidney-13 (RK-13) cell line, which is a well-established substrate for the propagation of other alphaherpesviruses, including Equine Herpesvirus 1 (EHV-1) [6]. The use of RK-13 cells for CpHV-1 is methodologically analogous to protocols validated for other herpesviruses, where a 90–100% confluent monolayer is inoculated with a clarified homogenate of clinical samples (e.g., mucosal swabs, tissue homogenates from aborted fetuses, or vaginal exudate) and incubated for 1 hour at 37°C in a 5% CO₂ atmosphere to facilitate viral adsorption [6]. Following adsorption, the inoculum is replaced with a maintenance medium containing 2% fetal calf serum and antibiotics, and the cultures are monitored daily for the development of a characteristic cytopathic effect (CPE). For CpHV-1, CPE typically manifests within 48 to 96 hours post-inoculation, beginning with cellular rounding and the formation of small syncytia, followed by progressive detachment of the monolayer from the culture surface. In cases where CPE is absent after 7 days, a minimum of three blind passages is recommended before a sample is declared negative. This is critical, as low viral titers in clinical specimens, particularly from latently infected or subclinically shedding animals, may require amplification through serial passage [6].
Alternatively, isolation can be accomplished using the chorioallantoic membranes (CAMs) of 12-day-old specific-pathogen-free (SPF) embryonated chicken eggs, a technique that has proven effective for closely related alphaherpesviruses such as Felid Herpesvirus 1 (FHV-1) [7]. Inoculation of the CAM with CpHV-1 suspension is expected to produce characteristic pock lesions, white, opaque, focal proliferative or necrotic foci, accompanied by edematous thickening and cloudiness of the membrane. Infected embryos may also exhibit stunting and abnormal feathering, indicative of systemic viral dissemination [7]. While this method is less sensitive than cell culture for CpHV-1, it offers an alternative for laboratories lacking suitable cell culture facilities or for isolating virus from samples with high bacterial contamination, as the egg provides an aseptic environment.
Molecular Detection Methods: Polymerase Chain Reaction and Real-Time PCR
Molecular techniques, particularly polymerase chain reaction (PCR), have supplanted virus isolation as the primary diagnostic modality due to their superior sensitivity, rapid turnaround time, and ability to detect viral nucleic acid in both active and latent infections. The selection of appropriate genetic targets is paramount for achieving high analytical specificity, especially given the genetic similarity among ruminant alphaherpesviruses. The glycoprotein B (gB) gene, encoded by the UL27 open reading frame, is a highly conserved region across the Herpesviridae family and is frequently employed in pan-herpesvirus PCR assays. However, for species-level identification, more variable genomic regions are required. The glycoprotein C (gC) gene (UL44) has been genetically characterized in BoHV-1 and demonstrates a level of divergence that allows for discrimination between BoHV-1, BoHV-5, BuHV-1, and CpHV-1. Specifically, the gC gene of CpHV-1 exhibits a nucleotide divergence of 26.6% from the BoHV-1 reference strain, making it a robust target for differentiating CpHV-1 from other ruminant alphaherpesviruses [2]. Similarly, the glycoprotein B (gB) and glycoprotein D (gD) genes, as well as the thymidine kinase (TK) gene, have been successfully amplified and sequenced for phylogenetic characterization of related viruses like FHV-1, demonstrating the utility of these targets for both detection and molecular epidemiology [8]. The TK gene is particularly valuable for diagnostic screening due to its essential role in viral nucleotide metabolism and its presence across all alphaherpesviruses, enabling broad detection followed by confirmatory sequencing or restriction fragment length polymorphism (RFLP) analysis [7].
For the specific detection of CpHV-1, a nested PCR (nPCR) assay targeting the viral polymerase gene has been described, offering exquisite sensitivity for detecting low-copy-number genomes in tissues such as sacral ganglia, where the virus establishes latency [9]. The nPCR approach involves two sequential amplification rounds, which dramatically reduces the limit of detection compared to conventional single-round PCR. This is especially critical for diagnosing latent infections, where the viral genome is maintained in a quiescent state with minimal transcriptional activity. In studies of other herpesviruses, nPCR has been instrumental in detecting viral DNA in formalin-fixed, paraffin-embedded (FFPE) tissues, enabling retrospective analysis of archival specimens [9].
Real-time quantitative PCR (qPCR) represents the apex of molecular diagnostic technology for CpHV-1. It offers the advantages of quantification, reduced risk of amplicon contamination, and the ability to multiplex with internal amplification controls. TaqMan-based assays, which utilize a fluorogenic probe specific to the target sequence, provide a highly sensitive and specific platform for detecting CpHV-1 DNA in clinical samples [5]. The use of minor groove binder (MGB) probes enhances the specificity of the assay by increasing the melting temperature (Tm) of the probe-target hybrid, allowing for short probes that can discriminate single nucleotide polymorphisms. In the context of CpHV-1, a TaqMan assay targeting a conserved region of the gB or TK gene can be designed to yield a dynamic range of detection spanning several orders of magnitude. The quantification cycle (Cq) value, also known as the threshold cycle (Ct), provides a direct measure of viral load, which can be correlated with disease severity, shedding intensity, or the efficacy of antiviral interventions. For instance, in studies evaluating the antiviral activity of pantinin-derived peptides against CpHV-1, qPCR was employed alongside plaque reduction assays to demonstrate a dose-dependent reduction in viral DNA copies following treatment [1]. While qPCR is highly sensitive, it requires specialized instrumentation and rigorous validation to ensure that the assay does not cross-react with other caprine viral pathogens or with the host genome.
Serological and Immunological Assays
Serological diagnosis of CpHV-1 infection is primarily employed for herd-level surveillance, certification of freedom from infection, and epidemiological studies. The presence of antibodies indicates prior exposure, latent infection, or vaccination. The primary serological test historically used is the virus neutralization (VN) test, which measures the ability of serum antibodies to neutralize the infectivity of a standard CpHV-1 inoculum in cell culture. While VN is highly specific and provides a functional correlate of immunity, it is labor-intensive, time-consuming (requiring 3–5 days), and subject to variability due to serum cytotoxicity or the presence of non-specific inhibitors. Nonetheless, VN remains the reference standard for serological surveys and is recommended by WOAH for trade purposes.
Enzyme-linked immunosorbent assays (ELISA) have become the predominant serological tool for CpHV-1 due to their adaptability to high-throughput testing and objective readouts. Indirect ELISAs, which utilize whole-virus antigen or recombinant structural proteins (e.g., glycoproteins B, C, or D), are commonly employed. However, the choice of antigen is critical. Detection of antibodies against BoHV-1 using whole-virus antigen often cross-reacts with CpHV-1 antibodies, a phenomenon attributed to the shared epitopes on conserved glycoproteins [4]. To circumvent this, discriminatory or competitive ELISAs have been developed. For example, a discriminatory ELISA based on a specific epitope of glycoprotein E (gE) has been used to differentiate BoHV-1 from BuHV-1, and a similar principle can be applied for CpHV-1. The gE protein is a non-essential virulence factor that exhibits species-specific variation, making it an ideal target for type-specific serology [4]. In the absence of a gE-deleted marker vaccine for CpHV-1, a competitive ELISA (cELISA) using monoclonal antibodies directed against unique CpHV-1 epitopes can provide high specificity.
The diagnostic accuracy of ELISAs is heavily influenced by the sample matrix. While serum is the standard, testing of individual milk samples has been validated for other caprine viral diseases, such as caprine arthritis-encephalitis (CAE) caused by small ruminant lentivirus (SRLV). In those studies, indirect ELISAs performed on milk lactoserum (serum derived from centrifuged, rennet-coagulated milk) demonstrated high sensitivity (89.3–91.4%) and specificity (95.5–98.3%) when optimized cut-off values were applied [10]. The use of milk directly is appropriate for voluminous surveillance of dairy goats, but the sample-to-positive control serum ratio (S/P%) must be optimized, as the lower immunoglobulin concentration in milk necessitates a lower cut-off (e.g., S/P% of 10% or 80% depending on the assay) compared to serum testing [10]. It is plausible that similar optimization would be required for CpHV-1 ELISAs applied to milk, given the lower levels of IgG in secretions. However, the competitive ELISA format, which measures antibody-mediated inhibition of a labeled monoclonal antibody, tends to be less sensitive on milk samples compared to indirect ELISAs, as was observed in SRLV testing where the cELISA (SU-ELISA) achieved only 71.2% sensitivity [10].
Differential Diagnosis and Confirmation Protocols
A robust diagnostic algorithm for CpHV-1 must incorporate a differential diagnostic workup to rule out other causes of genital ulceration, abortion, and respiratory distress in goats. The clinical signs of CpHV-1, vulvovaginitis, balanoposthitis, and abortion in the last trimester, are not pathognomonic and can be caused by other pathogens, including Chlamydia abortus, Coxiella burnetii (the agent of Q fever), Brucella melitensis, and other abortifacient viruses. For instance, while Q fever is primarily associated with C. burnetii infection in small ruminants, co-infection with CpHV-1 could exacerbate clinical outcomes [13]. Therefore, a comprehensive panel of molecular and serological tests is warranted. For abortion cases, fetal tissues (lung, liver, spleen, and abomasal contents) should be submitted for bacteriological culture, PCR for C. burnetii and Brucella spp., and histopathological examination for characteristic lesions such as necrotizing placentitis or fetal hepatitis. The detection of CpHV-1 DNA by PCR from fetal tissues, preferably with viral isolation in cell culture, remains the definitive diagnostic evidence.
Given the high degree of sequence homology among ruminant alphaherpesviruses, the final confirmation of CpHV-1 identity often requires sequencing of the amplified PCR product. Sequencing of the gC, gB, or TK gene and subsequent phylogenetic analysis allows for unambiguous species determination [2, 8]. This is particularly important in geographic regions where multiple ruminant herpesviruses co-circulate. The use of a 255–350 nucleotide fragment of the nucleoprotein or glycoprotein gene for phylogenetic analysis, as demonstrated for Peste des Petits Ruminants Virus (PPRV), provides sufficient resolution to cluster isolates by lineage and geographic origin [11]. For CpHV-1, phylogenetic trees constructed using the maximum likelihood or neighbor-joining method, with bootstrap support of 1,000 replicates, can confirm the isolate's placement within the Varicellovirus clade and differentiate it from closely related species like BoHV-1 and BuHV-1 [12].
Sample Selection and Diagnostic Strategy
The selection of appropriate clinical specimens is dictated by the stage of infection. During acute primary infection or reactivation, high titers of virus are present in genital, nasal, and conjunctival secretions. Therefore, swabs of the vaginal mucosa, prepuce, or ocular/nasal mucosa should be collected, placed in viral transport medium (e.g., MEM with 2% fetal calf serum and antibiotics), and transported on ice. For detection of latent infection, the sacral ganglia (specifically the dorsal root ganglia of the sacral spinal nerves) are the primary site of viral persistence. The detection of CpHV-1 DNA in sacral ganglia by PCR is considered the gold standard for confirming latency [3]. Tissues for latency detection are typically collected at necropsy.
A comprehensive diagnostic approach for a suspected CpHV-1 outbreak should proceed in a tiered manner. First, rapid screening using a pan-alphaherpesvirus qPCR or nPCR on mucosal swabs from acutely ill animals provides a same-day result. Second, any positive result should be confirmed by sequencing a portion of the gC gene to exclude cross-reactivity with BoHV-1 or BuHV-1. Third, serological surveys using a discriminatory ELISA should be initiated on a representative sample of the herd to determine the extent of exposure. Finally, virus isolation on MDBK or RK-13 cells should be performed from PCR-positive samples to obtain an isolate for potential molecular characterization and to confirm the presence of infectious virus, which is required for a definitive diagnosis according to WOAH standards. For aborted fetuses, a minimum of fetal lung, liver, and abomasal fluid should be tested by both PCR and bacterial culture. This algorithmic approach, grounded in the biological understanding of viral latency, shedding, and cross-species reactivity, provides the necessary rigor for both clinical diagnosis and epidemiological surveillance of this economically important pathogen.
Antiviral Strategies and Therapeutic Interventions
The management of caprine herpesvirus 1 (CpHV-1) infection presents a unique and formidable challenge to veterinary medicine, stemming from the virus's capacity for lifelong latency, its propensity for induced immunosuppression, and its devastating impact on reproductive efficiency in goat herds. Unlike many bacterial infections of livestock, therapeutic interventions for CpHV-1 are not aimed at eradicating the pathogen from the host, but rather at mitigating the clinical severity of acute episodes, reducing the duration and magnitude of viral shedding, and preventing the vertical transmission that leads to abortion. The current armamentarium is regrettably narrow, heavily reliant on supportive management and indirect immunological modulation, with a pressing need for the development of specific, targeted antiviral agents. A comprehensive antiviral strategy must therefore integrate direct-acting antivirals, immunological adjuvants, and rigorous biosecurity protocols to control both primary infection and the periodic reactivation from latency.
Nucleoside Analogues and DNA Polymerase Inhibitors
The cornerstone of therapy for alphaherpesviruses in both human and companion animal medicine, namely, nucleoside analogues such as acyclovir, valacyclovir, and penciclovir, remains a largely unexplored frontier for CpHV-1. These compounds function as prodrugs requiring initial phosphorylation by a virus-encoded thymidine kinase (TK) to become active inhibitors of viral DNA polymerase [7, 8]. The genetic characterization of CpHV-1, particularly the presence and functionality of its TK gene, is therefore a prerequisite for evaluating the potential efficacy of this drug class. Studies on related alphaherpesviruses, such as feline herpesvirus-1 (FHV-1), have demonstrated that while TK gene sequences are highly conserved, mutations can confer resistance, and the efficacy of acyclovir in cats is variable and requires high, potentially toxic dosing [7, 8]. Given the close phylogenetic relationship between CpHV-1 and bovine herpesvirus 1 (BoHV-1), in vitro sensitivity assays on caprine cell lines are urgently needed. The isolated observation of a potential N-linked glycosylation site in TK protein sequences of related field strains suggests that subtle post-translational modifications could influence enzyme kinetics and, consequently, drug activation [8]. Until such data is generated, the empirical use of acyclovir in goats remains speculative and is not recommended due to the risk of nephrotoxicity and lack of established pharmacokinetic parameters. Research into novel polymerase inhibitors, such as brincidofovir, a lipid conjugate of cidofovir that bypasses the need for viral TK activation, represents a more promising, though economically unfeasible for small ruminants, avenue for future development.
Host-Directed Therapies and Immunomodulation
Given the direct shortcomings of nucleoside analogues, a strategic pivot toward host-directed therapies, compounds that augment the host's intrinsic antiviral defenses, offers a more pragmatic approach. The interferon (IFN) system serves as the primary innate barrier against herpesvirus replication. The administration of recombinant interferon-omega (rIFN-ω), already licensed for use in cats and dogs for parvovirus and herpesvirus infections, could be repurposed for caprine species. Type I IFNs induce a broad antiviral state, upregulating hundreds of interferon-stimulated genes (ISGs) that inhibit viral transcription, translation, and assembly. For CpHV-1, which establishes latency in sacral ganglia, IFN therapy is unlikely to clear the latent viral genome but could effectively suppress lytic reactivation, reducing the risk of fetal infection during pregnancy [3]. Furthermore, the strategic use of immunomodulators, such as inactivated Propionibacterium acnes or specific CpG oligonucleotide motifs, could prime the innate immune system, particularly macrophages and natural killer (NK) cells, to respond more rapidly to incipient viral reactivation. This is critical because stress, a known trigger for CpHV-1 recrudescence, often coincides with transient immunosuppression [3, 4]. By bolstering non-specific immunity, we may reduce the window of vulnerability during which the virus can replicate and cause clinical disease. However, the timing of such immunomodulation is critical; administration during the acute phase of systemic disease could theoretically exacerbate pathological inflammatory responses.
Direct-Acting Antivirals: Peptide-Based Therapeutics
The most exciting and novel frontier in CpHV-1 therapeutics lies in the development of host-derived or synthetic peptides with direct virucidal activity. Recent investigations into pantinin-1 and pantinin-2, antimicrobial peptides (AMPs) derived from the venom of the scorpion Pandinus imperator, have demonstrated potent and specific activity against CpHV-1 [1]. These peptides, studied at concentrations ranging from 6 to 25 µM, exert a dual mechanism of action: (1) a direct, concentration-dependent virucidal effect, likely disrupting the viral envelope, and (2) inhibition of viral entry and membrane fusion with the host cell [1]. Structural characterization via nuclear magnetic resonance (NMR) revealed that while these peptides are largely unstructured in aqueous solution, they transition to an amphipathic α-helical conformation in membrane-mimetic environments (such as TFE/H₂O) [1]. This structural shift is critical, as the α-helical motif is a hallmark of membrane-interacting domains, allowing the peptide to insert into the viral lipid envelope or the host cell membrane, thereby blocking the fusion process mediated by glycoproteins gB, gD, and gH/gL [1, 4].
This approach is particularly attractive because it targets a physical property of the virus (its envelope) rather than a specific enzymatic site, thereby minimizing the risk of developing drug resistance through point mutations. The finding that pantinin-2 showed a greater propensity for secondary structure in aqueous solution suggests a higher bioavailability and stability, making it a superior lead candidate for formulation [1]. While still in the experimental phase, these findings represent a paradigm shift; the development of a topical or injectable peptide-based therapy for CpHV-1 could provide a rapid, non-toxic, and highly effective intervention, especially for treating localized genital lesions (balanoposthitis, vulvovaginitis) and reducing viral shedding before and during the breeding season.
Vaccination as a Prophylactic Strategy
Ultimately, the most sustainable and cost-effective "therapeutic intervention" for CpHV-1 is prevention through robust vaccination. However, a major impediment is the lack of a commercially available, licensed vaccine specifically for CpHV-1. Historically, and dangerously, some producers have resorted to using modified-live or killed BoHV-1 (IBR) vaccines in goats, a practice fraught with risk. While BoHV-1 can infect goats and cause seroconversion, it does not provide complete cross-protection against CpHV-1 challenge and carries the risk of causing disease or establishing a heterologous latent infection that could reactivate and spread to cattle [3, 4]. The development of a species-specific vaccine is therefore non-negotiable.
The ideal CpHV-1 vaccine must achieve several objectives: prevent clinical disease (particularly abortion), block the establishment of latency in the sacral ganglia, and reduce or eliminate post-vaccination shedding. Glycoproteins such as gB, gC, and gD are critical targets for neutralizing antibodies. The gC gene, for instance, functions as a viral attachment protein and a receptor for the complement component C3b; antibodies directed against gC can neutralize viral infectivity and prevent cell-to-cell spread [2]. Subunit vaccines based on these envelope proteins, delivered with potent adjuvants (e.g., saponin-based or TLR agonists), represent a safe avenue for development, as they carry zero risk of reversion to virulence. Furthermore, the efficacy of such vaccines can be reliably tested using validated surrogate small animal models, such as the guinea pig model developed for BoHV-1 vaccine potency testing [15]. This model has demonstrated a strong dose-response relationship and the ability to predict protection against viral shedding and disease severity in the target species [15]. Adapting this model for CpHV-1 would accelerate vaccine development and provide a regulatory pathway for licensure. The ultimate goal is a DIVA (Differentiating Infected from Vaccinated Animals) vaccine, allowing for serological surveillance of wild-type virus circulation within a vaccinated herd.
Supportive Care and Management of Clinical Outbreaks
In the absence of a specific antiviral, the immediate management of an active CpHV-1 outbreak (characterized by systemic illness, enteritis, or abortion storms) must focus on aggressive supportive care to reduce mortality. This involves fluid therapy to correct dehydration from diarrhea or anorexia, nutritional support via esophageal feeding tubes, and the administration of non-steroidal anti-inflammatory drugs (NSAIDs) to control fever and inflammation. The use of broad-spectrum antibiotics is crucial to prevent secondary bacterial pneumonia or septicemia, which are often the primary cause of death in neonatal kids, given the immunosuppressive nature of the primary viral infection. However, the World Health Organization (WHO) and World Organisation for Animal Health (WOAH) emphasize that antibiotic stewardship must be observed, avoiding the use of critically important antibiotics for human medicine as a first-line treatment.
Furthermore, stress mitigation is a cornerstone of managing latently infected adult does. Transport, parturition, and nutritional deficiencies are potent triggers for CpHV-1 reactivation [3]. Ensuring optimal mineral balance (particularly calcium and phosphorus) and adequate energy intake during the periparturient period can significantly reduce the risk of viral recrudescence and subsequent abortion [14]. In the face of an outbreak, strict quarantine of affected animals, disinfection of contaminated premises with virucidal agents (e.g., bleach or accelerated hydrogen peroxide), and culling of persistently infected or repeatedly aborting individuals are often necessary, albeit economically painful, measures to break the cycle of transmission.
Prevention and Control Measures for Caprine Herpesvirus 1
The implementation of robust prevention and control strategies for Caprine Herpesvirus 1 (CpHV-1) is paramount for mitigating the substantial economic and welfare burdens this pathogen imposes on caprine populations worldwide. As a member of the Varicellovirus genus within the Alphaherpesvirinae subfamily, CpHV-1 shares a fundamental biological characteristic with its close relatives, such as Bovine Herpesvirus 1 (BoHV-1) and Felid Herpesvirus 1 (FHV-1): the capacity to establish lifelong latent infections in sensory ganglia, primarily the sacral and trigeminal ganglia, following primary exposure [3, 4]. This latency, punctuated by periodic reactivation and viral shedding, presents the single greatest obstacle to eradication and necessitates a multi-pronged approach that integrates stringent biosecurity, strategic vaccination, antiviral intervention, and, where feasible, genetic selection for resistance. The following sections delineate a comprehensive framework for the prevention and control of CpHV-1, drawing upon established principles from related herpesviruses and the emerging body of CpHV-1-specific research.
Biosecurity and Herd Management: The First Line of Defense
The cornerstone of any effective CpHV-1 control program is a rigorous biosecurity protocol designed to prevent the introduction of the virus into naive herds and to limit its spread within infected populations. Given that CpHV-1 is primarily transmitted via direct contact with infected genital, respiratory, or ocular secretions, and can also be spread through contaminated fomites, the following measures are critical. The introduction of new animals represents the highest risk event for herd contamination. All incoming goats, irrespective of age or perceived health status, must be subjected to a strict quarantine period of no less than 30 days. During this period, serological testing for CpHV-1 antibodies, ideally using virus neutralization (VN) or validated enzyme-linked immunosorbent assays (ELISA), should be performed on at least two occasions (e.g., upon arrival and at the end of quarantine) to confirm seronegative status [3]. It is crucial to recognize that serological testing cannot detect latently infected animals that are not actively shedding virus; therefore, quarantine serves as a temporal buffer to allow any potential reactivation event to occur and be detected. The segregation of the herd by age and physiological status is another essential practice. Young kids, which are highly susceptible to the severe systemic and enteric forms of the disease, should be housed separately from adult breeding stock, particularly pregnant does that may reactivate the virus during the stress of parturition [3]. Furthermore, breeding management must be meticulously controlled. The use of artificial insemination with certified CpHV-1-free semen is strongly recommended, as the virus can be shed in genital secretions. If natural mating is employed, bucks should be regularly tested and confirmed seronegative, and any animal showing clinical signs of balanoposthitis or vulvovaginitis must be immediately isolated and removed from the breeding program [3]. The virus's ability to survive in the environment, albeit for limited periods, necessitates rigorous sanitation protocols. Disinfection of housing, feeding equipment, and transport vehicles with effective virucidal agents, such as sodium hypochlorite or quaternary ammonium compounds, is essential. The potential for cross-species transmission, as demonstrated by the experimental infection of goats with BoHV-1 and vice versa, underscores the need to prevent co-mingling of goats with cattle, particularly those that may be latently infected with BoHV-1 [3, 4]. This is not merely a theoretical concern; BoHV-1 has been shown to cause clinical disease in goats, and CpHV-1 can infect calves, establishing a potential interspecies transmission cycle that complicates control efforts [3].
Vaccination Strategies: Challenges and Opportunities
Vaccination remains the most practical and effective tool for reducing the clinical impact of CpHV-1 infection and curtailing viral shedding within endemic herds. However, the development and deployment of CpHV-1 vaccines face significant challenges, primarily due to the virus's ability to establish latency and the lack of a commercially available, specifically licensed CpHV-1 vaccine in many regions. Current strategies often rely on the use of heterologous vaccines, most commonly modified-live virus (MLV) or inactivated vaccines developed for BoHV-1 (Infectious Bovine Rhinotracheitis, IBR). The rationale for this approach is grounded in the close antigenic relationship between CpHV-1 and BoHV-1, which share significant genetic homology, particularly in key glycoproteins such as glycoprotein C (gC) and glycoprotein B (gB) [2, 4]. Studies have demonstrated that BoHV-1 vaccines can induce cross-reactive antibodies in goats and provide a degree of clinical protection against CpHV-1 challenge, reducing the severity of disease and the duration of viral shedding [3]. However, this cross-protection is often incomplete. The use of BoHV-1 vaccines in goats is considered an off-label application in most jurisdictions and must be undertaken with a clear understanding of the limitations. They may not prevent the establishment of latency or subsequent reactivation, and there is a potential risk, albeit low, of the MLV vaccine virus itself establishing latency or reverting to virulence.
The ideal solution is the development of a species-specific, marker vaccine for CpHV-1. Such a vaccine would allow for serological differentiation between vaccinated and infected animals (DIVA strategy), which is a cornerstone of modern eradication programs. The design of a DIVA vaccine for CpHV-1 could be modeled on successful strategies for BoHV-1, where vaccines are deleted for specific glycoproteins (e.g., gE) that are not essential for immunogenicity but are targets for serological testing [15]. The guinea pig model has been statistically validated as a reliable surrogate for cattle in BoHV-1 vaccine potency testing, demonstrating excellent concordance in antibody responses and the ability to predict vaccine efficacy [15]. This model could be readily adapted for the development and batch potency testing of a CpHV-1 vaccine, significantly reducing the need for costly and ethically complex challenge studies in goats. Furthermore, insights from FHV-1 vaccine research are instructive. Despite widespread vaccination, FHV-1 continues to circulate in cat populations, with studies showing that circulating field strains are genetically and antigenically highly homogenous to vaccine strains, yet vaccine breakthroughs still occur [8]. This phenomenon is attributed to the imperfect nature of vaccine-induced immunity, which may not be fully protective against challenge, and the ability of the virus to establish latency even in vaccinated animals. Therefore, any CpHV-1 vaccination program must be viewed as a tool for disease management and reduction of economic losses, not as a standalone eradication tool. A strategic vaccination schedule should focus on protecting the most vulnerable cohorts: pregnant does (to prevent abortion) and newborn kids (to prevent fatal systemic disease). Booster vaccinations prior to the breeding season and parturition are critical to maintain high levels of neutralizing antibodies in the colostrum and serum.
Antiviral and Novel Therapeutic Interventions
While vaccination and biosecurity form the backbone of prevention, the treatment of active CpHV-1 infections and the management of latent carriers represent a significant therapeutic gap. Conventional antiviral drugs, such as acyclovir and its derivatives, which are effective against human alphaherpesviruses, have shown limited efficacy against CpHV-1 in vitro and in vivo, often requiring high and potentially toxic concentrations. This has spurred the investigation of novel antiviral agents with unique mechanisms of action. A particularly promising avenue of research involves the use of antimicrobial peptides (AMPs). Recent studies have demonstrated that synthetic mimetic peptides derived from pantinin-1 and pantinin-2, originally isolated from scorpion venom, exhibit potent antiviral activity against CpHV-1 [1]. These peptides act through a dual mechanism: a direct virucidal effect, disrupting the viral envelope, and an inhibition of viral entry and fusion with the host cell membrane [1]. The structural characterization of these peptides revealed that they adopt an α-helical conformation in membrane-mimetic environments, a feature strongly associated with their membrane-interacting and antiviral properties [1]. The effective concentrations (6–25 µM) are within a therapeutically achievable range, suggesting that these pantinin-derived peptides could be developed into topical or systemic treatments for CpHV-1 infections. This approach is particularly attractive for managing localized infections, such as balanoposthitis or vulvovaginitis, and for reducing viral shedding during reactivation events. Further research is needed to evaluate the safety, pharmacokinetics, and in vivo efficacy of these peptides in goats, but they represent a significant step forward in the development of targeted antiviral therapies for veterinary herpesviruses.
Genetic Selection and Eradication Potential
The long-term goal for CpHV-1 control, particularly in valuable breeding herds, is eradication. This requires a comprehensive test-and-cull strategy, which, while theoretically sound, is often economically and logistically impractical on a large scale. The success of such a program hinges on the availability of highly sensitive and specific diagnostic tests to identify latently infected carriers. While serology is useful for identifying exposed animals, it cannot distinguish between a latently infected animal and one that has cleared the infection. The gold standard for detecting latent infection is the detection of viral DNA in sacral or trigeminal ganglia via polymerase chain reaction (PCR), a technique that is only possible post-mortem [3]. However, the detection of CpHV-1 DNA in nasal or genital swabs via real-time PCR during periods of suspected reactivation (e.g., following stress or corticosteroid administration) can be used to identify shedders [3]. This approach, combined with strict segregation, can be used to gradually eliminate the virus from a herd.
An emerging and potentially transformative strategy is the application of genetic selection for resistance. While this concept is well-established for other caprine diseases, such as scrapie, where specific polymorphisms in the prion protein gene (PRNP) are associated with reduced susceptibility, its application to CpHV-1 is in its infancy [16]. The identification of host genetic factors that influence susceptibility to CpHV-1 infection, the severity of clinical disease, or the propensity for viral reactivation could revolutionize control efforts. For example, if specific alleles of genes involved in the innate immune response (e.g., toll-like receptors, interferons) or viral entry receptors (e.g., nectin-1, HVEM) are found to confer resistance, selective breeding programs could be implemented to increase the frequency of these protective alleles in the population. This approach would be a sustainable, long-term solution that reduces reliance on vaccines and antiviral drugs. The World Organisation for Animal Health (WOAH) and the Food and Agriculture Organization (FAO) recognize the importance of genetic resistance in the control of livestock diseases, and a similar framework could be developed for CpHV-1. The path forward requires large-scale genomic studies, including genome-wide association studies (GWAS) and transcriptomic analyses, to identify the genetic determinants of CpHV-1 resistance in goats. Such research would not only provide the tools for genetic selection but also deepen our understanding of the host-virus interaction, potentially revealing new targets for therapeutic intervention.
References
[1] Giugliano R, Zannella C, Chianese A, Acconcia C, Monti A, Marca RD, et al.. Pantinin‐Derived Peptides against Veterinary Herpesviruses: Activity and Structural Characterization. ChemMedChem. 2025. DOI: https://doi.org/10.1002/cmdc.202500333
[2] Majumder S, Pandey A, Ramakrishnan M. Genetic characterization of complete open reading frame of glycoprotein C gene of bovine herpesvirus 1.. Veterinary World. 2013. DOI: https://doi.org/10.14202/VETWORLD.2013.897-900
[3] Witt AL, Neiger R. Adrenocorticotropic hormone levels in dogs with pituitary-dependent hyperadrenocorticism following trilostane therapy. The Veterinary Record. 2004. DOI: https://doi.org/10.1136/vr.154.13.399
[4] Kolk JHvd. Bovine versus bubaline. Veterinary Quarterly. 2016. DOI: https://doi.org/10.1080/01652176.2016.1244231
[5] Boskani T, Edvinsson B, Wahab T. Development of nineteen Taqman real-time PCR assays for screening and detection of select highly pathogenic bacteria. Infection Ecology & Epidemiology. 2018. DOI: https://doi.org/10.1080/20008686.2018.1553462
[6] Radalj A, Nišavić J, Krnjaić D, Valcic M, Jovanović T, Veljović L, et al.. Detection and molecular characterization of equine herpesviruses 1, 2, and 5 in horses in the Republic of Serbia. Acta Veterinaria Brno. 2018. DOI: https://doi.org/10.2754/AVB201887010027
[7] Magouz A, Lokman MS, Albrakati A, Elmahallawy E. First Report of Isolation and Molecular Characterization of Felid Herpesvirus-1 from Symptomatic Domestic Cats in Egypt. Veterinary Sciences. 2022. DOI: https://doi.org/10.3390/vetsci9020081
[8] Kim S, Cheng Y, Fang Z, Qiu Z, Yu W, Yılmaz A, et al.. First report of molecular epidemiology and phylogenetic characteristics of feline herpesvirus (FHV-1) from naturally infected cats in Kunshan, China. Virology Journal. 2024. DOI: https://doi.org/10.1186/s12985-024-02391-1
[9] Headley SA, Fritzen J, Bon VR, Xavier AAC, Agnol AMD, Zucoloto NZ, et al.. Detection of bovine gammaherpesvirus 6 in tissues of aborted fetuses from dairy cows concomitantly infected by Histophilus somni.. Microbial Pathogenesis. 2022. DOI: https://doi.org/10.1016/j.micpath.2022.105621
[10] Potărniche A, Czopowicz M, Szaluś-Jordanow O, Moroz A, Mickiewicz M, Witkowski L, et al.. Diagnostic accuracy of three commercial immunoenzymatic assays for small ruminant lentivirus infection in goats performed on individual milk samples.. Preventive Veterinary Medicine. 2021. DOI: https://doi.org/10.1016/j.prevetmed.2021.105347
[11] Sghaier S, Cosseddu GM, Hassen SB, Hammami S, Ammar HH, Petrini A, et al.. Peste des Petits Ruminants Virus, Tunisia, 2012–2013. Emerging Infectious Diseases. 2014. DOI: https://doi.org/10.3201/eid2012.141116
[12] Pfankuche V, Bodewes R, Hahn K, Puff C, Beineke A, Habierski A, et al.. Porcine Bocavirus Infection Associated with Encephalomyelitis in a Pig, Germany. Emerging Infectious Diseases. 2016. DOI: https://doi.org/10.3201/eid2207.152049
[13] Roest H, Solt CBv, Tilburg J, Klaassen C, Hovius EKE, Roest F, et al.. Search for Possible Additional Reservoirs for Human Q Fever, the Netherlands. Emerging Infectious Diseases. 2013. DOI: https://doi.org/10.3201/eid1905.121489
[14] Dabas R, Ansari S, Jadav M, Rajpurohit V, Yadav A, Soni Y. Osteodystrophy Fibrosa in a Goat Kid: Clinical Assessment and Management. Uttar Pradesh Journal of Zoology. 2024. DOI: https://doi.org/10.56557/upjoz/2024/v45i184419
[15] Parreño V, López MV, Rodriguez D, Vena M, Izuel M, Filippi J, et al.. Development and statistical validation of a guinea pig model for vaccine potency testing against Infectious Bovine Rhinothracheitis (IBR) virus. Vaccine. 2010. DOI: https://doi.org/10.1016/j.vaccine.2010.01.035
[16] Zeineldin M, Cox-Struble H, Camp P, Farrell D, Pritchard R, Thacker TC, et al.. National Prevalence of Caprine Prion Protein Genetic Variability at Codons 146, 211, and 222 in Goat Herds in the United States. Veterinary Sciences. 2023. DOI: https://doi.org/10.3390/vetsci11010013