Capripoxvirus vectors show partial promise against bluetongue and lumpy skin disease

Lumpy skin disease and bluetongue are transboundary viral diseases of cattle and other ruminants, and both pose persistent challenges for livestock production across Central Asia, where animals move over vast territories and epidemiological information is unevenly distributed among regions. A Mini Review published in Frontiers in Veterinary Science by researchers at the Research Institute for Biological Safety Problems in Kazakhstan critically evaluates capripoxvirus-based recombinant vaccine strategies for the two diseases. The authors, led by Alina Kurmasheva and Yerbol Bulatov, conclude that while capripoxvirus vectors can deliver bluetongue virus antigens and induce antigen-specific immune responses, the available challenge studies demonstrated only partial protection, and a proposed locally derived vaccine construct expressing three bluetongue virus proteins remains an unvalidated research hypothesis rather than a demonstrated vaccine platform.

The epidemiological context shapes the review’s argument. Lumpy skin disease was first identified in Kazakhstan in 2016 and subsequently affected additional territories, prompting vaccination in high-risk areas. Serological and molecular investigations have also reported bluetongue virus antibodies and viral RNA in Culicoides biting midges in the country. Bluetongue virus serotype 9, a western topotype, has been detected in Culicoides species and in clinically healthy livestock in southeastern Kazakhstan. The authors emphasize that these findings support continued surveillance but do not, by themselves, define which bluetongue virus serotypes a future vaccine should target. Antigen selection, they argue, would require current, geographically representative molecular surveillance and comparison of VP2 sequences from viruses actually circulating in the region.

Bluetongue virus has a segmented genome comprising ten double-stranded RNA segments and can undergo reassortment, a property that complicates long-term vaccine design. The outer capsid protein VP2 is a principal determinant of serotype-specific neutralizing immunity, which means that important neutralizing responses constrain cross-protection among the many bluetongue virus serotypes. Recent European events illustrate how quickly the epidemiological picture can change: bluetongue virus serotype 3 emerged in the Netherlands in 2023 and spread to other European countries, and serotype 12 was reported in Dutch sheep and cattle in 2024. The review stresses that these events reinforce the need for continuing surveillance and careful antigen matching, but should not be interpreted as direct evidence of the serotypes currently circulating in Central Asia.

No vaccine platform is optimal for every epidemiological and operational setting, and the review compares several options. Virus-like particles offer native conformational presentation and non-replicating safety but face assembly and purification complexity and are restricted by VP2 to particular serotypes; their use against bluetongue remains experimental. Subunit vaccines provide high biological safety and defined antigen composition but may require adjuvants and booster doses. Adenovirus and MVA vectors can induce both humoral and cellular immunity, though pre-existing vector immunity and manufacturing complexity are limitations. Inactivated bluetongue virus vaccines have substantial field experience and were authorized against serotype 3 in Europe during the recent outbreak response, but their protection is serotype-dependent and booster doses may be required. Capripoxvirus vectors, the focus of the review, are ruminant-associated and can accommodate heterologous antigens, but their multi-antigen cassettes carry unknown genetic stability, antivector immunity and vector shedding concerns.

Capripoxviruses have been investigated as vaccine vectors because their large double-stranded DNA genomes can accommodate foreign genes and their host range is associated with ruminants. However, the review is explicit that using capripoxvirus vectors to deliver bluetongue virus antigens is not a new concept; it was demonstrated decades ago. The relevant question, the authors argue, is therefore not whether the general idea is novel, but whether a locally characterized lumpy skin disease virus backbone and a proposed multi-antigen configuration address a defined research gap. The existing evidence, they caution, does not establish that the candidate strain would be safe or protective against bluetongue virus.

Two foundational studies are central to this critical assessment. Wade-Evans and colleagues in 1996 reported a recombinant capripoxvirus expressing VP7 from bluetongue virus serotype 1 and evaluated it in sheep. Vaccination induced antibodies to VP7 but no detectable neutralizing antibodies against the homologous or heterologous serotype before challenge. After heterologous challenge with virulent serotype 3, all animals developed clinical signs, indicating that infection was not prevented; six of eight vaccinated sheep recovered, whereas the control animals died. The study therefore demonstrated partial protection against a severe clinical outcome, not prevention of infection or sterilizing immunity, and does not establish broad neutralizing protection.

Perrin and colleagues in 2007 evaluated recombinant capripoxviruses expressing individual bluetongue virus serotype 2 proteins, namely VP2, VP7, NS1 or NS3, in small ruminants. Eleven sheep and four goats were immunized, and sheep were challenged with virulent serotype 2 three weeks after immunization. Seroconversion to VP2, VP7 and NS3 was reported in both species, and bluetongue virus-specific lymphoproliferative responses were demonstrated in goats, with challenged sheep showing partial protection. The study supports the immunogenicity of individual bluetongue virus antigens delivered by capripoxvirus vectors, but it does not demonstrate that combining these antigens in a single vector improves protection, nor does it establish efficacy in cattle. Differences in antigen, serotype, animal model and challenge design limit direct comparison between the two foundational studies.

The candidate backbone under discussion is LSDV Atyrau-5BJN(IL-18), derived from a field isolate from western Kazakhstan. Published descriptions report deletion of the LSDV005, LSDV008 and LSDV142 genes, with disruption of the LSDV066 locus by insertion of a cassette encoding bovine interleukin-18. The review stresses that these data do not validate the strain as a heterologous vaccine vector: the genome sequence alone does not demonstrate suitability, and evidence from the parental strain must not be presented as evidence of recombinant safety or efficacy. Additional expression cassettes could affect viral fitness, antigen expression, genetic stability, immunogenicity and protection against lumpy skin disease virus itself. Further assessment would need to address safety, replication, antigen expression, retention of lumpy skin disease protection, shedding, transmission and possible effects of the interleukin-18 insertion.

The proposed antigen set carries distinct but not equivalent biological rationales. VP2 would need to be selected using current surveillance and sequence comparison, because it determines serotype-specific neutralizing antibodies. VP7 is a relatively conserved core protein that can induce group-specific antibody responses and may contribute to cellular immune recognition, but conservation alone does not establish broad neutralizing activity or protection. NS3 is a non-structural protein involved in viral egress that has been investigated as an immunological target, but its contribution to protection when delivered by a capripoxvirus vector remains uncertain. Co-expression of all three proteins in one vector has never been experimentally evaluated in the proposed construct; it could affect the amount, stability or processing of each antigen and the fitness of the vector, and immunodominance or competition between antigen-specific responses cannot be confidently predicted from the available evidence. Pre-existing capripoxvirus immunity from vaccination or natural exposure could also alter vector replication and the duration or magnitude of heterologous antigen expression.

DIVA compatibility, the ability to differentiate infected from vaccinated animals, is a practical design constraint. NS3-based competitive ELISAs have been investigated to distinguish bluetongue virus infection from vaccination with vaccines that do not induce anti-NS3 antibodies. A recombinant vaccine expressing bluetongue virus NS3 could induce antibodies detected by such assays and thereby compromise their discriminatory value, a potential diagnostic conflict rather than a demonstrated outcome, because the construct has not been tested. An alternative companion assay targeting a non-vaccine antigen such as NS1 could be considered, but its performance would require independent development and validation. On safety, the review distinguishes documented properties of existing capripoxvirus vaccines from unresolved risks of the proposed recombinant: no experimental data establish shedding, Culicoides-mediated transmission or environmental dissemination of the hypothetical construct, and these remain open questions. PCR detection of viral nucleic acid alone cannot establish the presence of infectious virus, and conclusions about infectious shedding should be supported by appropriate infectivity testing. The European Medicines Agency’s 2026 guideline on combined vaccines remains a draft and should not be described as an adopted final guideline.

The authors also caution that potential manufacturing or economic benefits, including lower production costs or reduced import dependence, remain hypotheses that would require comparative evidence on yield, batch consistency, formulation, storage stability, scale-up, quality control and cost-effectiveness. Combining antigens in one vector does not by itself demonstrate lower costs or simpler manufacturing. For Central Asia, they argue, lumpy skin disease and bluetongue control should integrate vaccination with molecular surveillance, entomological monitoring and animal-movement management, since vector distribution and seasonal activity vary by location and species. Bluetongue surveillance should identify circulating serotypes and characterize VP2 sequences before antigen selection. Although a recombinant platform might eventually allow antigen updates, the feasibility and regulatory implications have not been demonstrated for this construct. Until surveillance-informed VP2 selection, evidence that each additional antigen contributes meaningfully to protection, assessment of antigen interactions and vector fitness, preservation of lumpy skin disease protection and a workable DIVA strategy are available, the proposed VP2, VP7 and NS3 combination should be regarded only as a preclinical research hypothesis, not as an established or demonstrably superior vaccine platform.

Subject of Research: Capripoxvirus-based recombinant vaccine strategies for bluetongue and lumpy skin disease in cattle

Article Title: Capripoxvirus-based recombinant vaccine strategies for bluetongue and lumpy skin disease in cattle: current evidence, challenges, and prospects for Central Asia

Article References: Kurmasheva, A., Bulatov, Y., Amanova, Z., Sametova, Z., Toktyrova, D., Turyskeldy, S., Abitayev, R., Ussembay, A., Mazbayeva, D., & Kondibayeva, Z. (2026). Capripoxvirus-based recombinant vaccine strategies for bluetongue and lumpy skin disease in cattle: current evidence, challenges, and prospects for Central Asia. Frontiers in Veterinary Science, 13, Article 1913890. https://doi.org/10.3389/fvets.2026.1913890

Image Credits: AI Generated

DOI: 10.3389/fvets.2026.1913890

Keywords: bluetongue, lumpy skin disease, Capripoxvirus, LSDV, BTV, recombinant vaccine, DIVA, Central Asia, Kazakhstan, veterinary virology, Capripoxvirus-based, recombinant