DIVA strategy in animal disease control and eradication: A review

Introduction

Infectious diseases in livestock continue to pose significant challenges to global food security, animal health, and agricultural economies. These diseases reduce productivity through decreased growth, milk yield, and fertility, while imposing substantial economic burdens due to treatment costs, trade restrictions, and control measures. A particularly critical group known as transboundary animal diseases (TADs) can spread rapidly across national borders, causing devastating outbreaks affecting entire livestock populations and disrupting international trade. Important TADs include foot and mouth disease (FMD), peste des petits ruminants (PPR), and classical swine fever (CSF), each requiring well coordinated control strategies beyond conventional approaches. Vaccination is the most effective and economical tool for preventing and controlling infectious diseases in animals. However, conventional vaccines whether live attenuated or inactivated induce immune responses that closely resemble those generated during natural infection. As a result, standard serological tests cannot distinguish vaccinated animals from naturally infected ones (Van Oirschot, 1999) [41] , creating a major barrier for disease surveillance, trade certification, and eradication programs. To overcome this fundamental limitation, the concept of Differentiating Infected from Vaccinated Animals (DIVA), also referred to as marker vaccination, was formally introduced by J.T. Van Oirschot of the Central Veterinary Institute, Netherlands, in 1999. The DIVA strategy uses specially designed marker vaccines combined with companion diagnostic tests to create a clear, exploitable immunological difference between vaccinated and infected animals. This integration of vaccination and precise diagnostics represents a major advancement in veterinary disease control, enabling continuous surveillance even during active vaccination campaigns (Pasick, 2004) [29] . In today's era of intensified global trade, climate change influenced disease dynamics, and growing societal concerns about mass culling of healthy animals, DIVA based strategies have become increasingly critical for achieving sustainable, scientifically robust disease control and eradication.

The Diva Concept: Principles and Immunological Basis

The DIVA principle relies on engineering a clear immunological distinction between the vaccine and the natural infection. Although vaccinated animals are protected by marker vaccines, their immune response differs fundamentally from that of naturally infected animals. This distinction is achieved either by removing a specific antigen from the vaccine (negative marker) or by incorporating a foreign antigen absent from the natural pathogen (positive marker) (Clavijo et al., 2004; Van Oirschot, 1999) [11,41] . The selected marker antigen is typically a non protective, non essential protein whose replacement or deletion does not affect vaccine efficacy. Animals in a vaccinated population remain seronegative for the marker protein but develop antibodies against all shared antigens. In contrast, naturally infected animals develop antibodies against all pathogen proteins, including the marker antigen. A highly specific companion diagnostic test usually a marker-specific ELISA detects this binary antibody response (Paton et al., 2006) [31] . A DIVA strategy is not just a vaccine but a complete system. It has two important parts that must work together: (i) a marker vaccine, which is specially designed to produce a unique immune response, and (ii) a companion diagnostic test, which helps detect or differentiate infected animals from vaccinated ones. If either of these components is missing, the DIVA approach cannot work properly. In addition, the diagnostic test must be highly accurate, with good sensitivity and specificity, because any error may result in missing infected animals or wrongly culling healthy ones (Uttenthal et al., 2010) [40] .

Types of Diva Vaccines 3.1 Negative Marker Vaccines (Gene Deletion Vaccines)

Negative marker vaccines represent the most extensively developed and field validated DIVA vaccine category. In this approach, genes encoding immunologically accessible but non protective antigens are precisely deleted from the pathogen genome using recombinant DNA technology.

Vaccinated animals seroconvert against all retained antigens while remaining seronegative for the deleted marker protein (Van Oirschot, 1999) [41] . The classical example is the gE (glycoprotein E)-deleted vaccine for Bovine Herpesvirus 1 (BoHV-1), causative agent of Infectious Bovine Rhinotracheitis (IBR). Since the gE protein is immunogenic but dispensable for protective immunity, its deletion creates a clear serological window exploited by a paired gE-ELISA. Similarly, gE-deleted marker vaccines were pivotal in eradicating Pseudorabies Virus (PRV) from domestic pig populations across Europe and North America (Kaashoek et al., 1998; Van Oirschot, 2001) [15,42] .

Positive Marker Vaccines

Positive marker vaccines incorporate a heterologous antigen absent from the wild type pathogen directly into the vaccine construct. This foreign protein acts as a unique serological tag: animals encountering only the field virus lack antibodies to the introduced marker, while vaccinated animals carry them exclusively (Van Oirschot, 1999) [41] . Although conceptually elegant, positive marker vaccines have seen limited commercial uptake, partly because the immune response to the marker antigen can sometimes interfere with responses to protective antigens. Experimental applications include recombinant poxvirus and adenovirus vectored vaccines encoding reporter antigens (Clavijo et al., 2004) [11] .

Subunit Marker Vaccines

Subunit marker vaccines present only defined, purified protective antigens, naturally excluding non structural and accessory proteins produced during active viral replication. Since these excluded proteins are generated during natural infection but absent in the vaccine, detection of antibodies directed against them forms the basis for DIVA differentiation (Paton et al., 2006) [31] . The FMD purified inactivated vaccine is the archetype: highly purified vaccines contain exclusively viral capsid proteins, while non structural proteins (NSPs) such as the 3ABC polyprotein are rigorously removed. Animals recovering from natural infection invariably develop anti NSP antibodies, while properly vaccinated animals do not (Clavijo et al., 2004; Lubroth and Brown, 1996) [11,19] . E2 subunit vaccines for Classical Swine Fever (CSF) follow analogous logic, with the companion E-rns-ELISA distinguishing vaccinated from infected animals (Moormann et al., 2000) [24] .

Live Attenuated Marker Vaccines

When combined with gene deletion, live attenuated vaccines become a powerful DIVA platform, retaining the immunological potency of replication competent strains inducing robust humoral and cellular immunity while carrying a defined molecular deletion that enables serological differentiation. The gE-deleted attenuated BoHV-1 and PRV vaccines exemplify this category and have demonstrated outstanding field performance in national eradication campaigns (Kaashoek et al., 1998) [15] .

Inactivated Marker Vaccines

Inactivated marker vaccines combine the high safety profile of killed preparations with engineered antigen exclusion. Because inactivated organisms cannot replicate, no post vaccination amplification of non structural proteins occurs, underpinning the FMD inactivated DIVA platform. Their main limitations include the need for adjuvantation, multiple booster doses, and rigorous cold chain compliance. They are

the preferred choice for disease-free zones and for susceptible animal groups where live vaccines are contraindicated (Van Oirschot, 2001; WOAH, 2021) [42,45] .

Recombinant and Vector Based Marker Vaccines

Advances in molecular biology have enabled the design of recombinant marker vaccines in which selected protective antigens are expressed within heterologous viral or bacterial vectors, offering precise control over antigen composition. The recombinant Vaccinia-Rabies Glycoprotein (V-RG) vaccine for oral wildlife rabies control is the most prominent field deployed example: it expresses only the rabies surface glycoprotein G while completely lacking the nucleoprotein N present in wild type virus, enabling DIVA discrimination by N-ELISA (Maki et al., 2017) [20] . DNA vaccine platforms, encoding only selected antigens, similarly offer inherent DIVA properties through restricted antigen expression profiles, though most remain in preclinical or early evaluation phases (Blome et al., 2020; Li et al., 2023) [6,18] .

Mechanisms of Action in Specific Diva Systems 4.1 Gene Deletion Strategy (Pseudorabies / IBR Model)

The deletion mutant approach exploits the fact that many enveloped herpesviruses encode glycoproteins that, while highly immunogenic, are dispensable for viral replication and for eliciting neutralizing immunity. For PRV, gE-deficient strains were demonstrated to be avirulent yet immunologically competent. Animals vaccinated with gEdeleted vaccines produce gE-negative serological profiles detectable by commercially validated gE-ELISAs, while naturally exposed animals uniformly develop gE antibodies (Van Oirschot et al., 1990) [43] . This clean binary output simplified herd classification and enabled systematic test and removal programs.

Non Structural Protein Differentiation (FMD Model)

During productive FMD virus replication, the genomic polyprotein is processed to yield not only structural capsid proteins but also non structural enzymes including the 3ABC precursor polyprotein. Animals recovering from natural infection invariably develop antibodies against 3ABC, while animals vaccinated with sufficiently pure vaccines do not. The 3ABC ELISA exploits this immunological distinction, with vaccine purity being the critical quality control parameter. Even residual NSP contamination from inadequate purification can yield false positive ELISA results in vaccinated animals, undermining the surveillance framework (Paton et al., 2006; Uttenthal et al., 2010; EFSA, 2022) [31,40,3] .

Heterologous Neuraminidase Strategy (Avian Influenza)

For Avian Influenza (AI), the DIVA mechanism operates at the level of the neuraminidase (NA) surface glycoprotein. Vaccine strains are engineered to share the same hemagglutinin (HA) type as the circulating field virus while carrying a different NA subtype. For example, an H5N2 vaccine used against an H5N1 outbreak ensures that all vaccinated birds develop anti-H5 antibodies, but only naturally infected birds acquire anti-N1 antibodies. Detection of N1-specific antibodies in a vaccinated flock thus serves as a reliable indicator of field virus circulation (Capua and Marangon, 2003; Suarez, 2005) [8,36] .

Diagnostic Tests in the Diva Framework

The companion diagnostic test is the operational core of any DIVA program. Multiple test formats have been developed and validated for different diseases:

• Marker specific ELISAs (e.g., gE-ELISA for IBR/PRV, NSP-ELISA for FMD, E-rns-ELISA for CSF, NA-ELISA for AI) offer high throughput, quantitative results, and suitability for large scale population screening. They are internationally recognized by WOAH and incorporated into official disease control protocols. • Virus Neutralization Tests (VNT) measure functional antibody activity against the pathogen and are used as confirmatory assays in reference laboratory settings when marker specific ELISA results require verification (Van Oirschot, 1999) [41] . • Molecular diagnostics, including conventional and real time quantitative PCR, detect pathogen nucleic acids in clinical samples and serve a complementary role during the pre seroconversion window after infection, when antibody based DIVA tests may yield false negative results (Pasick, 2004; WOAH, 2021) [29,45] . • Next Generation Sequencing (NGS) is increasingly being explored to support DIVA surveillance by enabling full genome characterization of field strains and ensuring that marker antigens remain conserved and diagnostic integrity is maintained (Li et al., 2023) [18] . [22,29] . Regulatory authorities mandated exclusive use of gE deleted vaccines, and the highly sensitive gE-ELISA enabled consistent identification of gEseropositive animals within vaccinated populations. Countries including Germany, the Netherlands, Belgium, Denmark, and the United States achieved official PRV free status through this approach (Muller et al., 2003; Stegeman et al., 1994) [25,35] . Paton and Reeve, 2022; EFSA, 2022) [3,31,30,13] . A persistent challenge is the carrier state in cattle, where the virus may persist in the pharynx for months despite vaccination. Recent work has focused on improving NSP-ELISA sensitivity for carrier detection and enhancing vaccine purity standards (Paton and Reeve, 2022) [30] . [2,7,24,6] .

Applications in

Infectious Bovine

Classical Swine

Avian Influenza (AI)

The heterologous neuraminidase DIVA strategy for AI has been most extensively applied in Italy during H7N1 outbreaks (1999-2000) and in Southeast Asia and China for various H5 subtypes. Vaccination with heterologous NA vaccines significantly reduced clinical disease and mortality while allowing surveillance systems to detect field virus circulation through NA-ELISA monitoring of sentinel flocks. This approach enabled targeted depopulation only of infected flocks, avoiding the catastrophic economic impact of blanket stamping-out policies (Capua et al., 2003; Suarez, 2005) [9,36] .

Lumpy Skin Disease (LSD)

A DIVA compatible vaccine for Lumpy Skin Disease, BIOLUMPIVAXIN, based on a live attenuated LSDV strain Ranchi/2019, has been developed through collaboration between Biovet (a Bharat Biotech subsidiary), ICAR-NRCE, and IVRI. This vaccine enables differentiation between vaccinated cattle and buffaloes and those naturally infected with field strains, strengthening the surveillance and eradication framework for this economically important disease in the Indian subcontinent (Kumar et al., 2025) [16] .

Recent studies have confirmed its field performance and safety profile (Kumar et al., 2025; Mohan et al., 2023) [16,23] .

Brucellosis

The RB51 live attenuated rough strain of Brucella abortus serves as a DIVA vaccine by lacking the O-polysaccharide side chain on its lipopolysaccharide. Standard brucellosis serological tests primarily detect antibodies to the O-chain; RB51-vaccinated animals do not generate O-chain antibodies and therefore test negative on these assays, whereas naturally infected animals are seropositive. This property facilitates surveillance of brucellosis in vaccinated herds, overcoming a key limitation of the traditional smooth S19 vaccine (Schurig et al., 2002,Blasko et al.,2023) [33, ] .

Rabies (Wildlife Reservoir Control)

The V-RG recombinant vaccine, distributed via oral baiting in wildlife reservoirs, has been employed across Europe and North America to eliminate sylvatic rabies from fox and raccoon populations. The DIVA property arises from the vaccine's exclusive expression of the rabies G protein, with complete absence of the N protein. Anti-N antibody ELISA surveys can identify animals with prior wild type virus exposure, guiding adaptive management of ongoing oral vaccination campaigns (Maki et al., 2017) [20] .

DIVA Strategy in India

In India, the DIVA strategy is actively strengthening disease surveillance and control frameworks for several economically significant livestock diseases. The development of BIOLUMPIVAXIN for LSD represents a notable indigenous achievement. India also utilizes DIVA vaccines for IBR (Raksha IBR), Bovine Brucellosis (Brucella abortus RB51 and S19DELTA), FMD (purified inactivated NSP free vaccines), and Pseudorabies. DIVA vaccines for Classical Swine Fever, Avian Influenza, Newcastle Disease, and Rabies are currently not commercially available within the country, highlighting the need for further research and regulatory development (Mohan et al., 2023) [23] . [4,38] . • Precision eradication: Targeted test and removal policies replace economically devastating whole herd

depopulation, identifying individual infected animals within immune populations while preserving vaccinated animals of high genetic and productive value (Muller et al., 2003; Pasick, 2004) [25,29] . • Ethical acceptability: DIVA vaccination enables a 'vaccinate to live' policy framework, reducing reliance on mass culling and aligning disease control with contemporary animal welfare expectations (Domenech et al., 2006; Scudamore and Harris, 2002) [12,34] . • One Health integration: Reducing pathogen load at the livestock wildlife human interface contributes to public health, as DIVA strategies enable sustained vaccination without compromising the surveillance needed to detect emerging zoonotic threats (OIE, 2019) [27] .

Limitations

• Diagnostic accuracy dependence: The DIVA strategy is only as robust as its companion diagnostic. Suboptimal sensitivity generates false negatives, allowing infected animals to remain in herds; suboptimal specificity generates false positives, eroding farmer confidence. A critical gap also exists immediately post infection before specific antibodies develop (Uttenthal et al., 2010) [40] . • Vaccine purity requirements: For subunit DIVA vaccines, the system's integrity depends entirely on the absence of diagnostic antigens from the final vaccine product. Even trace NSP contamination can render vaccinated cohorts serologically ambiguous, neutralizing the surveillance benefit (Lubroth and Brown, 1996; Paton et al., 2006) [19,31] . [3,12] . • Antigenic drift and marker stability: Continuous mutation of field virus populations can alter or eliminate the antigenic marker relied upon for DIVA differentiation, requiring vigilant molecular surveillance of circulating strains (Mettenleiter, 2016) [21] .

Future Prospects

The DIVA strategy is rapidly evolving with new technologies, and the coming years hold great promise for making it even more effective, affordable, and widely available. Below are some key areas where DIVA is likely to advance in simple terms:

Conclusion

The DIVA strategy represents one of the most significant advances in veterinary vaccinology, transforming vaccination from a potential barrier to disease surveillance into a powerful tool that supports it. By using specially engineered marker vaccines combined with highly specific companion diagnostic tests, DIVA allows veterinarians and disease control authorities to accurately distinguish infected animals from vaccinated ones even during active vaccination campaigns. This capability has already led to the eradication of Pseudorabies in multiple countries and the successful control of Infectious Bovine Rhinotracheitis, Foot and Mouth Disease, Avian Influenza, Classical Swine Fever, Brucellosis, Lumpy Skin Disease, and Rabies in various parts of the world. Despite remaining challenges including the need for high vaccine purity, accurate and affordable diagnostic tests, and the risk of antigenic drift in field virus populations the future

of DIVA is bright. Emerging technologies such as mRNA vaccines, rapid on farm diagnostic kits, AI assisted disease surveillance, and digital data integration are poised to overcome current limitations and expand the reach of DIVA based programs globally. As international animal trade grows and zoonotic diseases become more frequent, and as society increasingly opposes the mass culling of healthy animals, the DIVA approach's 'vaccinate to live' philosophy offers the most scientifically sound, economically efficient, and ethically acceptable path forward for animal disease control and eradication worldwide.

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