JVS_13_11-27

Introduction

Creating and implementing health care programs is the base of profitable farms. Prevention of microbial infections using vaccination is an essential part of such a program (Lacasta et al., 2015). Microbial infections are important; therefore, good healthcare practices must be done for adequate management. Vaccination is believed to be the most efficient means of disease prevention (Demirden et al., 2024). Conventional vaccines, such as killed and live attenuated, contain the entire pathogen in either a killed or attenuated state. On the other hand, vaccines of the new generation are made to trigger an immune response by genetic manipulation of the pathogen’s nucleic acid. These novel therapeutics include chimera, DNA plasmid, mRNA, and recombinant viral vector-based vaccines (Morens et al., 2023). Recombinant viral vectors represent an essential avenue for future study in innovative vaccine development since they can provide high immunogenicity and quickly respond to a new pandemic. Also, they are the best vehicles for delivering foreign proteins as they resemble natural infection and trigger an immune response with protective antibody levels (Liu et al., 2023). The viral vector has specific characteristics to be considered a vaccination vector: constant insertion of coding sequences into the genome, activation of an immune response that is protective, the potential for enormous production, and a proven safety record, for example, poxvirus and adenovirus (Lauer et al., 2017). Moreover, lumpy skin disease (LSD), sheep pox (SPP), rift valley fever (RVF), goat pox (GTP), and peste des petits ruminants (PPR) circulate throughout the same African regions, impacting public health and economic activity. Although commercial vaccinations against these viruses exist, most African farmers cannot afford to conduct routine immunization regimens against several diseases. Therefore, African livestock farmers would greatly benefit from a single, affordable multivalent vaccine that concurrently protects against different diseases (Boshra et al., 2013).

Importance of vaccination

Vaccination is a highly successful and economical method for preventing a wide range of viral infectious diseases in aquatic and terrestrial species, including birds (Jogi et al., 2024). The major challenge with viral infection pathogens is the lack of antiviral medications that can effectively combat the wide range of viruses responsible for many infectious diseases in industrial animals (Kausar et al., 2021). Vaccination is among the most popular and efficient interventions in veterinary medicine that aim to reduce fatalities and output losses.

Several platforms have been developed in the last few decades besides conventional live and non-live immunizations. These include viral vectors, RNA and DNA vaccines based on nucleic acids, and particles that resemble viruses. High vaccine stability, long-lasting immune responses, and ease of large-scale production are some of the advantages of employing nucleic acid vaccines (Travieso et al., 2022). Live vaccines are designed to generate an adequate immune response but not enough to result in noticeable disease (Pollard and Biker, 2021). Live attenuated vaccines elicit an immune response similar to the immunological response to an infection with a live virus. This covers both the B cells’ generation of antibodies and the T cells’ initiation of a cellular immune response. Memory cells, which “remember” the infection and enable a speedier and more efficient reaction in the event of subsequent exposure, can develop from both B-cells and T-cells. (Gupta and Pellett, 2023). Therefore, it minimizes or eliminates clinical symptoms and potentially prevents the generation of disease following infection (Pollard and Bijker, 2021). Non-live vaccines’ antigenic component has the ability to destroy polysaccharides, recombinant proteins, entire organisms, or purified proteins from the organism (Akter and Kumar, 2023).

Protein antigens that trigger immunity and offer defense are a crucial part of the majority of vaccinations (Iqbal et al., 2023). Polysaccharide antigens, on the other hand, are the fundamental components of vaccines that were previously created to avert a number of bacterial diseases and can also elicit protective immune responses (Nam et al., 2024). Adjuvants are frequently added to non-live vaccines to increase their immunogenicity or capacity to elicit an immune response (Habib et al., 2023). Other ingredients used in vaccines include stabilizers, emulsifiers (like polysorbate 80), and preservatives (such as sorbitol or gelatine) (Khan et al., 2024). Theoretically, a number of products used in the production of vaccines, such as antibiotics, egg or yeast proteins, latex, formaldehyde and/or glutaraldehyde, and acidity regulators (like potassium or sodium salts), might also be incorporated as possible trace elements in the vaccine (Domachowske, 2021).

Remarkably, a further advantage of vaccinating food-producing animals is that it minimizes the effect of drug residues that the animals receive and then consumed by humans through drinking or eating dairy or meat products, respectively (Khalifa et al., 2024). Also, it should be mentioned that the European Union (EU) has drastically restricted the utilization of antibiotics in food-producing animals (European Environmental Agency, 2024).

Dual vaccines

Definition

Dual vaccines are known as vaccines intended to confer protection against two distinct diseases or pathogens at the same time. It is also identified as Dual-Antigen Vaccines that target two antigens from multiple pathogens. For example, the dual-antigen vaccine of COVID-19 contains genes for the SARS-CoV-2 virus’s spike and nucleocapsid proteins. This kind of vaccination aims to stimulate a more extensive immune response and improves defense against different viral strains (Gabitzsch et al., 2021). Additionally, the human coronavirus known as Middle East respiratory syndrome coronavirus (MERS-CoV) is extremely harmful (Milne Price et al., 2014). A glycoprotein called MERS-CoV spike (s) protein is incorporated into the membrane of MERS-CoV virions and plays a part in immune system stimulation. People and animals in locations where MERS-CoV is widespread may benefit from vaccinations using the S1 domain of its s protein, which was produced on the surface of a dead rabies virus and has been shown to elicit strong immune responses against both rabies virus (RABV) and MERS-CoV (Kato et al., 2019).

Benefits and examples of dual vaccines

Furthermore, herpesviruses are frequently used as vectors in veterinary medicine because they strengthen potent cell and antibody-mediated immune responses (Kamel et al., 2023). Because of their long-life latency and numerous unnecessary genes, they have been shown to be the most promising vehicles for developing multivalent vaccinations. These genes include thymidine kinase (TK), protein kinase (PK), glycoprotein E (gE), and glycoprotein I (gI) (Cottingham et al., 2021).

For example, feline herpesvirus-1 (FHV-1) mutant (WH2020-ΔTK/gI/gE), a TK/gI/gE-deleted FHV-1 mutant based on the FHV-1 felid strain WH2020, which effectively protected felines from the FHV-1 infection and was safe for them (Yang et al., 2023), expresses the feline parvovirus (FPV) VP2 protein, that can induce the production of a high amount of parvovirus neutralizing antibodies, (WH2020-ΔTK/gI/gE-VP2) seems to be a potentially cost-effective, safe, and efficient dual vaccine against FPV and FHV-1 (Yang et al., 2024). Additionally, using FHV-1 as a vector, a recombinant vaccine encoding the FeLV glycoprotein gene was created, and it was demonstrated that the vaccine protected cats against FeLV-induced viremia through oronasal vaccination (Willemse et al., 1996). In a different investigation, RABV strain BD06 glycoprotein (G) was expressed using an isolate of felid herpesvirus 1 (FHV-1) as a carrier (Chen et al., 2019) because it is the sole outer membrane protein that can be relied upon to initiate the production of antibodies that neutralize the rabies virus (Benmansour et al., 1991) by inserting the glycoprotein (G) of rabies instead of gI/E in the FHV-1 and it has been demonstrated that the dual vaccine FHV-RVG is potent and protects cats from both FHV-1 and RABV infections (Chen et al., 2019). Furthermore, recombinant vaccines for the oral rabies vaccination of wildlife have been created using adenovirus as a vector. (Brown et al., 2014). Under the influence of internal or external viral promoters, the human adenovirus type 5 produces the rabies virus G gene rather than its deleted E3 transcription unit. Foxes and skunks were protected against rabies virus infection by oral administration of the recombinant rabies adenovirus vaccine (Yamanouchi et al., 1998).

Moreover, poultry has received dual vaccinations to enhance disease protection. One notable example is the LaSota strain (LS), a low-virulent recombinant Newcastle disease virus (NDV), widely used as a live vaccine to prevent Newcastle disease in poultry worldwide. In a study by Dimitrov et al. (2017), LS was utilized as a vector to deliver the Marek’s disease virus (MDV) gB protein. MDV glycoproteins such as gB, gI, gE, and gC play a crucial role in viral infection, cell-to-cell transmission, and the initiation of host immune responses (Swayne et al., 2013). The results demonstrated that the recombinant virus (rLS/MDV-gB) effectively protected vaccinated birds from both MDV-induced tumor formation and velogenic NDV infection, making it a promising dual vaccine candidate (He et al., 2023).

Additionally, a recombinant herpesvirus of turkeys (HVT) vaccine was developed by incorporating the NDV fusion protein gene or haemagglutinin-neuraminidase gene into a non-essential HVT gene. This recombinant vaccine provided partial immunity to NDV without compromising the birds’ immunity against HVT (Iqbal, 2012).

In another study, a modified live strain of Salmonella Gallinarum was engineered to express a consensus sequence of the spike protein’s N-terminal domain (S1-NTD) and a conserved immunogenic region of the nucleocapsid protein (N 321–406 aa) from infectious bronchitis virus (IBV) strains (Hewawaduge et al., 2024). The S1 domain contains multiple epitopes that trigger immune responses, induce neutralizing antibodies, and include the receptor-binding domain (Cavanagh, 2007). Additionally, the N protein plays a key role in stimulating cell-mediated immunity (Fan et al., 2005). The study demonstrated that this vaccine provided protection against both fowl typhoid and IBV, as evidenced by neutralizing antibody levels, gross and histological studies, and reduced viral load (Hewawaduge et al., 2024).

Dual vaccines in ruminant

Dual vaccines provide protection against two diseases with a single vaccination, simplifying the vaccination program (Berhe et al., 2003). For instance, a recombinant capripoxvirus vaccine expressing the PPR virus fusion protein can protect goats against PPR and capripox with effective immune responses observed even at low doses (Berhe, 2006). Moreover, the combined vaccines have been evaluated for safety and immunogenicity, showing that the components do not interfere with each other’s effectiveness. This characteristic is vital for ensuring that the vaccine can provide comprehensive protection without adverse effects (Liu et al., 2014; Berhe, 2006). According to the field application of a combined vaccine against PPR and SPP, the combined PPR/SGP vaccination provides good protection against both PPR and SGP infection, with no discernible difference from monovalent vaccines. (Fakri et al., 2015). Furthermore, the LSD and dual (bivalent) vaccines for GPV and SPV were more immunogenic than the vaccines for Held goat pox (HGP) and Romanian sheep pox (RSP), and they might be used to vaccinate cattle against LSD safely (A Mikhael et al., 2017). In addition, the use of dual vaccines can significantly reduce the logistical and financial burdens associated with vaccination campaigns. By providing protection against multiple diseases in a single shot, these vaccines can lower the costs related to vaccine administration and distribution, which is particularly beneficial in resource-limited settings (Berhe et al., 2003; Berhe, 2006). Localized inflammation at the injection site is the most frequent side effect. This reaction frequently indicates an immune response, usually brought on by the vaccine virus’s local replication (Bamouh et al., 2021).

Common dual vaccines in small ruminants

Dual vaccines against PPRV: PPR is a member of the Morbillivirus genus within the family Paramyxoviridae. PPRV infects small ruminants and can cause up to 70–80% of deaths. (Rweyemamu et al., 2000). A wide range of symptoms, such as fever, ulcers, coughing, diarrhea, ocular and nasal discharge, and abortions, are caused by infection (Eloiflin et al., 2022; Hammouchi et al., 2012). Furthermore, immunosuppression from PPRV infection increases the chance of acquiring infections from other pathogens. (Rajak et al., 2005). The OIE and FAO have initiated a global eradication effort to eradicate it. The most popular and authorized vaccination currently is the PPR live attenuated vaccine; nevertheless, its usage conflicts with the PPR elimination program’s serological testing and poses a possible safety concern. One of the most promising approaches to resolve this issue is the use of viral vector vaccines. Because of its obvious advantages as a vaccine vector delivery platform, the full-length infectious clone plasmid of the RABV was utilized as the backbone.

First, the Rabies virus can effectively proliferate and transcribe in target cells. Additionally, since few animals have antibodies against the RABV in their serum, the preexisting rabies virus seropositivity rate is low. Thus, it is possible to prevent and control RABV by using the Rabies virus as the foundation for creating a recombinant PPRV vaccine using RABV as a vector. To create infectious clones that express the PPRV F and H genes, the backbone plasmid was modified to incorporate the envelope glycoprotein F (fusion protein) or H (hemagglutinin protein) gene of PPRV (Wang et al., 2022) as these glycoproteins are the major antigens against which protective immune responses are generated (Choppin andScheid, 1980; Fournier et al., 1997) and the constructed viruses had good proliferative activity and stability and offered promising bivalent inactivated vaccine candidate strains for the protection against PPR and livestock rabies (Wang et al., 2022). Additionally, the bovine Herpesvirus-4 is employed as a vector for transmitting the PPRV-H protein because the recombinant BoHV4-based viral vector is simple to make and manipulate and has a high capacity for accommodating foreign DNA, making it a viable option for gene delivery in vaccinations (Rodriguez-Martin et al., 2021). Hemagglutinin (H) is a highly immunogenic glycoprotein found in the PPRV envelope exhibiting hemagglutinin and neuraminidase activities. It is essential for the attachment and penetration of viruses (Macchi et al., 2018), and the vaccinated sheep were protected and did not shed the virus. This indicates that BoHV-4-A-PPRV-H-DTK could be a promising new approach for PPRV eradication programs. Additionally, bivalent vaccines against CPV and other significant ruminant animal viral infections have been created using the attenuated CPV as a vector, including rinderpest (Ngichabe et al., 2002; Romero et al., 1993) bluetongue disease (BT) (Boone et al., 2007; Perrin et al., 2007) and PPR (Berhe et al., 2003; Diallo et al., 2002). Two recombinant capripoxviruses that express the PPR virus (PPRV) glycoproteins H and F (rCPV-PPRVH and rCPV-PPRVF) were produced, and these vaccines may be a viable option. DIVA vaccination in nations where stamp-out strategies have not yet been implemented or where PPR is a recent occurrence Sero conversion and challenge studies demonstrated that a bivalent vaccine against PPR and GTP was safe and produced a protective immune response in goats, suggesting that component vaccines did not affect one another’s immunogenicity (Hosamani et al., 2006). Additionally, recommended doses of both vaccine viruses were included in a lyophilized form of a combined SPP and PPR vaccine. The viruses did not interact with one another and may be employed in the target population for cost-effective vaccination techniques (Chaudhary et al., 2009).

Dual vaccines against FMD and PPR in small ruminants: Goats, sheep, and other small ruminants are at risk from three significant infectious illnesses that fall under WOAH’s category A virulent infectious disease: foot-and-mouth disease (FMD), PPR, and GTP. PPR, GTP, SPP, and FMD are currently prevented mainly by their respective vaccines, and a number of immunization protocols must be developed and implemented. In addition, the expense of vaccination is relatively high, and the effort is also quite heavy. It is crucial to create a vaccination that offers several preventative benefits in a single dose in order to address the aforementioned issues. The GPV genome is genetically stable and roughly 150 kb in size. Since the GPV thymidine kinase gene coding region is not required for replication, it permits a high degree of exogenous gene insertion and expression (Li et al., 2023). One of the primary immunogens that Peste des petits ruminant’s virus (PPRV) uses to trigger the production of neutralizing antibodies is the viral capsule membrane’s fusion protein F (Das et al., 2000; Gaafar et al., 2019; Wang et al., 2013). Furthermore, research on the foot-and-mouth disease virus (FMDV) has demonstrated that P1, which contains VP1, VP2, VP3, VP4, and 2A, makes up the viral capsid. As a result, it can be utilized as an FMDV antigenic gene in associated recombinant vaccination experiments. FMDV’s 3C is in charge of cleaving polyproteins to create the viral capsid (Kristensen et al., 2018; Li et al., 2008). A recombinant capripoxvirus efficiently expressed the P12A3C of FMDV and the F protein of PPRV, and the recombinant GPV can significantly raise the antibody levels of FMD, GP and PPR (Li et al., 2023). Additionally, dual live vector vaccines against PPR and FMD that express FMDVP12A3C and PRRV HF proteins have been successfully constructed using the Modified Vaccinia virus Ankara strain (MVA) because of its high immunogenicity, broad host range, excellent safety, and enormous capacity of foreign genes (Zhao et al., 2023).

Dual vaccines against RVF: Two significant ruminant diseases spread by arthropods are BT and RVF. These pathogens generate severe disease epidemics, especially in sheep, and have a significant impact on trade and agricultural cattle. Due to the significant geographic distribution of both viruses, the bluetongue virus (BTV) is endemic in both Europe and Africa (Calvo-Pinilla et al., 2020). The three segments that make up the RVFV genome are large (L), medium (M), and small (S). The M segment encodes two auxiliary proteins and the glycoproteins Gc and Gn, which are important for viral cell attachment and cell membrane fusion (Suzich et al., 1990). As Gn and Gc are the viral membrane’s main antigenic components and the primary catalysts for the production of neutralizing antibodies (Besselaar and Blackburn, 1992), They make perfect targets for the creation of vaccines. Together with VP5, the BTV VP2 protein forms the virus particle’s outer capsid and has a role in both virus entry and cell attachment (Mertens et al., 1984; Mertens et al., 1989). Neutralizing antibodies are primarily directed against this protein (Huismans et al., 1987). Moreover, BTV-infected cells produce the most viral protein, NS1, contributing to the increase in viral protein synthesis. (Boyce et al., 2012). The cell-mediated immunity to NS1 or its N-terminal domain (NS1-Nt) has been demonstrated to be protective against heterologous serotypes, and it is significant since the amino acid sequence of the BTV NS1 protein is highly conserved across BTV serotypes (Marín-López et al., 2017; Marín-López et al., 2018). A bivalent vaccine that simultaneously produces protective immunity against BTV and RVFV was reported. It was based on modified vaccinia Ankara virus (MVA) expressing BTV proteins VP2, NS1, or a shortened form of NS1 (NS1-Nt), and RVFV Gn and Gc glycoproteins. After being challenged with BTV-4 or RVFV, Vaccinated sheep displayed a marked decrease in viremia and no clinical signs. These findings suggest that the MVA-GnGc-NS1 vaccine protects sheep against BTV and RVFV (Calvo-Pinilla et al., 2020).

Since RVF virus immunization is not commonly administered unless there is an epidemic that reduces the effectiveness of vaccination, it would be very advantageous to combine RVF vaccination with routine capripoxvirus vaccination (Teffera andBabiuk, 2019). For example, the virulent LSDV Warmbaths (WB) isolate ORF 005 (IL-10 gene) was knocked out to create the field isolate of the Lumpy Skin Disease Virus (LSDV) from Warmbaths (WB), South Africa (LSDV WB005KO), which was effective in preventing sheep and goats from contracting SPP and GTP. (Boshra et al., 2015) used as a vector, and the protective genes for PPR (PPRV-F protein gene) and RVF (RVFV GnGc glycoproteins genes) were inserted. Sheep and goats can be protected against a variety of viral illnesses using this multivalent vaccination candidate (Boshra et al., 2024). Additionally, by growing the viruses together in Vero cells and using various infectious dosages for animal testing, a live dual vaccine against RVF and PPR was created. For major vaccination campaigns to protect animals from RVFV and PPRV diseases in enzootic regions, this combination live vaccine can be administered safely as a single dose to sheep and goats (Wattsb et al., 2021). Additionally, mice immunized with the inactivated RVF Vaccine Based on Rabies Virus Vector developed humoral and cellular immunity and produced IgG antibodies specific to RVFV. However, no neutralizing antibodies were produced. Because prophylactic therapy trials are scarce, it is impossible to anticipate if this vaccine can prevent RVFV infection with just high titers of IgG antibodies against RVFV and no neutralizing antibodies; therefore, confirmation of protection requires additional testing. Nonetheless, this RVFV vaccine that uses the rabies virus as the vector offers suggestions for creating vaccines that guard against both RABV and RVFV infections (Zhang et al., 2019).

Common dual vaccines in large ruminants

Dual vaccine against rabies: With a genomic size of roughly 12 kb, the rabies virus is a single-stranded negative-strand RNA virus that codes for five structural proteins: large transcription protein (L), matrix protein (M), glycoprotein (G), phosphoprotein (P), and nucleoprotein (N). Among these, the rabies virus G protein is a trimeric transmembrane protein that the rabies virus expresses on its surface. It has particular B cell and T cell recognition sites that might trigger an immunological response and is a crucial protein that triggers the synthesis of virus-specific neutralizing antibodies (VNA). As a result, recombinant rabies vaccinations frequently contain RABV G protein (Zhao et al., 2022). Additionally, the double-stranded DNA virus known as Bovine Herpes Virus 1 (BHV-1) is a member of the Herpesviridae family. Envelope glycoproteins comprise ten of the proteins it encodes. Its genome is roughly 138 kb long. Among these, the transmembrane glycoprotein gE is a protein that is not necessary for virus replication. The current BHV-1 live vaccine, which is extensively used in Europe, has gE deleted. Hence, BHV-1 without the gE gene can be used safely as a vector to produce a recombinant rabies vaccine (Petrini et al., 2019). Moreover, the herpesvirus genome is stable because it is large enough to accept the insertion of important foreign genes. Furthermore, recombinant construction technologies are well established. For instance, recombinant BHV-4 or BHV-1 expressing antigens from various viruses have been used in animals and demonstrated a strong ability to stimulate the immune system (Chowdhury et al., 2021; Kweon et al., 1999; Pedrera et al., 2020). In intramuscularly immunized mice and cattle, bovine herpes virus type I (BHV-1) that expressed rabies virus glycoprotein (RABVG) instead of its gE glycoprotein produced a protective level of rabies virus-specific neutralizing antibodies (VNA) without causing any clinical symptoms, suggesting that the BHV-1 vector-based rabies vaccine is a promising option for cattle (Zhao et al., 2022).

Combined LSD and contagious bovine pleuropneumonia (CBPP) live vaccine: The pathogen that causes contagious bovine pleuropneumonia (CBPP), a dangerous and contagious respiratory affection of calves manifested by fever, anorexia, and respiratory symptoms such as coughing, nasal discharge, dyspnea, and polypnea, is Mycoplasma mycoides subspecies mycoides (Mmm) (Francis et al., 2018). The virus that causes LSD in cattle is called the lumpy skin disease virus (LSDV). Both CBPP and LSD are transboundary illnesses prevalent in the same parts of Asia and Africa. A combined vaccine for the management of CBPP and LSD provides substantial benefits to small-scale livestock producers with only one injection. A combination of live LSDV/Mmm vaccines elicits a measurable antibody response comparable to monovalent immunizations, with few side effects in the vaccinated animals (Safini et al., 2022) (Table 1).

A combined vaccine against BT viruses and LSD: BT and LSD are two arthropod-borne viral illnesses of cattle that are reportable to the World Organization for Animal Health (Rojas et al., 2019). Fever, reduction in both meat and milk production, miscarriage, susceptibility to subsequent bacterial infections, skin nodules, mastitis, peripheral lymphadenopathy, anorexia, nasal discharge, low mortality, and high morbidity are all signs of LSD (Madhavan et al., 2016; Sohier et al., 2019). Vaccination is an efficient technique for the elimination and management of LSD, achievable through a modified live vaccine derived from KSGP or Neethling strains, as well as Heterologous vaccinations derived from the viruses that cause goat or SPP (Kononov et al., 2019).

BT belongs to the genus Orbivirus in the family Reoviridae (Rojas et al., 2019). The virulence of the virus strain and the ruminant host’s susceptibility determine how severe BTV infections will be. Compared to cattle and goats, sheep are more susceptible and may have more severe clinical symptoms. Although they rarely show signs of illness, cattle are thought to be a substantial epidemiological reservoir for BTV because they are easily infected. Vaccination remains the recommended strategy for controlling BT. Modified live and killed vaccines exist, but the killed vaccine has fewer serotypes and is expensive (Van Rijn, 2019).

The killed, oil-adjuvanted bivalent LSDV-BTV4 vaccine, utilizing the LSDV Neethling strain and BTV4, offers an effective means of protecting livestock from the two diseases in a single formulation. The vaccine is completely safe and efficacious for utilization in both endemic and disease-free countries as a potential combination vaccine against both diseases (Es-Sadeqy et al., 2021).

Dual vaccines against bovine ephemeral fever (BEF) and LSD: Using the BEF glycoprotein (G) gene, with or without using the BEFV matrix (M) protein gene, incorporated into one of two different LSDV backbones (nLSDV∆SOD-UCT or nLSDVSODis-UCT) dual vaccines targeting both BEF and LSD were generated. The prospective combined vaccines were firstly assessed in a rabbit; Neutralization tests using the South African BEFV vaccine (B-Phemeral) strain revealed that the African consensus (G) protein gene (Gb) offered better neutralization than the Australian (Ga) gene. The two LSDV backbones that express the (Gb) and (M) BEFV genes were evaluated in cattle. They demonstrated the ability to generate neutralizing reactions to both LSD and BEF following two inoculations spaced four weeks apart. In contrast to a group of control naïve animals that displayed clinical LSD, all vaccinated cattle showed resistance against the virulent LSDV challenge, demonstrating the effectiveness of the immunizations. Upon challenge, LSDV produced both neutralizing and T-cell responses. All vaccinated animals developed BEFV-neutralizing antibodies after two doses at a level of ≥ 1/20, deemed protective against BEF (Douglass et al., 2021).

Dual vaccine against foot and mouth disease virus (FMDV) serotype A24: Foot and mouth disease (FMD) is the most infectious illness affecting cloven-hoofed animals, leading to severe economic repercussions globally (OIE, 2007). A replication-deficient, human adenovirus-vectored FMDV serotype A24 Cruzeiro capsid-based subunit vaccine demonstrated safety, immunogenicity, and consistent protection of cattle at 7 days post-vaccination against direct homologous FMDV challenge. It also facilitated the differentiation of infected from vaccinated cattle before the challenge (Schutta et al., 2016).

Challenges in developing dual vaccines

Developing dual vaccines presents several significant challenges that can hinder their effectiveness and implementation (Figure 1).

Complex Antigen Selection: Identifying suitable antigens that elicit strong immune responses against both pathogens is complicated. The biological complexity of pathogens, such as their life cycles and genetic variability, makes it challenging to choose conserved antigens that can provide broad protection (Heaton, 2020).

Table 1: Summarizes the different dual vaccines used in veterinary medicine.

Species	Pathogens targeted	Genes/proteins used	Immune response	Other important information
Small ruminants	Foot-and-Mouth Disease Virus (FMDV), Peste des Petits Ruminants Virus (PPRV)	FMDV: P1-2A, 3C proteins. PPRV: Fusion (F) protein.	Induced antibodies against both pathogens' antigens.	Simplifies vaccination for small ruminants; good antibody response observed.
	Bluetongue Virus (BTV), Rift Valley Fever Virus (RVFV)	BTV: VP2 and NS1 proteins. RVFV: Gc and Gn glycoproteins.	Protection against both viruses, neutralizing antibodies, and T-cell activation.	No significant clinical signs or viremia post-vaccination, safe for sheep.
	Sheep Pox Virus (SPPV), Peste des Petits Ruminants Virus (PPRV)	SPPV and PPRV: Virus from live attenuated strains.	Protective immunity against both viruses.	The vaccine viruses did not interfere with each other, ideal for field use in sheep.
	Goat Pox Virus (GPV), Peste des Petits Ruminants Virus (PPRV)	PPRV: Glycoproteins F and H.	Strong immune response; neutralizing antibodies observed.	Effective in goats, safe and immunogenic, with no significant side effects.
	Foot-and-Mouth Disease Virus (FMDV), Peste des Petits Ruminants Virus (PPRV)	FMDV: P12A3C. PPRV: H and F proteins.	Strong immunogenic response protects against both diseases.	Potential for broad application in small ruminants, stable production system.
Large ruminants	Lumpy Skin Disease Virus (LSDV), Rabies Virus (RABV)	LSDV: vector RABV: Glycoprotein (G).	Induced neutralizing antibodies for both viruses.	Safe for cattle and effective in protecting against both diseases.
	Mycoplasma mycoides subsp. mycoides (Mmm), Lumpy Skin Disease Virus (LSDV)	Mmm: Respiratory antigens; LSDV: Neethling strain.	Protective antibody response, similar to monovalent vaccines.	Minimal adverse reactions in cattle, suitable for large-scale cattle vaccination.
	Bluetongue Virus (BTV), Lumpy Skin Disease Virus (LSDV)	LSDV: Neethling strain. BTV: VP2	Effective immune response to both diseases.	Suitable for use in both endemic and disease-free areas, safe for cattle.

Efficacy and immunogenicity: Achieving a balance in immunogenicity for both components of the dual vaccine is challenging. The immune response may differ significantly between the two antigens, leading to suboptimal protection against one or both diseases (Kling et al., 2014). Also, there is a possibility of antigenic interference, where the presence of one antigen could potentially affect the immune response to the other. This could lead to a variation in the expected immune response and associated side effects (McCafferty et al., 2022).

Short-lived Immunity: Many vaccines tend to induce waning immunity over time. For dual vaccines, ensuring long-lasting protection for different diseases can be particularly difficult, necessitating the development of novel adjuvants or improved antigen formulations (Heaton, 2020).

Based on the information provided in the search results, it is recommended to use a dual vaccination strategy for ruminants in most cases. Here is why:

Benefits of dual vaccination

Dual vaccines can provide broader protection by targeting multiple pathogens simultaneously, enhancing immunity against different diseases (Islam et al., 2024; Kumar et al., 2017) (Figure 1).
Combination vaccines reduce the number of injections needed, improving convenience for farmers and increasing vaccination compliance (Islam et al., 2024; Zhao et al., 2021). They can also minimize stress for ruminants, which is important for their overall well-being and productivity. Stress can negatively affect growth rates and milk production (Gao et al., 2023).
Dual vaccines may be more cost-effective than administering two separate vaccines by lowering production and distribution costs (Islam et al., 2024).
Vaccinating against multiple diseases contributes to better public health outcomes by controlling zoonotic diseases that can affect humans (Islam et al., 2024).
Administering dual vaccines can lead to a stronger and more robust immune response by targeting multiple pathogens at once, enhancing the overall immunological memory of the animals (Gao et al., 2023).
Dual vaccinations enabling the identification of diseased from vaccinated animals (DIVA) are being developed to enhance disease surveillance and control initiatives (Libeau et al., 2015).
Dual vaccination strategies can reduce disease incidence and decrease the need for antibiotics and other treatments, promoting more sustainable livestock management practices (Gao et al., 2023).

Prospects for developing dual vaccines

The future of developing dual vaccines holds significant promise, particularly in the context of emerging infectious diseases and the need for efficient immunization strategies. Several innovative approaches and technologies are shaping this field:

Types of different vaccine technologies

Recombinant vaccines: Recombinant vaccine platforms, such as modified BCG (Bacillus Calmette-Guérin) strains, are gaining traction. These can be engineered to express antigens from multiple pathogens, allowing for the development of vaccines simultaneously targeting diseases like COVID-19 and tuberculosis. This approach leverages the immunogenic properties of BCG to enhance the immune response to both pathogens (Guthrie et al., 2023).
mRNA and DNA vaccines: The adaptability of mRNA and DNA vaccination platforms facilitates the rapid integration of several antigen sequences. These vaccines can be engineered to incorporate conserved epitopes from several diseases, enabling extensive protection. For instance, the development of bivalent mRNA vaccines that encode antigens from both the original SARS-CoV-2 strain and its variants exemplifies this potential (Al-Fattah Yahaya et al., 2023).
Nanoparticle vaccines: Nanoparticle technology enables the presentation of multiple antigens on a single particle, which can enhance the immune response. This method allows for the simultaneous targeting of different pathogens, making it a promising avenue for dual vaccine development (Brisse et al., 2020).
Rational vaccine design: Advances in bioinformatics and reverse vaccinology enable the identification of protective epitopes across various pathogens. This rational design approach can lead to the development of multi-epitope vaccines that provide comprehensive protection against multiple diseases (Brisse et al., 2020; Chalmers, 2006).

Conclusion

While single vaccinations are effective in preventing specific diseases, a dual vaccination strategy provides several distinct advantages, making it a preferable approach in many cases. By offering broader protection against multiple pathogens, dual vaccines enhance overall immunity, reduce the number of injections required, and improve compliance among farmers and animal caretakers. This not only minimizes handling stress in animals but also optimizes resource utilization, making vaccination programs more efficient and cost-effective.

Moreover, dual vaccines contribute significantly to disease control efforts, particularly in preventing co-infections and reducing the spread of zoonotic diseases, which have implications for both animal and human health. However, the successful implementation of a dual vaccination strategy requires careful planning and adherence to best practices. Key factors such as the appropriate timing of administration, maintaining the cold chain to ensure vaccine potency, and continuous monitoring for efficacy and safety must be considered. Additionally, understanding potential immunological interactions between vaccine components is crucial to avoid interference that may compromise the desired immune response.

As research in vaccine technology advances, including the development of recombinant and vector-based vaccines, dual vaccination strategies are expected to become even more effective and widely adopted. Future innovations in formulation stability, antigen compatibility, and delivery mechanisms will further enhance their role in comprehensive disease management programs. By addressing logistical and scientific challenges, dual vaccines have the potential to revolutionize veterinary immunization strategies, improving animal health, welfare, and productivity on a global scale.

Acknowledgement

The authors want to thank the Animal Medicine and Infectious Diseases Department staff members at the Faculty of Veterinary Medicine, University of Sadat City, Egypt, for their continuous support during this study.

Novelty Statement

This manuscript provides a comprehensive and up-to-date overview of dual vaccines in ruminants, highlighting their strategic importance in modern livestock immunization programs.

Author’s Contribution

Shahd Khalid and Mohamed Nayel: Organized the whole process and drafted the manuscript, performed the data analysis, wrote the work, read and approved the final manuscript.

Walid Mousa: Designed the work, performed the data analysis, wrote the work, read and approved the final manuscript.

Alyaa Elrashedy: Performed the data analysis, read and approved the final manuscript.

Akram Salama, Ahmed Zaghawa and Ahmed Elsify: Designed the work, read and approved the final manuscript.

Conflict of interest

The authors have declared no conflict of interest.

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