key: cord-009383-ozx5u0t3 authors: Sheppard, Michael title: Viral Vectors for Veterinary Vaccines date: 2007-09-28 journal: Adv Vet Med DOI: 10.1016/s0065-3519(99)80014-7 sha: doc_id: 9383 cord_uid: ozx5u0t3 nan Numerous reviews have described the use of viral vectors for possible vaccine delivery (e.g., Cavanagh, 1985; Sheppard and Fahey, 1989; Wray and Woodward, 1990; Graham and Prevec, 1992; Boyle and Heine, 1993; Hilleman, 1994; Martin, 1994; Dorner, 1995; Babiuk et al., 1996; Perkus and Paoletti, 1996) . However, in this review I will focus solely on the use of viral vectors for delivery of veterinary vaccines. It is without question that vaccination plays an essential role in veterinary medicine, providing the major and often the only prophylatic approach for the control of infectious diseases. In spite of the vast array of currently available vaccines veterinarians and the livestock producers continue to express the need for vaccines that not only maintain the best features of killed or subunit vaccines (such as safety) as well as the best features of conventional modified live vaccines (such as efficacy) but improve on them. As well as the need for continual improvement of vaccines there exists a need for new vaccines either to new diseases (e.g., chicken anemia virus or porcine reproductive and respiratory syndrome virus) or to old diseases for which vaccines are not available or no longer meet the requirements of the end user (e.g., bovine virus diarrhea virus vaccines). As well as new vaccines there is also need for vaccines with special features that allow potential customers to design disease control programs that suit their specific needs on top of offering greater safety and improved protection. The design and construction of these new veterinary vaccines is a major challenge facing the field ofvaccinology. With the continued demand of improving vaccines and producing new ones it is easier for potential vaccine candidates to fail to meet the increased level of requirements that are expected. The failure of some vaccines can result from problems associated with delivery, such as insufficient or no induction of the appropriate protective immune response. The development of delivery systems to produce vaccines that are more effective, offer greater safety, are convenient to administer, and are compatible with customer practices is part of the challenge for vaccinologists. The development of safe and convenient live viral vectors for the delivery of veterinary vaccines is one possible way of meeting some of these challenges. Recombinant DNA technology has allowed more detailed characterization of the genetic organization of many viruses to such an extent that regions suitable for insertion of foreign genetic material have been identified. This has resulted in the development of numerous types of viral vectors from a wide variety of viral families. Some of these viral vectors have been developed with the potential for delivering and expressing gene(s) from a foreign pathogen and so act as a vaccine vector (Table I) . The viral vector is often genetically attenuated or cannot complete its replication cycle in the animal to be immunized, and thus produces no clinical disease. Although initially the majority of viral vector development centered around poxviruses, especially vaccinia (Panicali and Paoletti, 1982; Macket et al., 1982) , it was not long before viral vector development witnessed a virtual explosion in the types of viruses developed into vectors. These included herpeviruses (Post et al., 1982) , adenoviruses (Berkner and Sharp, 1982) , retroviruses (Wei et al., 1981) , papoviruses (Southern and Berg, 1982) , polyoma virus (Fried and Ruley, 1982) , picornaviruses (Kitson et al., 1991), Semliki Forest virus (SFV; Zhou et al., 1994) , Sindbis virus (Pugachev et al., 1995) , and even some plant viruses (Jagadish et al., 1996; Dalsgaard et al., 1997) . Greater understanding of the structure and function of a wide range of viruses at the genetic level has opened up ways of designing novel viral vaccine vectors which should improve the quality and effectiveness of some future vaccines as major prophylatic tools. Viral vaccine vectors have really developed from a greater technological understanding of viruses at the genetic level, where today they have become a viable alternative strategy as one method for the delivery of vaccines. The concept of viral vectors was first highlighted by Bernard Moss and others in the early 1980s (Mackett et al., 1982; Panicali and Paoletti, 1982) , where they showed that vaccinia virus could be engineered to carry and express foreign genes (Panicali and Paoletti, 1982; Mackett et al., 1982) . From the time when Moss and others first demonstrated that vaccinia virus could be developed as a vector for the expression of foreign genes, the technology has been exploited to apply to a variety of virus families as well as a variety of foreign genes including those that encode antigens from pathogens. As a result both DNA and RNA viruses have been developed as viral vaccine vectors (Table I) . To produce viral vaccine vectors it is first necessary to study the genome of the vector to a stage of understanding where at least one region suitable for insertion of foreign genetic material has been iden-tiffed. Second, genes from pathogens that encode proteins that will induce an appropriate protective immune response and can be stably integrated into the vector's genome and expressed need to be identified. Finally, it is necessary to insert the foreign gene(s) in such a way as to ensure the correct and sufficient expression of the foreign gene(s). The ideal viral vaccine vector would have all or at the very least some of the following features: 9 Safe and nonpathogenic for the vaccinate 9 Evoke the appropriate protective immune response 9 Single host or limited host range 9 Stable genome 9 No integration into the host genome 9 Readily accessible region(s) for insertion of foreign genetic material 9 Able to tolerate well insertion of foreign genetic material and expression of foreign gene(s) 9 Convenient to deliver and fits with management practices 9 Relatively simple and cost effective to produce 9 Limited background gene expression by the vector Live viral vectors offer several advantages for vaccine delivery compared to killed, subunit, or conventional modified live vaccines. First, because of the possibility of delivering divalent or even perhaps multivalent vaccines, using a single type of vector can result in a single manufacturing process rather than several and possibly even a single vaccination rather than several. Therefore, vectored vaccines have the potential to be less expensive to the manufacturer and the end user. Because the foreign gene is being expressed in the cells of its natural host, it is expected that any post-translational modifications required will be correct and produce an authentic antigen, as opposed to Escherichia coli or baculovirus systems (among others) that do not always produce authentic foreign proteins. Depending on the vector selected it may be possible to deliver the vectored vaccine more conveniently to the mammal or bird by spray or water or some other means rather than by needle injection. Such a mass administration approach may be particularly relevant to the poultry industry. The vector could also be constructed to deliver simultaneously an immunomodulator (e.g., gamma interferon), which could modify the type or magnitude of the immune response to allow the vaccine to be successful or more successful than it would be otherwise. The vector only expresses the antigens from the pathogen that are required to elicit a protective immune response and therefore reduces or eliminates the chance of disease by being exposed to the whole pathogen as with a killed or modified live vaccine. Finally, the appropriate viral vectors will induce both cell-mediated and humoral immune responses and in some cases are particularly suitable for inducing a local immune response in the mucosal surfaces. One of the main disadvantages of using viral vectors for vaccine delivery is that like subunit vaccines each vector can only deliver one or a relatively small number of foreign antigens to the host animal and therefore rely on those being able to elicit a completely protective immune response. Also the only antigens that can be delivered are those that are encoded by nucleic acid. Thus such things as lipopolysaccharides are not deliverable. With any vector, regardless of type, only a limited amount of foreign genetic material can be inserted into the vector's genome stably and expressed appropriately. One must always be wary of altered tissue tropisms due to the expression of the foreign gene(s). Of course the effectiveness of a viral vector is limited by preexisting immune response in the animal from prior exposure to the virus used to construct the vector. Finally, as with all live vaccines there is the problem of shelf life and compatibility with other vaccine preparations. To produce viral vaccine vectors successfully it is necessary to ensure that the vector itself does not pose any disease threat to the animal that receives the vaccination or to the person delivering the vaccine to the animal. Most often this is achieved by attenuating the viral vector in some way. Until recent times the means of generating a live attenuated virus had been entirely empirical. This process usually involved the passaging of the virus in cell culture or animals that were not the natural host, followed by testing of the resulting viruses for decreased virulence in the natural host. The basis for attenuation is most often unknown, and may be a result from as minor as a single base change, and thus the chance of reversion back to virulence is always a possibility. This type of traditional method for generating a live attenuated virus is not necessarily the most attractive method for generating a viral vaccine vector. With the advent of molecular biology and our improved knowledge of viruses at the genetic level it is now possible to generate live attenuated viruses with precise genetic changes, improving their safety and thus make them more suitable as vectors for vaccine delivery. A good example is the deletion of the thymidine kinase (TK) gene. While the deletion of the TK gene has little or no effect on virus growth in cell culture, TK deleted viruses can be significantly attenuated in vivo ((Buller et al., 1985; Kit et al., 1985 Kit et al., , 1986 Becker et al., 1986) . This feature has been exploited successfully for the development of live attenuated herpesvirus vaccines (McGregor et al., 1985; Kit et al., 1985; Marchioli et al., 1987; Moorman et al., 1990) as well as safer herpesvirus and poxvirus vectors (e.g., Buller et al., 1985; Bayliss et al., 1991; Mulder et al., 1994; Hu et al., 1997) . If an essenential gene is deleted from a virus, the virus can only grow if the gene or gene product is provided in trans. This virus is phenotypically normal but genotypically defective and cannot replicate in the host because the deleted gene product is not available. This type of virus can replicate in vitro with the help of a genetically engineered supporting cell line that expresses the deleted gene product. The stage of the virus life cycle of which the gene product is required will govern how far through the replication cycle a virus will proceed. In some cases (e.g., if the essential deleted gene is required for virus penetration of the cell) the virus will complete a single round of replication in the host but the progeny viruses will not be able to invade any other cell. (Farrell et al., 1994; McLean et al., 1994; Peeters et al., 1994) . However, if the deleted essential gene is an early gene that is required to activate other viral genes, then the number of viral proteins synthesized may be limited and the viral genome may not be able to complete even a single cycle of replication (Chen and Knipe, 1996; Brehm et al., 1997; Da Costa et al., 1997) . A third alternative, which has been exploited successfully, is to use a virus that can only completely replicate in one species as a vector in another species, where it cannot complete an entire cycle of replication but can commence a replication cycle sufficiently to allow expression of the foreign gene (Tartaglia et al., 1992) . The canarypox virus (CPV) vector, termed ALVAC, has successfully been exploited to the degree of commercial success. The CPV is restricted to avian cells only for productive replication but can be used to vaccinate mammals where it can elicit an immune response to the foreign gene product without completing an entire cycle of replication (Tartaglia et al., 1992 (Tartaglia et al., , 1993 Taylor et al., 1995) . The human adenovirus type 5 (HAV-5) has also been exploited in a similar fashion to the CPV (Table III ) but has the disadvantage that this virus is a human pathogen and so has yet to be exploited commercially. Several other strategies are also available and in some cases have been exploited successfully in order to generate safe viral vectors for vaccine delivery. Table V (next section) provides a summary of some of these possible approaches. Even though there are a great many examples of viral vectors reported in the literature since they were first described in 1982, the number of publications reporting the use of viral vectors for veterinary vaccine delivery is not that large. After searching for published papers that describe viral vectors with veterinary vaccine applications, especially those that could be described as purposely developed for veterinary use, the obvious conclusion was that even though this research was first described in 1982 the veterinary side is still in its infancy. Publications describing viral vectors for veterinary vaccine delivery can be divided into several groups, which are represented in the following tables: Table II, poxvirus vectors; Table III, adenovirus vectors; Table IV, herpesvirus vectors; and Table V , other virus vectors. Although these four tables probably do not include every single publication describing viral vectors for veterinary vaccine delivery they do describe the majority of published papers and present the reader with an idea of the limited amount of research that has occurred in this field during the last 15 years. At the time of writing this review only three viral vectored vaccines for use in the veterinary field have been licensed for release. All three are based on poxvirus vectors and the three vectors represent the Gonin et al., (1995) HAV-5 PRCV Spike Swine Callebaut et al., (1994) HAV-5 PrV gD Swine Adam et al., (1994) HAV-5 Rabies G Dog Prevec et al., (1990) HAV-5 PrV gp50 Rabbit/mouse Eloit et al., (1990) Key: OAV, ovine adenovirus; HAV-5, human adenovirus type 5; PRCV, porcine respiratory corona virus; TGE, transmissible gastroenteritis virus; BCV, bovine corona virus; PrV, pseudorabies virus. evolution in poxvirus vector development. The first vector approved was the vaccinia virus vector carrying the rabies G glycoprotein gene (e.g., Kieny et al., 1984; Blancou et al., 1986; Brochier et al., 1991) . In terms of complying with the characteristics of a desirable vector for vaccine delivery in the veterinary setting, this vector has the greatest number of undesirable characteristics. However, it satisfied an unmet need and as a result was released in various parts of the world. The second vector to be licensed for release was the fowlpox virus vector. This vector delivers the Newcastle disease virus HN and F genes and is designed to vaccinate poultry (e.g., Boursnell et al., 1990a,b; Taylor et al., 1996) . While this vector has the desirable characteristic of only replicating in poultry it also has some limitations that affect its use in the field. The third vector licensed is the canarypox virus vector and represents the state-of-the-art poxvirus vector. This vector was developed to deliver the HA and F genes of canine distemper virus and is the most recently available of the three vector vaccines (e.g., Stephensen et al., 1997) . Whatever strategy is adopted for the development of viral vectors for delivery of veterinary vaccines there are several key points to consider: (1) Will the vectored vaccine give a delivery advantage compared to (1995 ( ) Fink et al. (1996 Pechan et al. (1996 ( ) Starr et al. (1996 Jagadish et al. (1996 ( ) Porter et al. (1996 Roy ( what's already available? (2) Will the vectored vaccine give a manufacturing advantage compared to what's already available? (3) Will the vectored vaccine provide improved safety compared to what's already available? (5) Will the vectored vaccine increase the duration of immunity compared to what's already available? (6) Will the vectored vaccine be more convenient to store compared to what's already available? (7) Is the vectored vaccine compatible with other vaccines? If there is no other alternative available then the answer to these questions is easy. However, if there are alternative vaccines available then the answers to these questions become very important because the answers will determine whether a vectored vaccine is merely a good laboratory idea or a successful vaccine. Vaccination of pigs with replicationdefective adenovirus vectored vaccines: The example of pseudorabies Manipulation of the Semliki Forest virus genome and its potential for vaccine construction Novel viral vaccines for livestock Induction of mucosal immunity in cotton rats to haemagglutinin-esterase glycoprotein of bovine coronavirus by recombinant adenovirus Protective immune responses induced by the immunization of mice with a recombinant bacteriophage displaying an epitope of the human respiratory syncytial virus A recombinant fowlpox virus that expresses the VP2 antigen of infectious bursal disease virus induces protection against mortality caused in the virus A sequence in HpaI P fragment of herpes simplex virus 1 DNA determines intraperitoneal virulence in mice Preparation of adenovirus recombinants using plasmids of viral DNA Oral vaccination of the fox against rabies using a live recombinant vaccinia virus A fowlpox virus vaccine vector within insertion sites in the terminal repeats: Demonstration of the efficacy using the fusion gene of Newcastle disease virus A recombinant fowlpox virus expressing the hemagglutinin-neuraminidase gene of Newcastle disease virus (NDV) Recombinant fowlpox virus vaccines for poultry Immunization with a replication-deficient mutant of herpes simplex virus type 1 (HSV-1) induces a CD8 + cytotoxic T-lymphocyte response and confers a level of protection comparable to that of wild-type HSV-1 Large-scale eradication of rabies using recombinant vaccinia-rabies vaccine Decreased virulence of recombinant vaccinia virus expressed vectors is associated with a thymidine kinase negative phenotype Construction of a recombinant adenovirus for the expression of the glycoprotein S antigen of porcine respiratory coronavirus An adenovirus recombinant expressing the spike glycoprotein of porcine respiratory coronavirus is immunogenic in swine Viral and bacterial vectors of immunogens A dominant mutant form of the herpes simplex virus ICP8 protein decreases viral late gene transcription Construction and characterization of a replication-defective herpes simplex virus 2 ICP8 mutant strain and its use in immunization studies in a guinea pig model of genital disease Plant-delivered vaccine protects target animals against a viral disease An overview of vaccine vectors Construction of a defective adenovirus vector expressing the pseudorabies virus glycoprotein gp50 and its use as a live vaccine Vaccine potential of a herpes simplex virus type 1 mutant with an essential gene deleted Gene transfer to neurons using herpes simplex virus based vectors A recombinant canarypox virus protects rabbits against a lethal rabbit hemorrhagic disease virus (RHDV) challenge Minireview: The herpes simplex virus amplicon--a versatile defective virus vector Use of polyoma virus vector Feline leukemia virus envelope protein expression encoded by a recombinant vaccinia virus: Apparent lack of immunogenicity in vaccinated animals Immunization trial of cats with a replication defective adenovirus type 5 expressing the ENV gene of feline immunodeficiency virus Adenovirus-based expression vectors and recombinant vaccines Expression in recombinant vaccinia virus of the equine herpesvirus 1 gene encoding glycoprotein 13 and protection of immunized animals Recombinant vector vaccines in vaccinology Raccoon poxvirus live recombinant feline panleukopenia virus VP2 and rabies virus glycoprotein bivalent vaccine Retrovirus-expressed hemagglutinin protects against lethal influenza virus infections Chimeric potyvirus-like particles as vaccine carriers Myxoma virus as a vaccine vector for rabbits--antibody levels to influenza virus hemagglutinin presented by a recombinant myxoma virus Expression of rabies virus glycoprotein from a recombinant vaccinia virus Bovine herpesvirus-1 (infectious bovine rhinotracheitis virus)-based viral vectors which expresses foot-andmouth disease epitopes Attenuated properties of thymidine kinasenegative deletion mutant of pseudorabies virus Intramuscular and intravaginal vaccination of pregnant cows with thymidine kinase-negative, temperature-resistant infectious bovine rhinotracheitis virus (bovine herpesvirus 1) Modified-live infectious bovine rhinotracheitis virus vaccine expressing monomer and dimer forms of footand-mouth disease cupsid protein epitopes on surface of hybrid virus particles Expression of porcine pseudorabies virus genes by a bovine herpesvirus-1 (infectious bovine rhinotracheitis virus) vector Chimeric polioviruses that include sequences derived from two independent antigenic sites of foot-and-mouth disease virus (FMDV) induce neutralizing antibodies against FMDV in guinea pigs Biological evaluation of glycoproteins mapping to two distinct mRNAs within the BamHI fragment 7 of pseudorabies virusi expression of the coding regions by vaccinia virus Construction of a pigeonpox virus recombinant: expression of the Newcastle disease virus (NDV) fusion glycoprotein and protection of chickens against NDV challenge Vaccinia virus: A selectable eukaryotic cloning and expression vector A vaccine strain of pseudorabies virus with deletions in the thymidine kinase and glycoprotein X genes Vaccine design: Future possibilities and potentials Vaccination of swine with thymidine kinase-deficient mutants of pseudorabies virus Protective vaccination against primary and recurrent disease caused by herpes simplex virus (HSV) type 2 using a genetically disabled HSV-1 Inactivation of the thymidine kinase gene of a gI deletion mutant of pseudorabies virus generates a safe but still highly immunogenic vaccine strain Retroviral expressed hemagglutinin-neuraminidase protein protects chickens from Newcastle disease virus induced disease Protection against lethal simian immunodeficiency virus SIVsmmPBjl4 disease by a recombinant Semliki Forest virus gpl60 vaccine and by a gpl20 subunit vaccine Virulence and pathogenesis of non-virulent and virulent strains of pseudorabies virus expressing envelope glycoprotein E1 of hog cholera virus Induction of neutralizing antibodies against bovine leukosis virus in rabbits by vaccination with recombinant vaccinia virus expressing bovine leukosis virus envelope glycoprotein Construction of poxviruses as cloning vectors: Insertion of the thymidine kinase gene from herpes simplex virus into the DNA of infectious vaccinia virus A novel 'piggyback' packaging system for herpes simplex virus amplicon vectors Non-transmissible pseudorabies virus gp50 mutants: A new generation of safe live vaccines Recombinant virus as vaccination carrier of heterologous antigens Release of viruslike particles from cells infected with poliovirus replicons which express human immunodeficiency virus type 1 Gag Chicken ovalbumin gene fused to a herpes simplex virus a promoter and linked to a thymidine kinase gene is regulated like a viral gene A recombinant human adenovirus vaccine against rabies Double-subgenomic sindbis virus recombinants expressing immunogenic proteins of Japanese encephalitis virus induce significant protection in mice against lethal JEV infection Protective efficacy at a recombinant herpesvirus of turkeys as an in ovo vaccine against Newcastle and Marek's disease in specific-pathogen-free chickens Construction and properties of a turkey herpesvirus recombinant expressing the Marek's disease virus homologue of glycoprotein B of herpes simplex virus Sequential nucleic acid and recombinant adenovirus vaccination induces host-protective immune responses against Taenia ovis infection in sheep Genetically engineered particulate virus-like structures and their use as vaccine delivery systems Hepatitis B virus core particles as a vaccine carrier moiety Immunity to malaria elicited by hybrid hepatitis B virus core particles carrying circumsporozoite protein epitopes Herpesviruses and adenoviruses as potential vectors for the poultry industry Long-term expression in sensory neurons in tissue culture from herpes simplex virus type 1 (HSV-1) promoters in an HSV-l-derived vector Mammalian cell transformation with SV40 vector Longterm persistence of defective HSV-1 vectors in the rat brain is demonstrated by reactivation of vector gene expression Canine distemper virus (CDV) infection of ferrets as a model for testing Morbillivirus vaccine strategies: NYVAC-and ALVAC-based CDV recombinants protect against symptomatic infection NYVACP: A highly attenuated strain of vaccinia virus Protection of cats against feline leukemia virus by vaccination with a canarypox virus recombinant, ALVAC-FL Recombinant fowlpox virus inducing protective immunity in non-avian species Biological and immunogenic properties of a canarypox-rabies recombinant, ALVAC-RG (vCP65) in non-avian species Efficacy of a recombinant fowlpox-based Newcastle disease virus vaccine candidate against velogenic and respiratory challenge Evaluation of swinepox virus as a vaccine vector in pigs using Aujeszky's disease (pseudorabies) virus gene insert coding for glycoproteins gp50 and gp63 Live attenuated pseudorabies virus expressing envelope glycoprotein E1 of hog cholera virus protects swine against both pseudorabies and hog cholera The use of feline herpesvirus and baculovirus as vaccine vectors for the gag and env genes of feline leukemia virus Construction and isolation of a transmissible retrovirus containing the src gene of Harvey murine sarcoma virus and the thymidine kinase gene of herpes simplex virus type 1 Vaccination against feline leukemia using a new feline herpesvirus type I vector Biotechnology and veterinary science: Production of veterinary vaccines Human adenovirus type 5 vectors expressing rabies glycoprotein Self replicating Semliki Forest virus RNA as recombinant vaccine Generation of cytotoxic and humoral immune responses by nonreplicative recombinant Semliki Forest virus