Pseudorabies is a viral disease in swine that is endemic in most parts of the world. It is caused by porcine herpesvirus 1, which is also called pseudorabies virus (PRV) or suid herpesvirus-1 (SHV-1) and is also known as Aujeszky's disease, and in cattle as mad itch. PRV is considered to be the most economically important viral disease of swine in areas where hog cholera has been eradicated. Other domestic and wild mammals, such a cattle, sheep, dogs, raccoons are also susceptible. The disease is usually fatal in these hosts. The virus is shed in the saliva and nasal secretions of infected swine and is spread through oral or nasal contact. Aerosolization of the virus and transmission by fomites also may occur. The virus may potentially survive for seven hours in humid air and spread up to two kilometers. Furthermore, it may survive on well water for up to seven hours, in green grass, soil, and feces for up to two days, in contaminated feed for up to three days, and in straw bedding for up to four days (Wiki: Pseudorabies).
4. Microbial Pathogenesis
After natural infection, the primary site of viral replication is nasal, pharyngeal, or tonsillar epithelium. The virus spreads via the lymphatics to regional lymph nodes, where replication continues. Virus also spreads via nervous tissue to the brain, where it replicates, preferentially in neurons of the pons and medulla. In addition, virus has been isolated from alveolar macrophages, bronchial epithelium, spleen, lymph nodes, trophoblasts, embryos, and luteal cells (Merck Vet Manual: Pseudorabies).
5. Host Ranges and Animal Models
Although the pig is the only natural host, the virus can infect cattle, sheep, cats, dogs, and goats as well as wildlife, including raccoons, opossums, skunks, and rodents. Experimental studies in nonhuman primates indicate that rhesus monkeys and marmosets are susceptible but chimpanzees are not. Reports of human infection are limited and are based on seroconversion rather than virus isolation. Infections in horses are rare (Merck Vet Manual: Pseudorabies).
Molecule Role Annotation :
Recombinant adenovirus expressing gB (rAd-gB) was found to induce effective protective immunity against a virulent viral infection, regardless of whether it was administered via the muscular or systemic route (Han et al., 2008).
Molecule Role Annotation :
Vaccination of mice with fusion proteins containing the N terminus of gI from Suid herpesvirus 1 are able to confer protection to mice against a lethal challenge of PRV (Fuchs et al., 1990).
Molecule Role Annotation :
A NYVAC vaccinia vector containing genes for pseudorables virus glycoproteins gII and gp50 was administered to pigs to determine if it would have a greater protective effect than a vector containing the gene for gp50 alone. Both NYVAC vectors protected pigs similarly from virulent pseudorabies virus challenge (Brockmeier and Mengeling, 1996).
Molecule Role Annotation :
Mice immunized with either gII, gIII, gVI antigen or a mixture of them were challenged intraperitoneally with 8.5 x 10(3) plaque forming units of PRV. All the mice immunized with 1.5 and 4.5 micrograms of the mixture and 4.5 micrograms of the gIII antigen survived (Matsuda et al., 1992).
Molecule Role Annotation :
A glycoprotein E mutant, in combination with UL23 and glycoprotein G mutations, is attenuated in raccoons, with a 75% survival rate. This mutant also provides some protection from wild type PRV (Weigel et al., 2003).
Molecule Role Annotation :
A glycoprotein G mutant, in combination with UL23 and glycoprotein E mutations, is attenuated in raccoons, with a 75% survival rate. This mutant also provides some protection from wild type PRV (Weigel et al., 2003).
Molecule Role Annotation :
A glycoprotein M, gM, deletion in pseudorabies virus was attenuated and induced protection in piglets against intranasal challenge with 10^8 p.f.u. of the highly virulent PrV strain NIA-3 ((Dijkstra et al., 1997).
Molecule Role Annotation :
A NYVAC vaccinia vector containing genes for pseudorables virus glycoproteins gII and gp50 was administered to pigs to determine if it would have a greater protective effect than a vector containing the gene for gp50 alone. Both NYVAC vectors protected pigs similarly from virulent pseudorabies virus challenge (Brockmeier and Mengeling, 1996).
Molecule Role Annotation :
A gp50+gp63 deletion mutant in Pseudorabies virus was attenuated and provided protection from clinical signs of Aujeszky's disease after a challenge inoculation with the virulent wild-type PRV strain NIA-3 (Peeters et al., 1994).
Molecule Role Annotation :
A gp50+gp63 deletion mutant in Pseudorabies virus was attenuated and provided protection from clinical signs of Aujeszky's disease after a challenge inoculation with the virulent wild-type PRV strain NIA-3 (Peeters et al., 1994).
Protein Note :
transcriptional regulator ICP4; the Herpesviridae are non-segmented dsDNA viruses with genomes ranging from 120-230kbp; although herpes viruses vary greatly in sequence identity and homology, they all share four common elements: an envelope, a tegument which is composed of viral enzymes, a capsid of 162 capsomers, and a core composed of genomic DNA; transcriptional regulator ICP4 ( infected-cell polypeptide 4) is a sequence-specific transcriptional activator that is required for efficient transcription of early and late viral genes; ICP4 is essential for productive infection
Molecule Role Annotation :
To examine the response by IE180 more closely, a vaccine trial in mice with a vector DNA construct that contains the gene encoding for IE180, designated pcDNAIE180 was conducted. Seven months after immunization with pcDNAIE180, an overall 25% of BALB/c, C3H/HeJ, and C57BL/6 mice receiving a lethal PrV challenge were protected (Chang et al., 1998).
Molecule Role Annotation :
A UL23 mutant, in combination with mutations in glycoproteins G and E, is attenuated in raccoons, with a 75% survival rate. This mutant also provides some protection from wild type PRV (Weigel et al., 2003).
Protein Note :
envelope glycoprotein C; the Herpesviridae are non-segmented dsDNA viruses with genomes ranging from 120-230kbp; although herpes viruses vary greatly in sequence identity and homology, they all share four common elements: an envelope, a tegument which is composed of viral enzymes, a capsid of 162 capsomers, and a core composed of genomic DNA;virion envelope glycoproteins bind to cellular receptors; the nonessential glycoprotein gC interacts with cell surface proteoglycans, whereas the essential glycoprotein gD is involved in stable secondary attachment
Molecule Role Annotation :
A trial vaccine containing pseudorabies virus (PRV) glycoprotein gC as the main component showed excellent protection against virulent virus infection in pigs (Katayama et al., 1997).
Molecule Role Annotation :
A UL50 mutant is attenuated in pseudorabies virus and induces significant protection in pigs from challenge with the highly virulent NIA-3 strain of PrV (Jöns et al., 1997).
Molecule Role Annotation :
Researchers intranasally inoculated pigs, the natural host of this virus, with mutant PRV strains in which the genes encoding the protein kinase (US3) proteins were inactivated. After challenge infection with the virulent PRV strain NIA-3, no virus was excreted by wt PRV- and PK- mutant-immunized animals, indicating complete protective immunity (Kimman et al., 1994).
Protein Note :
envelope glycoprotein D; the Herpesviridae are non-segmented dsDNA viruses with genomes ranging from 120-230kbp; although herpes viruses vary greatly in sequence identity and homology, they all share four common elements: an envelope, a tegument which is composed of viral enzymes, a capsid of 162 capsomers, and a core composed of genomic DNA;virion envelope glycoproteins bind to cellular receptors; the nonessential glycoprotein gC interacts with cell surface proteoglycans, whereas the essential glycoprotein gD is involved in stable secondary attachment
Molecule Role Annotation :
The pseudorabies virus (PrV) DNA vaccine carrying the glycoprotein D (gD) gene delivered by E. coli was able to induce protective immune responses in mice against a lethal PrV challenge (Shiau et al., 2001). Immunization of mice with affinity-purified gD of Aujeszky's disease virus (ADV, Suid herpesvirus 1) induced a strong humoral immune response and protected mice against lethal ADV challenge (Vrublevskaia et al., 2007).
Molecule Role Annotation :
IFN-gamma plays a critical role in Th1 type immune response. It is important for protection against infections by various viruses and intracellular bacteria.
Additional Molecule Role :
Vaximmutor
Additional Molecule Role Annotation :
The experimental data demonstrated that three time vaccinations with BCG in BALB/c mice induced strong TB Ag-specific IFN-gamma immune responses in splenocytes (Wang et al., 2009).
Vaccination Protocol:
The pigs were vaccinated via intramuscular injection in the thigh with 10^7 CCID50 of NYVAC/gp50 or NYVAC/gpII,gp50, 4 weeks apart (Brockmeier and Mengeling, 1996).
Vaccine Immune Response Type:
VO_0003057
Challenge Protocol:
Vaccinated pigs were challenged with 10^8 PFU of Indiana-Funkhauser strain of PRV oronasally, 4 weeks after the second vaccination (Brockmeier and Mengeling, 1996).
Efficacy:
Both NYVAC vectors protected pigs similarly from virulent pseudorabies virus challenge (Brockmeier and Mengeling, 1996).
Vaccination Protocol:
Pigs of each group were immunized intramuscularly with one ml of the different trial vaccines at two week intervals. Control pigs were vaccinated with unifected cell lysate antigens (Katayama et al., 1997).
Challenge Protocol:
One week after immunization pigs were challenged intranasally with 10^6 TCID50 of PRV Yamagata S-81 strain (Katayama et al., 1997).
Efficacy:
Immunized pigs had a high (87.5%) rate of survival against lethal PRV challenge (Katayama et al., 1997).
3. Pseudorabies Modified Live Virus Vaccine (USDA: 1891.20)
a. Manufacturer:
Wyeth, Boehringer Ingelheim Vetmedica, Inc., Pfizer, Inc.
Vaccination Protocol:
4-6 wk old male pigs from a PRV negative herd were vaccinated intramuscularly with two injections in the thigh of 10^7 CCID50 of NYVAC/gp50gpII 4 weeks apart. The control group was not vaccinated (Brockmeier and Mengeling, 1996).
Challenge Protocol:
Challenge consisted of administering 10^8 PFU of Indiana-Funkhauser strain of PRV oranasally, 4 weeks after the 2nd immunization (Brockmeier and Mengeling, 1996).
Vaccination Protocol:
4-6 wk old male pigs from a PRV negative herd were vaccinated intramuscularly with two injections in the thigh of 10^7 CCID50 of NYVAC/gpSO 4 weeks apart. The control group was not vaccinated (Brockmeier and Mengeling, 1996).
Challenge Protocol:
Challenge consisted of administering 10^8 PFU of Indiana-Funkhauser strain of PRV oranasally, 4 weeks after the 2nd immunization (Brockmeier and Mengeling, 1996).
Vaccination Protocol:
Groups of female mice were immunized with replication-incompetent adenoviruses expressing PrV glycoprotein (rAd-gB) by either the intranasal (i.n.) or intramuscular (i.m.) route. For i.m. administration, recombinant adenoviruses (10^6 pfu/mouse) were injected into the anterior tibialis muscle three times at weekly intervals (0, 7, and 14 days). The i.n. immunizations were also performed three times at weekly intervals (0, 7, and 14 days) by depositing 10^6 pfu of recombinant adenovirus onto the nares of deeply anesthetized mice. Control mice were immunized with replication-incompetent adenovirus expressing the LacZ gene (rAd-LacZ) (Han et al., 2008).
Challenge Protocol:
The immunized mice were infected i.n. with the virulent PrV YS strain (10 LD50) two weeks after the final immunization. The challenged mice were examined daily to quantify the number of dead animals. Mice generally began to exhibit clinical signs of illness 3 to 4 days post-challenge (Han et al., 2008).
Efficacy:
Recombinant adenovirus expressing gB (rAd-gB) was found to induce effective protective immunity against a virulent viral infection, regardless of whether it was administered via the muscular or systemic route (Han et al., 2008).
Host Gene Response of
Ifng (Interferon gamma)
Gene Response:
In splenocytes and popliteal lymph node cells, IFN-gamma was induced to a significantly higher level in immunized animals as compared to replication-incompetent adenovirus expressing LacZ (rAd-LacZ) vaccinated mice. These elevated levels were detected 2 weeks after the final immunization
Gene Response:
In splenocytes and popliteal lymph node cells, IL-2 was induced to a significantly higher level in immunized animals as compared to replication-incompetent adenovirus expressing LacZ (rAd-LacZ) vaccinated mice. These elevated levels were detected 2 weeks after the final immunization (Han et al., 2008).
Gene Response:
In splenocytes and popliteal lymph node cells, IL-4 was induced to a significantly higher level in immunized animals as compared to replication-incompetent adenovirus expressing LacZ (rAd-LacZ) vaccinated mice. These elevated levels were detected 2 weeks after the final immunization (Han et al., 2008).
Vaccination Protocol:
For active immunization mice were injected i.m. (hind leg) with different concentrations of emulsified purified (by electroelution) fusion protein (Fuchs et al., 1990).
Challenge Protocol:
Twenty-four h later the animals were infected intramuscularly (i.m.) into a hind leg using 0-1 ml of a lethal dose ( > 100 LD50) of strain Phylaxia, and the mice were observed for at least 10 days (Fuchs et al., 1990).
Efficacy:
Vaccination of mice with fusion proteins containing the N terminus of gI from Suid herpesvirus 1 are able to confer protection to mice against a lethal challenge of PRV (Fuchs et al., 1990).
Vaccination Protocol:
Two shots of DNA/mouse (1 /Ag/shot) were delivered with helium at 200 psi via the Helios Gene Gun to the shaven abdominal skin of 10 male mice of each strain, BALB/c, C57BL/6, C3H/HeJ. The mice received a booster once 14 days later with the same dose of DNA. In some experiments, pregnant mice of each strain were vaccinated immediately before mating and a booster was given 2 weeks later (Chang et al., 1998).
Challenge Protocol:
Six months after second vaccination, groups of pcDNAIE180 immunized mice were challenged intraperitoneally with a precalibrated mouse acute lethal dose of wild-type PrV-Ka TK+ (15 plaque-forming units (PFU)/g of body weight). The challenged mice were observed three times daily for clinical signs, and percent survival was assessed within 4 to 5 days postchallenge (Chang et al., 1998).
Efficacy:
Seven months after immunization with pcDNAIE180, an overall 25% of BALB/c, C3H/HeJ, and C57BL/6 mice receiving a lethal PrV challenge were protected (Chang et al., 1998).
16. Psuedorabies virus glycoprotein M mutant vaccine
Based on the attenuated ORFV strain D1701-V, recombinants were produced that express the glycoproteins gC (D1701-VrVgC) or gD (D1701-VrVgD) of the alphaherpesvirus of swine, pseudorabies virus (PRV) (Fischer et al., 2003).
f. Immunization Route
Intramuscular injection (i.m.)
g.
Mouse Response
Vaccination Protocol:
Mice were injected intramuscularly (i.m.) with 107 TCID50s of the ORFV recombinants expressing the PRV glycoproteins in a total volume of 0.2 ml (0.1 ml for each hind leg). Immunization was repeated at 2-week intervals (Fischer et al., 2003).
Vaccine Immune Response Type:
VO_0003057
Challenge Protocol:
Mice were challenge infected intraperitoneally (i.p.) with 10^2 PFU of the highly virulent PRV strain NIA-3, and the C57BL/6 and 129/Sv/Ev mice were infected with 10^3 PFU
Efficacy:
Single or combined immunization with the ORFV recombinants protected different mouse strains of a host species nonpermissive for ORFV against a fulminant, lethal PRV challenge infection equal to immunization with PRV live vaccine. Most notably, even a single immunization with D1701-VrVgC was protective, whereas two applications of D1701-VrVgD were required for immune protection (Fischer et al., 2003).
1. Brockmeier and Mengeling, 1996: Brockmeier SL, Mengeling WL. Comparison of the protective response induced by NYVAC vaccinia recombinants expressing either gp50 or gII and gp50 of pseudorabies virus. Canadian journal of veterinary research = Revue canadienne de recherche veterinaire. 1996; 60(4); 315-317. [PubMed: 8904669].
2. Chang et al., 1998: Chang SW, Bu J, Rompato G, Garmendia AE. A vector DNA vaccine encoding pseudorabies virus immediate early protein demonstrates partial protection in mice against lethal virus challenge. Viral immunology. 1998; 11(1); 27-36. [PubMed: 9586695].
3. Dijkstra et al., 1997: Dijkstra JM, Gerdts V, Klupp BG, Mettenleiter TC. Deletion of glycoprotein gM of pseudorabies virus results in attenuation for the natural host. The Journal of general virology. 1997; 78 ( Pt 9); 2147-2151. [PubMed: 9292000].
4. Eo et al., 2006: Eo SK, Yoon HA, Aleyas AG, Park SO, Han YW, Chae JS, Lee JH, Song HJ, Cho JG. Systemic and mucosal immunity induced by oral somatic transgene vaccination against glycoprotein B of pseudorabies virus using live attenuated Salmonella typhimurium. FEMS immunology and medical microbiology. 2006; 47(3); 451-461. [PubMed: 16872383].
5. Ferrari et al., 2000: Ferrari M, Brack A, Romanelli MG, Mettenleiter TC, Corradi A, Dal Mas N, Losio MN, Silini R, Pinoni C, Pratelli A. A study of the ability of a TK-negative and gI/gE-negative pseudorabies virus (PRV) mutant inoculated by different routes to protect pigs against PRV infection. Journal of veterinary medicine. B, Infectious diseases and veterinary public health. 2000; 47(10); 753-762. [PubMed: 11204130].
6. Fischer et al., 2003: Fischer T, Planz O, Stitz L, Rziha HJ. Novel recombinant parapoxvirus vectors induce protective humoral and cellular immunity against lethal herpesvirus challenge infection in mice. Journal of virology. 2003; 77(17); 9312-9323. [PubMed: 12915547].
7. Fuchs et al., 1990: Fuchs W, Rziha HJ, Lukàcs N, Braunschweiger I, Visser N, Lütticken D, Schreurs CS, Thiel HJ, Mettenleiter TC. Pseudorabies virus glycoprotein gI: in vitro and in vivo analysis of immunorelevant epitopes. The Journal of general virology. 1990; 71 ( Pt 5); 1141-1151. [PubMed: 1693164].
9. Han et al., 2008: Han YW, Aleyas AG, George JA, Kim SJ, Kim HK, Yoon HA, Yoo DJ, Kang SH, Kim K, Eo SK. Polarization of protective immunity induced by replication-incompetent adenovirus expressing glycoproteins of pseudorabies virus. Experimental & molecular medicine. 2008; 40(6); 583-595. [PubMed: 19116444].
10. Jöns et al., 1997: Jöns A, Gerdts V, Lange E, Kaden V, Mettenleiter TC. Attenuation of dUTPase-deficient pseudorabies virus for the natural host. Veterinary microbiology. 1997; 56(1-2); 47-54. [PubMed: 9228681].
11. Katayama et al., 1997: Katayama S, Okada N, Yoshiki K, Okabe T, Shimizu Y. Protective effect of glycoprotein gC-rich antigen against pseudorabies virus. The Journal of veterinary medical science / the Japanese Society of Veterinary Science. 1997; 59(8); 657-663. [PubMed: 9300361].
12. Kimman et al., 1994: Kimman TG, De Wind N, De Bruin T, de Visser Y, Voermans J. Inactivation of glycoprotein gE and thymidine kinase or the US3-encoded protein kinase synergistically decreases in vivo replication of pseudorabies virus and the induction of protective immunity. Virology. 1994; 205(2); 511-518. [PubMed: 7975253].
13. Matsuda et al., 1992: Matsuda Tsuchida A, Katayama S, Okada N, Okabe T, Sasaki N. Protection from pseudorabies virus challenge in mice by a combination of purified gII, gIII and gVI antigens. The Journal of veterinary medical science / the Japanese Society of Veterinary Science. 1992; 54(3); 447-452. [PubMed: 1322712].
15. Peeters et al., 1994: Peeters B, Bouma A, de Bruin T, Moormann R, Gielkens A, Kimman T. Non-transmissible pseudorabies virus gp50 mutants: a new generation of safe live vaccines. Vaccine. 1994; 12(4); 375-380. [PubMed: 8178562].
16. Shiau et al., 2001: Shiau AL, Chu CY, Su WC, Wu CL. Vaccination with the glycoprotein D gene of pseudorabies virus delivered by nonpathogenic Escherichia coli elicits protective immune responses. Vaccine. 2001; 19(23-24); 3277-3284. [PubMed: 11312026].
