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Review
Use of a current varicella vaccine as a live polyvalent vaccine vector Kouki Murakami a,b , Yasuko Mori a,∗ a b
Division of Clinical Virology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan Kanonji Institute, Seto Center, The Research Foundation for Microbial Diseases of Osaka University, 4-1-70, Seto-cho, Kanonji, Kagawa 768-0065, Japan
a r t i c l e
i n f o
Article history: Received 1 September 2014 Received in revised form 3 October 2014 Accepted 15 October 2014 Available online xxx Keywords: Varicella vaccine Oka strain Live polyvalent vaccine
a b s t r a c t Varicella-zoster virus (VZV) is the causative agent of varicella and zoster. The varicella vaccine was developed to control VZV infection in children. The currently available Oka vaccine strain is the only live varicella vaccine approved by the World Health Organization. We previously cloned the complete genome of the Oka vaccine strain into a bacterial artificial chromosome vector and then successfully reconstituted the virus. We then used this system to generate a recombinant Oka vaccine virus expressing mumps virus gene(s). The new recombinant vaccine may be an effective polyvalent live vaccine that provides protection against both varicella and mumps viruses. In this review, we discussed about possibility of polyvalent live vaccine(s) using varicella vaccine based on our recent studies. © 2014 Elsevier Ltd. All rights reserved.
1. The varicella-zoster virus – Oka vaccine strain Varicella-zoster virus (VZV), which belongs to the family Herpesviridae, causes varicella at the time of primary infection. Latent VZV resides in the ganglia and can sometimes reactivate to a lytic state; this can cause zoster, particularly in elderly and immunosuppressed individuals [1]. A live attenuated vaccine (vOka) was developed from the Oka parental strain (pOka) to control primary VZV infections in children [2]. Attenuation was achieved by passaging the virus in semi-permissive guinea pig embryo fibroblasts [2]. Because the vOka strain is highly effective and causes few adverse events, it is used worldwide and is the only live VZV vaccine approved by the World Health Organization (WHO) [3–6]. Recently, vOka has been used as a zoster vaccine in several countries [7–9]. 2. The varicella vaccine genome as a candidate live polyvalent vaccine vector vOka has a double stranded DNA genome of approximately 125 kbp that contains at least 71 ORFs. Because the vOka genome is large and contains several genes that are not required for viral replication [10], it is relatively easy to insert foreign genes. Therefore, it has been thought that it is possible to generate recombinant polyvalent live vOka vaccines expressing antigens derived from other pathogens. Several studies report the use of vOka as a vector for
∗ Corresponding author. Tel.: +81 78 382 6272; fax: +81 78 382 6879. E-mail address: [email protected] (Y. Mori).
expressing foreign genes, including the Epstein–Barr virus membrane glycoprotein (gp350/220) [11], hepatitis B surface antigen [12], human immunodeficiency virus env [13], and herpes simplex virus type2 glycoproteins B and D [14]. A live vaccine may induce long-lasting humoral and cellmediated immunity, even after a single dose. Therefore, the development of a novel attenuated live vaccine that is both effective and safe is feasible. Nowadays, children receive many different vaccines within a short period of time; therefore, polyvalent live vaccines that protect against several different pathogens after a single immunization have many advantages. Such vaccines may also be given at lower doses than current single vaccines. 3. Cloning of the VZV vOka genome into a bacterial artificial chromosome and reconstitution of infectious viruses Previously, we successfully cloned the pOka genome (pOka) into a bacterial artificial chromosome (BAC) [15]. This BAC system allows the VZV genome to be maintained in Escherichia coli to easily generate recombinant virus [16]. This method has enabled researchers to maintain various herpesvirus genomes [17–24] and to use the genome as a vector [25–30]. This is of particular value for VZV, which is difficult to maintain at a high titer in tissue culture. Next, we successfully isolated infectious BAC clones containing the full genome of the VZV Oka vaccine strain (vOka) [31]. To construct the vOka BAC genome, the BAC sequence was inserted into the region between open reading frame (ORF) 11 and ORF12 of VZV. This region was chosen because it is nonessential for the replication of herpes simplex virus type 1, which belongs to the same subfamily and has similar characteristics [32]. The full vOka containing the
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Please cite this article in press as: Murakami K, Mori Y. Use of a current varicella vaccine as a live polyvalent vaccine vector. Vaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.11.001
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Fig. 1. Cytopathic effects (CPEs) in reconstituted vOka-infected cells. MRC-5 cells were electroporated with rvOka-BAC DNA and infectious rvOka was reconstituted. CPEs were observed in the cells.
BAC sequence was then obtained by homologous recombination in vOka-infected MRC-5 cells, and independent vOka BAC clones were isolated after transformation into E. coli as described by Yoshii et al. [31]. The vOka BAC genome was then transfected into MRC-5 cells to generate the recombinant virus. Generally after several days of culture, typical cytopathic effects (CPEs) are observed as shown in Fig. 1. 4. Development of safe and effective polyvalent vaccine based on the current vOka As described above, we recently cloned the vOka genome [31] into a BAC and successfully reconstituted recombinant viruses from the BAC genome. Using this system, we then constructed a recombinant vOka containing the mumps virus hemagglutinin–neuraminidase (HN) gene [33] and demonstrated that recombinant vOka has potential utility as a polyvalent vaccine that provides protection against both VZV and mumps virus. Mumps is an acute viral infection that primarily affects the salivary glands. Although the virus generally causes a mild, selflimiting, disease in children, it can cause severe complications, such as aseptic meningitis and encephalitis, in adolescents and adults [34]. All commercially available mumps vaccines contain live, attenuated virus and are usually given as part of a mumps–rubella vaccine (MMR) [35], as recommended by the WHO [36]. However, some mumps virus vaccine strains can cause post-vaccination aseptic meningitis in a small minority of cases [37–39]. Therefore, MMR vaccines are no longer used in Japan, although a monovalent mumps vaccine is available. Moreover, an outbreak of mumps was recently reported in United States, despite widespread use of the MMR vaccine [40]. Although vaccination is recommended, the vaccine strain carries a risk of adverse effects. Therefore, a new safe and effective mumps vaccine is required. Mumps virions express two major glycoproteins on the capsid surface: HN and fusion (F) protein. HN is an integral membrane protein that is required for viral attachment to target cells. Several studies suggest that HN is the major initiator of humoral immune responses to mumps virus [41–45]. Therefore, we decided to construct a recombinant vOka expressing the mumps virus HN protein with the aim of generating a safe and effective polyvalent live vaccine against VZV and mumps virus.
was reconstituted as reported previously (Fig. 2) [33]. The expression of HN gene in rvOka-HN-infected cells was confirmed by an indirect immunofluorescence assay and Western blotting with an HN-specific antibody [33]. The HN protein was not expressed in the viral particles, even though it was expressed in rvOka-HN-infected cells [33]. We next used a guinea pig model to confirm induction of antibodies against VZV and mumps virus by immunization of cell-free rvOka-HN (Fig. 2). Serum from guinea pigs inoculated with rvOkaHN contained neutralizing antibodies against both VZV and mumps virus, confirming the induction of virus-specific immune responses [33]. Thus, rvOka-HN is a promising candidate polyvalent vaccine against both VZV and mumps virus. Also, rvOka-HN is a strong candidate novel mumps vaccine that may have fewer side effects than the current mumps vaccine. It may be possible to insert several foreign genes into the vOka genome to generate trivalent or quadrivalent live vOka vaccines. As a safety precaution, anti-viral drugs will be able to control unwanted infection by the recombinant virus because the TK gene is preserved within the rvOka genome. More recently, we constructed an rvOka vaccine strain expressing the mumps virus F protein [47,48]. In addition, recombinant viruses could be constructed that contain genes encoding pathogen antigens for which effective vaccines have not yet been developed.
5. A varicella vaccine containing the mumps virus HN gene (rvOka-HN) The mumps virus HN gene replaced the ORF 13 gene within the vOka genome (ORF 13 is nonessential for viral replication) [10,46] and recombinant virus containing the HN gene (rvOka-HN)
Fig. 2. Reconstitution of infectious virus from the vOka-HN-BAC genome and inoculation of rvOka to guinea pigs. MRC-5 cells were electroporated with vOka-HN genome in BAC vector and infectious vOka-HN was reconstituted. The rvOka-HN virus was used to inoculate guinea pigs.
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Since the vOka vaccine upon which the novel vaccine is based is currently approved for use worldwide, it is thought to be an ideal live vaccine vector. Further studies will be required toward trialing the novel vaccine in humans. Conflict of interest Kouki Murakami belongs to BIKEN which produces varicella vaccine. References [1] Arvin AM. Varicella-zoster virus. In: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE, et al., editors. Fields virology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001. p. 2731–68. [2] Takahashi M, Otsuka T, Okuno Y, Asano Y, Yazaki T. Live vaccine used to prevent the spread of varicella in children in hospital. Lancet 1974;2:1288–90. [3] Chaves SS, Haber P, Walton K, Wise RP, Izurieta HS, Schmid DS, et al. Safety of varicella vaccine after licensure in the United States: experience from reports to the vaccine adverse event reporting system, 1995–2005. J Infect Dis 2008;197(Suppl. 2):S170–7. [4] Galea SA, Sweet A, Beninger P, Steinberg SP, Larussa PS, Gershon AA, et al. The safety profile of varicella vaccine: a 10-year review. J Infect Dis 2008;197(Suppl. 2):S165–9. [5] Gershon AA. Varicella–zoster vaccine. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanishi K, editors. Human Herpesviruses: Biology,Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. p. 1262–73. Chapter 70. [6] Takahashi M. Effectiveness of live varicella vaccine. Expert Opin Biol Ther 2004;4:199–216. [7] National Advisory Committee on Immunization. An Advisory Committee Statement (ACS). In: National Advisory Committee on Immunization (NACI): update on the use of herpes zoster vaccine. Public Health Agency of Canada; 2014. [8] National Health and Medical Research Council. The Australian immunisation handbook. 10th ed. Canberra: Australian Government Department of Health and Ageing; 2013. [9] Pinot de Moira A, Nardone A. Varicella zoster virus vaccination policies and surveillance strategies in Europe. Euro Surveill 2005;10:43–5. [10] Zhang Z, Selariu A, Warden C, Huang G, Huang Y, Zaccheus O, et al. Genomewide mutagenesis reveals that ORF7 is a novel VZV skin-tropic factor. PLoS Pathog 2010;6:e1000971. [11] Lowe RS, Keller PM, Keech BJ, Davison AJ, Whang Y, Morgan AJ, et al. Varicellazoster virus as a live vector for the expression of foreign genes. Proc Natl Acad Sci U S A 1987;84:3896–900. [12] Shiraki K, Hayakawa Y, Mori H, Namazue J, Takamizawa A, Yoshida I, et al. Development of immunogenic recombinant Oka varicella vaccine expressing hepatitis B virus surface antigen. J Gen Virol 1991;72(Pt 6):1393–9. [13] Shiraki K, Sato H, Yoshida Y, Yamamura JI, Tsurita M, Kurokawa M, et al. Construction of Oka varicella vaccine expressing human immunodeficiency virus env antigen. J Med Virol 2001;64:89–95. [14] Heineman TC, Pesnicak L, Ali MA, Krogmann T, Krudwig N, Cohen JI. Varicellazoster virus expressing HSV-2 glycoproteins B and D induces protection against HSV-2 challenge. Vaccine 2004;22:2558–65. [15] Nagaike K, Mori Y, Gomi Y, Yoshii H, Takahashi M, Wagner M, et al. Cloning of the varicella-zoster virus genome as an infectious bacterial artificial chromosome in Escherichia coli. Vaccine 2004;22:4069–74. [16] Wagner M, Ruzsics Z, Koszinowski UH. Herpesvirus genetics has come of age. Trends Microbiol 2002;10:318–24. [17] Borst EM, Hahn G, Koszinowski UH, Messerle M. Cloning of the human cytomegalovirus (HCMV) genome as an infectious bacterial artificial chromosome in Escherichia coli: a new approach for construction of HCMV mutants. J Virol 1999;73:8320–9. [18] Chang WL, Barry PA. Cloning of the full-length rhesus cytomegalovirus genome as an infectious and self-excisable bacterial artificial chromosome for analysis of viral pathogenesis. J Virol 2003;77:5073–83. [19] Kanda T, Yajima M, Ahsan N, Tanaka M, Takada K. Production of high-titer Epstein–Barr virus recombinants derived from Akata cells by using a bacterial artificial chromosome system. J Virol 2004;78:7004–15. [20] Mahony TJ, McCarthy FM, Gravel JL, West L, Young PL. Construction and manipulation of an infectious clone of the bovine herpesvirus 1 genome maintained as a bacterial artificial chromosome. J Virol 2002;76:6660–8. [21] Messerle M, Crnkovic I, Hammerschmidt W, Ziegler H, Koszinowski UH. Cloning and mutagenesis of a herpesvirus genome as an infectious bacterial artificial chromosome. Proc Natl Acad Sci U S A 1997;94:14759–63.
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[22] Smith GA, Enquist LW. A self-recombining bacterial artificial chromosome and its application for analysis of herpesvirus pathogenesis. Proc Natl Acad Sci U S A 2000;97:4873–8. [23] Tanaka M, Kagawa H, Yamanashi Y, Sata T, Kawaguchi Y. Construction of an excisable bacterial artificial chromosome containing a full-length infectious clone of herpes simplex virus type 1: viruses reconstituted from the clone exhibit wild-type properties in vitro and in vivo. J Virol 2003;77:1382–91. [24] Zhou FC, Zhang YJ, Deng JH, Wang XP, Pan HY, Hettler E, et al. Efficient infection by a recombinant Kaposi’s sarcoma-associated herpesvirus cloned in a bacterial artificial chromosome: application for genetic analysis. J Virol 2002;76:6185–96. [25] Cicin-Sain L, Brune W, Bubic I, Jonjic S, Koszinowski UH. Vaccination of mice with bacteria carrying a cloned herpesvirus genome reconstituted in vivo. J Virol 2003;77:8249–55. [26] Gillet L, Daix V, Donofrio G, Wagner M, Koszinowski UH, China B, et al. Development of bovine herpesvirus 4 as an expression vector using bacterial artificial chromosome cloning. J Gen Virol 2005;86:907–17. [27] Petherbridge L, Howes K, Baigent SJ, Sacco MA, Evans S, Osterrieder N, et al. Replication-competent bacterial artificial chromosomes of Marek’s disease virus: novel tools for generation of molecularly defined herpesvirus vaccines. J Virol 2003;77:8712–8. [28] Redwood AJ, Messerle M, Harvey NL, Hardy CM, Koszinowski UH, Lawson MA, et al. Use of a murine cytomegalovirus K181-derived bacterial artificial chromosome as a vaccine vector for immunocontraception. J Virol 2005;79:2998–3008. [29] Stavropoulos TA, Strathdee CA. An enhanced packaging system for helperdependent herpes simplex virus vectors. J Virol 1998;72:7137–43. [30] Suter M, Lew AM, Grob P, Adema GJ, Ackermann M, Shortman K, et al. BACVAC, a novel generation of (DNA) vaccines: a bacterial artificial chromosome (BAC) containing a replication-competent, packaging-defective virus genome induces protective immunity against herpes simplex virus 1. Proc Natl Acad Sci U S A 1999;96:12697–702. [31] Yoshii H, Somboonthum P, Takahashi M, Yamanishi K, Mori Y. Cloning of full length genome of varicella-zoster virus vaccine strain into a bacterial artificial chromosome and reconstitution of infectious virus. Vaccine 2007;25:5006–12. [32] Zhang Y, McKnight JL. Herpes simplex virus type 1 UL46 and UL47 deletion mutants lack VP11 and VP12 or VP13 and VP14, respectively, and exhibit altered viral thymidine kinase expression. J Virol 1993;67:1482–92. [33] Somboonthum P, Yoshii H, Okamoto S, Koike M, Gomi Y, Uchiyama Y, et al. Generation of a recombinant Oka varicella vaccine expressing mumps virus hemagglutinin–neuraminidase protein as a polyvalent live vaccine. Vaccine 2007;25:8741–55. [34] Carbone KM, Wolinsky JS. Fields virology. 4th ed. Philadelphia: Lippincott; 2001. [35] Wellington K, Goa KL. Measles, mumps, rubella vaccine (Priorix; GSK-MMR): a review of its use in the prevention of measles, mumps and rubella. Drugs 2003;63:2107–26. [36] Mumps virus, vaccines. Wkly Epidemiol Rec 2001;76:346–55. [37] Kimura M, Kuno-Sakai H, Yamazaki S, Yamada A, Hishiyama M, Kamiya H, et al. Adverse events associated with MMR vaccines in Japan. Acta Paediatr Jpn 1996;38:205–11. [38] Miller E, Goldacre M, Pugh S, Colville A, Farrington P, Flower A, et al. Risk of aseptic meningitis after measles, mumps, and rubella vaccine in UK children. Lancet 1993;341:979–82. [39] Nalin DR. Mumps vaccine complications: which strain? Lancet 1989;2:1396. [40] Kancherla VS, Hanson IC. Mumps resurgence in the United States. J Allergy Clin Immunol 2006;118:938–41. [41] Orvell C. Immunological properties of purified mumps virus glycoproteins. J Gen Virol 1978;41:517–26. [42] Orvell C. The reactions of monoclonal antibodies with structural proteins of mumps virus. J Immunol 1984;132:2622–9. [43] Server AC, Merz DC, Waxham MN, Wolinsky JS. Differentiation of mumps virus strains with monoclonal antibody to the HN glycoprotein. Infect Immun 1982;35:179–86. [44] Tsurudome M, Yamada A, Hishiyama M, Ito Y. Monoclonal antibodies against the glycoproteins of mumps virus: fusion inhibition by anti-HN monoclonal antibody. J Gen Virol 1986;67(Pt 10):2259–65. [45] Wolinsky JS, Waxham MN, Server AC. Protective effects of glycoprotein-specific monoclonal antibodies on the course of experimental mumps virus meningoencephalitis. J Virol 1985;53:727–34. [46] Cohen JI, Seidel KE. Generation of varicella-zoster virus (VZV) and viral mutants from cosmid DNAs: VZV thymidylate synthetase is not essential for replication in vitro. Proc Natl Acad Sci U S A 1993;90:7376–80. [47] Matsuura M, Somboonthum P, Murakami K, Ota M, Shoji M, Kawabata K, et al. Novel polyvalent live vaccine against varicella-zoster and mumps virus infections. Microbiol Immunol 2013;57:704–14. [48] Somboonthum P, Koshizuka T, Okamoto S, Matsuura M, Gomi Y, Takahashi M, et al. Rapid and efficient introduction of a foreign gene into bacterial artificial chromosome-cloned varicella vaccine by Tn7-mediated site-specific transposition. Virology 2010;402:215–21.
Please cite this article in press as: Murakami K, Mori Y. Use of a current varicella vaccine as a live polyvalent vaccine vector. Vaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.11.001
ARTICLE IN PRESS
JVAC-15913; No. of Pages 3
Vaccine xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
Use of a current varicella vaccine as a live polyvalent vaccine vector Kouki Murakami a,b , Yasuko Mori a,∗ a b
Division of Clinical Virology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan Kanonji Institute, Seto Center, The Research Foundation for Microbial Diseases of Osaka University, 4-1-70, Seto-cho, Kanonji, Kagawa 768-0065, Japan
a r t i c l e
i n f o
Article history: Received 1 September 2014 Received in revised form 3 October 2014 Accepted 15 October 2014 Available online xxx Keywords: Varicella vaccine Oka strain Live polyvalent vaccine
a b s t r a c t Varicella-zoster virus (VZV) is the causative agent of varicella and zoster. The varicella vaccine was developed to control VZV infection in children. The currently available Oka vaccine strain is the only live varicella vaccine approved by the World Health Organization. We previously cloned the complete genome of the Oka vaccine strain into a bacterial artificial chromosome vector and then successfully reconstituted the virus. We then used this system to generate a recombinant Oka vaccine virus expressing mumps virus gene(s). The new recombinant vaccine may be an effective polyvalent live vaccine that provides protection against both varicella and mumps viruses. In this review, we discussed about possibility of polyvalent live vaccine(s) using varicella vaccine based on our recent studies. © 2014 Elsevier Ltd. All rights reserved.
1. The varicella-zoster virus – Oka vaccine strain Varicella-zoster virus (VZV), which belongs to the family Herpesviridae, causes varicella at the time of primary infection. Latent VZV resides in the ganglia and can sometimes reactivate to a lytic state; this can cause zoster, particularly in elderly and immunosuppressed individuals [1]. A live attenuated vaccine (vOka) was developed from the Oka parental strain (pOka) to control primary VZV infections in children [2]. Attenuation was achieved by passaging the virus in semi-permissive guinea pig embryo fibroblasts [2]. Because the vOka strain is highly effective and causes few adverse events, it is used worldwide and is the only live VZV vaccine approved by the World Health Organization (WHO) [3–6]. Recently, vOka has been used as a zoster vaccine in several countries [7–9]. 2. The varicella vaccine genome as a candidate live polyvalent vaccine vector vOka has a double stranded DNA genome of approximately 125 kbp that contains at least 71 ORFs. Because the vOka genome is large and contains several genes that are not required for viral replication [10], it is relatively easy to insert foreign genes. Therefore, it has been thought that it is possible to generate recombinant polyvalent live vOka vaccines expressing antigens derived from other pathogens. Several studies report the use of vOka as a vector for
∗ Corresponding author. Tel.: +81 78 382 6272; fax: +81 78 382 6879. E-mail address: [email protected] (Y. Mori).
expressing foreign genes, including the Epstein–Barr virus membrane glycoprotein (gp350/220) [11], hepatitis B surface antigen [12], human immunodeficiency virus env [13], and herpes simplex virus type2 glycoproteins B and D [14]. A live vaccine may induce long-lasting humoral and cellmediated immunity, even after a single dose. Therefore, the development of a novel attenuated live vaccine that is both effective and safe is feasible. Nowadays, children receive many different vaccines within a short period of time; therefore, polyvalent live vaccines that protect against several different pathogens after a single immunization have many advantages. Such vaccines may also be given at lower doses than current single vaccines. 3. Cloning of the VZV vOka genome into a bacterial artificial chromosome and reconstitution of infectious viruses Previously, we successfully cloned the pOka genome (pOka) into a bacterial artificial chromosome (BAC) [15]. This BAC system allows the VZV genome to be maintained in Escherichia coli to easily generate recombinant virus [16]. This method has enabled researchers to maintain various herpesvirus genomes [17–24] and to use the genome as a vector [25–30]. This is of particular value for VZV, which is difficult to maintain at a high titer in tissue culture. Next, we successfully isolated infectious BAC clones containing the full genome of the VZV Oka vaccine strain (vOka) [31]. To construct the vOka BAC genome, the BAC sequence was inserted into the region between open reading frame (ORF) 11 and ORF12 of VZV. This region was chosen because it is nonessential for the replication of herpes simplex virus type 1, which belongs to the same subfamily and has similar characteristics [32]. The full vOka containing the
http://dx.doi.org/10.1016/j.vaccine.2014.11.001 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Murakami K, Mori Y. Use of a current varicella vaccine as a live polyvalent vaccine vector. Vaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.11.001
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Fig. 1. Cytopathic effects (CPEs) in reconstituted vOka-infected cells. MRC-5 cells were electroporated with rvOka-BAC DNA and infectious rvOka was reconstituted. CPEs were observed in the cells.
BAC sequence was then obtained by homologous recombination in vOka-infected MRC-5 cells, and independent vOka BAC clones were isolated after transformation into E. coli as described by Yoshii et al. [31]. The vOka BAC genome was then transfected into MRC-5 cells to generate the recombinant virus. Generally after several days of culture, typical cytopathic effects (CPEs) are observed as shown in Fig. 1. 4. Development of safe and effective polyvalent vaccine based on the current vOka As described above, we recently cloned the vOka genome [31] into a BAC and successfully reconstituted recombinant viruses from the BAC genome. Using this system, we then constructed a recombinant vOka containing the mumps virus hemagglutinin–neuraminidase (HN) gene [33] and demonstrated that recombinant vOka has potential utility as a polyvalent vaccine that provides protection against both VZV and mumps virus. Mumps is an acute viral infection that primarily affects the salivary glands. Although the virus generally causes a mild, selflimiting, disease in children, it can cause severe complications, such as aseptic meningitis and encephalitis, in adolescents and adults [34]. All commercially available mumps vaccines contain live, attenuated virus and are usually given as part of a mumps–rubella vaccine (MMR) [35], as recommended by the WHO [36]. However, some mumps virus vaccine strains can cause post-vaccination aseptic meningitis in a small minority of cases [37–39]. Therefore, MMR vaccines are no longer used in Japan, although a monovalent mumps vaccine is available. Moreover, an outbreak of mumps was recently reported in United States, despite widespread use of the MMR vaccine [40]. Although vaccination is recommended, the vaccine strain carries a risk of adverse effects. Therefore, a new safe and effective mumps vaccine is required. Mumps virions express two major glycoproteins on the capsid surface: HN and fusion (F) protein. HN is an integral membrane protein that is required for viral attachment to target cells. Several studies suggest that HN is the major initiator of humoral immune responses to mumps virus [41–45]. Therefore, we decided to construct a recombinant vOka expressing the mumps virus HN protein with the aim of generating a safe and effective polyvalent live vaccine against VZV and mumps virus.
was reconstituted as reported previously (Fig. 2) [33]. The expression of HN gene in rvOka-HN-infected cells was confirmed by an indirect immunofluorescence assay and Western blotting with an HN-specific antibody [33]. The HN protein was not expressed in the viral particles, even though it was expressed in rvOka-HN-infected cells [33]. We next used a guinea pig model to confirm induction of antibodies against VZV and mumps virus by immunization of cell-free rvOka-HN (Fig. 2). Serum from guinea pigs inoculated with rvOkaHN contained neutralizing antibodies against both VZV and mumps virus, confirming the induction of virus-specific immune responses [33]. Thus, rvOka-HN is a promising candidate polyvalent vaccine against both VZV and mumps virus. Also, rvOka-HN is a strong candidate novel mumps vaccine that may have fewer side effects than the current mumps vaccine. It may be possible to insert several foreign genes into the vOka genome to generate trivalent or quadrivalent live vOka vaccines. As a safety precaution, anti-viral drugs will be able to control unwanted infection by the recombinant virus because the TK gene is preserved within the rvOka genome. More recently, we constructed an rvOka vaccine strain expressing the mumps virus F protein [47,48]. In addition, recombinant viruses could be constructed that contain genes encoding pathogen antigens for which effective vaccines have not yet been developed.
5. A varicella vaccine containing the mumps virus HN gene (rvOka-HN) The mumps virus HN gene replaced the ORF 13 gene within the vOka genome (ORF 13 is nonessential for viral replication) [10,46] and recombinant virus containing the HN gene (rvOka-HN)
Fig. 2. Reconstitution of infectious virus from the vOka-HN-BAC genome and inoculation of rvOka to guinea pigs. MRC-5 cells were electroporated with vOka-HN genome in BAC vector and infectious vOka-HN was reconstituted. The rvOka-HN virus was used to inoculate guinea pigs.
Please cite this article in press as: Murakami K, Mori Y. Use of a current varicella vaccine as a live polyvalent vaccine vector. Vaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.11.001
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ARTICLE IN PRESS K. Murakami, Y. Mori / Vaccine xxx (2014) xxx–xxx
Since the vOka vaccine upon which the novel vaccine is based is currently approved for use worldwide, it is thought to be an ideal live vaccine vector. Further studies will be required toward trialing the novel vaccine in humans. Conflict of interest Kouki Murakami belongs to BIKEN which produces varicella vaccine. References [1] Arvin AM. Varicella-zoster virus. In: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE, et al., editors. Fields virology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001. p. 2731–68. [2] Takahashi M, Otsuka T, Okuno Y, Asano Y, Yazaki T. Live vaccine used to prevent the spread of varicella in children in hospital. Lancet 1974;2:1288–90. [3] Chaves SS, Haber P, Walton K, Wise RP, Izurieta HS, Schmid DS, et al. Safety of varicella vaccine after licensure in the United States: experience from reports to the vaccine adverse event reporting system, 1995–2005. J Infect Dis 2008;197(Suppl. 2):S170–7. [4] Galea SA, Sweet A, Beninger P, Steinberg SP, Larussa PS, Gershon AA, et al. The safety profile of varicella vaccine: a 10-year review. J Infect Dis 2008;197(Suppl. 2):S165–9. [5] Gershon AA. Varicella–zoster vaccine. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanishi K, editors. Human Herpesviruses: Biology,Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. p. 1262–73. Chapter 70. [6] Takahashi M. Effectiveness of live varicella vaccine. Expert Opin Biol Ther 2004;4:199–216. [7] National Advisory Committee on Immunization. An Advisory Committee Statement (ACS). In: National Advisory Committee on Immunization (NACI): update on the use of herpes zoster vaccine. Public Health Agency of Canada; 2014. [8] National Health and Medical Research Council. The Australian immunisation handbook. 10th ed. Canberra: Australian Government Department of Health and Ageing; 2013. [9] Pinot de Moira A, Nardone A. Varicella zoster virus vaccination policies and surveillance strategies in Europe. Euro Surveill 2005;10:43–5. [10] Zhang Z, Selariu A, Warden C, Huang G, Huang Y, Zaccheus O, et al. Genomewide mutagenesis reveals that ORF7 is a novel VZV skin-tropic factor. PLoS Pathog 2010;6:e1000971. [11] Lowe RS, Keller PM, Keech BJ, Davison AJ, Whang Y, Morgan AJ, et al. Varicellazoster virus as a live vector for the expression of foreign genes. Proc Natl Acad Sci U S A 1987;84:3896–900. [12] Shiraki K, Hayakawa Y, Mori H, Namazue J, Takamizawa A, Yoshida I, et al. Development of immunogenic recombinant Oka varicella vaccine expressing hepatitis B virus surface antigen. J Gen Virol 1991;72(Pt 6):1393–9. [13] Shiraki K, Sato H, Yoshida Y, Yamamura JI, Tsurita M, Kurokawa M, et al. Construction of Oka varicella vaccine expressing human immunodeficiency virus env antigen. J Med Virol 2001;64:89–95. [14] Heineman TC, Pesnicak L, Ali MA, Krogmann T, Krudwig N, Cohen JI. Varicellazoster virus expressing HSV-2 glycoproteins B and D induces protection against HSV-2 challenge. Vaccine 2004;22:2558–65. [15] Nagaike K, Mori Y, Gomi Y, Yoshii H, Takahashi M, Wagner M, et al. Cloning of the varicella-zoster virus genome as an infectious bacterial artificial chromosome in Escherichia coli. Vaccine 2004;22:4069–74. [16] Wagner M, Ruzsics Z, Koszinowski UH. Herpesvirus genetics has come of age. Trends Microbiol 2002;10:318–24. [17] Borst EM, Hahn G, Koszinowski UH, Messerle M. Cloning of the human cytomegalovirus (HCMV) genome as an infectious bacterial artificial chromosome in Escherichia coli: a new approach for construction of HCMV mutants. J Virol 1999;73:8320–9. [18] Chang WL, Barry PA. Cloning of the full-length rhesus cytomegalovirus genome as an infectious and self-excisable bacterial artificial chromosome for analysis of viral pathogenesis. J Virol 2003;77:5073–83. [19] Kanda T, Yajima M, Ahsan N, Tanaka M, Takada K. Production of high-titer Epstein–Barr virus recombinants derived from Akata cells by using a bacterial artificial chromosome system. J Virol 2004;78:7004–15. [20] Mahony TJ, McCarthy FM, Gravel JL, West L, Young PL. Construction and manipulation of an infectious clone of the bovine herpesvirus 1 genome maintained as a bacterial artificial chromosome. J Virol 2002;76:6660–8. [21] Messerle M, Crnkovic I, Hammerschmidt W, Ziegler H, Koszinowski UH. Cloning and mutagenesis of a herpesvirus genome as an infectious bacterial artificial chromosome. Proc Natl Acad Sci U S A 1997;94:14759–63.
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Please cite this article in press as: Murakami K, Mori Y. Use of a current varicella vaccine as a live polyvalent vaccine vector. Vaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.11.001
