Varicella zoster virus (VZV) is the causative agent of varicella (chicken pox) and herpes zoster (shingles). After primary infection, the virus remains latent in sensory ganglia, and reactivates upon weakening of the cellular immune system due to various conditions, erupting from sensory neurons and infecting the corresponding skin tissue. The current varicella vaccine (v-Oka) is highly attenuated in the skin, yet retains its neurovirulence and may reactivate and damage sensory neurons. The reactivation is sometimes associated with postherpetic neuralgia (PHN), a severe pain along the affected sensory nerves that can linger for years, even after the herpetic rash resolves. In addition to the older population that develops a secondary infection resulting in herpes zoster, childhood breakthrough herpes zoster affects a small population of vaccinated children. There is a great need for a neuro-attenuated vaccine that would prevent not only the varicella manifestation, but, more importantly, any establishment of latency, and therefore herpes zoster. The development of a genetically-defined live-attenuated VZV vaccine that prevents neuronal and latent infection, in addition to primary varicella, is imperative for eventual eradication of VZV, and, if fully understood, has vast implications for many related herpesviruses and other viruses with similar pathogenic mechanisms.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price includes VAT (USA)
Tax calculation will be finalised during checkout.
Abendroth A, Arvin A. 1999. Varicella-zoster virus immune evasion. Immunological reviews, 168: 143–156.
Arvin A M. 1995. Aspects of the host response to varicella-zoster virus: a review of recent observations. Neurology, 45: S36–37.
Arvin A M. 2001. Varicella-zoster virus: molecular virology and virus-host interactions. Curr Opin Microbiol, 4: 442–449.
Chesnut G, McClain D, Galeckas K. 2012. Varicella-zoster virus in children immunized with the varicella vaccine. Cutis, 90: 114–116.
Choo P W, Donahue J G, Manson J E, Platt R. 1995. The epide-miology of varicella and its complications. J Infect Dis, 172: 706–712.
Cohen J I, Seidel K E. 1993. 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, 90: 7376–7380.
Cole N L, Grose C. 2003. Membrane fusion mediated by herpesvirus glycoproteins: the paradigm of varicella-zoster virus. Rev Med Virol, 13: 207–222.
Collaco A M, Rahman S, Dougherty E J, Williams B B, Geusz M E. 2005. Circadian regulation of a viral gene promoter in live transgenic mice expressing firefly luciferase. Mol Imaging Biol, 7: 342–350.
Contag C H, Bachmann M H. 2002. Advances in in vivo bioluminescence imaging of gene expression. Annu Rev Biomed Eng, 4: 235–260.
Contag C H, Spilman S D, Contag P R, Oshiro M, Eames B, Dennery P, Stevenson D K, Benaron D A. 1997. Visualizing gene expression in living mammals using a bioluminescent reporter. Photochem Photobiol, 66: 523–531.
Doyle T C, Burns S M, Contag C H. 2004. In vivo bioluminescence imaging for integrated studies of infection. Cell Microbiol, 6: 303–317.
Drolet M, Brisson M, Schmader K E, Levin M J, Johnson R, Oxman M N, Patrick D, Blanchette C, Mansi J A. 2010. The impact of herpes zoster and postherpetic neuralgia on healthrelated quality of life: a prospective study. CMAJ: Canadian Medical Association journal = journal de l’Association medicale canadienne, 182: 1731–1736.
Dulal K, Zhang Z, Zhu H. 2009. Development of a gene capture method to rescue a large deletion mutant of human cytomegalovirus. Journal of Virological Methods, 157: 180–187.
Dulal K, Silver B, Zhu H. 2012. Use of Recombination-Mediated Genetic Engineering for Construction of Rescue Human Cytomegalovirus Bacterial Artificial Chromosome Clones. Biomed and Biotechnol.
Fan S, Maguire C A, Ramirez S H, Bradel-Tretheway B, Sapinoro R, Sui Z, Chakraborty-Sett S, Dewhurst S. 2005. Valproic acid enhances gene expression from viral gene transfer vectors. J Virol Methods, 125: 23–33.
Gershon M D, Gershon A A. 2010. VZV infection of keratinocytes: production of cell-free infectious virions in vivo. Curr Top Microbiol Immunol, 342: 173–188.
Gilden D H, Kleinschmidt-DeMasters B K, LaGuardia J J, Mahalingam R, Cohrs R J. 2000. Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med, 342: 635–645.
Harnisch J P. 1984. Zoster in the elderly: clinical, immunologic and therapeutic considerations. J Am Geriatr Soc, 32: 789–793.
Hastings J W. 1983. Biological diversity, chemical mechanisms, and the evolutionary origins of bioluminescent systems. J Mol Evol, 19: 309–321.
Hatchette T, Tipples G A, Peters G, Alsuwaidi A, Zhou J, Mailman T L. 2008. Foscarnet salvage therapy for acyclovir-resistant varicella zoster: report of a novel thymidine kinase mutation and review of the literature. Pediatr Infect Dis J, 27: 75–77.
Kimberlin D W, Whitley R J. 2007. Varicella-zoster vaccine for the prevention of herpes zoster. N Engl J Med, 356: 1338–1343.
Klassen T P, Hartling L, Wiebe N, Belseck E M. 2005. Acyclovir for treating varicella in otherwise healthy children and adolescents. Cochrane Database Syst Rev: CD002980.
Kurfurst M, Ghisla S, Hastings J W. 1983. Bioluminescence emission from the reaction of luciferase-flavin mononucleotide radical with O2. Biochemistry, 22: 1521–1525.
Leung J, Harpaz R, Molinari N A, Jumaan A, Zhou F. 2011. Herpes zoster incidence among insured persons in the United States, 1993–2006: evaluation of impact of varicella vaccination. Clin Infect Dis, 52: 332–340.
Liesegang T J. 2004. Herpes zoster virus infection. Curr Opin Ophthalmol, 15: 531–536.
Lydick E, Epstein R S, Himmelberger D, White C J. 1995. Herpes zoster and quality of life: a self-limited disease with severe impact. Neurology, 45: S52–53.
Nagaike K, Mori Y, Gomi Y, Yoshii H, Takahashi M, Wagner M, Koszinowski U, Yamanishi K. 2004. Cloning of the varicellazoster virus genome as an infectious bacterial artificial chromosome in Escherichia coli. Vaccine, 22: 4069–4074.
Niizuma T, Zerboni L, Sommer M H, Ito H, Hinchliffe S, Arvin A M. 2003. Construction of varicella-zoster virus recombinants from parent Oka cosmids and demonstration that ORF65 protein is dispensable for infection of human skin and T cells in the SCID-hu mouse model. J Virol, 77: 6062–6065.
Opstelten W, Mauritz J W, de Wit N J, van Wijck A J, Stalman W A, van Essen G A. 2002. Herpes zoster and postherpetic neuralgia: incidence and risk indicators using a general practice research database. Fam Pract, 19: 471–475.
Rehemtulla A, Stegman L D, Cardozo S J, Gupta S, Hall D E, Contag C H, Ross B D. 2000. Rapid and quantitative assessment of cancer treatment response using in vivo bioluminescence imaging. Neoplasia, 2: 491–495.
Reichelt M, Zerboni L, Arvin A M. 2008. Mechanisms of varicellazoster virus neuropathogenesis in human dorsal root ganglia. J Virol, 82: 3971–3983.
Saksena M M, Wakisaka H, Tijono B, Boadle R A, Rixon F, Takahashi H, Cunningham A L. 2006. Herpes simplex virus type 1 accumulation, envelopment, and exit in growth cones and varicosities in mid-distal regions of axons. J Virol, 80: 3592–3606.
Uebe B, Sauerbrei A, Burdach S, Horneff G. 2002. Herpes zoster by reactivated vaccine varicella zoster virus in a healthy child. Eur J Pediatr, 161: 442–444.
Vazquez M. 2004. Varicella zoster virus infections in children after the introduction of live attenuated varicella vaccine. Curr Opin Pediatr, 16: 80–84.
Warden C, Tang Q, Zhu H. 2011. Herpesvirus BACs: past, present, and future. J Biomed Biotechnol, 2011: 124595.
Warming S, Costantino N, Court D L, Jenkins N A, Copeland N G. 2005. Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res, 33: e36.
White M R, Masuko M, Amet L, Elliott G, Braddock M, Kingsman A J, Kingsman S M. 1995. Real-time analysis of the transcriptional regulation of HIV and hCMV promoters in single mammalian cells. J Cell Sci, 108( Pt 2): 441–455.
Whitley R J. 2005. Changing dynamics of varicella-zoster virus infections in the 21st century: the impact of vaccination. J Infect Dis, 191: 1999–2001.
Yih W K, Brooks D R, Lett S M, Jumaan A O, Zhang Z, Clements K M, Seward J F. 2005. The incidence of varicella and herpes zoster in Massachusetts as measured by the Behavioral Risk Factor Surveillance System (BRFSS) during a period of increasing varicella vaccine coverage, 1998–2003. BMC Public Health, 5: 68.
Zerboni L, Arvin A. 2011. Investigation of varicella-zoster virus neurotropism and neurovirulence using SCID mouse-human DRG xenografts. J Neurovirol, 17: 570–577.
Zerboni L, Reichelt M, Arvin A. 2010. Varicella-zoster virus neurotropism in SCID mouse-human dorsal root ganglia xenografts. Curr Top Microbiol Immunol, 342: 255–276.
Zhang Y, Muyrers J P, Testa G, Stewart A F. 2000. DNA cloning by homologous recombination in Escherichia coli. Nat Biotechnol, 18: 1314–1317.
Zhang Z, Huang Y, Zhu H. 2008. A highly efficient protocol of generating and analyzing VZV ORF deletion mutants based on a newly developed luciferase VZV BAC system. J Virol Methods, 148: 197–204.
Zhang Z, Rowe J, Wang W, Sommer M, Arvin A, Moffat J, Zhu H. 2007. Genetic analysis of varicella-zoster virus ORF0 to ORF4 by use of a novel luciferase bacterial artificial chromosome system. J Virol, 81: 9024–9033.
Zhang Z, Selariu A, Warden C, Huang G, Huang Y, Zaccheus O, Cheng T, Xia N, Zhu H. 2010. Genome-wide mutagenesis reveals that ORF7 is a novel VZV skin-tropic factor. PLoS pathogens, 6: e1000971.
About this article
Cite this article
Silver, B., Zhu, H. Varicella zoster virus vaccines: potential complications and possible improvements. Virol. Sin. 29, 265–273 (2014). https://doi.org/10.1007/s12250-014-3516-9
- varicella zoster virus
- latent infection
- herpes zoster
- chicken pox