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Virologica Sinica logoLink to Virologica Sinica
. 2014 Oct 24;29(5):265–273. doi: 10.1007/s12250-014-3516-9

Varicella zoster virus vaccines: potential complications and possible improvements

Benjamin Silver 1, Hua Zhu 1,
PMCID: PMC8206391  PMID: 25358998

Abstract

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.

Keywords: varicella zoster virus, herpesvirus, vaccine, neurovirulence, neuro-attenuation, latency, latent infection, herpes zoster, shingles, chicken pox, ORF7

References

  1. Abendroth A, Arvin A. Varicella-zoster virus immune evasion. Immunological reviews. 1999;168:143–156. doi: 10.1111/j.1600-065X.1999.tb01289.x. [DOI] [PubMed] [Google Scholar]
  2. Arvin A M. Aspects of the host response to varicella-zoster virus: a review of recent observations. Neurology. 1995;45:S36–37. doi: 10.1212/WNL.45.12_Suppl_8.S36. [DOI] [PubMed] [Google Scholar]
  3. Arvin A M. Varicella-zoster virus: molecular virology and virus-host interactions. Curr Opin Microbiol. 2001;4:442–449. doi: 10.1016/S1369-5274(00)00233-2. [DOI] [PubMed] [Google Scholar]
  4. Chesnut G, McClain D, Galeckas K. Varicella-zoster virus in children immunized with the varicella vaccine. Cutis. 2012;90:114–116. [PubMed] [Google Scholar]
  5. Choo P W, Donahue J G, Manson J E, Platt R. The epide-miology of varicella and its complications. J Infect Dis. 1995;172:706–712. doi: 10.1093/infdis/172.3.706. [DOI] [PubMed] [Google Scholar]
  6. Cohen J I, Seidel K E. 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;90:7376–7380. doi: 10.1073/pnas.90.15.7376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cole N L, Grose C. Membrane fusion mediated by herpesvirus glycoproteins: the paradigm of varicella-zoster virus. Rev Med Virol. 2003;13:207–222. doi: 10.1002/rmv.377. [DOI] [PubMed] [Google Scholar]
  8. Collaco A M, Rahman S, Dougherty E J, Williams B B, Geusz M E. Circadian regulation of a viral gene promoter in live transgenic mice expressing firefly luciferase. Mol Imaging Biol. 2005;7:342–350. doi: 10.1007/s11307-005-0019-y. [DOI] [PubMed] [Google Scholar]
  9. Contag C H, Bachmann M H. Advances in in vivo bioluminescence imaging of gene expression. Annu Rev Biomed Eng. 2002;4:235–260. doi: 10.1146/annurev.bioeng.4.111901.093336. [DOI] [PubMed] [Google Scholar]
  10. Contag C H, Spilman S D, Contag P R, Oshiro M, Eames B, Dennery P, Stevenson D K, Benaron D A. Visualizing gene expression in living mammals using a bioluminescent reporter. Photochem Photobiol. 1997;66:523–531. doi: 10.1111/j.1751-1097.1997.tb03184.x. [DOI] [PubMed] [Google Scholar]
  11. Doyle T C, Burns S M, Contag C H. In vivo bioluminescence imaging for integrated studies of infection. Cell Microbiol. 2004;6:303–317. doi: 10.1111/j.1462-5822.2004.00378.x. [DOI] [PubMed] [Google Scholar]
  12. Drolet M, Brisson M, Schmader K E, Levin M J, Johnson R, Oxman M N, Patrick D, Blanchette C, Mansi J A. 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. 2010;182:1731–1736. doi: 10.1503/cmaj.091711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dulal K, Zhang Z, Zhu H. Development of a gene capture method to rescue a large deletion mutant of human cytomegalovirus. Journal of Virological Methods. 2009;157:180–187. doi: 10.1016/j.jviromet.2008.12.021. [DOI] [PubMed] [Google Scholar]
  14. Dulal K, Silver B, Zhu H. Biomed and Biotechnol. 2012. Use of Recombination-Mediated Genetic Engineering for Construction of Rescue Human Cytomegalovirus Bacterial Artificial Chromosome Clones. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fan S, Maguire C A, Ramirez S H, Bradel-Tretheway B, Sapinoro R, Sui Z, Chakraborty-Sett S, Dewhurst S. Valproic acid enhances gene expression from viral gene transfer vectors. J Virol Methods. 2005;125:23–33. doi: 10.1016/j.jviromet.2004.11.023. [DOI] [PubMed] [Google Scholar]
  16. Gershon M D, Gershon A A. VZV infection of keratinocytes: production of cell-free infectious virions in vivo. Curr Top Microbiol Immunol. 2010;342:173–188. doi: 10.1007/82_2010_13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gilden D H, Kleinschmidt-DeMasters B K, LaGuardia J J, Mahalingam R, Cohrs R J. Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med. 2000;342:635–645. doi: 10.1056/NEJM200003023420906. [DOI] [PubMed] [Google Scholar]
  18. Harnisch J P. Zoster in the elderly: clinical, immunologic and therapeutic considerations. J Am Geriatr Soc. 1984;32:789–793. doi: 10.1111/j.1532-5415.1984.tb06298.x. [DOI] [PubMed] [Google Scholar]
  19. Hastings J W. Biological diversity, chemical mechanisms, and the evolutionary origins of bioluminescent systems. J Mol Evol. 1983;19:309–321. doi: 10.1007/BF02101634. [DOI] [PubMed] [Google Scholar]
  20. Hatchette T, Tipples G A, Peters G, Alsuwaidi A, Zhou J, Mailman T L. Foscarnet salvage therapy for acyclovir-resistant varicella zoster: report of a novel thymidine kinase mutation and review of the literature. Pediatr Infect Dis J. 2008;27:75–77. doi: 10.1097/INF.0b013e3181598315. [DOI] [PubMed] [Google Scholar]
  21. Kimberlin D W, Whitley R J. Varicella-zoster vaccine for the prevention of herpes zoster. N Engl J Med. 2007;356:1338–1343. doi: 10.1056/NEJMct066061. [DOI] [PubMed] [Google Scholar]
  22. Klassen T P, Hartling L, Wiebe N, Belseck E M. Cochrane Database Syst Rev: CD002980. 2005. Acyclovir for treating varicella in otherwise healthy children and adolescents. [DOI] [PubMed] [Google Scholar]
  23. Kurfurst M, Ghisla S, Hastings J W. Bioluminescence emission from the reaction of luciferase-flavin mononucleotide radical with O2. Biochemistry. 1983;22:1521–1525. doi: 10.1021/bi00276a001. [DOI] [PubMed] [Google Scholar]
  24. Leung J, Harpaz R, Molinari N A, Jumaan A, Zhou F. Herpes zoster incidence among insured persons in the United States, 1993–2006: evaluation of impact of varicella vaccination. Clin Infect Dis. 2011;52:332–340. doi: 10.1093/cid/ciq077. [DOI] [PubMed] [Google Scholar]
  25. Liesegang T J. Herpes zoster virus infection. Curr Opin Ophthalmol. 2004;15:531–536. doi: 10.1097/01.icu.0000143686.68103.46. [DOI] [PubMed] [Google Scholar]
  26. Lydick E, Epstein R S, Himmelberger D, White C J. Herpes zoster and quality of life: a self-limited disease with severe impact. Neurology. 1995;45:S52–53. doi: 10.1212/WNL.45.12_Suppl_8.S52. [DOI] [PubMed] [Google Scholar]
  27. Nagaike K, Mori Y, Gomi Y, Yoshii H, Takahashi M, Wagner M, Koszinowski U, Yamanishi K. Cloning of the varicellazoster virus genome as an infectious bacterial artificial chromosome in Escherichia coli. Vaccine. 2004;22:4069–4074. doi: 10.1016/j.vaccine.2004.03.062. [DOI] [PubMed] [Google Scholar]
  28. Niizuma T, Zerboni L, Sommer M H, Ito H, Hinchliffe S, Arvin A M. 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. 2003;77:6062–6065. doi: 10.1128/JVI.77.10.6062-6065.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Opstelten W, Mauritz J W, de Wit N J, van Wijck A J, Stalman W A, van Essen G A. Herpes zoster and postherpetic neuralgia: incidence and risk indicators using a general practice research database. Fam Pract. 2002;19:471–475. doi: 10.1093/fampra/19.5.471. [DOI] [PubMed] [Google Scholar]
  30. Rehemtulla A, Stegman L D, Cardozo S J, Gupta S, Hall D E, Contag C H, Ross B D. Rapid and quantitative assessment of cancer treatment response using in vivo bioluminescence imaging. Neoplasia. 2000;2:491–495. doi: 10.1038/sj.neo.7900121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Reichelt M, Zerboni L, Arvin A M. Mechanisms of varicellazoster virus neuropathogenesis in human dorsal root ganglia. J Virol. 2008;82:3971–3983. doi: 10.1128/JVI.02592-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Saksena M M, Wakisaka H, Tijono B, Boadle R A, Rixon F, Takahashi H, Cunningham A L. Herpes simplex virus type 1 accumulation, envelopment, and exit in growth cones and varicosities in mid-distal regions of axons. J Virol. 2006;80:3592–3606. doi: 10.1128/JVI.80.7.3592-3606.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Uebe B, Sauerbrei A, Burdach S, Horneff G. Herpes zoster by reactivated vaccine varicella zoster virus in a healthy child. Eur J Pediatr. 2002;161:442–444. doi: 10.1007/s00431-002-0981-1. [DOI] [PubMed] [Google Scholar]
  34. Vazquez M. Varicella zoster virus infections in children after the introduction of live attenuated varicella vaccine. Curr Opin Pediatr. 2004;16:80–84. doi: 10.1097/00008480-200402000-00015. [DOI] [PubMed] [Google Scholar]
  35. Warden C, Tang Q, Zhu H. Herpesvirus BACs: past, present, and future. J Biomed Biotechnol. 2011;2011:124595. doi: 10.1155/2011/124595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Warming S, Costantino N, Court D L, Jenkins N A, Copeland N G. Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res. 2005;33:e36. doi: 10.1093/nar/gni035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. White M R, Masuko M, Amet L, Elliott G, Braddock M, Kingsman A J, Kingsman S M. Real-time analysis of the transcriptional regulation of HIV and hCMV promoters in single mammalian cells. J Cell Sci. 1995;108(Pt2):441–455. doi: 10.1242/jcs.108.2.441. [DOI] [PubMed] [Google Scholar]
  38. Whitley R J. Changing dynamics of varicella-zoster virus infections in the 21st century: the impact of vaccination. J Infect Dis. 2005;191:1999–2001. doi: 10.1086/430328. [DOI] [PubMed] [Google Scholar]
  39. Yih W K, Brooks D R, Lett S M, Jumaan A O, Zhang Z, Clements K M, Seward J F. 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. 2005;5:68. doi: 10.1186/1471-2458-5-68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zerboni L, Arvin A. Investigation of varicella-zoster virus neurotropism and neurovirulence using SCID mouse-human DRG xenografts. J Neurovirol. 2011;17:570–577. doi: 10.1007/s13365-011-0066-x. [DOI] [PubMed] [Google Scholar]
  41. Zerboni L, Reichelt M, Arvin A. Varicella-zoster virus neurotropism in SCID mouse-human dorsal root ganglia xenografts. Curr Top Microbiol Immunol. 2010;342:255–276. doi: 10.1007/82_2009_8. [DOI] [PubMed] [Google Scholar]
  42. Zhang Y, Muyrers J P, Testa G, Stewart A F. DNA cloning by homologous recombination in Escherichia coli. Nat Biotechnol. 2000;18:1314–1317. doi: 10.1038/78475. [DOI] [PubMed] [Google Scholar]
  43. Zhang Z, Huang Y, Zhu H. A highly efficient protocol of generating and analyzing VZV ORF deletion mutants based on a newly developed luciferase VZV BAC system. J Virol Methods. 2008;148:197–204. doi: 10.1016/j.jviromet.2007.11.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Zhang Z, Rowe J, Wang W, Sommer M, Arvin A, Moffat J, Zhu H. Genetic analysis of varicella-zoster virus ORF0 to ORF4 by use of a novel luciferase bacterial artificial chromosome system. J Virol. 2007;81:9024–9033. doi: 10.1128/JVI.02666-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zhang Z, Selariu A, Warden C, Huang G, Huang Y, Zaccheus O, Cheng T, Xia N, Zhu H. Genome-wide mutagenesis reveals that ORF7 is a novel VZV skin-tropic factor. PLoS pathogens. 2010;6:e1000971. doi: 10.1371/journal.ppat.1000971. [DOI] [PMC free article] [PubMed] [Google Scholar]

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