Image of a virus

Infection, latency and reactivation

The virus–host relationship

The incidence of shingles, unlike that of many other vaccine-preventable diseases, is not temporally related to environmental exposure to the causative pathogen, in this case varicella zoster virus (VZV).1 Instead, the onset of shingles depends on the virus–host relationship allowing reactivation of latent VZV, typically decades after the primary infection that causes chickenpox.1

1. Primary VZV infection leads to durable immune responses

During the primary infection, VZV mainly infects T cells, epithelial cells and sensory dorsal root ganglia, causing the symptoms of chickenpox.2,3 High titres of cell-free VZV in the skin facilitate viral transmission to other people.3 Innate immune responses provide the first line of defence, but complete resolution of acute infection requires adaptive immune responses, which ultimately lead to the formation of durable T- and B-cell memory.4,5

An illustrated drawing of a virus. Three arrows are pointing from the virus to a T cell, an epithelial cell, and a nerve cell.

2. Latent VZV is controlled by cell-mediated immunity

Following primary infection, VZV lies dormant in neurons of cranial nerve ganglia, dorsal root ganglia, and enteric and autonomic ganglia.3,6 Almost all (90–95%) adults in the UK have latent infection with VZV.6,7

While VZV lies dormant, its DNA is non-replicating, no virions are produced and no obvious neuronal damage occurs.3 Cell-mediated immunity, induced by primary VZV infection, plays a major role in limiting the ability of the latent virus to reactivate.1,8,9

Immunity to shingles correlates with VZV-induced cell-mediated immunity.10

An illustrated drawing of a nerve cell with viral DNA latent within it.
An illustrated drawing of a T cell

Crib card on cell-mediated immunity

In contrast with humoral or antibody mediated-immunity, cell-mediated immunity is governed primarily by T cells.11

Cell-mediated immunity involves:

  • Activation of antigen-specific cytotoxic T cells
  • Activation of macrophages and natural killer cells
  • Cytokine stimulation

3. Reactivation of VZV causes shingles

Primary infection with VZV is a prerequisite for the development of shingles.6 Reactivation of VZV is associated with deterioration of the immune system as a result of ageing or suppression of the immune system due to a disease or therapy.6

When VZV reactivates to cause shingles, ganglia become necrotic and haemorrhagic.3 Reactivated VZV multiplies, forming intact virions that travel through axons to the skin.2,8,12 Subsequent viral replication in keratinocytes and epithelial cells is associated with alterations in keratinocytic differentiation resulting in blistering and vesicle formation.5,12

Sporadic VZV reactivation gives the virus an evolutionary advantage by enabling infection of new, susceptible birth cohorts.3

An illustrated drawing of a nerve cell with a virus inside it. More viruses are shown coming out of the nerve cell and travelling along the sensory nerve.

An insightful early theory is guiding ongoing investigations

The sporadic nature of shingles was first recorded by Hope-Simpson in 1965 in his landmark study exploring the interplay between chickenpox and shingles.9 Hope-Simpson noted the lack of a temporal relationship between chickenpox occurrence and reactivation of VZV as shingles, from observations in his medical practice over the course of 16 years.8,9 This contrasts with recurrent herpes simplex, the frequency of which decreases over time after primary infection.8

To help explain these observations, Hope-Simpson made a series of insightful proposals about the role of VZV and the immune response in VZV reactivation, which are still being investigated today.8,9

Could exogenous and endogenous exposure to VZV periodically boost immunity?

Hope-Simpson proposed that immunity to VZV may be boosted periodically in an individual’s lifetime in two ways, and evidence has since accumulated in support of these theories:3,9,13

  • Exogenous boosting, i.e. by environmental exposure to VZV, such as looking after a child with chickenpox3,8,9,14
  • Endogenous boosting i.e. asymptomatic reactivation of VZV may also occur, triggering an immune response that controls VZV before a rash develop9,14

However, the importance of exogenous boosting of immunity is subject to debate.3,15 Exogenous boosting predicts, for example, that reduced VZV circulation in a population after the introduction of childhood vaccination against chickenpox would increase the incidence of shingles.15 However, there is no evidence that shingles rates have accelerated in the USA during the >20 years after the introduction of an effective chickenpox vaccination programme, despite reductions in chickenpox incidence.15

Could waning of immunity explain VZV reactivation?

Hope-Simpson also proposed that waning of immunity to below a threshold level allows latent VZV to reactivate and cause shingles.8,9

Evidence has since been gathered in support of this theory. For example, levels of cell-mediated immunity against VZV decline with age, and there is still a clear association between increasing age and shingles incidence, with the highest incidence in the elderly.3,6,8,16 The risk of shingles is also higher in individuals with conditions that affect the immune system and those receiving immunosuppressive therapy than in immunocompetent individuals.6

However, the relevant molecular triggers for VZV reactivation remain largely unknown.15

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Possible changes in levels of immunity to VZV across a person's lifespan, based on Hope-Simpson's early theories9,17

Find out more

Risk of VZV reactivation

Increasing age and immunocompromised status are key risk factors for shingles

References

  1. Harpaz R et al. Prevention of herpes zoster: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008;57:1-30: quiz CE2-4.
  2. Centers for Disease Control and Prevention. Zoster. https://www.cdc.gov/vaccines/pubs/pinkbook/herpes-zoster.html (accessed February 2024).
  3. Gershon AA et al. Varicella zoster virus infection. Nat Rev Dis Primers 2015;1:15016.
  4. Laing KJ et al. Immunobiology of varicella-zoster virus infection. J Infect Dis 2018;218(Suppl 2):S68-S74.
  5. Arnold N and Messaoudi I. Herpes zoster and the search for an effective vaccine. Clin Exp Immunol 2017;187:82-92.
  6. UK Health Security Agency. Shingles: The Green Book, chapter 28a (July 2023). https://assets.publishing.service.gov.uk/media/64c1153cd4051a000d5a9409/Shingles_Green_Book_on_Immunisation_Chapter_28a_26_7_23.pdf (accessed February 2024).
  7. UK Health Security Agency. Varicella: The Green Book, chapter 34 (June 2019). https://assets.publishing.service.gov.uk/media/6213ba8d8fa8f54915f43779/Green_Book_Chapter_34_v3_0.pdf (accessed February 2024).
  8. Oxman MN. Herpes zoster pathogenesis and cell-mediated immunity and immunosenescence. J Am Osteopath Assoc 2009;109(6 Suppl 2):S13-S17.
  9. Hope-Simpson RE. The nature of herpes zoster: A long-term study and a new hypothesis. Proc R Soc Med 1965;58:9-20.
  10. Kimberlin DW and Whitley RJ. Varicella-zoster vaccine for the prevention of herpes zoster. N Engl J Med 2007;356:1338-1343.
  11. Marshall JS et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol 2018;14:49.
  12. Werner RN et al. European consensus-based (S2k) guideline on the management of herpes zoster - guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV), Part 1: Diagnosis. J Eur Acad Dermatol Venereol 2017;31:9-19.
  13. Marra F et al. Risk factors for herpes zoster infection: A meta-analysis. Open Forum Infect Dis 2020;7:ofaa005.
  14. Forbes H et al. Risk of herpes zoster after exposure to varicella to explore the exogenous boosting hypothesis: Self controlled case series study using UK electronic healthcare data. BMJ 2020;368:l6987.
  15. Harpaz R. How little we know herpes zoster. J Infect Dis 2020;222:708-711.
  16. van Hoek AJ et al. Estimating the cost-effectiveness of vaccination against herpes zoster in England and Wales. Vaccine 2009;27:1454-1467.
  17. Arvin A. Aging, immunity, and the varicella-zoster virus. N Engl J Med 2005;352:2266-2267.

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July 2024 | NP-GB-HZU-WCNT-240009 (V1.0)