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Varicella, known as chickenpox, is caused by the varicella zoster virus (VZV), with an estimated 84 million cases annually. It primarily affects children, for most of whom it is a self-limiting illness. However, there are an estimated 950 000 disability-adjusted life years attributed to VZV annually, disproportionately affecting lower-income settings. Children with impaired immunity and neonates are particularly at risk for severe varicella. Epidemiology varies between tropical and temperate regions with infections occurring at an earlier age in temperate climates. Varicella is a vaccine-preventable disease and over 40 countries have a universal one-dose or two-dose paediatric immunisation programme, either administered alone or combined with the measles, mumps and rubella vaccination (MMRV). The UK’s Joint Committee on Vaccination and Immunisation recommended the introduction of MMRV in November 2024. The vaccine, whether monovalent or MMRV, is effective in reducing varicella cases and hospital admissions, and two-dose regimens have further reduced breakthrough infections of shingles, a recognised concern in varicella vaccination programmes. Long-term data on shingles incidence in later life are not yet available and may be mitigated through paired universal shingles vaccination programmes for adults. Cost-effectiveness studies in high-resource settings support vaccination due to reduced hospitalisations and societal costs, such as missed caregiver employment. However, more research is needed for lower-resource regions to determine whether universal vaccination is feasible and cost-effective. While global varicella elimination is unlikely without sterilising immunity, vaccination can significantly reduce the disease burden, depending on regional epidemiology and available resources.
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Correspondence to Dr Eva Louise Wooding; [email protected]
Introduction
Chickenpox, or varicella, is the primary infection of varicella zoster virus (VZV), a double-stranded DNA virus in the Herpesviridae family. Varicella primarily affects children. Following primary infection, VZV lays dormant in sensory nerve ganglia, and later may reactivate leading to its second clinical syndrome, herpes zoster, also known as shingles. The WHO estimates there are 84 million cases of varicella annually, with 950 000 associated disability-adjusted life years attributed to VZV in 2019 and 14 553 deaths.1 Complications are primarily localised in the skin, lungs and brain, including secondary bacterial infections of varicella lesions, varicella pneumonitis or secondary bacterial pneumonia, cerebellar ataxia, encephalitis and stroke.2 Morbidity and mortality are more common in immunocompromised patients.3 This review will discuss the burden of varicella in children, outline current vaccine programmes and their impact, and consider the rationale for universal implementation.
Background
Epidemiology
In Europe, the annual burden of varicella in an unvaccinated population is estimated at 5.5 million cases. An estimated 0.82 severe cases per 100 000 children annually were described in a UK surveillance study during 2002–2003, including secondary infection, organ impairment and death.4 Humans are the only reservoirs of VZV, and the virus has a single known serotype. In temperate regions, varicella acquisition is most common during winter to spring with peak incidence between 3 years and 6 years of age. In tropical regions, transmission is highest in the cool, dry months, with large outbreaks occurring every 2–5 years.1 Exposure to varicella occurs earlier in urban, temperate environments, and in children attending formal childcare settings, where exposure is greater. Varicella is highly contagious with an estimated R0 of 3.3–16.9 across 11 European countries.5
If infection is introduced, an estimated 61%–100% of susceptible household contacts would develop varicella. Seroprevalence data from other tropical and island populations corroborates that later acquisition of varicella immunity occurs in these groups. In Saint Lucia, a seroprevalence study of 1810 people found that 90% of the population studied remained susceptible to varicella at 15 years of age, a figure that would be unthinkable in most temperate countries.6 90% of people in the USA were found to be seropositive for varicella by 20 years of age.7
Natural history
Primary varicella infection has an incubation period of 14–16 days (range 10–21 days) and is characterised by a rash usually commencing on the face, scalp or trunk, developing into clusters of vesicles which appear over 3–5 days, referred to as cropping, and resemble ‘dew drops on a rose petal’. Transmission is via inhalation of droplets from nasopharyngeal secretions, or from direct contact or aerosolisation of viral particles from skin lesions via a respiratory route. The varicella prodrome generally includes high-grade fever, lethargy, anorexia and headache for up to 2 days prerash, during which time the person is already contagious.7 The vesicular rash is intensely itchy and scratching may result in localised scarring.4 Varicella can be distinguished from other vesicular rashes by the differing ages of the lesions at the same time, which usually approximates 250–500 vesicles which eventually crust over, although in some cases very few vesicles are present, hampering identification.7 8 VZV infection induces strong T cell and humoral (IgG, IgM and IgA) responses. Early production of IgG and IgM is not predictive of severity of infection, although early CD4+ T cell response is a more accurate predictor of severity of illness and viral load.9
Shingles is the reactivation of VZV from latency in the neural ganglia and is not contracted de novo from people with active varicella. It is characterised by a unilateral vesicular rash, ordinarily in a single dermatomal distribution with associated radicular pain. Pain can last for weeks or months, and occasionally much longer in the case of postherpetic neuralgia, which persists for at least 3 months and can be extremely debilitating.10 Subclinical reactivations are common, and symptomatic shingles occurs in 10%–20% of seropositive people. Both the severity and incidence of shingles increases with advancing age, especially over 50 years, related to declining T cell-mediated immunity.11 However, shingles can occur in children, and in the immunocompromised, it may disseminate. There are an estimated 1.7 million cases annually in Europe across all ages. The acute rash is infectious to anyone who does not have immunity to varicella, via direct contact with lesions or aerosolisation from the infected vesicles.7
At-risk groups and sequelae
High-risk groups include neonates and infants, adults and the immunocompromised, including those with congenital and acquired immunodeficiencies. Individuals with T cell deficiencies including those with HIV, haematological malignancies and on chemotherapy are particularly susceptible.12 13 Low CD4+ T cell counts have been associated with increased and prolonged viral load and severe disease.14
In children skin complications are the most common, particularly due to Streptococcus pyogenes (group A Streptococcus) infections of varicella lesions.7 15 S. pyogenes skin infections may lead to invasive disease, which can be catastrophic, causing sepsis, toxic shock syndrome (with a varicella-associated mortality of 56%) or necrotising fasciitis (7% mortality).15 Neurological complications of varicella include cerebellar ataxia, which occurs in around 1/4000 cases and is generally self-limiting, and encephalitis (1/33 000–50 000 cases) which has a poor prognosis. Meningitis, febrile convulsions, and cranial nerve palsies have also been described.16 Rarely (1/40 000 cases), neurological complications may lead to mortality, especially where there is concurrent immunodeficiency.17 Following varicella infection, there is an increased risk of stroke, which is greater in adults, but also observed in children. Respiratory sequelae including primary pneumonitis and secondary pneumonia are more common in adults infected with varicella, with severity increasing with age.16
Congenital and neonatal varicella
Congenital varicella syndrome affects up to 2% of children whose mothers contract varicella in early pregnancy, for example, before 20 weeks’ gestation but can occur up to 28 weeks. It is characterised by low birth weight, skin scarring, and abnormalities affecting the limbs, brain and/or eyes. Untreated congenital varicella has an approximately 30% case fatality rate.18 In utero exposure to VZV is associated with an increased risk of developing shingles in infancy.19 VZV exposure peripartum results in neonatal varicella in 20%–50% of cases, with a 20% fatality rate where the infant develops a rash at 5–12 days of life (0%–3% at 0–4 days of life). Where varicella is identified 7 days prior to or following delivery, varicella zoster immunoglobulin (VZIG) can be given as prophylaxis in addition to antiviral therapy. VZIG can be considered in pregnancy where there is concern about congenital varicella infection following varicella infection, or in seronegative mothers with known exposure.20
Varicella vaccination programmes worldwide
Universal VZV vaccination programmes have been introduced in 45 countries worldwide to date (24%) with a further 14 countries (7%) offering varicella vaccination for at-risk groups, for example, adolescents who are seronegative for VZV, or offering universal vaccination in some areas of the country.21 There is a broad geographical spread of countries who have implemented varicella vaccination programmes worldwide, but there has been no introduction in any African or South Asian country yet (see figure 1).
Figure 1. Global coverage of varicella vaccination programmes including universal vaccination programmes (one or two dose regimens, monovalent or combined vaccines), and programmes targeting at-risk populations only. Adapted from WHO data. Figure created in Biorender.com
The WHO recommends the varicella vaccine be considered for routine immunisation in countries where varicella constitutes a significant public health burden, and where resources and uptake are sufficient to achieve at least 80% vaccine coverage. They recommend that one to two doses are given from 12 months to 18 months of age. Countries with a higher age of acquisition may want to consider targeted vaccination of seronegative adults.1
Some countries with universal varicella vaccine use a single-dose regimen and others a two-dose regimen. Some use a monovalent varicella vaccination and others a tetravalent vaccine with varicella given combined with the measles, mumps and rubella (MMRV) vaccination. All countries with established varicella vaccination programmes offer a first dose in infancy (range 11–20 months). The USA initially introduced a single-dose schedule and increased it to a two-dose schedule in 2006 due to concerns about breakthrough infections, including catch-up doses for previously vaccinated individuals. Mexico and Turkey are examples of countries who have introduced a one-dose regimen (see box 1).21
Box 1Universal vaccination programmes by country
One-dose regimens, monovalent varicella vaccine: Antigua and Barbuda, Barbados, Costa Rica, Ecuador, Republic of Korea, Niue, New Zealand, Oman, Peru, Russian Federation*, Türkiye.
Two-dose regimens, monovalent varicella vaccine: Anguilla, Andorra, United Arab Emirates, Argentina, Bahrain, Bahamas, Bermuda, Switzerland, Chile, Colombia, Cayman Islands, Cyprus, Hungary, Iceland, Japan, Kuwait, Latvia, Malta, Marshall Islands, Panama, Paraguay, Qatar, Saudi Arabia, El Salvador, San Marino, Trinidad and Tobago, Uruguay, British Virgin Islands.
Two-dose regimens, quadrivalent vaccine including measles, mumps, rubella and varicella (MMRV): Australia, Israel, Luxembourg.
Two-dose regimens, other combinations:
First dose of monovalent varicella vaccine, second dose of MMRV vaccine: Brazil, Germany, Finland, China, Hong Kong SAR, China, Macao SAR, Northern Mariana Islands, Singapore.
Monovalent varicella vaccine or MMRV vaccines for either dose: Greece, Italy, USA.
First dose of monovalent varicella vaccine or MMRV, second dose of MMRV: Canada, Spain.
*Universal vaccination programme not offered across all Russian regions.
One-dose or two-dose regimens
Ten countries have adopted a universal single-dose varicella vaccination programme (see box 1). One dose of varicella vaccination confers 85%–89% immunity, measured according to a protective IgG antibody response of ≥5 units/mL. This increases to over 99% in children receiving two doses.1 Evidence synthesis of five studies evaluating the effectiveness of two-dose monovalent varicella vaccination found that it offered greater reduction in varicella cases and their complications than single-dose vaccination.1 22 The benefit of a second dose is dynamic dependent on vaccine coverage. Modelling suggested that if vaccine coverage from dose 1 increased from 83% to 95% by 2 years of age, the incremental benefit of a two-dose regimen would fall by 70%, considering hospital admissions and associated costs.23 Some countries, for example, USA, Australia and Brazil, began with a one-dose policy and have since increased to two doses to address concerns about breakthrough infections.21 24
Silva et al. examined the difference in hospital admissions between a one-dose and two-dose regimen in a single centre over 9 years. They demonstrated 61.5% fewer admissions with one dose and 95.2% with two doses (816 admissions prevaccination, 356 during the single-dose regimen and 21 during the two-dose regimen).25 In Turkey, a one-dose monovalent varicella vaccination reduced admissions in the vaccinated under-fives by 93%.26
Monovalent versus combined vaccine
The varicella vaccine can be given in a quadrivalent vaccine where it is combined with MMR (MMRV), or separately (MMR+V). MMR+V separate vaccinations may be given simultaneously, or after a gap of at least 28 days.7 MMRV has been evaluated in over 24 studies totalling over 23 000 children. In a meta-analysis of 15 randomised control trials, MMRV demonstrated favourable immunogenic outcomes (seroconversion or seroprotection >91%). There was a lower seroprotection rate observed with the combined vaccine, but protection remained adequate overall.27 In Brazil, the introduction of the MMRV vaccination reduced all-cause mortality in children under 15 years by 49%–57% and hospitalisations by 40%–47%.25 Both MMRV and MMR+V are suitable for use in a universal vaccine programme. MMRV is not recommended as first-line in the USA because it has been linked with increased risk of febrile convulsions in infants (96/10 000) compared with when MMR and varicella vaccines are given separately at the same visit (44/10 000).28 The absolute risk remains very low; therefore, both can be considered safe and are suitable to be offered as part of a universal vaccine schedule so long as caregivers are counselled appropriately.
Varicella and shingles
The ‘exogenous boosting hypothesis’ postulates that frequent varicella exposure boosts antibody response to varicella and offers protection against future episodes of shingles.29 When encountering wild-type VZV subclinical reactivations occur, leading to a host immune response which boosts protection against shingles (see figure 2). An important question is if universal varicella vaccination would interfere with this natural booster to immunity, leading to an increase in cases of shingles.
Figure 2. Reactivations of latent varicella zoster virus (VZV) and maintenance of host-immune response as a result of VZV exposures. Figure created in Biorender.com.
Is the varicella vaccination acceptable to stakeholders?
Safety
The safety of both single and combined (MMRV) varicella vaccines has been evaluated in the USA via the Vaccines Adverse Events (AEs) Reporting System from 2006 to 2020. AEs were reported for an average of 30.6/100 000 (0.03%) doses of varicella vaccine, which is lower than the rate of AEs across the whole US childhood vaccination programme at 13.7%. Injection site reactions comprised 31% of all reported cases, as did rash (28%) and fever (12%). 23% of AEs reported related to procedural errors rather than the vaccine itself, such as vaccines not stored correctly. There were 78 reports of death following varicella immunisation (median 4 days afterwards) from 138.2 million doses given. Most common causes of death were described as due to sudden infant death syndrome (n=16), neurological causes (n=14) or respiratory conditions (n=13). These rates are within the expected numbers for children of these age groups, and there is not a suggestion that varicella vaccination is associated with excess deaths.30
Feasibility of achieving high vaccine uptake
If only 50% vaccine uptake is achieved, there will be a significant volume of varicella circulating with many seronegative, unvaccinated individuals at risk of infection during an outbreak, whose risk of more serious infection may be higher as they are older at first exposure.1 Of 596 parents surveyed in the UK about willingness to accept a varicella vaccine, including MMRV, as part of the routine immunisation schedule, 74% were positive about accepting the vaccination,31 but vaccine hesitancy is an important threat to herd immunity, which in Europe necessitates an estimated 70%–94% varicella vaccine-eligible coverage to achieve.5
Epidemiological data to inform modelling for varicella vaccination in resource-limited settings are scarce. We know that in tropical regions, the age of acquisition of VZV is generally later, but most data are from moderate to low-quality cross-sectional studies.32 In lower-resourced settings, varicella vaccination is unlikely to be a major public health priority. In these areas, targeted vaccination may be more appropriate. To understand the value of universal vaccination for varicella in lower-resource settings, it is important that high-quality research is carried out in these settings to support evidence-based policy making.
Cost-effectiveness
The UK’s Joint Committee on Vaccination and Immunisation (JCVI) has been considering the introduction of a varicella vaccination programme since 2009. At that time, it was concluded that varicella vaccination was not cost-effective in the short term and would be likely to lead to an increase in adult varicella and shingles infections. The introduction of a shingles vaccine for adults over 70 years was instead recommended.33 From 2022–2023 new evidence was evaluated focusing on disease burden, longer-term follow-up of exogenous boosting and cost-effectiveness. Analysis of the US vaccination programme, first recommended in 1995, demonstrated an impact on varicella but one dose was insufficient to interfere with community transmission. A two-dose regimen was introduced in 2007 with a catch-up vaccination programme. 25 years after initial introduction, there was a 97% reduction in varicella incidence in those under 20 years old, and lower shingles incidence was seen in both healthy and immunocompromised vaccinated children.34 This and other evidence led to a recommendation from the JCVI that varicella be included in the UK universal vaccination schedule, although this has not yet been approved for funding.33
Some of the funding for introducing varicella vaccination could be recouped from the cost savings associated with fewer hospitalised and severe cases. The cost saving identified in a Mexican study of hospitalised varicella cases was estimated at US$4434 per case.35 Varicella admissions with a complication had a mean hospital stay of 6.6 days (95% CI 6.2 to 6.9) and a mean care cost of €2143; this was €1272 in uncomplicated varicella, analysed across 31 European countries. The costs were greatest for neonatal varicella and those with cardiovascular or hepatic complications.36 We have limited data on cost-effectiveness from lower-resource settings.
Effect of varicella vaccination on shingles
The incidence of shingles is increasing, and this trend precedes the introduction of the varicella vaccine. On meta-analysis, an additional increase in hospitalisation due to shingles has been demonstrated for those aged 10–49 years after vaccination was introduced, but the absolute numbers were small. There were an estimated two additional cases per 100 000 people, with a change in trend of 0.29 (0.18–0.39, p<0.001).37 Since varicella vaccination has been in use for just under 30 years, we do not yet have long-term data to inform us on shingles risk in older populations. Shingles vaccinations are licensed for adults over 50 years and both a live and a recombinant (subunit) vaccine are available. The newer recombinant vaccine demonstrates greater protection compared with the live attenuated vaccine.10 37 While exploring the specifics of the shingles vaccinations is beyond the scope of this paper, it is reasonable to consider that the putative disadvantage of increased cases of shingles in a postvaricella vaccination era might be alleviated by a highly effective shingles vaccination for older adult populations.
Societal costs
While hospitalisation and sequelae are undoubtedly key, consideration needs to be given to the wider family and societal cost of varicella infection. There is an opportunity cost for children who miss educational and social opportunities during periods of infectivity, and caregivers who are likely to miss work during this period too, lengthened further by the spread of disease to siblings.38 39 The cost burden of varicella in an unvaccinated population has been estimated at over €660 million across 31 European countries (€309 552 363–€1015 631 760), largely from caregiver work loss.38 Research into the community and hospital effects on quality of life for children and caregivers affected by varicella is ongoing to quantify this further.39
Conclusion
The varicella vaccine is effective at reducing infections and hospital admissions when given as a monovalent or combined MMRV vaccine. It has an acceptable side-effect profile and caregivers are open to vaccination. Depending on vaccine uptake levels in the population, both a single-dose or two-dose vaccination regimen can be advocated, although the latter offers enhanced protection against breakthrough infections and hospitalisation, so might be preferable. Cost modelling based on hospital admission savings and societal costs such as missed employment, demonstrate significant projected or actual savings from varicella vaccination in high-resource settings, but net benefit remains unclear in resource-limited settings. More high-quality research is needed to quantify this before global vaccination can be advocated currently.
The long-term effects of universal varicella vaccination on shingles reactivation remain unclear at present, and the risk of a shift in age of VZV acquisition to adulthood remains concerning. The advent of a highly effective subunit shingles vaccination alleviates these concerns somewhat, and a plan for universal varicella vaccination should include consideration of a shingles booster in older adults. Further research into the duration of protection from subunit shingles vaccinations will inform this policy. The value of introducing varicella vaccination will be dependent on the epidemiology of VZV in the region, resources available to support the vaccination roll-out, and the likely uptake and acceptability. As these factors differ from country to country, a global universal vaccination programme cannot be advocated.
The authors thank Dr Dominic Kelly for the critical review of an earlier version of this manuscript.
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Contributors The original manuscript was drafted by EW with supervisory support from AW. Detailed feedback was given by SK leading to subsequent redrafting of the manuscript. All authors reviewed and revised the manuscript and approved the final version before submission.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.
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