Sage Journals: Discover world-class research

Abstract

Varicella is a highly contagious disease caused by primary infection with varicella zoster virus (VZV). VZV infection, as well as varicella vaccination, induces VZV-specific antibody and T-cell-mediated immunity, essential for recovery. The immune responses developed contribute to protection following re-exposure to VZV. When cell-mediated immunity declines, as occurs with aging or immunosuppression, reactivation of VZV leads to herpes zoster (HZ). It has been almost 20 years since universal varicella vaccination has been implemented in many areas around the globe and this has resulted in a significant reduction of varicella-associated disease burden. Successes are reviewed here, whilst emphasis is put on the challenges ahead. Most countries that have not implemented routine childhood varicella vaccination have chosen to vaccinate high-risk groups alone. The main reasons for not introducing universal vaccination are discussed, including fear of age shift of peak incidence age and of HZ incidence increase. Possible reasons for not observing the predicted increase in HZ incidence are explored. The advantages and disadvantages of universal vs targeted vaccination as well as different vaccination schedules are discussed.

Keywords

Varicella vaccination varicella zoster virus epidemiology herpes zoster incidence VZV-cellular immunity

Introduction

Varicella zoster virus

Varicella zoster virus (VZV) is an alpha herpesvirus that infects exclusively humans [Hambleton and Gershon, 2005]. Each VZV virion consists of four parts: (1) the core (made of a linear double-stranded DNA); (2) the capsid; (3) the tegument (that surrounds the capsid); and (4) the envelope (that surrounds the tegument and incorporates the major viral glycoproteins [gps]) [Arvin, 1996]. VZV’s virion is spherical with a diameter of 180–200 nm while the core consists of a single linear double-stranded DNA 125 kb long. VZV is the smallest of the human herpes viruses and its envelope is made out of gps of about 8 nm long. During lytic infection the virus produces at least 12 gps which are expressed both on the surface of the virions and the envelope of infected human cells [Gershon and Gershon, 2010].

VZV associated diseases

VZV DNA is present in respiratory secretions (upper respiratory) and fluid secretions from skin vesicles. It is transmitted through direct contact with the skin lesions, through respiratory secretions or through inhalation of the airborne particles of the virus.

Primary infection is manifested as varicella (or chickenpox) and leads to lifelong latent infection of sensory ganglion neurons. Reactivation of the latent infection causes HZ (HZ, shingles) [Hambleton and Gershon, 2005].

Varicella (or chickenpox) is a highly contagious disease in children with an estimated household secondary attack rate of 90% [Arvin, 1996; Ross, 1962]. During the incubation period (10–21 days), the virus initially replicates in the upper respiratory tract and through a primary subclinical viremia, the virus spreads to the reticuloendothelial system (liver, spleen) and other organs. Following additional viral replication, a second viremic phase ensues and prodromal clinical symptoms (fever, malaise) appear followed by the eruption of the typical rash. The rash consists of pruritic, maculopapules, vesicles and crusted lesions in varying stages of evolution. They quickly progress from one stage to the next. In the beginning, each skin vesicle develops on an erythematous base, then progresses into a pustule and then into a crusted pustule. The distribution of the lesions is mainly central. It affects the trunk and the face and spreads rapidly to the rest of the body. New crops of vesicles are generated for 3–7 days from virus colonies in the peripheral blood mononuclear cells. The average number of lesions is 300 (10–1500).

Importantly, during the late phase of the incubation period, the virus is transported to the respiratory system, spreading to susceptible contacts, before the characteristic rash appears.

Although varicella is a generally benign disease, even uncomplicated cases experience significant discomfort due to itching. Complications are not uncommon and mainly involve secondary skin and soft tissue infections (streptococcal and staphylococcal) and central nervous system involvement including either viral encephalitis or post-infectious cerebellitis [Arvin, 1996]. However, it should be noted that most patients suffering from complications were previously healthy individuals. Moreover, among immunocompetent patients there are not identifiable risk factors for complications [Boelle and Hanslik, 2002; Bonhoeffer et al. 2005; Galil et al. 2002a]. Moreover, varicella infection in immunocompromised patients and healthy adults is associated with increased morbidity and mortality [Arvin, 1996]. Congenital infection can result in fetal varicella syndrome in up to 2% of cases, if the mother develops varicella during weeks 8–20 of gestation. The associated pathology may involve the skin, limbs, central nervous system and eyes. If maternal varicella onset coincides with the perinatal period, neonatal varicella follows which is very severe since no maternal antibodies are produced to be transferred vertically and to protect the newborn. If the infection left untreated, the mortality rate can be high at up to 30% [Enders et al. 1994; Paryani and Arvin, 1986].

VZV infection leads to lifetime immunity against the virus. Both cellular and humoral immunity contribute for the protection against a second infection, but cell-mediated immunity plays the predominant role. Patients with impaired cellular immunity are at greater risk of getting sick with varicella and reactivating VZV as herpes zoster (HZ) [Gershon and Gershon, 2010].

Reactivation of latent VZV infection can cause HZ also known as shingles. HZ is a unilateral vesicular lesion with dermatomal distribution. The most common dermatomes affected are thoracic and lumbar. HZ is more common in adults than children and its clinical manifestations differ between these age groups. In children, unlike adults, local pain, hyperesthesia and pruritus are not common. The lesions are mild and they appear as erythematous maculopapular lesions that rapidly evolve into vesicles. These vesicles coalesce to form bullous formations. The disease lasts up to 15 days and it might take over a month for the skin to completely heal. Common complications of HZ are post-herpetic neuralgia, iridocyclitis, secondary glaucoma, meningoencephalitis and encephalitis [Arvin, 1996].

Aim of the review

The best way to prevent varicella infection and effectively decrease the disease and associated economic burden is to provide primary prevention. Following that principle, a live attenuated varicella vaccine has been developed. Universal vaccination was first introduced in the United States in 1995 [ACIP, 1996; Marin et al. 2007]. The same year, the World Health Organization (WHO) adopted the mass vaccination against varicella [WHO, 1998]. Up to now only few countries around the world have implemented universal vaccination namely Australia, Canada, Germany, Qatar, Republic of Korea, Saudi Arabia, Taiwan, Uruguay, Italy (Sicily only) and Spain (Madrid only) [Bonanni et al. 2009]. This is mainly attributable to the preference of many countries’ public health authorities to recommend targeted varicella vaccination of the high-risk population and/or different prioritization with the availability of few new vaccines over the past decade (human papillomavirus [HPV] vaccine, rotavirus vaccine, etc.). Furthermore, concerns have been raised including the fear of increase of HZ incidence, the fear of age shift of the disease towards older age groups, the possible difficulties in achieving high coverage rates and last but not least the economic burden of universal vaccination implementation [Bonanni et al. 2009].

The aim of this review is to discuss the successes achieved by universal varicella vaccination and to address challenges needed to be tackled in the future.

Varicella vaccine

The live attenuated varicella vaccine was first developed in Japan by Takahashi [Takahashi et al. 1974]. Initially, the vaccine was solely used to protect high-risk leukemic children [Gershon et al. 1984; Takahashi et al. 1985]. In 1989, the vaccine was first introduced to healthy children in Japan and Korea and in 1995 the US Food and Drug Administration (FDA) approved the vaccine for children aged at least 12 months with a negative varicella history [Hambleton and Gershon, 2005].

There are two available live attenuated virus vaccines, Varilrix (GlaxoSmithKline Biologicals S.A., Rixensart, Belgium) and Varivax (Sanofi Pasteur Limited, Lyon, France). Both vaccines contain the Japanese varicella viral strain, Oka, and are safe and highly immunogenic [Arvin, 1996; Marin et al. 2007].

The adverse effects of the vaccine are few and are benign in nature [Arvin, 1996; Plotkin et al. 1985]. About 20% of the vaccinated population may develop mild pain, redness or swelling in the injection site, while 3–5% of the vaccinated population may present a vesicular rash either at the site of injection or more generalized. Up to 15% of recipients may suffer from fever [Arvin, 1996; Marin et al. 2007; Plotkin et al. 1985]. Serious complications of the vaccine are rarely reported (2.6/100,000 doses) [Chaves et al. 2008; Wagenpfeil et al. 2004]. Transmission of Oka strain varicella from a vaccinated child is a very rare phenomenon, since only 3 cases have been reported after 16 million doses of the vaccine had been administered [Hambleton and Gershon, 2005].

The live attenuated varicella vaccine poses a threat to immunocompromised patients. However, the vaccine can be safely administered to leukemic children under remission and HIV-infected children without severe immunodeficiency [Gershon et al. 1984, 2009]. Rarely, severe generalized varicella infection due to the Oka strain post-immunization has been reported in children vaccinated before the diagnosis of severe immunodeficiency [Chaves et al. 2008; Levin et al. 2003; Levy et al. 2003].

The Oka vaccine strain is capable of causing latent infection and it has been clearly shown that, as wild virus, it remains in the dorsal root ganglia [Chen et al. 2003; Gershon and Gershon, 2010]. Importantly, however, the risk of developing zoster among the vaccinated population is significantly lower when compared with children post-natural varicella [Baxter et al. 2013; Civen et al. 2009; Tseng et al. 2009]. It has been hypothesized that this is due to the lower viral loads induced [Gershon and Gershon, 2010].

Data from pre-licensure clinical trials have indicated that 95% of children develop protective antibodies following one dose of varicella vaccine [Provost et al. 1991]. Based on these studies one dose of varicella vaccine was initially proposed for the vaccination of healthy children <12 years of age [CDC, 1995]. However, as described below, outbreaks of varicella in schools due to breakthrough infection among immunized children were described and post-licensure studies estimated an overall effectiveness of 85% [Vazquez et al. 2004]. In 2006, both the CDC and ACIP recommended the administration of two doses of varicella vaccine to healthy children [ACIP, 2008; Marin et al. 2007]. A second dose of varicella vaccine elicits a robust anamnestic response in individuals partially primed by a single dose, with increases in both humoral and cellular immunity [Nader et al. 1995; Ngai et al. 1996; Watson et al. 1995a]. The implementation of two-dose vaccination has significantly decreased the incidence of breakthrough disease [Marin et al. 2007]. In addition, varicella vaccination may be administered as a tetravalent vaccine in combination with measles–mumps–rubella (MMR) vaccine. The measles–mumps–rubella–varicella (MMRV) vaccine produced by Merk & Co., contains higher dose of the Oka strain compared with the monovalent vaccines and was licensed in the USA in 2005. However, in the USA, post-licensure data however in the USA, indicated that the rate of febrile seizures doubled 7–10 days post-administration of the quadrivalent vaccine to 12–23-month-old children [CDC, 2008]. It was calculated that post-MMRV, one additional febrile seizure may occur for every 2300 doses given than with monovalent vaccines [Klein et al. 2010]. In Europe, MMR-V vaccine produced by GSK was initially introduced in Germany in 2006 [Siedler and Arndt, 2010]. Most recently, in July 2012, STIKO, the German National Committee on Immunization Practices, also updated their recommendations, expressing the preference of separate vaccination for the first dose due to the slight increased risk for febrile seizures 5–12 days after application of the combined MMRV vaccine compared to the simultaneous vaccination with a varicella and MMR vaccine (see http://www.rki.de/EN/Content/Prevention/Vaccination/recommandations/STIKO_Recommendations_2012_en.pdf?__blob=publicationFile, accessed 20 July 2013). However, for the second dose, MMRV is preferred [Jacobsen et al. 2009].

Pre-vaccine epidemiology

Incidence

Chickenpox is a very common disease with estimated 60 million new cases annually worldwide [Plotkin et al. 1985]. In the USA, in the pre-vaccine era, 4 million cases occurred annually (15–16/100,000) with the birth rate adding up to the same number [Marin et al. 2007]. In Germany, with an annual birth cohort of 800,000, new varicella cases reached 760,000 cases/year [Wagenpfeil et al. 2004]. Chickenpox is a disease of childhood affecting mainly children up to 12 years of age. Peak incidence age used to be between 5 and 9 years old. However, over the past 50 years, the increased use of daycare centers and childcare facilities decreased the peak incidence age to 1–4 years. Moreover, an increase in varicella incidence among infants was observed [Bonhoeffer et al. 2005]. Seroprevalence data indicate that 95% of young adults 20–29 years old are immune [Aebi et al. 2001; Nardone et al. 2007].

Climate factors and varicella incidence

The epidemiology of varicella infection is remarkably different between temperate and tropical regions [Liyanage et al. 2007; Tseng et al. 2005]. It is well known that the disease incidence is significantly lower among children living in tropical areas [Pollock and Golding, 1993]. Therefore, while varicella is a disease of pre-school and school-age children during winter and spring in temperate regions, in the tropics it often affects older age groups all year around [Garnett et al. 1993; Lee, 1998; Lolekha et al. 2001]. In addition, in tropical regions the seroprevalence rate of VZV is higher in urban than rural populations while this has not been observed in areas with temperate climate [Lolekha et al. 2001; Mandal et al. 1998]. More recently, seroepidemiologic data from Europe has revealed that the seropositivity rate of VZV is lower in subjects living in the Southern Mediterranean countries possibly linked to their climate [Katsafadou et al. 2008]. Although, some have supported that humidity negatively affects VZV transmission [Garnett et al. 1993], other factors such as population density, nursery attendance and socioeconomic development also may influence the epidemiology of VZV [Yawn et al. 1997]. Although the association between climate and varicella epidemiology has been mainly studied in tropical regions, recently it was shown that even in temperate regions the recent climate changes due to the ozone phenomenon and following global warming may have an impact on varicella incidence. More specifically, in Greece over the last two decades (1982–2003) it was noted that the frequency of hospitalized varicella cases was positively associated with wind speed, inversely associated with air temperature but not correlated with humidity [Critselis et al. 2012a].

Hospitalization

Although varicella is considered a mild disease, it may cause severe complications, leading to hospitalization in about 2–6% of infected subjects [Bonanni et al. 2009]. However, it should be noted that most hospitalized individuals due to VZV infection have no history of underlying disease [Liese et al. 2008]. In the pre-vaccine era in USA, hospitalization rates due to chickenpox ranged between 2.3 and 6.3/100,000 population [Galil et al. 2002a]. Children younger than 5 years of age accounted for more than 40% of varicella hospitalizations while infants and adults aged >20 years had 6- and 13-fold higher risk, respectively, for hospitalization [Davis et al. 2004; Galil et al. 2002a]. Hospitalization incidence in Europe ranged from 1.3 to 4.5/100,000 varicella cases and was higher in children younger than 16 years old (12.9–28/100,000) [Bonanni et al. 2009]. The average duration of hospitalization ranges between 3 and 8 days.

Morbidity and mortality

The most common complications that contribute to varicella-associated mortality include pneumonia, central nervous system involvement (encephalitis, meningoencephalitis), secondary bacterial systematic infections (mainly streptococcal and staphylococcal), hemorrhagic conditions and cardiovascular involvement (myocarditis). In the USA, during a period of 25 years (1970–1994) the average number of annual deaths due to varicella was 105 (rate 0.04/100,000) [Meyer et al. 2000]. Increased mortality rates are observed in adults older than 20 years old with a 25-fold higher death risk compared with children 1–4 years old (case-fatality rate: 21.3 and 0.8/100,000 cases, respectively) [Choo et al. 1995]. In Europe, the overall annual death rate is below 0.05/100,000 cases but again adults have significant higher mortality when compared to children [Boelle and Hanslik, 2002; Bonanni et al. 2009]. In England and Wales the rate is 0.04–0.05/100,000 per year [Rawson et al. 2001], in France 0.04/100,000 per year [Deguen et al. 1998; Dubos et al. 2007], in Germany 0.08/100,000 annually [Ziebold et al. 2001].

VZV vaccine successes

Varicella vaccine effectiveness in the USA

In the USA, universal varicella vaccination was first implemented in 1995. Initially one dose of varicella vaccine was recommended for all toddlers 12–18 months of age, while catch-up vaccination for all susceptible children <12 years of age was also recommended [ACIP, 1996]. Vaccination coverage increased in children under 19–35 months old from <30% in 1997 to >80% in 2006 [Marin et al. 2007]. Importantly, studies indicated that the varicella vaccine coverage did not differ by ethnicity or race [Luman et al. 2006]. Although prospective data on varicella incidence was not available since varicella infection was not reportable, significant reduction of varicella incidence was noted in two regions with active surveillance. Compared with 1995 (pre-vaccination era) a decrease of 77% and 90% were noted by 2000 and 2005, respectively [Guris et al. 2008; Seward et al. 2002]. Although the largest decrease was observed among children 1–9 years of age, other age groups were also protected by herd immunity and varicella rates decreased in adults as well [Marin et al. 2008; Seward et al. 2002]. Importantly, a decrease by almost 90% in the incidence of varicella was noted in infants, a particularly vulnerable group ineligible for vaccination [Chaves et al. 2011]. Moreover, during the first decade after varicella implementation a significant decrease in varicella associated morbidity, hospitalization and mortality were noted [Davis et al. 2004; Marin et al. 2011; Nguyen et al. 2005; Shah et al. 2010; Zhou et al. 2005]. Ambulatory visits due to varicella significantly decreased by 66% from 106.6 to 36.4/100,000 population and as expected this was mostly evident in the age group mainly affected, i.e. young children 1–4 years old [Shah et al. 2010]. Moreover, hospitalization rates decreased significantly [Dubos et al. 2007; Reynolds et al. 2008; Zhou et al. 2005]. As hospitalizations rates decreased to a greater extent among children when compared with adults, consequently, an increase in the proportion of adult cases was observed [Zhou et al. 2005]. The overall medical expenditure associated with varicella infection was also significantly decreased [Marin et al. 2008].

Despite these successes, outbreaks of varicella continued to occur despite the high vaccination coverage achieved. This was mainly due to breakthrough disease defined as a usually mild form of varicella occurring in a child with a documented vaccination against varicella at least 42 days prior to the eruption of the characteristic rash [Chaves et al. 2007]. However, it soon became clear that children with breakthrough disease were contagious and could transmit the virus to susceptible peers. Outbreaks of breakthrough varicella among vaccinated children in daycare centers and schools were reported in several US states since the introduction of the one-dose universal vaccination program. One-dose varicella vaccine effectiveness during these outbreaks was as low as 44%, but ranged from 80% to 89% [Marin et al. 2008]. This was not significant different from that described in non-placebo-controlled pre-licensure trials while a review of post-licensure studies of vaccine effectiveness found a median vaccine effectiveness of 84.5% for preventing all disease [Seward et al. 2008]. Based on clinical presentation it is difficult to distinguish between primary and secondary vaccine failure. Primary vaccine failure represents failure to mount a protective immune response after vaccination, whereas secondary vaccine failure is the gradual waning of immunity over time [Bonanni et al. 2013]. There have been many studies trying to distinguish whether breakthrough disease is due to primary or secondary vaccine failure as described more in detail below. In addition, several studies tried to identify risk factors associated with varicella vaccine effectiveness during outbreaks [Marin et al. 2008]. It has been supported that vaccination at a younger age, time since vaccination, vaccination within 28 days post-MMR and a history of asthma, eczema or steroid intake may be associated with varicella vaccine failure [Bayer et al. 2007; Black et al. 2008; Galil et al. 2002b; Marin et al. 2008; Silber et al. 2007; Verstraeten et al. 2003]. Moreover, commercially available most serologic tests lack sufficient sensitivity and specificity while among tests currently in use, only FAMA, a labor intensive test that cannot be automated, has been shown to correlate well with protective antibodies from both natural and vaccine-induced immunity [Breuer et al. 2008]. Over the first decade of varicella vaccine implementation, data from active surveillance revealed that the proportion of cases that occurred in vaccinated children significantly increased reaching 60% of cases in 2004. In addition, the age distribution of varicella cases was shifted to older children, since the peak age moved from 3–6 years old to older age groups. More specifically, it was noted that the peak age was between 6–9 years and 9–12 years for vaccinated and unvaccinated children, respectively [Chaves et al. 2007].

Therefore a two-dose childhood varicella vaccination schedule was recommended in 2006 by the Advisory Committee on Immunization Practices and the American Academy of Pediatrics [AAP, 2007; Marin et al. 2007]. The recommendations included a first dose between 12 and 15 months of age and a second dose to be administered between 4 and 6 years of age. Moreover, a second dose was recommended to be given as a catch-up dose to all those (children, adolescents, and adults) who were previously vaccinated with a single dose. The recommendation of a second dose was supported by previous data indicating that the second dose of varicella vaccine produces an improved humoral and cellular immune response that correlates with improved protection against disease [Kuter et al. 2004; Watson et al. 1995a, 1995b]. More importantly, a post-licensure clinical trial estimated that the risk for breakthrough disease was 3.3-fold lower among those children receiving two doses of varicella vaccine [Kuter et al. 2004]. Finally, most recently a case control study estimated the two doses vaccine effectiveness as 98.3% while the matched odds ratio for two doses versus one dose of the vaccine was 0.053 [Shapiro et al. 2011].

Varicella vaccine effectiveness in areas outside USA

In 1998, the WHO recommended that routine childhood varicella vaccination should be considered in countries where the disease is considered an important public health and socioeconomic problem. The WHO stressed that in areas where vaccination is implemented it will be necessary to achieve and maintain a high vaccine coverage in order to avoid disease shift to older age groups [WHO, 1998]. Universal varicella vaccination has been implemented by a few more countries since then including Australia, Canada, Germany, Greece, Qatar, Republic of Korea, Saudi Arabia, Taiwan, Uruguay and parts of Italy (Sicily) and Spain (Autonomous Community of Madrid) [Bonanni et al. 2009]. To date there has been evidence showing a significant decline in the varicella incidence from a few of those countries. In Australia, where the vaccine has been available since 1999 but only recently became publically funded (2005) data has indicated a 7% decline in varicella associated hospitalization between 2000 and 2007, which was even higher among children <5 years of age [Carville et al. 2010]. Active surveillance data from Canada has shown that hospitalization rates have decreased by 80–88% depending on the length of the universal vaccination program [Tan et al. 2012]. In Germany varicella vaccination of all toddlers was implemented in 2004 while active surveillance was started in 2005. Sentinel data from April 2005 to March 2009 showed a reduction of 55% of varicella cases in all ages, 63% in the age group 0–4 years and 38% in 5–9 year olds [Siedler and Arndt, 2010]. Moreover, using a multivariate time-series regression model, the effectiveness of one-dose vaccine administered during the second year of life was estimated as 83.2% (95% CI 80.2–85.7) [Hohle et al. 2011]. In Greece, data from a tertiary pediatric hospital in Metropolitan Athens indicated that the incidence of varicella associated ambulatory visits significantly decreased by 73.6% during the post-licensure period [Critselis et al. 2012b]. Notably, however, the incidence remained unchanged in children >10 years of age as well as in non-Greek and Roma children. These observations require attention to ensure that high vaccination coverage is achieved in susceptible adolescents and underserved children. On the other hand, in Sicily, a two-cohort universal vaccination program was implemented aiming to obtain high vaccine coverage in toddlers in their second year of life as well as susceptible adolescents [Giammanco et al. 2009]. Moreover, a surveillance study involving family pediatricians showed a significant decline in incidence rates from 2004 to 2009 involving all age groups. Finally, data from Uruguay have shown that 6 years after the introduction of varicella vaccine in routine immunization at the age of 12 months, hospitalization rates and ambulatory visits were decreased by 81% and 87%, respectively [Quian et al. 2008].

Challenges in varicella vaccine

Universal VZV vaccination has been delayed in many countries throughout the world. This is due to several reasons, including fear for an upward shift in the peak of age of the disease and fear of an increase in HZ incidence due to elimination of the circulation of the virus. Only few countries have mandatory reporting of varicella cases making comparisons between studies difficult, due to differences in surveillance practices and nations’ policies. Moreover as a result, cost-effectiveness studies evaluating universal childhood varicella vaccination programs are hard to interpret. Major concerns and challenges regarding varicella vaccination are further analyzed in the following paragraphs.

Fear of age shift of varicella cases to older age groups

Recent data from countries where varicella vaccination has been implemented indicate that the burden of varicella (varicella-related morbidity and mortality) has decreased substantially after the introduction of the vaccination programs almost in all age groups. As the highest decline of the incidence is recorded mostly in children <10 years of age, adolescents and young adults may be more susceptible to the disease while the possibility of outbreaks rises [Marin et al. 2008]. Over the past few years, data from the USA suggest an upward shift in the age distribution of varicella. Data from the 10-year varicella surveillance in Antelope Valley indicate that a shift in peak varicella incidence occurred over time from 3–6 year olds (in 1995) to 9–11 year olds (in 2004) [Chaves et al. 2007; Guris et al. 2008; Miller et al. 1993; Seward et al. 2002; Sloan and Burlison, 1992]. Consequently, the proportion of complications may increases as clinical presentation is more severe in this age group. However, it should be noted and stressed that to date the overall rates of adolescents and adults are declining [Seward et al. 2002; Chaves et al. 2007]. Surveillance data from Germany reveal reduced VZV incidence in all age groups [Siedler and Arndt, 2010]. Post-vaccination data from Uruguay reveal no change in age epidemiology [Quian et al. 2008]. Data from Slovenia, where vaccination coverage is low, have shown a downward shift in the age of varicella infection towards pre-school age with highest incidence at 3 years old [Socan and Blasko, 2007].

Data from Mediterranean countries reveal a similar picture of epidemiological alterations [Bonanni et al. 2009; Pinot de Moira and Nardone, 2005]. More specifically, data from Greece indicate high susceptibility in adolescence which may lead to an upwards shift in the future [Katsafadou et al. 2009]. Epidemiological data from Spain are confusing due to the high number of immigrants in the population, revealing a group with high susceptibility in childhood and another with greater susceptibility in adulthood [Valerio et al. 2009]. Finally, results after 5 years of universal vaccination in Sicily, one of the three Italian region which have introduced vaccination programs, do not suggest any shift in the epidemiology of varicella [Giammanco et al. 2009].

It is generally believed that adolescents and adults may be protected by decreasing circulating VZV in early childhood [Giammanco et al. 2009]. In countries, where less than 90% of children are covered by universal vaccination, VZV infection is not completely eradicated and therefore peak incidence age may increase from childhood to young adults which may suffer from serious complications [Doerr, 2013]. This expected shift is not a cause for concern, as long as the overall rates in adults are declining [Marin et al. 2008; Seward et al. 2002]. In countries that introduce universal varicella vaccination, continuous surveillance will be necessary to assess the need for catch-up vaccination in specific populations at risk.

Fear of HZ incidence increase among naturally infected individuals

HZ occurs in 10–20% of immune subjects and mainly affects older age groups, with the majority of cases involving individuals >50 years of age [Gnann and Whitley, 2002]. The major risk factor for HZ is the reduced T-cell-mediated immunity to VZV. Varicella infection as well as the administration of a varicella vaccine generates VZV-specific humoral and cellular immunity which protects from following re-exposure to VZV [Weinberg et al. 2010]. When these responses decline, as in the elderly and immunosuppressed individuals, reactivation of VZV by means of HZ is possible. These essential immune responses are boosted by the VZV vaccine developed to prevent HZ [Weinberg and Levin, 2010].

Re-exposure to VZV through contact with an infected person possibly protects latently infected individuals against HZ [Brisson and Edmunds, 2002; Jumaan et al. 2005]. Therefore, in areas with universal varicella vaccination, there is a concern that HZ incidence will increase among those with pre-existing natural immunity since their opportunity for re-exposure will significantly diminish [Brisson and Edmunds, 2002]. However, a rise in HZ incidence has been observed in countries in the absence of a varicella vaccination program (Canada and the United Kingdom), while in the USA, the age-specific HZ incidence has remained stable despite vaccine-associated decrease of varicella and does not differ between states with high and low varicella coverage [Brisson et al. 2001; Jumaan et al. 2005; Leung et al. 2011; Reynolds et al. 2008]. In addition, in two recent retrospective case-control studies, HZ incidence was not associated with varicella contacts [Rimland and Moanna, 2010; Yih et al. 2005].

Recently, Brisson and colleagues proposed a mathematical model in order to predict the impact of a two-dose varicella vaccine program on the incidence of HZ. The model showed that a two-dose of varicella live attenuated vaccine program will initially lead to an increase (~30%) of the incidence of HZ. Nevertheless, a reduction will follow as the proportion of individuals with a history of VZV infection will be limited [Brisson et al. 2010].

However, over the past decade it has become evident that although some studies have indicated a slight increase of HZ incidence in areas where universal varicella vaccination has been implemented, this issue still remains controversial. In addition, as mentioned above, it has been shown that HZ incidence has increased in many areas in the absence of universal varicella vaccination. The main conclusions from studies examining HZ incidence in countries where universal vaccination has been implemented are summarized in Table 1.

Table 1.

HZ incidence changes in countries where universal vaccination has been implemented.

Study	Country	Year of implementation of vaccination	Author’s conclusions	Increase in HZ incidence
Goldman [2005]	USA	1995	No increase seen in HZ incidence pre- and post-varicella vaccination licensure	No
Jumaan et al. [2005]	USA	1995	No increase seen in HZ incidence following vaccination-associated decrease in varicella	No
Carville et al. [2010]	Australia	2005	HZ hospitalization rates increased before the introduction of the varicella vaccine	No
Leung et al. [2011]	USA	1995	Increase in HZ incidence seen prior to varicella vaccination program introduction	No
Tanuseputro et al. [2011]	Canada	2000	No increase seen in HZ incidence for the overall population, a decrease for children <9 years.	No
Yih et al. [2005]	USA	1995	Increase in HZ incidence; widespread varicella vaccination one of several possible explanations	Yes
Patel et al. [2008]	USA	1995	Increase in HZ-related hospital discharges due to varicella universal vaccination	Yes
Civen et al. [2009]	USA	1995	Increase in HZ incidence in 10–19 year olds following varicella URV	Yes
Rimland and Moanna [2010]	USA	1995	Increasing incidence of HZ among veterans	Yes
Nelson et al. [2010]	Australia	2005	Evidence of increasing frequency of HZ management in Australian general practice since the introduction of a varicella vaccine	Yes
Jardine et al. [2011]	Australia	2005	Increasing trends in HZ may contributed directly to varicella immunization program	Yes
Ultsch et al. [2011]	Germany	2004	Increase in HZ incidence; needed to monitor the impact of VZV vaccinations	Yes

HZ, herpes zoster, URV, universal vaccination.

It has become evident that no systematic significant incidence of HZ has been observed. Exposure to wild VZV by travelling to areas where varicella vaccine has not been implemented as well as importation through immigration may play a minor role.

Importantly, however, it has now become evident that patients with HZ are an important source of transmission of wild varicella virus in the community [Bloch and Johnson, 2012]. It is well known that HZ patients, even those with localized lesions in covered body areas, may transmit VZV to their contacts, either through direct contact or via aerosolized virus [Josephson and Gombert, 1988; Lopez et al. 2008; Schmid and Jumaan, 2010; Suzuki et al. 2004]. A recent retrospective analysis of data collected from active varicella and HZ surveillance reported from schools and daycare facilities in Philadelphia over a 7-year period clearly indicated that patients with HZ transmit VZV to their contacts, contributing significantly to varicella morbidity [Viner et al. 2012]. Interestingly, it was documented that 15% of varicella and 9% of HZ cases transmitted VZV infection to a susceptible individual in their environment resulting in varicella cases. The severity of these varicella cases was similar for those exposed to HZ and those exposed to varicella. Furthermore, recent studies have clearly indicated that most patients with HZ have viremia which may persist for months, while VZV DNA viral load is associated with longer duration of symptoms and risk factors for PHN [Quinlivan et al. 2007, 2011]. Moreover, VZV DNA has been detected in the saliva of 100%, 52% and 59% of patients with acute HZ, Ramsey Hunt syndrome and zoster sine herpete, respectively [Furuta et al. 2001; Nagel et al. 2011]. Finally, prospective molecular epidemiologic data from UK, using genotyping methods on VZV DNA isolated from saliva in children with varicella, provided further evidence supporting the hypothesis that HZ patients are an important source of VZV transmission in the community. Clade 5 viruses (non-European virus) were significantly more prevalent among nonwhite children than white children with varicella possibly reflecting population mixing patterns, with susceptible children more likely to be exposed in their community, household, or daycare to others of the same ethnicity and their indigenous viruses [Quinlivan et al. 2013].

In addition, the role of endogenous boosting might have been underestimated. Although, subclinical reactivation of VZV has been postulated since Hope–Simpsons hypothesis, recent data has indeed revealed that this phenomenon is common and potentially provides significant protection against HZ. Detection of VZV DNA in blood has been well described. Cell-associated and whole-blood VZV subclinical viremia have been detected in 9% of healthy blood donors, 17% of immunocompromised patients and 27% of healthy elderly subjects [Devlin et al. 1992; Kimura et al. 2000; Ljungman et al. 1986; Schunemann et al. 1998; Wilson et al. 1992]. Moreover, salivary shedding of VZV DNA has been detected in a third of healthy astronauts during and after space flights supporting the hypothesis that asymptomatic VZV reactivation occurs more often than considered previously, and that it may occur in response to stress [Mehta et al. 2004]. More importantly, viable virus has been detected indicating that subclinical reactivation not only provides boosting of cell-mediated immunity in the individual, but also that viral transmission to their contacts may follow [Cohrs et al. 2008]. Most recently, in a small prospective study, VZV reactivation was observed in 17% of children hospitalized in ICU. Among those severely stressed children, only those post natural varicella infection reactivated, while none of the varicella-vaccinated children or healthy controls had detectable VZV DNA in any blood or saliva samples examined [Papaevangelou et al. 2013].

In conclusion, these two phenomena, namely varicella virus transmission from HZ cases and endogenous boosting, had not been included in the mathematic models exploring HZ incidence in the era of universal vaccination and might explain the absence of the predicted (up to 30%) HZ increase [Brisson et al. 2000, 2010].

Cost-effectiveness studies evaluating the introduction of varicella vaccine

Few economic analyses conducted in the USA, Australia and Europe have shown varicella vaccination programs to be cost-effective from a healthcare perspective and even cost saving from a societal perspective [Beutels et al. 1996; Bonanni et al. 2008; Coudeville et al. 1999; Diez Domingo et al. 1999; Scuffham et al. 1999; Thiry et al. 2004]. Most of these studies, however, performed the economic evaluation using a one-dose varicella vaccine immunization scheme without taking into account breakthrough varicella infection or potential increase of zoster incidence [Rozenbaum et al. 2008]. It is clear that if the doubling of cost by the two-dose schedule is not compensated for by a reduction in the cost of vaccine failures, it will negatively impact the vaccination program’s cost-effectiveness. Indeed, Zhou and colleagues have shown that the two-dose regimen is cost-effective when compared with no vaccination but not when compared with the one-dose regimen [Zhou et al. 2008]. Moreover, it is important to understand that there is a considerable heterogeneity in the methodologies used in different studies which have an impact on their results [Soarez et al. 2009]. More specifically, the type of model used (static versus dynamic), the perspective examined (whether society’s perspective is added to that of providers), the inclusion of the herd immunity effect and vaccination coverage and the different amounts used for vaccine price and parental wages also had a significant impact on the computed results. Finally, other than the perspective adopted, other factors such as public opinion and public health priorities may also have an influence on the interpretation of such studies.

Universal versus high-risk population vaccination

As mentioned previously, many European public health authorities have elected to implement targeted varicella vaccination of high-risk populations, mainly focusing on susceptible adolescents and household contacts of immunocompromised patients [Bonanni et al. 2009]. This strategy prevents varicella in older age groups where morbidity and mortality are significantly higher and in childbearing women, decreasing the risk of congenital and perinatal varicella [Sengupta et al. 2008]. Furthermore, minimizes alleged risk of future peak age incidence shift to older age and addresses fear of HZ incidence increase. However, targeted population vaccination has failed multiple times in the recent past, as for example in HBV and rubella vaccination [Mongua-Rodriguez et al. 2013; Van Damme et al. 1997]. This is mainly due to difficulties in reaching populations at risk. Specifically, when discussing varicella vaccination one has to face the challenge of reaching adolescents since it has been well documented that this is a group with poor preventive care [McCauley et al. 2008; Wong et al. 2013]. Therefore, this strategy remains an option solely in countries with very well-organized catch-up vaccination programs or school vaccination. This is particularly problematic in areas such as Southern Europe where a higher percentage of adolescents are susceptible [Gabutti et al. 2001; Katsafadou et al. 2008]. Moreover, this strategy may not be as effective in preventing infection in infants, a particularly vulnerable group [Boelle and Hanslik, 2002].

Dose interval in universal varicella vaccination

In most countries recommending varicella vaccination, the first dose (either using the monovalent vaccine or MMRV) is administered at 12–15 months of age [Bonanni et al. 2009]. The second dose, however, may be administered either during the second year of life, at least 1 month after the first dose (Germany) or at the age of 4–6 years of age (USA and most other countries). Both schedules have advantages and disadvantages. The main advantage of administering both doses during the second year of life is the increased vaccine coverage and the reduced risk of breakthrough disease [Bonanni et al. 2009]. This is more apparent if one postulates that breakthrough disease is rather due to primary vaccine failure (= no take) than secondary vaccine failure (= waning of immunity). This question was addressed in a recently published review by Bonanni and colleagues [Bonanni et al. 2013]. A relatively high rate of primary vaccine failure amongst recipients of one-dose varicella vaccine and limited convincing evidence of secondary vaccine failure was concluded. This supports the administration of a second dose of varicella vaccine with a short interval aiming to reduce the number of subjects remaining susceptible to varicella. This is most relevant in countries that plan to or have recently introduced varicella vaccination where wild virus is still prevalent and therefore preventing breakthrough disease is especially important. Prospective data collected from Northern California (Kaiser Permanente) clearly indicates that breakthrough varicella rates were higher over the first 4 years post-varicella implementation and were reduced thereafter even before the introduction of the second vaccine dose [Baxter et al. 2013].

Conversely, when the period between the two doses increases to 2–6 years, breakthrough cases of varicella can be expected, especially during the first years post-universal vaccination implementation. This could not only result in outbreaks in daycare centers and schools but also in transmission to susceptible adolescents and adults. Furthermore, once breakthrough disease occurs the subject might lose the advantage of low HZ risk later in life. However, consideration of potential disturbance of vaccine and associated routine doctors’ visits schedule is very important when planning the introduction of new vaccines in immunization schedules.

Conclusion

Varicella-associated morbidity and mortality can be effectively prevented by the implementation of universal varicella vaccination. Targeted vaccination of susceptible high-risk patients and/or their household contacts, recommended in many European countries, is an alternative strategy which necessitates a well-organized healthcare system. Although a slight increase in the peak incidence age of varicella has been observed post-universal varicella implementation, the incidence rates among adolescents and adults have decreased when compared with the pre-vaccination era. To avoid an age shift to older age groups it is necessary to ensure catch-up vaccination and maintain high vaccine coverage. The predicted increase of HZ incidence among naturally immune adults following varicella vaccination has not been observed, possibly because travelling, contact with HZ patients and subclinical reactivation offer greater boosting effects on the cell-mediated immunity than expected.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of interest

The authors declare no conflicts of interest in preparing this article.

References

AAP (2007) Prevention of varicella: recommendations for use of varicella vaccines in children, including a recommendation for a routine 2-dose varicella immunization schedule. Pediatrics 120: 221–231.

ACIP (1996) Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Centers for Disease Control and Prevention. MMWR Recomm Rep 45(RR-11): 1–36.

ACIP (2008) Update: recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine. MMWR Morb Mortal Wkly Rep 57: 258–260.

Aebi

Fischer

Gorgievski

Matter

Muhlemann

(2001) Age-specific seroprevalence to varicella-zoster virus: study in Swiss children and analysis of European data. Vaccine 19: 3097–3103.

Arvin

(1996) Varicella-zoster virus. Clin Microbiol Rev 9: 361–381.

Baxter

Ray

Tran

Black

Shinefield

Coplan

. (2013) Long-term effectiveness of varicella vaccine: a 14-Year, prospective cohort study. Pediatrics 131: e1389–e1396.

Bayer

Heininger

Heiligensetzer

von Kries

(2007) Metaanalysis of vaccine effectiveness in varicella outbreaks. Vaccine 25: 6655–6660.

Beutels

Clara

Tormans

Van Doorslaer

Van Damme

(1996) Costs and benefits of routine varicella vaccination in German children. J Infect Dis 174(Suppl. 3): S335–S341.

Black

Ray

Shinefield

Saddier

Nikas

(2008) Lack of association between age at varicella vaccination and risk of breakthrough varicella, within the Northern California Kaiser Permanente Medical Care Program. J Infect Dis 197(Suppl. 2): S139–S142.

10.

Bloch

Johnson

(2012) Varicella zoster virus transmission in the vaccine era: unmasking the role of herpes zoster. J Infect Dis 205: 1331–1333.

11.

Boelle

Hanslik

(2002) Varicella in non-immune persons: incidence, hospitalization and mortality rates. Epidemiol Infect 129: 599–606.

12.

Bonanni

Boccalini

Bechini

Banz

(2008) Economic evaluation of varicella vaccination in Italian children and adolescents according to different intervention strategies: the burden of uncomplicated hospitalised cases. Vaccine 26: 5619–5626.

13.

Bonanni

Breuer

Gershon

Hryniewicz

Papaevangelou

. (2009) Varicella vaccination in Europe - taking the practical approach. BMC Med 7: 26.

14.

Bonanni

Gershon

Kulcsar

Papaevangelou

Rentier

. (2013) Primary versus secondary failure after varicella vaccination: implications for interval between 2 doses. Pediatr Infect Dis J 32: e305–e313.

15.

Bonhoeffer

Baer

Muehleisen

Aebi

Nadal

Schaad

. (2005) Prospective surveillance of hospitalisations associated with varicella-zoster virus infections in children and adolescents. Eur J Pediatr 164: 366–370.

16.

Breuer

Schmid

Gershon

(2008) Use and limitations of varicella-zoster virus-specific serological testing to evaluate breakthrough disease in vaccinees and to screen for susceptibility to varicella. J Infect Dis 197(Suppl. 2): S147–S151.

17.

Brisson

Edmunds

(2002) The cost-effectiveness of varicella vaccination in Canada. Vaccine 20: 1113–1125.

18.

Brisson

Edmunds

Gay

Law

De Serres

(2000) Modelling the impact of immunization on the epidemiology of varicella zoster virus. Epidemiol Infect 125: 651–669.

19.

Brisson

Edmunds

Law

Gay

Walld

Brownell

. (2001) Epidemiology of varicella zoster virus infection in Canada and the United Kingdom. Epidemiol Infect 127: 305–314.

20.

Brisson

Melkonyan

Drolet

De Serres

Thibeault

De Wals

(2010) Modeling the impact of one- and two-dose varicella vaccination on the epidemiology of varicella and zoster. Vaccine 28: 3385–3397.

21.

Carville

Riddell

Kelly

(2010) A decline in varicella but an uncertain impact on zoster following varicella vaccination in Victoria, Australia. Vaccine 28: 2532–2538.

22.

CDC (1995) Licensure of varicella virus vaccine, live. MMWR Morb Mortal Wkly Rep 44: 264.

23.

CDC (2008) Update: recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine. MMWR Morb Mortal Wkly Rep 57: 258–260.

24.

Chaves

Gargiullo

Zhang

Civen

Guris

Mascola

. (2007) Loss of vaccine-induced immunity to varicella over time. N Engl J Med 356: 1121–1129.

25.

Chaves

Haber

Walton

Wise

Izurieta

Schmid

. (2008) 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 197(Suppl. 2): S170–S177.

26.

Chaves

Lopez

Watson

Civen

Watson

Mascola

. (2011) Varicella in infants after implementation of the US varicella vaccination program. Pediatrics 128: 1071–1077.

27.

Chen

Gershon

Lungu

Gershon

(2003) Latent and lytic infection of isolated guinea pig enteric ganglia by varicella zoster virus. J Med Virol 70(Suppl. 1): S71–S78.

28.

Choo

Donahue

Manson

Platt

(1995) The epidemiology of varicella and its complications. J Infect Dis 172: 706–712.

29.

Civen

Chaves

Jumaan

Mascola

Gargiullo

. (2009) The incidence and clinical characteristics of herpes zoster among children and adolescents after implementation of varicella vaccination. Pediatr Infect Dis J 28: 954–959.

30.

Cohrs

Mehta

Schmid

Gilden

Pierson

(2008) Asymptomatic reactivation and shed of infectious varicella zoster virus in astronauts. J Med Virol 80: 1116–1122.

31.

Coudeville

Paree

Lebrun

Sailly

(1999) The value of varicella vaccination in healthy children: cost-benefit analysis of the situation in France. Vaccine 17: 142–151.

32.

Critselis

Nastos

Theodoridou

Tsolia

Hadjichristodoulou

. (2012a) Time trends in pediatric hospitalizations for varicella infection are associated with climatic changes: a 22-year retrospective study in a tertiary Greek referral center. PLoS One 7(12): e52016.

33.

Critselis

Nastos

Theodoridou

Tsolia

Papaevangelou

(2012b) Association between variations in the epidemiology of varicella infection and climate change in a temperate region. In 30th Annual Meeting of the European Society For Paediatric Infectious Diseases, 8–12 May 2012, Thessaloniki, Greece.

34.

Davis

Patel

Gebremariam

(2004) Decline in varicella-related hospitalizations and expenditures for children and adults after introduction of varicella vaccine in the United States. Pediatrics 114: 786–792.

35.

Deguen

Chau

Flahault

(1998) Epidemiology of chickenpox in France (1991–1995). J Epidemiol Community Health 52(Suppl. 1): 46S-49S.

36.

Devlin

Gilden

Mahalingam

Dueland

Cohrs

(1992) Peripheral blood mononuclear cells of the elderly contain varicella-zoster virus DNA. J Infect Dis 165: 619–622.

37.

Diez Domingo

Ridao

Latour

Ballester

Morant

(1999) A cost benefit analysis of routine varicella vaccination in Spain. Vaccine 17: 1306–1311.

38.

Doerr

(2013) Progress in VZV vaccination? Some concerns. Med Microbiol Immunol, in press.

39.

Dubos

Grandbastien

Hue

, Hospital Network for Evaluating Management of Common Childhood Diseases and Martinot, A. (2007) Epidemiology of hospital admissions for paediatric varicella infections: a one-year prospective survey in the pre-vaccine era. Epidemiol Infect 135: 131–138.

40.

Enders

Miller

Cradock-Watson

Bolley

Ridehalgh

(1994) Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet 343: 1548–1551.

41.

Furuta

Ohtani

Sawa

Fukuda

Inuyama

(2001) Quantitation of varicella-zoster virus DNA in patients with Ramsay Hunt syndrome and zoster sine herpete. J Clin Microbiol 39: 2856–2859.

42.

Gabutti

Penna

Rossi

Salmaso

Rota

Bella

. (2001) The seroepidemiology of varicella in Italy. Epidemiol Infect 126: 433–440.

43.

Galil

Brown

Lin

Seward

(2002a) Hospitalizations for varicella in the United States, 1988 to 1999. Pediatr Infect Dis J 21: 931–935.

44.

Galil

Fair

Mountcastle

Britz

Seward

(2002b) Younger age at vaccination may increase risk of varicella vaccine failure. J Infect Dis 186: 102–105.

45.

Garnett

Cox

Bundy

Didier

St Catharine

(1993) The age of infection with varicella-zoster virus in St Lucia, West Indies. Epidemiol Infect 110: 361–372.

46.

Gershon

(2010) Perspectives on vaccines against varicella-zoster virus infections. Curr Top Microbiol Immunol 342: 359–372.

47.

Gershon

Levin

Weinberg

Song

LaRussa

Steinberg

. (2009) A phase I–II study of live attenuated varicella-zoster virus vaccine to boost immunity in human immunodeficiency virus-infected children with previous varicella. Pediatr Infect Dis J 28: 653–655.

48.

Gershon

Steinberg

Gelb

Galasso

Borkowsky

LaRussa

. (1984) Live attenuated varicella vaccine. Efficacy for children with leukemia in remission. JAMA 252: 355–362.

49.

Giammanco

Ciriminna

Barberi

Titone

Lo Giudice

Biasio

(2009) Universal varicella vaccination in the Sicilian paediatric population: rapid uptake of the vaccination programme and morbidity trends over five years. Euro Surveill 14(35): 19321.

50.

Gnann

Jr Whitley

(2002) Clinical practice. Herpes zoster. N Engl J Med 347: 340–346.

51.

Goldman

(2005) Universal varicella vaccination: efficacy trends and effect on herpes zoster. International journal of toxicology 24(4): 205–213.

52.

Guris

Jumaan

Mascola

Watson

Zhang

Chaves

. (2008) Changing varicella epidemiology in active surveillance sites–United States, 1995–2005. J Infect Dis 197(Suppl. 2): S71–S75.

53.

Hambleton

Gershon

(2005) Preventing varicella-zoster disease. Clin Microbiol Rev 18: 70–80.

54.

Hohle

Siedler

Bader

Ludwig

Heininger

Von Kries

(2011) Assessment of varicella vaccine effectiveness in Germany: a time-series approach. Epidemiol Infect 139: 1710–1719.

55.

Jacobsen

Ackerson

Tran

Jones

Yao

. (2009) Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting. Vaccine 27: 4656–4661.

56.

Jardine

Conaty

Vally

(2011) Herpes zoster in Australia: evidence of increase in incidence in adults attributable to varicella immunization? Epidemiology and Infection 139(5): 658–665.

57.

Josephson

Gombert

(1988) Airborne transmission of nosocomial varicella from localized zoster. J Infect Dis 158: 238–241.

58.

Jumaan

Jackson

Bohlke

Galil

Seward

(2005) Incidence of herpes zoster, before and after varicella-vaccination-associated decreases in the incidence of varicella, 1992–2002. J Infect Dis 191: 2002–2007.

59.

Katsafadou

Ferentinos

Constantopoulos

Papaevangelou

(2008) The epidemiology of varicella in school-aged Greek children before the implementation of universal vaccination. Eur J Clin Microbiol Infect Dis 27: 223–226.

60.

Katsafadou

Kallergi

Ferentinos

Goulioti

Foustoukou

Papaevangelou

(2009) Presumptive varicella vaccination is warranted in Greek adolescents lacking a history of disease or household exposure. Eur J Pediatr 168: 23–25.

61.

Kimura

Kido

Ozaki

Tanaka

Ito

Williams

. (2000) Comparison of quantitations of viral load in varicella and zoster. J Clin Microbiol 38: 2447–2449.

62.

Klein

Fireman

Yih

Lewis

Kulldorff

Ray

. (2010) Measles–mumps–rubella–varicella combination vaccine and the risk of febrile seizures. Pediatrics 126(1): e1–e8.

63.

Kuter

Matthews

Shinefield

Black

Dennehy

Watson

. (2004) Ten year follow-up of healthy children who received one or two injections of varicella vaccine. Pediatr Infect Dis J 23: 132–137.

64.

Lee

(1998) Review of varicella zoster seroepidemiology in India and Southeast Asia. Trop Med Int Health 3: 886–890.

65.

Leung

Harpaz

Molinari

Jumaan

Zhou

(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.

66.

Levin

Dahl

Weinberg

Giller

Patel

Krause

(2003) Development of resistance to acyclovir during chronic infection with the Oka vaccine strain of varicella-zoster virus, in an immunosuppressed child. J Infect Dis 188: 954–959.

67.

Levy

Orange

Hibberd

Steinberg

LaRussa

Weinberg

. (2003) Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells. J Infect Dis 188: 948–953.

68.

Liese

Grote

Rosenfeld

Fischer

Belohradsky

v Kries

for the ESPED Varicella Study Group (2008) The burden of varicella complications before the introduction of routine varicella vaccination in Germany. Pediatr Infect Dis J 27: 119–124.

69.

Liyanage

Fernando

Malavige

Mallikahewa

Sivayogan

Jiffry

. (2007) Seroprevalence of varicella zoster virus infections in Colombo district, Sri Lanka. Indian J Med Sci 61: 128–134.

70.

Ljungman

Lonnqvist

Gahrton

Ringden

Sundqvist

Wahren

(1986) Clinical and subclinical reactivations of varicella-zoster virus in immunocompromised patients. J Infect Dis 153: 840–847.

71.

Lolekha

Tanthiphabha

Sornchai

Kosuwan

Sutra

Warachit

. (2001) Effect of climatic factors and population density on varicella zoster virus epidemiology within a tropical country. Am J Trop Med Hyg 64: 131–136.

72.

Lopez

Kolasa

Seward

(2008) Status of school entry requirements for varicella vaccination and vaccination coverage 11 years after implementation of the varicella vaccination program. J Infect Dis 197(Suppl. 2): S76–S81.

73.

Luman

Ching

Jumaan

Seward

(2006) Uptake of varicella vaccination among young children in the United States: a success story in eliminating racial and ethnic disparities. Pediatrics 117: 999–1008.

74.

Mandal

Mukherjee

Murphy

Mukherjee

Naik

(1998) Adult susceptibility to varicella in the tropics is a rural phenomenon due to the lack of previous exposure. J Infect Dis 178(Suppl. 1): S52–S54.

75.

Marin

Guris

Chaves

Schmid

Seward

for the Advisory Committee on Immunization Practices . (2007) Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 56(RR-4): 1–40.

76.

Marin

Watson

Chaves

Civen

Watson

Zhang

. (2008) Varicella among adults: data from an active surveillance project, 1995–2005. J Infect Dis 197(Suppl. 2): S94–S100.

77.

Marin

Zhang

Seward

(2011) Near elimination of varicella deaths in the US after implementation of the vaccination program. Pediatrics 128: 214–220.

78.

McCauley

Stokley

Stevenson

Fishbein

(2008) Adolescent vaccination: coverage achieved by ages 13–15 years, and vaccinations received as recommended during ages 11–12 years, National Health Interview Survey 1997–2003. J Adolesc Health 43: 540–547.

79.

Mehta

Cohrs

Forghani

Zerbe

Gilden

Pierson

(2004) Stress-induced subclinical reactivation of varicella zoster virus in astronauts. J Med Virol 72: 174–179.

80.

Meyer

Seward

Jumaan

Wharton

(2000) Varicella mortality: trends before vaccine licensure in the United States, 1970–1994. J Infect Dis 182: 383–390.

81.

Miller

Vardien

Farrington

(1993) Shift in age in chickenpox. Lancet 341: 308–309.

82.

Mongua-Rodriguez

Diaz-Ortega

Garcia-Garcia

Pina-Pozas

Ferreira-Guerrero

Delgado-Sanchez

. (2013) A systematic review of rubella vaccination strategies implemented in the Americas: impact on the incidence and seroprevalence rates of rubella and congenital rubella syndrome. Vaccine 31: 2145–2151.

83.

Nader

Bergen

Sharp

Arvin

(1995) Age-related differences in cell-mediated immunity to varicella-zoster virus among children and adults immunized with live attenuated varicella vaccine. J Infect Dis 171: 13–17.

84.

Nagel

Choe

Cohrs

Traktinskiy

Sorensen

Mehta

. (2011) Persistence of varicella zoster virus DNA in saliva after herpes zoster. J Infect Dis 204: 820–824.

85.

Nardone

de Ory

Carton

Cohen

van Damme

Davidkin

. (2007) The comparative sero-epidemiology of varicella zoster virus in 11 countries in the European region. Vaccine 25: 7866–7872.

86.

Nelson

Britt

Harrison

(2010) Evidence of increasing frequency of herpes zoster management in Australian general practice since the introduction of a varicella vaccine. The Medical journal of Australia 193(2): 110–113.

87.

Ngai

Staehle

Kuter

Cyanovich

Cho

Matthews

. (1996) Safety and immunogenicity of one vs. two injections of Oka/Merck varicella vaccine in healthy children. Pediatr Infect Dis J 15: 49–54.

88.

Nguyen

Jumaan

Seward

(2005) Decline in mortality due to varicella after implementation of varicella vaccination in the United States. N Engl J Med 352: 450–458.

89.

Papaevangelou

Quinlivan

Lockwood

Papaloukas

Sideri

Critselis

. (2013) Subclinical VZV reactivation in immunocompetent children hospitalized in the ICU associated with prolonged fever duration. Clin Microbiol Infect 19: E245–E251.

90.

Paryani

Arvin

(1986) Intrauterine infection with varicella-zoster virus after maternal varicella. N Engl J Med 314: 1542–1546.

91.

Patel

Gebremariam

Davis

(2008) Herpes zoster-related hospitalizations and expenditures before and after introduction of the varicella vaccine in the United States. Infection Control and Hospital Epidemiology: The official journal of the Society of Hospital Epidemiologists of America 29(12): 1157–1163.

92.

Pinot de Moira

Nardone

(2005) Varicella zoster virus vaccination policies and surveillance strategies in Europe. Euro Surveill 10: 43–45.

93.

Plotkin

Arbetter

Starr

(1985) The future of varicella vaccine. Postgrad Med J 61(Suppl. 4): 155–162.

94.

Pollock

Golding

(1993) Social epidemiology of chickenpox in two British national cohorts. J Epidemiol Community Health 47: 274–281.

95.

Provost

Krah

Kuter

Morton

Schofield

Wasmuth

. (1991) Antibody assays suitable for assessing immune responses to live varicella vaccine. Vaccine 9: 111–116.

96.

Quian

Ruttimann

Romero

Dall’Orso

Cerisola

Breuer

. (2008) Impact of universal varicella vaccination on 1-year-olds in Uruguay: 1997–2005. Arch Dis Child 93: 845–850.

97.

Quinlivan

Sengupta

Papaevangelou

Sauerbrei

Grillner

Rousseva

. (2013) Use of oral fluid to examine the molecular epidemiology of varicella zoster virus in the United Kingdom and continental Europe. J Infect Dis 207: 588–593.

98.

Quinlivan

Ayres

Ran

McElwaine

Leedham-Green

Scott

. (2007) Effect of viral load on the outcome of herpes zoster. J Clin Microbiol 45: 3909–3914.

99.

Quinlivan

Ayres

Kelly

Parker

Scott

Johnson

. (2011) Persistence of varicella-zoster virus viraemia in patients with herpes zoster. J Clin Virol 50: 130–135.

100.

Rawson

Crampin

Noah

(2001) Deaths from chickenpox in England and Wales 1995–7: analysis of routine mortality data. BMJ 323: 1091–1093.

101.

Reynolds

Watson

Plott-Adams

Jumaan

Galil

Maupin

. (2008) Epidemiology of varicella hospitalizations in the United States, 1995–2005. J Infect Dis 197(Suppl. 2): S120–S126.

102.

Rimland

Moanna

(2010) Increasing incidence of herpes zoster among Veterans. Clin Infect Dis 50: 1000–1005.

103.

Ross

(1962) Modification of chicken pox in family contacts by administration of gamma globulin. N Engl J Med 267: 369–376.

104.

Rozenbaum

van Hoek

Vegter

Postma

(2008) Cost-effectiveness of varicella vaccination programs: an update of the literature. Expert Rev Vaccines 7: 753–782.

105.

Schmid

Jumaan

(2010) Impact of varicella vaccine on varicella-zoster virus dynamics. Clin Microbiol Rev 23: 202–217.

106.

Schunemann

Mainka

Wolff

(1998) Subclinical reactivation of varicella-zoster virus in immunocompromised and immunocompetent individuals. Intervirology 41: 98–102.

107.

Scuffham

Lowin

Burgess

(1999) The cost-effectiveness of varicella vaccine programs for Australia. Vaccine 18: 407–415.

108.

Sengupta

Booy

Schmitt

Peltola

Van-Damme

Schumacher

. (2008) Varicella vaccination in Europe: are we ready for a universal childhood programme? Eur J Pediatr 167: 47–55.

109.

Seward

Marin

Vazquez

(2008) Varicella vaccine effectiveness in the US vaccination program: a review. J Infect Dis 197(Suppl. 2): S82–S89.

110.

Seward

Watson

Peterson

Mascola

Pelosi

Zhang

. (2002) Varicella disease after introduction of varicella vaccine in the United States, 1995–2000. JAMA 287: 606–611.

111.

Shah

Wood

Luan

Ratner

(2010) Decline in varicella-related ambulatory visits and hospitalizations in the United States since routine immunization against varicella. Pediatr Infect Dis J 29: 199–204.

112.

Shapiro

Vazquez

Esposito

Holabird

Steinberg

Dziura

. (2011) Effectiveness of 2 doses of varicella vaccine in children. J Infect Dis 203: 312–315.

113.

Siedler

Arndt

(2010) Impact of the routine varicella vaccination programme on varicella epidemiology in Germany. Euro Surveill 15(13): article 4.

114.

Silber

Chan

Wang

Matthews

Kuter

(2007) Immunogenicity of Oka/Merck varicella vaccine in children vaccinated at 12–14 months of age versus 15–23 months of age. Pediatr Infect Dis J 26: 572–576.

115.

Sloan

Burlison

(1992) Shift in age in chickenpox. Lancet 340: 974.

116.

Soarez

Novaes

Sartori

(2009) Impact of methodology on the results of economic evaluations of varicella vaccination programs: is it important for decision-making? Cad Saude Publica 25(Suppl. 3): S401–S414.

117.

Socan

Blasko

(2007) Surveillance of varicella and herpes zoster in Slovenia, 1996–2005. Euro Surveill 12(2).

118.

Suzuki

Yoshikawa

Tomitaka

Matsunaga

Asano

(2004) Detection of aerosolized varicella-zoster virus DNA in patients with localized herpes zoster. J Infect Dis 189: 1009–1012.

119.

Takahashi

Kamiya

Baba

Asano

Ozaki

Horiuchi

(1985) Clinical experience with Oka live varicella vaccine in Japan. Postgrad Med J 61(Suppl. 4): 61–67.

120.

Takahashi

Otsuka

Okuno

Asano

Yazaki

(1974) Live vaccine used to prevent the spread of varicella in children in hospital. Lancet 2: 1288–1290.

121.

Tan

Bettinger

McConnell

Scheifele

Halperin

Vaudry

. (2012) The effect of funded varicella immunization programs on varicella-related hospitalizations in IMPACT centers, Canada, 2000–2008. Pediatr Infect Dis J 31: 956–963.

122.

Tanuseputro

Zagorski

Chan

K.J.

Kwong

J.C.

(2011) Population-based incidence of herpes zoster after introduction of a publicly funded varicella vaccination program. Vaccine 29(47): 8580–8584.

123.

Thiry

Beutels

Tancredi

Romano

Zanetti

Bonanni

. (2004) An economic evaluation of varicella vaccination in Italian adolescents. Vaccine 22: 3546–3562.

124.

Tseng

Smith

Marcy

Jacobsen

(2009) Incidence of herpes zoster among children vaccinated with varicella vaccine in a prepaid health care plan in the United States, 2002–2008. Pediatr Infect Dis J 28: 1069–1072.

125.

Tseng

Tan

Chang

Wang

Yang

Liau

. (2005) A seroepidemiology study of varicella among children aged 0–12 years in Taiwan. Southeast Asian J Trop Med Public Health 36: 1201–1207.

126.

Ultsch

Siedler

Rieck

Reinhold

Krause

Wichmann

(2011) Herpes zoster in Germany: Quantifying the burden of disease. BMC Infectious Diseases 11: 173.

127.

Valerio

Escriba

Fernandez-Vazquez

Roca

Milozzi

Solsona

. (2009) Biogeographical origin and varicella risk in the adult immigration population in Catalonia, Spain (2004–2006). Euro Surveill 14(37).

128.

Van Damme

Kane

Meheus

(1997) Integration of hepatitis B vaccination into national immunisation programmes. Viral Hepatitis Prevention Board. BMJ 314: 1033–1036.

129.

Vazquez

LaRussa

Gershon

Niccolai

Muehlenbein

Steinberg

. (2004) Effectiveness over time of varicella vaccine. JAMA 291: 851–855.

130.

Verstraeten

Jumaan

Mullooly

Seward

Izurieta

DeStefano

. (2003) A retrospective cohort study of the association of varicella vaccine failure with asthma, steroid use, age at vaccination, and measles-mumps-rubella vaccination. Pediatrics 112(2): e98–e103.

131.

Viner

Perella

Lopez

Bialek

Newbern

Pierre

. (2012) Transmission of varicella zoster virus from individuals with herpes zoster or varicella in school and day care settings. J Infect Dis 205: 1336–1341.

132.

Wagenpfeil

Neiss

Banz

Wutzler

(2004) Empirical data on the varicella situation in Germany for vaccination decisions. Clin Microbiol Infect 10: 425–430.

133.

Watson

Boardman

Laufer

Piercy

Tustin

Olaleye

. (1995a) Humoral and cell-mediated immune responses in healthy children after one or two doses of varicella vaccine. Clin Infect Dis 20: 316–319.

134.

Watson

Rothstein

Bernstein

Arbeter

Arvin

Chartrand

. (1995b) Safety and cellular and humoral immune responses of a booster dose of varicella vaccine 6 years after primary immunization. J Infect Dis 172: 217–219.

135.

Weinberg

Lazar

Zerbe

Hayward

Chan

Vessey

. (2010) Influence of age and nature of primary infection on varicella-zoster virus-specific cell-mediated immune responses. J Infect Dis 201: 1024–1030.

136.

Weinberg

Levin

(2010) VZV T cell-mediated immunity. Curr Top Microbiol Immunol 342: 341–357.

137.

WHO (1998) Varicella vaccines. WHO position paper. Wkly Epidemiol Rec 73: 241–248.

138.

Wilson

Sharp

Koropchak

Ting

Arvin

(1992) Subclinical varicella-zoster virus viremia, herpes zoster, and T lymphocyte immunity to varicella-zoster viral antigens after bone marrow transplantation. J Infect Dis 165: 119–126.

139.

Wong

Taylor

Wright

Opel

Katzenellenbogen

(2013) Missed opportunities for adolescent vaccination, 2006–2011. J Adolesc Health, in press.

140.

Yawn

Lydick

(1997) Community impact of childhood varicella infections. J Pediatr 130: 759–765.

141.

Yih

Brooks

Lett

Jumaan

Zhang

Clements

. (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.

142.

Zhou

Harpaz

Jumaan

Winston

Shefer

(2005) Impact of varicella vaccination on health care utilization. JAMA 294: 797–802.

143.

Ziebold

von Kries

Lang

Weigl

Schmitt

(2001) Severe complications of varicella in previously healthy children in Germany: a 1-year survey. Pediatrics 108(5): E79.

Successes and challenges in varicella vaccine

Abstract

Keywords

Introduction

Varicella zoster virus

VZV associated diseases

Aim of the review

Varicella vaccine

Pre-vaccine epidemiology

Incidence

Climate factors and varicella incidence

Hospitalization

Morbidity and mortality

VZV vaccine successes

Varicella vaccine effectiveness in the USA

Varicella vaccine effectiveness in areas outside USA

Challenges in varicella vaccine

Fear of age shift of varicella cases to older age groups

Fear of HZ incidence increase among naturally infected individuals

Cost-effectiveness studies evaluating the introduction of varicella vaccine

Universal versus high-risk population vaccination

Dose interval in universal varicella vaccination

Conclusion

Footnotes

Funding

Conflicts of interest

References