Efficacy of varicella (VZV) vaccination: an update for the clinician

Abstract

Varicella-zoster virus (VZV) infection causes two distinct clinical conditions. Primary varicella infection results in chickenpox, a contagious rash illness typically seen among children. VZV can reactivate years after the initial infection to cause herpes zoster (HZ) and lead to post-herpetic neuralgia, a common complication resulting in persistent pain that may last for years after the zoster rash resolves. A person’s risk of having longer lasting and more severe pain associated with HZ increases with age. Since the introduction of VZV vaccines, the rates of infection, hospitalizations, and mortality have declined. In this review, we discuss in detail current VZV vaccines available for the prevention of VZV and HZ infections. Varilrix (GSK Biologicals, UK), Varivax (Merck, USA) and the combined measles, mumps, rubella, and varicella (MMRV) vaccine contain the live attenuated Oka strain of VZV for routine varicella vaccination. While Zostavax is the only HZ vaccine currently approved for use in the United States and the European Union [EMEA, 2011], a subunit vaccine candidate called HZ/su has recently shown improved efficacy for zoster prevention in two clinical trial phase III studies. VariZIG, a post-exposure prophylactic, uses zoster immune globulin to prevent VZV infection in those who have recently been in contact with VZV but lack evidence of varicella immunity and are contraindicated to receive the varicella vaccine. Further, we discuss the skin tropic and neurotropic factor VZV ORF7 gene and its involvement in varicella infection, reactivation and latency in ganglia. Ultimately, these studies can contribute to the development of a neuroattenuated vaccine candidate against varicella or a vector for delivery of other virus antigens.

Keywords

Chickenpox Shingles Vaccine Varicella-zoster virus VZV Varilrix Varivax

Varicella-zoster virus

Varicella-zoster virus (VZV) is a double-stranded DNA virus and a member of the herpesviridae family [Arvin, 2013]. Human beings are the only known hosts of this virus. VZV has an envelope with viral glycoproteins inserted in the membrane. Within the envelope, a tegument layer consisting of viral regulatory proteins surrounds an icosahedral nucleocapsid core that contains the linear double-stranded DNA genome [Arvin, 2013]. The VZV genome (125 kb) encodes 71 open reading frames (ORFs), approximately 44 of which are genes essential for viral replication and pathogenesis [Cohen, 2010; Zhang et al. 2010]. Primary infection with VZV results in the diffuse vesicular rash of varicella, or chickenpox. The incubation period usually ranges between 7–23 days, during which the virus spreads to the tonsils and other local lymphoid tissues, from where infected T-cells can transport the virus via the bloodstream to the skin [Ku et al. 2004]. The major route of transmission is airborne; however, transmissions via aerosols or direct contact with the blister fluid have also been reported [Zerboni et al. 2014]. Acute varicella infection is generally a mild disease and self-limiting compared with the more severe presentations found in adults and immunocompromised patients. VZV has the capacity to persist in the body after primary infection as a latent infection in sensory nerve ganglia. Reactivation of VZV causes herpes zoster (HZ), also known as zoster or shingles [Mahalingam et al. 1991; Zerboni et al. 2014]. When viral replication is reactivated, VZV reaches the skin via anterograde axonal transport to produce the symptoms of HZ [Gershon and Gershon, 2010], characterized by pain and rashes involving one to three dermatomes [Ozaki et al. 1996]. Anyone who has been infected with VZV is at risk of developing HZ, although this is more prevalent in the elderly and immunocompromised individuals. Persons over the age of 50 years are at a higher risk for VZV reactivation and the incidence of HZ after age 60 is 8 to 10-fold higher than in those under 60 years old [Harnisch, 1984]. The decline of VZV-specific cell-mediated immunity (CMI) is the principal factor in the disruption of the dynamic containment process responsible for VZV latency within the sensory ganglion. VZV-specific CMI may limit reactivation of latent VZV in sensory neurons and prevent the development of HZ by inhibiting the spread of VZV infection from these neurons. VZV-specific CD4+ and CD8+ T-cells are both involved, but CD4+ T-cells appear predominant [Malavige et al. 2008; Steain et al. 2014]. Older adults and people with compromised or suppressed immune systems are more likely to have complications from HZ [Harpaz et al. 2008], including postherpetic neuralgia (PHN), ophthalmicus, bacterial superinfections, local muscle weakness, and scarring. The most common complication of HZ is PHN, a persistent, debilitating nerve pain in areas where the HZ skin lesions appear. This pain can last for months or even years after the episode of HZ, directly interfering with a patient’s quality of life. A person’s risk of developing PHN increases with age. In the central nervous system, manifestations of varicella range from aseptic meningitis to encephalitis. Encephalitis is an infrequent complication of varicella, but may lead to seizures and coma. Diffuse cerebral involvement is more common in adults than in children. Some studies suggest that exposure to varicella boosts a person’s immunity to VZV and reduces the risk for VZV reactivation [Jumaan et al. 2005; Leung et al. 2011; Yih et al. 2005]. In the United States, HZ rates are increasing among adults. This increase has been gradual over a long period of time. Despite concerns that routine childhood varicella vaccination could lead to an increase in HZ due to reduced opportunities for exposure to VZV [Brisson et al. 2002; Ferguson et al. 1996; Reynolds et al. 2008], the current two-dose varicella vaccination program has lowered varicella incidence, outbreaks and hospitalizations in the US [Bialek et al. 2013; Leung et al. 2015b; Seward et al. 2002].

Vaccines

Varicella is one of the leading causes of vaccine-preventable deaths in children [CDC, 1999]. Routine childhood immunization has markedly reduced the incidence of varicella in the US [Marin et al. 2007, 2008; Schmid and Jumaan, 2010; Seward et al. 2008]. The varicella vaccination may provide protection against 85% of cases of chickenpox and 95% of cases of severe secondary infection [Vazquez et al. 2001]. Prior to 1995, nearly four million cases of chickenpox occurred each year in the US, resulting in 11,000 hospital admissions and 100 deaths [Galil et al. 2002]. However, the introduction of a universal vaccination in many countries such as Japan [Takahashi et al. 1974], Korea [Sadzot-Delvaux et al. 2008], and the US [Marin et al. 2007] has led to a dramatic reduction in the varicella incidence, its associated complications, hospitalizations, and fatality rate [Holmes, 1996]. There are two live, attenuated VZV-containing vaccines available for the prevention of varicella. Varivax (Merck, USA), is a single-antigen varicella vaccine introduced in 1995 for use among healthy individuals 12 months of age and older [CDC, 1996]. A combination measles, mumps, rubella, and varicella vaccine (MMRV) was licensed in the US in 2005 for healthy children aged 12 months to 12 years [Marin et al. 2010]. The zoster vaccine, Zostavax, from the Shingles Prevention Study is a live, attenuated virus vaccine used in the prevention of HZ and PHN in individuals 50 years of age and older [Harpaz et al. 2008; Lu et al. 2009; Oxman et al. 2005; Oxman and Levin, 2008]. In two recent randomized phase III trials, the HZ/su HZ vaccine candidate (GSK Biologicals, UK) showed improved, lasting efficacy in adults 50 years of age and older [Lal et al. 2015a, 2015b]. VariZIG is a zoster immune globulin (ZIG) recommended for immunocompromised patients, pregnant women, preterm infants, and neonates whose mothers have signs and symptoms of varicella around the time of delivery [Brunell et al. 1969; CDC, 2013]. Our group previously identified the unique VZV ORF7 to be both a skin tropic and neurotropic factor for efficient primary VZV infection. Currently, ORF7 is the only known gene required for viral spread in human neurons and its role could lead to the potential development of a neuroattenuated vaccine against HZ or a vector for delivery of other antigens [Zhang et al. 2008, 2010].

Varicella vaccines

Varivax and Varilrix

Varivax (Merck, USA) is a live, attenuated varicella vaccine, derived from the Oka strain of VZV [Takahashi et al. 1974]. The vaccine was licensed for general use in Japan and Korea in 1988 [Sadzot-Delvaux et al. 2008; Takahashi et al. 1974] and licensed in the US in 1995 for persons 12 months of age and older. Varivax is administered by subcutaneous injection. Two routine doses of Varivax are recommended for children; the first dose at 12–15 months old and second dose at 4–6 years old. The second dose catch-up vaccination can be given three months after the first dose for children younger than 13 years of age. For adolescents and adults 13 years old and above, two doses should be administered 4–8 weeks apart [Marin et al. 2007]. The virus was attenuated by sequential passages in human embryonic lung cell culture, embryonic guinea pig fibroblasts, and in WI-38 human diploid cells [Takahashi et al. 1974]. The Oka/Merck vaccine has undergone further passage through MRC-5 human diploid cell cultures for a total of 31 passages. This reconstituted vaccine contains small amounts of sucrose, processed porcine gelatin, sodium chloride, monosodium L-glutamate, sodium diphosphate, potassium phosphate, potassium chloride, trace quantities of residual components of MRC-5 cells (DNA and protein), EDTA, neomycin, and fetal bovine serum. The vaccine is reconstituted with sterile water and contains no preservatives [Marin et al. 2007]. Another equally effective varicella vaccine is Varilrix (GSK Biologicals, UK). Both vaccines contain live attenuated VZV, which can reactivate and cause HZ [Brunell and Argaw, 2000; Cimolai et al. 2014; Civen et al. 2009; Gilden et al. 1983; Schmid and Jumaan, 2010]. However, children vaccinated against varicella appear to have a lower risk of HZ than people who were infected with wild-type VZV [Sadzot-Delvaux et al. 2008; Schmid and Jumaan, 2010]. This is because vaccinated children are less likely to become infected with wild-type VZV, and the risk of Oka/Merck strain VZV reactivation is lower than the risk of wild-type VZV reactivation. In a study of children with leukemia, those who received varicella vaccination had a 67% lower risk of developing HZ as compared with those who had natural infection with wild-type VZV [Hardy et al. 1991]. Healthy children vaccinated against varicella demonstrated a reduced risk of HZ than children infected with wild-type VZV [Weinmann et al. 2013]. In addition, studies have proven that the varicella vaccine is both well tolerated and efficacious, as 97% of children display detectable antibody titers 7–10 years after vaccination [Johnson et al. 1997; Seward et al., 2008]. Vaccine efficacy is estimated to be 70–90% effective against varicella infection, and 90–100% effective against moderate and severe disease [Krause and Klinman, 1995]. Among healthy adolescents and adults 13 years of age and older, an average of 78% developed antibodies against VZV after one dose, and 99% developed antibodies after a second dose given 4–8 weeks later. Antibodies persisted for at least one year in 97% of vaccinated individuals who received the second dose 4–8 weeks after the first dose [Krause and Klinman, 1995]. In those with breakthrough varicella infection, most did not present with a fever [Krause and Klinman, 1995]. Recent investigations have identified the presence of asthma, use of steroids, and vaccination at an age younger than 15 months as risk factors for breakthrough varicella. Classification of varicella infection as breakthrough could be a result of several factors, including interference of vaccine virus replication by circulating antibodies, errors in storage or handling causing an impotent vaccine, and inaccurate record keeping. Interference from a live viral vaccine administered before the varicella vaccine could also reduce vaccine effectiveness [Marin et al. 2007]. A study of children in two health maintenance organizations during 1995–1999 found that children who received varicella vaccination <30 days after the measles-mumps-rubella (MMR) vaccination had a three-fold increased risk of breakthrough varicella as compared with those who received the varicella vaccine before, simultaneously with, or >30 days after the MMR vaccine [Lapphra and Scheifele, 2009].

Measles–mumps–rubella–varicella vaccine

In September 2005, the US Food and Drug Administration (FDA) licensed a combined live, attenuated MMRV vaccine (ProQuad, Merck, USA) for use in persons 12 months through 12 years of age. A 0.5 ml dose for subcutaneous or intramuscular injection is administered at 12–15 months of age and a second dose, if needed, is usually administered at 4–6 years of age [Marin et al. 2010]. A study showed support of the implementation of a two-dose MMRV vaccination to ensure optimal protection [Prymula et al. 2014]. The vaccine viruses in the MMRV vaccine are identical and of equal titer to those in the original MMR vaccine [Marin et al. 2010]. The titer of Oka/Merck however, is higher in the MMRV vaccine than in a single-antigen varicella vaccine such as Varivax or Varilrix, with a minimum of 9772 plaque-forming units (PFUs) versus 1350 PFUs, respectively. Each 0.5 ml dose contains small quantities of sucrose, hydrolyzed gelatin, sodium chloride, sorbitol, monosodium L-glutamate, sodium phosphate dibasic, human albumin, sodium bicarbonate, potassium phosphate monobasic, potassium chloride, potassium phosphate dibasic, residual components of MRC-5 cells (DNA and protein), neomycin, bovine calf serum, and other buffer and media ingredients. The vaccine is reconstituted with sterile water and contains no preservatives [Marin et al. 2010]. The efficacies and immunogenicities of the varicella and MMRV vaccines are comparable [Kuter et al. 2006; Leung et al. 2015a; Shinefield et al. 2005a, 2005b; Vesikari et al. 2012]. In mega-analysis studies, the MMRV vaccine demonstrated well tolerated safety profiles, except for a higher incidence of fever (relative risks 1.12–1.60) and a measles/rubella-like rash (relative risks 1.44–1.45) in MMRV groups [Leung et al. 2015a; Ma et al. 2015a]. Some children who received the MMRV vaccine may have an increased risk of fever and febrile seizure 6–12 days after the first vaccine dose when the peak in replication of the live attenuated measles virus occurs [Barlow et al. 2001; Ma et al. 2015b; MacDonald et al. 2014]. This risk period has been defined variably in clinical and epidemiologic studies as 8–14 days, 7–12 days, or 5–12 days [Barlow et al. 2001; Jacobsen et al. 2009; Vestergaard et al. 2004]. However, febrile seizures are not common and have not been associated with any long-term problems [Klein et al. 2010; Rowhani-Rahbar et al. 2013]. The risk for febrile seizures in children during measles illness is in fact higher than the risk after either MMRV or MMR vaccination [Perry and Halsey, 2004]. In the 12–47 month age group, the Centers for Disease Control and Prevention recommends that the first dose be administered by separate injections of MMR vaccine and varicella vaccine, except in the case of patient preference for the MMRV vaccine or provider assessment of potential adverse events. For the second dose of MMRV vaccine in the 15 months to 12 years age group and for the first dose at age 48 months and older, the MMRV vaccine is generally preferred over separate injections of its equivalent component vaccines [Marin et al. 2010]. The use of the MMRV vaccine simplifies immunization delivery by providing protection against more diseases with one less injection. This improves timely vaccination coverage and reduces healthcare costs for additional health visits [Knuf et al. 2008; Marin et al. 2010]. However, administering the MMR and varicella vaccines separately avoids the increased risk for a febrile seizure after the first dose of MMRV vaccine [Barlow et al. 2001; Ma et al. 2015a; MacDonald et al. 2014]. Given the balance of risks, benefits and the importance of individual preferences, decisions should be made by caregivers and parents on a case-by-case basis.

Herpes zoster vaccines

Zostavax

Zostavax (Merck, USA) is the only shingles vaccine currently used in persons 60 years of age and older who have no contraindications [CDC, 2011a; Oxman et al. 2005]. It is a lyophilized preparation containing at least a 14-fold greater titer of the same live attenuated Oka/Merck strain of VZV used in the varicella and MMRV vaccines. Zostavax is administered subcutaneously and each dose contains a minimum of 19,400 PFUs of VZV active ingredient, compared with the varicella vaccine which contains 1350 PFUs [CDC, 2011a; Oxman et al. 2005]. For people with a severe allergic reaction to particular vaccine components, other clinically relevant ingredients include hydrolyzed porcine gelatin, neomycin and residual DNA and protein from the MRC-5 human cell line. The vaccine is reconstituted with sterile water and contains no preservatives [CDC, 2011b; Oxman et al. 2005]. The US FDA approved Zostavax for persons aged 50 years and older based on a study showing that the vaccine decreased the risk of developing HZ by 69.8% (95% CI, 54.1–80.6%) in the age group of 50–59 years old over a mean follow-up time of 1.3 years [Merck and Co., 2011; Schmader et al. 2012a]. However, the Advisory Committee on Immunization Practices (ACIP) recommends its use in adults aged 60 years and older [CDC, 2011b]. This is partially due to vaccine supply shortages from Merck and Co, Inc. [CDC, 2007] and the need for more data on short- and long-term vaccine efficacy, safety, and immunogenicity. As mentioned previously, the zoster vaccine administered to adults aged 50–59 years reduced the risk of developing HZ over a mean follow-up period of 1.3 years [Schmader et al. 2012a]. In the subset of patients aged 60–69 years from the Shingles Prevention Study (SPS), the vaccine group had an efficacy of 51.3% (CI 44.2–57.6%) for prevention of HZ and 66.5% fewer PHN complications in recipients that developed HZ (CI 47.5–79.2%). In adults aged 70 years and older, efficacy decreased to 37.6% for HZ prevention and 66.8% fewer PHN complications over a three year period [Oxman et al. 2005] (Table 1). Zostavax efficacy against HZ and PHN decreased with age and is contraindicated for immunocompromised persons [Langan et al. 2013; Oxman et al. 2005]. Moreover, the Short-Term Persistence Sub-Study (STPS) showed declining vaccine efficacies after 5 years post-vaccination for HZ burden of illness (BOI) (61.1–50.1%), incidence of PHN (66.5–60.1%), and the incidence of HZ (51.3–39.6%) [Schmader et al. 2012b].Vaccine persistence declined further in year 8 post-vaccination in the Long-Term Persistence Study (LTPS) [Morrison et al. 2015]. Although initial zoster vaccine efficacy was significant, Zostavax has a clinically relevant declining efficacy in reducing HZ incidence in post-vaccination years 3–11. [Cook and Flaherty, 2015; Morrison et al. 2015; Oxman et al. 2005; Oxman and Levin, 2008; Schmader et al. 2012b].

Table 1.

Zostavax shingles vaccine and HZ/su vaccine candidate.

	Zostavax (SPS)	(GSK clinical trial III)
Vaccine type	Live, attenuated VZV Oka strain	Nonlive, recombinant subunit glycoprotein E + adjuvant AS01
Recommendations	⩾60 years immunocompetent adults	⩾50 years immunocompetent adults
Administration	1 subcutaneous injection	2 intramuscular injections (2 months apart)
Vaccine efficacy for HZ incidence (95% CI)	Overall: 51.3%* (44.2–57.6) 50–59 years: 69.8% (54.1–80.6) 60–69 years: 63.9% (55.5–70.9) ⩾70 years: 37.6% (25.0–48.1)	Overall: 97.2%* (93.7–99.0) 50–59 years: 96.6% (89.6–99.3) 60–69 years: 97.4% (90.1–99.7) ⩾70 years: 97.9% (87.9–100.0)
Immunity duration	Age-dependent	Age-independent
FDA approval	Yes	Not yet

Percentage reduction in vaccine, compared with placebo.

CI, confidence interval; FDA, US Food and Drug Administration; GSK, GlaxoSmithKline; HZ, herpes zoster; HZ/Su, HZ-adjuvanted subunit vaccines ZOSTER-006 and ZOSTER-022; SPS, Shingles Prevention Study; VZV, varicella-zoster virus.

HZ/su Vaccine

Recent results from studies on the HZ-adjuvanted subunit vaccine, HZ/su vaccine (ZOE-50, GSK Biologicals, UK), show its promise as a candidate for the prevention of HZ in adults aged 50 years and older [Lal et al. 2015a; Leroux-Roels et al. 2012]. ZOE-50 is a randomized, placebo-controlled, observer-blind, phase III study. The HZ/su candidate vaccine is nonlive and combines glycoprotein E (gE), a VZV envelop protein, with an adjuvant system, AS01B, that enhances the immunological response to gE. Glycoprotein E plays a critical role in VZV replication and is the main target of VZV-specific CD4⁺ T-cell responses [Arvin and Abendroth, 2007; Moffat et al. 2007]. The VZV gE subunit consists of a truncated molecule lacking the anchor and carboxy-terminal tail domains, which is transfected into Chinese hamster ovary (CHO) cells (CHO-gE-2-9) [Haumont et al. 1996]. The AS01 adjuvant system contains QS-21 Stimulon (Agenus, Massachusetts, US), MPL (3-O-desacyl-4’-monophosphoryl lipid A) and liposomes [Lal et al. 2013; Leroux-Roels et al. 2012]. MPL and saponin QS-21 boost immune responses by activating Toll-like receptor 4 (TLR-4) and increasing antigen uptake and retention by dendritic cells [Coffman et al. 2010]. The HZ/su vaccine combines 50 μg recombinant VZV gE antigen with AS01B adjuvant (50 μg MPL and 50 μg QS-21), and is administered via two doses intramuscularly into the left deltoid area. Participants (n = 15,411) were stratified into age groups 50–59, 60–69, and ⩾70 years. The primary efficacy end point of ZOE-50 exhibited an overall vaccine efficacy of 97.2% in reducing the risk of HZ (95% CI, 93.7–99.0%) for all age groups from 50–70 years and over. Vaccine efficacy was calculated as one minus the ratio of the incidence of HZ in the HZ/su vaccine group to the incidence of HZ in the placebo group, multiplied by 100. During a mean follow up of 3.2 years, HZ incidence rates were 0.3 and 9.1 per 1000 person-years in the vaccine group and placebo group, respectively [Lal et al. 2015a]. There were solicited or unsolicited reports of grade 3 symptoms in 17% of vaccine recipients and in 3.2% of placebo recipients [Lal et al. 2015a]. The safety profile of HZ/su vaccine was tolerable and no severe adverse events were reported [Leroux-Roels et al. 2012]. Further safety and immunogenicity assessments up to six years post-vaccination in healthy older adults confirm that gE-specific cellular and humoral immune responses persisted [Chlibek et al. 2015] and that the two-dose regimen of HZ/su exhibits an acceptable safety profile for healthy young (10–30 years old) and older (50–69 years old) Japanese adults [Lal et al. 2013]. Unlike Zostavax, HZ/su is a recombinant adjuvanted vaccine and induces higher immunogenicity than a live attenuated VZV vaccine. The ZOE-50 study shows that HZ/su provides age-independent protection against HZ and that vaccine efficacy does not wane in older individuals. In comparison, Zostavax tends to lose efficacy as patients age and over time post-vaccination [Cook and Flaherty, 2015; Morrison et al. 2015; Oxman et al. 2005; Oxman and Levin, 2008; Schmader et al. 2012b]. Previous studies have found that higher VZV cell mediated immunity (CMI) at HZ onset, as indicated by high vaccine-induced CD4+ T-cell responder frequency, was associated with reduced HZ severity and lower PHN incidence [Weinberg et al. 2009]. Two doses of the HZ/su vaccine induced stronger gE- and VZV-specific CD4+ T-cell and antibody responses than two doses of a live, attenuated Oka strain VZV vaccine. The addition of a second dose of the Oka strain VZV vaccine did not further boost immune responses elicited by the initial dose of HZ/su injection [Leroux-Roels et al. 2012]. The Zostavax vaccine is recommended for adults aged ⩾60 years; however, it is contraindicated for immunocompromised persons. The HZ/su vaccine efficacy is also being evaluated in adults aged ⩾70 years (ZOE-70) [Lal et al. 2015a] and immunocompromised patients, including solid and hematological cancer patients, hematopoietic stem cell and renal transplant recipients and HIV-infected people [GSK, 2015]. Further evaluations of the HZ/su vaccine is necessary to ensure persistent efficacy in the prevention of PHN, HZ-associated morbidity, mortality, and hospitalizations. Long-term studies on vaccine safety and immunogenicity are also necessary in order for federal agencies to approve its future use in the general population.

Current research and applications

ORF7

During latency, VZV is found in ganglia but the mechanisms involved in the establishment of latency and varicella reactivation are still unknown. The current varicella vaccines are highly attenuated in the skin and may reactivate to damage sensory neurons [Ku et al. 2004; Mahalingam et al. 1991; Silver and Zhu, 2014]. VZV genome (125 kb) encodes 71 ORFs, including factors required for efficient invasion of and egress from specific tissues during the course of natural infection. Using a comprehensive library of whole-VZV genome deletion mutants, our laboratory identified ORF7 to be both a skin tropic and neurotropic factor [Selariu et al. 2012; Zhang et al. 2010]. The VZV ORF7 deletion mutant inhibited viral spread in human nervous tissue ex vivo and in an in vivo mouse model. Unlike the commonly used vaccine viral strain Oka, the ORF7 mutant is a pure and genetically defined strain lacking the ability to infect human skin and nervous tissue in vivo, thus meeting crucial safety and genetic stability criteria for a promising next-generation chickenpox vaccine. Using bacterial artificial chromosome engineering to generate recombinant ORF7 mutants is useful in studying viral replication, latency and pathogenesis [Selariu et al. 2012; Zhang et al. 2010]. While current varicella vaccines have been shown to significantly reduce the incidence rates of VZV infections, studies examining the impact of varicella vaccination have found conflicting results regarding trends in HZ incidence [Johnson et al. 2015; Jumaan et al. 2005; Yih et al. 2005]. Therefore, further understanding of VZV neurotropism and the role of ORF7 in neuropathogenesis could contribute to the development of a neuroattenuated vaccine against chickenpox or a vector for delivery of other antigens to inhibit VZV reactivation.

Varicella zoster immune globulin (VariZIG)

In March 2013, VariZIG (Cangene Corporation, Winnipeg, Canada) was licensed by the US FDA for postexposure prophylaxis of varicella for persons at high risk for severe disease who lack evidence of immunity to varicella and for whom the varicella vaccine is contraindicated [CDC, 2006]. VariZIG is a purified immune globulin preparation made from human plasma containing high levels of anti-VZV immunoglobulin G (IgG). It is the only varicella ZIG preparation currently available in the US [CDC, 2006] and is administered intramuscularly at a recommended dose of 125 IU/10 kg of body weight, up to a maximum dose of 625 IU. Studies have indicated that clinical varicella was prevented in susceptible, healthy children by administration of ZIG (prepared from patients recovering from HZ) within 72 hours of household exposure [Brunell et al. 1969]. ZIG also lowered attack rates and modified disease severity among susceptible immunocompromised children when administered within 72 hours after exposure [Brunell et al. 1972; Mona Marin et al. 2013]. VariZIG is now approved for administration as soon as possible following VZV exposure, ideally within 96 hours for greatest effectiveness [CDC, 2013]. The CDC recommends administration of VariZIG as soon as possible after exposure to the VZV and within 10 days. The ACIP also recommends receiving VariZIG by extending the period of eligibility for previously recommended premature infants exposed to VZV during the neonatal period. Because the immune systems of premature infants may be compromised, they are considered to be at high risk for severe varicella [Marin et al. 2007]. The decision to administer VariZIG depends on three factors: (1) whether the patient lacks evidence of immunity to varicella, (2) whether the exposure is likely to result in infection, and (3) whether the patient is at a greater risk for varicella complications than the general population. For high-risk patients who have additional exposure to VZV for more than three weeks after initial VariZIG administration, another dose of VariZIG should be considered [CDC, 2013]. For pregnant women who lack evidence of immunity to varicella and are at an increased risk for developing a varicella infection if exposed to a contagious individual, the possibility of receiving VariZIG was discussed [Bapat and Koren, 2013].

Summary

Currently, the commonly used varicella vaccines (Varilrix/Varivax and MMRV) and zoster vaccine (Zostavax) contain the live attenuated Oka strain of VZV as the vaccine active ingredient. Since the introduction of the Oka strain varicella vaccine, varicella incidence [Galil et al. 2002; Guris et al. 2008; Seward et al. 2008], morbidity, mortality [Marin et al. 2011; Nguyen et al. 2005] and hospitalization rates [Davis et al. 2004; Shah et al. 2010; Zhou et al. 2005] have been reduced significantly.

Although the Oka vaccine virus is highly attenuated in the skin, it may reactivate to damage sensory neurons [Ku et al. 2004; Mahalingam et al. 1991; Silver and Zhu, 2014]. Vaccination of adults with the Oka varicella vaccine produces both antibody and CMI responses [Hayward et al. 1992], and the vaccines maintain high antibody levels as a result of endogenous reactivation of the Oka vaccine virus [Krause and Klinman, 2000]. Following naturally acquired VZV infection, VZV-specific antibody and CMI responses continue to be re-boosted not only by reactivation of latent virus, but also exogenous re-exposure to VZV. Without the occasional exogenous VZV re-exposure, VZV-specific immune responses decline and VZV reactivation could lead to clinical manifestations of HZ [Hope-Simpson, 1965; Luyten et al. 2014]. Although more evidence is needed to support the exogenous-boosting hypothesis [Ogunjimi et al. 2013], future studies on its long-term effect on HZ incidence may shed more light.

While current varicella vaccines have been shown to significantly reduce the incidence rates of VZV infections, studies examining the impact of varicella vaccination have found conflicting results regarding trends in HZ incidence [Johnson et al. 2015; Jumaan et al. 2005; Yih et al. 2005]. In a recent comprehensive review on the incidence of HZ, Kawai and colleagues examined 130 studies conducted in 26 countries during the pre- and post-varicella eras [Kawai et al. 2014]. Some studies reported no change in HZ incidence rates in the post vaccination era, while others reported an increase in HZ before the introduction of the varicella vaccine that continued into the post-vaccination era. There is no clear evidence however that these trends are the result of the varicella vaccine, as similar trends can be seen in countries in the absence of a national varicella vaccination program. We may have to wait a longer period of time to determine whether the varicella vaccination has an impact on HZ incidence.

For those who lack evidence of immunity to varicella after VZV exposure, VariZIG can be administered to reduce the risk of developing varicella infection. Unlike Zostavax, the new AS01-adjuvanted zoster vaccine, HZ/su, consists of gE and appears to be a promising candidate with an age-independent efficacy for HZ prevention maintained across age groups, from 50–70 years and over. The US FDA, however, has not yet approved this vaccine and further assessment is needed to ensure its efficacy in preventing HZ in the general population.

Meanwhile, genetic analysis of VZV ORFs offers insights into viral invasion of and egress from specific tissues during the course of natural infection. ORF7 is currently the only identified skin tropic and neurotropic factor in the VZV genome. A greater understanding of VZV ORF7 skin tropism and neurotropism could contribute to the development of a neuroattenuated vaccine against chickenpox and a vaccine vector for delivery of other antigens. Chickenpox and shingles are public health concerns because of their potential for serious complications, such as PHN, that worsen with age and have a negative impact on quality of life and cost of care. This raises the need for future studies to understand the impact of the varicella vaccine on HZ incidence and the development of zoster vaccines that provides long-term efficacy, safety, and protection for adults of all ages, especially persons in immunocompromised conditions.

Footnotes

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Arvin

Abendroth

(2007) VZV: immunobiology and host response. In: Arvin

Campadelli-Fiume

Mocarski

Moore

Roizman

Whitley

. (eds), Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press, pp. 1–13.

Arvin

Fields

Knipe

Howley

(2013) Virology 6: 2015–2057.

Bapat

Koren

(2013) The role of VariZIG in pregnancy. Expert Rev Vaccines 12: 1243–1248.

Barlow

Davis

Glasser

Rhodes

Thompson

Mullooly

. (2001) The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine. N Engl J Med 345: 656–661.

Bialek

Perella

Zhang

Mascola

Viner

Jackson

. (2013) Impact of a routine two-dose varicella vaccination program on varicella epidemiology. Pediatrics 132: e1134–e1140.

Brisson

Gay

Edmunds

Andrews

(2002) Exposure to varicella boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox. Vaccine 20: 2500–2507.

Brunell

Argaw

(2000) Chickenpox attributable to a vaccine virus contracted from a vaccinee with zoster. Pediatrics 106: e28.

Brunell

Granat

Gershon

(1972) The antigens of varicella-zoster virus. J Immunol 108: 731–737.

Brunell

Ross

Miller

Kuo

(1969) Prevention of varicella by zoster immune globulin. N Engl J Med 280: 1191–1194.

10.

CDC (1996) Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb Mortal Wkly Rep 45: 451–436.

11.

CDC (1999) Prevention of varicella: update recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 48: 1–5.

12.

CDC (2006) A new product (VariZIG) for postexposure prophylaxis of varicella available under an investigational new drug application expanded access protocol. MMWR Morb Mortal Wkly Rep 55: 209–210.

13.

CDC (2007) Notice to readers: update on supply of vaccines containing varicella-zoster. JAMA 298: 736.

14.

CDC (2011a) Immunization of health-care personnel: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 60: 1–45.

15.

CDC (2011b) Update on herpes zoster vaccine: licensure for persons aged 50 through 59 years. MMWR Morb Mortal Wkly Rep 60: 1528.

16.

CDC (2013) Updated recommendations for use of VariZIG United States, 2013. MMWR Morb Mortal Wkly Rep 62: 574–576.

17.

Chlibek

Pauksens

Rombo

van Rijckevorsel

Richardus

Plassmann

. (2015) Long-term immunogenicity and safety of an investigational herpes zoster subunit vaccine in older adults. Vaccine 34: 863–868.

18.

Cimolai

Krajden

Petric

(2014) Herpes zoster eruption associated with vaccine-strain varicella-zoster virus: a case report. BC Med J 56: 135–136.

19.

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.

20.

Coffman

Sher

Seder

(2010) Vaccine adjuvants: putting innate immunity to work. Immunity 33: 492–503.

21.

Cohen

(2010) The varicella-zoster virus genome. Curr Top Microbiol Immunol 342: 1–14.

22.

Cook

Flaherty

(2015) Review of the persistence of herpes zoster vaccine efficacy in clinical trials. Clin Ther 37: 2388–2397.

23.

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.

24.

EMEA (2011) Zostavax European Public Assessment Report. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000674/human_med_001185.jsp&mid=WC0b01ac058001d124

25.

Ferguson

Anderson

Garnett

(1996) Mass vaccination to control chickenpox: the influence of zoster. Proc Natl Acad Sci USA 93: 7231–7235.

26.

Galil

Brown

Lin

Seward

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

27.

Gershon

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

28.

Gilden

Vafai

Shtram

Becker

Devlin

Wellish

(1983) Varicella-zoster virus DNA in human sensory ganglia. Nature 306: 478–480.

29.

GSK (2015) GSK Candidate Vaccine for the Prevention of Shingles Demonstrates Overall Efficacy of 97.2% Which Does Not Diminish in the Age Groups Studied. London: GSK.

30.

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.

31.

Hardy

Gershon

Steinberg

LaRussa

(1991) The incidence of zoster after immunization with live attenuated varicella vaccine: a study in children with leukemia. Varicella Vaccine Collaborative Study Group. N Engl J Med 325: 1545–1550.

32.

Harnisch

(1984) Zoster in the elderly: clinical, immunologic and therapeutic considerations. J Am Geriatr Soc 32: 789–793.

33.

Harpaz

Ortega-Sanchez

Seward

(2008) Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 57: 1–30.

34.

Haumont

Jacquet

Massaer

Deleersnyder

Mazzu

Bollen

. (1996) Purification, characterization and immunogenicity of recombinant varicella-zoster virus glycoprotein gE secreted by Chinese hamster ovary cells. Virus Res 40: 199–204.

35.

Hayward

Villanueba

Cosyns

Levin

(1992) Varicella-zoster virus (VZV)-specific cytotoxicity after immunization of nonimmune adults with Oka strain attenuated VZV vaccine. J Infect Dis 166: 260–264.

36.

Holmes

(1996) Review of recommendations of the Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention, on varicella vaccine. J Infect Dis 174(Suppl. 3):s342–s344.

37.

Hope-Simpson

(1965) The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med 58: 9–20.

38.

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.

39.

Johnson

Palmer

Gatwood

Lenhart

Kawai

Acosta

(2015) Annual incidence rates of herpes zoster among an immunocompetent population in the United States. BMC Infect Dis 15: 502.

40.

Johnson

Stancin

Fattlar

Rome

Kumar

(1997) A long-term prospective study of varicella vaccine in healthy children. Pediatrics 100: 761–766.

41.

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.

42.

Kawai

Gebremeskel

Acosta

(2014) Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ Open 4: e004833. DOI: 10.1136/bmjopen-2014-004833.

43.

Klein

Fireman

Yih

Lewis

Kulldorff

Ray

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

44.

Knuf

Faber

Barth

Habermehl

(2008) A combination vaccine against measles, mumps, rubella and varicella. Drugs Today (Barc) 44: 279–292.

45.

Krause

Klinman

(1995) Efficacy, immunogenicity, safety, and use of live attenuated chickenpox vaccine. J Pediatr 127: 518–525.

46.

Krause

Klinman

(2000) Varicella vaccination: evidence for frequent reactivation of the vaccine strain in healthy children. Nat Med 6: 451–454.

47.

Zerboni

Ito.

Graham

Wallace

Arvin

(2004) Varicella-zoster virus transfer to skin by T cells and modulation of viral replication by epidermal cell interferon-alpha. J Exp Med 200: 917–925.

48.

Kuter

Brown

Hartzel

Williams

EvesiKaren

Black

. (2006) Safety and immunogenicity of a combination measles, mumps, rubella and varicella vaccine (ProQuad). Hum Vaccine 2: 205–214.

49.

Lal

Cunningham

Godeaux

Chlibek

Diez-Domingo

Hwang

. (2015a) Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 372: 2087–2096.

50.

Lal

Cunningham

Heineman

(2015b) Adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 373: 1576–1577.

51.

Lal

Zahaf

Heineman

(2013) Safety and immunogenicity of an AS01-adjuvanted varicella zoster virus subunit candidate vaccine (HZ/su): a phase-I, open-label study in Japanese adults. Hum Vaccine Immunother 9: 1425–1429.

52.

Langan

Smeeth

Margolis

Thomas

(2013) Herpes zoster vaccine effectiveness against incident herpes zoster and post-herpetic neuralgia in an older US population: a cohort study. PLoS Med 10: e1001420. DOI: 10.1371/journal.pmed.1001420.

53.

Lapphra

Scheifele

(2009) Does vaccination with the varicella vaccine within four weeks after the measles, mumps and rubella vaccine reduce protection? Paediatr Child Health 14: 501.

54.

Leroux-Roels

Clement

Vandepapeliere

Vassilev

Ledent

. (2012) A phase 1/2 clinical trial evaluating safety and immunogenicity of a varicella zoster glycoprotein e subunit vaccine candidate in young and older adults. J Infect Dis 206: 1280–1290.

55.

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.

56.

Leung

Hirai

Tsoi

(2015a) Immunogenicity and reactogenicity of tetravalent vaccine for measles, mumps, rubella and varicella (MMRV) in healthy children: a meta-analysis of randomized controlled trials. Expert Rev Vaccines 14: 1149–1157.

57.

Leung

Lopez

Blostein

Thayer

Zipprich

Clayton

. (2015b) Impact of the US two- dose varicella vaccination program on the epidemiology of varicella outbreaks: data from nine states, 2005–2012. Pediatr Infect Dis J 34: 1105–1109.

58.

Euler

Jumaan

Harpaz

(2009) Herpes zoster vaccination among adults aged 60 years or older in the united states, 2007: uptake of the first new vaccine to target seniors. Vaccine 27: 882–887.

59.

Luyten

Ogunjimi

Beutels

(2014) Varicella-zoster virus vaccination under the exogenous boosting hypothesis: two ethical perspectives. Vaccine 32: 7175–7178.

60.

Xiong

Yao

Chen

(2015a) Combination measles-mumps-rubella-varicella vaccine in healthy children: a systematic review and meta-analysis of immunogenicity and safety. Medicine (Baltimore) 94: e1721. DOI: 10.1097/MD.0000000000001721.

61.

Xiong

Jiang

Chen

(2015b) Risk of febrile seizure after measles-mumps-rubella-varicella vaccine: a systematic review and meta-analysis. Vaccine 33: 3636–3649.

62.

MacDonald

Dover

Simmonds

Svenson

(2014) Risk of febrile seizures after first dose of measles-mumps-rubella-varicella vaccine: a population-based cohort study. CMAJ 186:824–829.

63.

Mahalingam

Smith

Wellish

Wolf

Dueland

Cohrs

. (1991) Simian varicella virus DNA in dorsal root ganglia. Proc Natl Acad Sci USA 88: 2750–2752.

64.

Malavige

Jones

Black

Ogg

(2008) Varicella zoster virus glycoprotein E-specific CD4⁺ T-cells show evidence of recent activation and effector differentiation, consistent with frequent exposure to replicative cycle antigens in healthy immune donors. Clin Exp Immunol 152: 522–531.

65.

Marin

Broder

Temte

Snider

Seward

and Centers for Disease Control and Prevention. (2010) Use of combination measles, mumps, rubella, and varicella vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 59: 1–12.

66.

Marin

Guris

Chaves

Schmid

Seward

and Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC) (2007) Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 56: 1–40.

67.

Marin

Meissner

Seward

(2008) Varicella prevention in the United States: a review of successes and challenges. Pediatrics 122: e744–e751.

68.

Marin

Zhang

Seward

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

69.

Merck and Co. (2011) Available at: https://www.merck.com/product/usa/pi_circulars/z/zostavax/zostavax_pi2.pdf

70.

Moffat

Zerboni

Sommer

Arvin

(2007) VZV: pathogenesis and the disease consequences of primary infection. In: Arvin

Campadelli-Fiume

Mocarski

Moore

Roizman

Whitley

. (eds), Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press, pp. 1–14.

71.

Mona Marin

Bialek

Jane

(2013) Updated recommendations for use of VariZIG — United States. CDC 24/7 62: 574–576.

72.

Morrison

Johnson

Schmader

Levin

Zhang

Looney

. (2015) Long-term persistence of zoster vaccine efficacy. Clin Infect Dis 60: 900–909.

73.

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.

74.

Ogunjimi

Van Damme

Beutels

(2013) Herpes zoster risk reduction through exposure to chickenpox patients: a systematic multidisciplinary review. PloS One 8: e66485. DOI: 10.1371/journal.pone.0066485.

75.

Oxman

Levin

(2008) Vaccination against herpes zoster and postherpetic neuralgia. J Infect Dis 197(Suppl. 2): s228–s236.

76.

Oxman

Levin

Johnson

Schmader

Straus

. (2005) A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352: 2271–2284.

77.

Ozaki

Kajita

Namazue

Yamanishi

(1996) Isolation of varicella-zoster virus from vesicles in children with varicella. J Med Virol 48: 326–328.

78.

Perry

Halsey

(2004) The clinical significance of measles: a review. J Infect Dis 189(Suppl. 1): s4–s16.

79.

Prymula

Bergsaker

Esposito

Gothefors

Man

Snegova

. (2014) Protection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine versus one dose of monovalent varicella vaccine: a multicentre, observer-blind, randomised, controlled trial. Lancet 383: 1313–1324.

80.

Reynolds

Chaves

Harpaz

Lopez

Seward

(2008) The impact of the varicella vaccination program on herpes zoster epidemiology in the United States: a review. J Infect Dis 197(Suppl. 2): s224–s227.

81.

Rowhani-Rahbar

Fireman

Lewis

Nordin

Naleway

. (2013) Effect of age on the risk of fever and seizures following immunization with measles-containing vaccines in children. J Am Med Assoc Pediatr 167: 1111–1117.

82.

Sadzot-Delvaux

Rentier

Wutzler

Asano

Suga

Yoshikawa

. (2008) Varicella vaccination in Japan, South Korea, and Europe. J Infect Dis 197(Suppl. 2): s185–s190.

83.

Schmader

Levin

Gnann

McNeil

Vesikari

Betts

. (2012a) Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50–59 years. Clin Infect Dis 54: 922–928.

84.

Schmader

Oxman

Levin

Johnson

Zhang

Betts

. (2012b) Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. Clin Infect Dis 55: 1320–1328.

85.

Schmid

Jumaan

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

86.

Selariu

Cheng

Tang

Silver

Yang

Liu

. (2012) ORF7 of varicella-zoster virus is a neurotropic factor. J Virol 86: 8614–8624.

87.

Seward

Marin

Vázquez

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

88.

Seward

Watson

Peterson

Mascola

Pelosi

Zhang

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

89.

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.

90.

Shinefield

Black

Digilio

Reisinger

Blatter

Gress

. (2005a) Evaluation of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr Infect Dis J 24: 665–669.

91.

Shinefield

Black

Williams

Marchant

Reisinger

Stewart

. (2005b) Dose-response study of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr Infect Dis J 24: 670–675.

92.

Silver

Zhu

(2014) Varicella zoster virus vaccines: potential complications and possible improvements. Virol Sin 29: 265–273.

93.

Steain

Sutherland

Rodriguez

Cunningham

Slobedman

Abendroth

(2014) Analysis of T-cell responses during active varicella-zoster virus reactivation in human ganglia. J Virol 88: 2704–2716.

94.

Takahashi

Okuno

Asano

Yazaki

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

95.

Vazquez

LaRussa

Gershon

Steinberg

Freudigman

Shapiro

(2001) The effectiveness of the varicella vaccine in clinical practice. N Engl J Med 344: 955–960.

96.

Vesikari

Becker

Gajdos

Fiquet

Thomas

Richard

. (2012) Immunogenicity and safety of a two-dose regimen of a combined measles, mumps, rubella and varicella live vaccine (ProQuad(®)) in infants from 9 months of age. Vaccine 30: 3082–3089.

97.

Vestergaard

Hviid

Madsen

Wohlfahrt

Thorsen

Schendel

. (2004) MMR vaccination and febrile seizures: evaluation of susceptible subgroups and long-term prognosis. J Am Med Assoc 292: 351–357.

98.

Weinberg

Zhang

Oxman

Johnson

Hayward

Caulfield

. (2009) Varicella-zoster virus-specific immune responses to herpes zoster in elderly participants in a trial of a clinically effective zoster vaccine. J Infect Dis 200: 1068–1077.

99.

Weinmann

Chun

Schmid

Roberts

Vandermeer

Riedlinger

. (2013) Incidence and clinical characteristics of herpes zoster among children in the varicella vaccine era, 2005–2009. J Infect Dis 208: 1859–1868.

100.

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.

101.

Zerboni

Sen

Oliver

Arvin

(2014) Molecular mechanisms of varicella zoster virus pathogenesis. Nat Rev Microbiol 12:197–210.

102.

Zhang

Huang

Zhu

(2008) A highly efficient protocol of generating and analyzing VZV ORF deletion mutants based on a newly developed luciferase VZV BAC system. J Virol Methods 148: 197–204.

103.

Zhang

Selariu

Warden

Huang

Zaccheus

. (2010) Genome-wide mutagenesis reveals that ORF7 is a novel VZV skin-tropic factor. PLoS Pathog 6: e1000971. DOI: 10.1371/journal.ppat.1000971.

104.

Zhou

Harpaz

Jumaan

Winston

Shefer

(2005) Impact of varicella vaccination on health care utilization. J Am Med Assoc 294: 797–802.