Varicella vaccines: background

A live attenuated varicella vaccine, the Oka strain, was developed by Takahashi and his colleagues in Japan the early 1970s (Takahashi et al., 1974). This vaccine is now being adminstered to varicella-susceptible healthy children and adults in many countries; it is produced by at least 3 manufacturers worldwide (Merck and Co., Glaxo SmithKline, and Biken Institute/Aventis Pasteur). Although the vaccine was developed in Japan, the largest experience with it comes from the United States, where the Merck formulation was licensed for routine use in healthy susceptible individuals over the age of 1 year in 1995 (Centers for Disease Control, 1996). In both pre- and postlicensure studies (Gershon et al., 1984a, b; White, 1997; Sharrar et al., 2000) the vaccine was demonstrated to be extremely safe. Adverse effects in healthy persons are few and quite transient: a sore arm after the injection in 20%–25%, and a very minor rash resembling mild varicella in about 5%, usually appearing a month after immunization (White, 1997). A small proportion of vaccinees (15%) may also experience mild fever. It takes about a week to demonstrate antibodies to varicella-zoster virus (VZV) after immunization, but protection often results even after an exposure has occurred. As a result of widespread immunization of children, the epidemiology of varicella has begun to change in the United States, with a reported marked decline in incidence in sentinel areas, where active surveillance for the disease is being carried out (Seward et al., 2002). Vaccination is now being explored for the possibility of its preventing or modifying zoster. In a very real sense, the development of live varicella vaccine paved the way for the development of other vaccines against herpesviruses.

A number of possible misconceptions concerning varicella and varicella vaccine are listed in Table 70.1. This manuscript will discuss these misconceptions in the framework of the history of development of the live vaccine and its record regarding safety and efficacy of prevention, with regard to varicella as well as zoster.

Table 70.1

Misconceptions concerning varicella vaccine and its use.

History of development of the live attenuated vaccine

In 1974, when the first publication concerning the Oka varicella vaccine appeared, there was considerable controversy concerning whether use of a vaccine against a herpesvirus was likely to be safe and could possibly be effective. In Japan, the strategy used was first to vaccinate healthy children and then to gradually try to immunize safely immunocompromised children, progressing from the mildly to the severely immunocompromised. This possibly protective approach was taken because at that time, many young children were surviving cancer only to die of varicella. In studies in Japan, involving less than 200 healthy and immunocompromised children, it was found that the Oka strain appeared to be safe, although more needed to be learned about its efficacy. Because immunocompromised children in the Untied States were similarly faced with the possibility of surviving malignancy but not surviving chickenpox, interest in the Oka strain began to increase during the decade of the 1970s. While vaccine use remained controversial in the United States, most experts in the field believed that the risk-benefit ratio had become, by the late 1970s, appropriate to explore the safety and efficacy of varicella vaccine in children with underlying acute lymphoblastic leukemia in remission, because they had a 7% mortality from varicella (Feldman et al., 1975). Studies showed that the vaccine could be used safely in these high-risk children, although some developed fairly extensive vaccine-associated rashes that required treatment with antiviral drugs (Gershon, 1995). Importantly, the vaccine proved to be highly protective against varicella, despite the weakened immune systems of these children. Because of the high-risk nature of varicella in children with malignancies, it was not possible to conduct a controlled efficacy study. Vaccine efficacy, however, could be tested because of the high clinical attack rate of varicella in susceptible children following a household exposure to VZV(Gershon et al., 1984a,b). As data regarding the clinical efficacy of the vaccine began to emerge, significant interest developed in determining if the vaccine would prove safe and effective in healthy children, thus eventually eliminating much of the necessity to immunize immunocompromised children.

Virology of the attenuated Oka strain of VZV

The original virus was isolated from a 3-year-old, otherwise healthy Japanese boy with varicella. To prepare the seed lot, the virus was passaged 11 times at 34 ℃ in human embryonic fibroblasts, 12 times at 37 ℃ in guinea pig fibroblasts, and 5 times in human diploid fibroblasts (WI-38 and MRC-5 cells) at 37 ℃. (Takahashi et al., 1974) Additional passages were carried out by the manufacturers to prepare the vaccine to be marketed. Because VZV is so strongly cell-associated, the final product had to be sonicated and clarified by centrifugation to produce live cell-free virus.

Fortunately, it was possible soon after the vaccine was developed, to be able to distinguish between the wild type virus and the Oka strain, which made possible the reliable analysis of clinical information following vaccination. Initially it was necessary to propagate VZV from a rash or other body tissue or fluid in order to identify whether the vaccine type virus was implicated when a complication of vaccination was suspected (Gelb, et al., 1987). Eventually, however, it became possible to distinguish between vaccine and wild type VZV using polymerase chain reaction (PCR) without having to resort to virus isolation. (LaRussa et al., 1992; Gomi et al., 2000, 2001; Loparev et al., 2000a, b) A number of mutations have been found to be present in the Oka vaccine strain that are not present in the parental Oka virus (Gomi et al., 2000, 2001; Loparev, et al., 2000a, b). Although it is known that most of the mutations in the vaccine strain are in open reading frame (ORF) 62, exactly which mutations are associated with attenuation have not yet been identified. The Oka strain replicates less efficiently in human skin than does wild type VZV, as studied in the SCID-hu mouse model (Moffat et al., 1998).

Based on the vast quantity of clinical experience with the live VZV vaccine, there is overwhelming clinical evidence that the vaccine virus is attenuated. Both the incidence and severity of rash following vaccination compared to natural infection are decreased by a factor of about 20, whether vaccination is given by injection or inhalation (Bogger-Goren et al., 1982; Gershon, 2001). Transmission of the Oka strain from healthy vaccinees with rash to other susceptibles is extremely rare and has been reported only on 4 occasions (LaRussa et al., 1997; Salzman et al., 1997; Sharrar et al., 2000). This is in marked contrast to the extraordinarily high degree of contagion of the wild type virus in which roughly 90% of susceptibles develop clinical varicella after family exposures (Ross et al., 1962). Finally contact cases of Oka varicella, which occur with some frequency after vaccinating leukemic children as well as rarely from healthy populations, are extremely mild or subclinical (Tsolia et al., 1990; Sharrar et al., 2000). Transmission has only occurred when the vaccinee has manifested a rash due to the Oka strain, and there has been no clinical evidence of reversion of the vaccine strain to virulence.

Safety of the varicella vaccine for healthy individuals

With any preventive medical intervention that is to be used widely on a routine basis, particularly in children, safety is the major concern. Live varicella vaccine has proven to be extremely safe when given to susceptible children, as indicated by extensive pre- and postmarketing studies in the United States. Prior to licensure over 9000 healthy children and 2000 adults were safely immunized in clinical trials (Gershon, 1995; White, 1997). Adverse effects were minor and transient.

A post-marketing safety study of the vaccine was begun at its licensure in 1995, by investigators at Merck and Company and at Columbia University (Sharrar et al., 2000). Medical providers and consumers were asked on a voluntary basis, to submit information on possible adverse reactions to the vaccine they observed. In addition to clinical information, samples of rashes and other possibly involved fluids and tissues were submitted to analyze first for VZV by PCR, and then to distinguish between the two types of virus if VZV was identified (LaRussa et al., 1992). Although these data were collected passively, and the information therefore is necessarily incomplete, important data emerged from the study. It was crucial to be able to distinguish between vaccine and wild-type viruses because the temporal relationship of vaccination and development of rash and other symptoms would seem to implicate the vaccine virus without laboratory identification. Had it not been possible to distinguish between the two viruses, many adverse events would have erroneously been attributed to the vaccine type virus.

In the first 4 years after licensure, over 16 million doses of varicella vaccine were distributed in the United States. In the postmarketing study covering this period, rash was the most frequently reported adverse event, and almost all rashes consisting of more than 50 skin lesions were found to be caused by the wild type virus. There were fewer than five patients with more than 200 skin lesions shown to be caused by the Oka strain; this is below the average number seen in children experiencing natural varicella. There were 19 reports of encephalitis and 24 reports of ataxia during the year following vaccination, but the Oka strain of virus was not implicated in any of these illnesses. Wild-type VZV was, however, implicated in one patient with ataxia and one with encephalitis. Although there have been many reported fatalities due to wild type VZV, there have been no reports of fatal VZV infection caused by the Oka strain (Sharrar et al., 2000).

A handful of serious disseminated infections have been reported in children who were thought to be immunologically normal when vaccinated, but were eventually identified as immunodeficient. The varicella vaccine virus remains sensitive to acyclovir and other antiviral drugs. All of these children received antiviral therapy and recovered from the VZV infection. These include one child each with human immunodeficiency virus (HIV) infection and essentially no CD4 lymphocytes (Kramer et al., 2001), asthma and high dose steroids (Sharrar et al., 2000), adenosine deaminase (ADA) deficiency with immunodeficiency (Ghaffar et al., 2000), neuroblastoma diagnosed and treated right after vaccination (Levin, 2003), and a deficiency in natural killer cells (Levy et al., 2003).

Zoster has been reported after vaccination but infrequently. In the first 4 years after licensure, the Oka strain was identified in 22 patients and wild type VZV in 10 with zoster (Sharrar et al., 2000). To date, after distribution of over 40 million doses in the United States, there have been less than 50 reported cases of zoster shown to be due to the Oka strain (Galea et al., 2002).

Immunogenicity of varicella vaccine in healthy children and adolescents

In prelicensure studies, children under 12 years of age had a seroconversion rate of 97% after one dose of vaccine, as determined by the exquisitely sensitive glycoprotein immunosorbent assay (ELISA) 6 weeks after immunization. This test is not available on a commercial basis. Adolescents and adults had a seroconversion rate of 82% after one dose of vaccine, which rose to 99% after 2 doses (Provost et al., 1991; Gershon, 1995). A seroconversion rate of 91.5% was noted after one dose of vaccine, using an immune adherence antibody assay (IAHA), in 2565 Japanese children immunized between 1987–1993 (Asano, 1996). Unfortunately, commercially available ELISAs are neither sensitive nor specific enough to detect reliably antibodies after VZV immunization (Saiman, et al., 2001). There were a number of reports of failure to seroconvert (using a commercial ELISA test) in healthy children and adults in the Merck-Columbia post-licensure study (Sharrar et al., 2000). Most of these probably represent a failure of the test used rather than of the vaccine itself. The most sensitive and reliable method to measure antibodies to VZV, the fluorescent antibody to membrane antigen test (FAMA), is not amenable to performance on a large scale, and therefore remains a research tool (Williams et al., 1974; Gershon, 1995). In studies in leukemic children, this assay indicated a seroconversion rate of 82% after one dose of vaccine and 95% after two doses (Gershon et al., 1996). A convenient test that is sensitive and specific to reliably measure VZV antibody titers on a large scale basis continues to be sorely needed.

Efficacy and post-licensure effectiveness of varicella vaccine

Early studies in vaccinated leukemic children who were in remission from their illness and usually received two doses of varicella vaccine indicated not only that the vaccine was safe but also that it was highly protective against varicella (Gershon et al., 1984a,b). About 85% of vaccinated leukemic children were completely protected against varicella after household exposure and those who developed breakthrough infection had mild disease requiring no antiviral therapy. In contrast, one would expect that, in varicella-susceptibles, about 90% would become obviously infected following a household exposure to the virus (Ross et al., 1962). Early studies in healthy children indicated a similar degree of protection against household exposure, following 1 dose of vaccine, with breakthrough disease in about 15% (White, 1996).

Two double blind placebo-controlled studies of varicella vaccine in healthy children were performed, involving a total of about 1500 children. Both indicated that the vaccine provided protection of about 90% (Weibel et al., 1984; 1985; Varis and Vesikari, 1996). In these studies, higher doses of vaccine (10 000–17 000 plaque forming units-pfu) were associated with better protection than lower doses (1000 pfu). Many different doses of varicella vaccine have been studied in various clinical trials. The currently licensed Merck vaccine contains about 3000 pfu per dose, and the Glaxo SmithKline (GSK) vaccine contains about 10 000 pfu at the time of release, which prior to expiration date falls to about 3000 pfu. The Merck vaccine is lyophilized and frozen, while the GSK product is lyophilized and stored in the refrigerator (Gershon et al., 2002). No direct comparison of efficacy of these vaccines has been performed, and therefore it is assumed that they are similar in efficacy. Clearly both are highly efficacious.

A postlicensure case-control effectiveness study involving PCR-proven cases of varicella in otherwise healthy children examined the performance of varicella vaccine in clinical practice in New Haven, CT. This study indicated that the vaccine in the US is about 85% effective in preventing all varicella, and virtually 100% protective against severe varicella in otherwise healthy children (Vazquez et al., 2001). There were 202 children with varicella and 389 matched controls. Of these, 23% with varicella and 61% of controls had been vaccinated (vaccine effectiveness 85%). Of 56 vaccinated children with varicella, 86% had only mild disease; in contrast 48% of the 187 unvaccinated children had mild varicella. Studying the vaccine as it is used in clinical practice is especially significant because the vaccine itself is labile and loses potency if it is not stored properly, as indicated in the package insert, lyophilized and frozen.

Perhaps the best indication of the effectiveness of varicella vaccine, however, is the reported dramatic decline in the disease since 1995. This has been observed in sentinel areas of the USA (Seward et al., 2002). Varicella is often mild and uncomplicated in otherwise healthy children, but it may unpredictably be associated with significant morbidity and even mortality. In the United States, in the pre-vaccine era, there were about 100 annual deaths from varicella and and 11 000 hospitalizations. Most reported deaths from varicella occurred in otherwise healthy individuals. Beginning in 1995, active surveillance of varicella in three sentinel counties in Texas, California, and Pennsylvania, was carried out by investigators at the Centers for Disease Control (CDC). Vaccination coverage in the year 2000 in the sentinel counties in children aged 19 to 35 years of age ranged from 73.6% to 83.8%. For the period of study, the number of cases of varicella and hospitalizations decreased sharply, with a reduction ranging between 71%–84% in the 3 counties. Hospitalizations for varicella per 100 000 persons decreased from 2.7–4.2 in 1995–1998 to 0.6 in 1999 and 1.5 in 2000. The long-standing recognized seasonality of varicella with increases in incidence of disease in winter and early spring also disappeared after 2000. The decrease in varicella occurred in individuals of all age groups including infants too young to be immunized and also adults, who were less likely to be immunized than children, indicating that herd immunity had developed (Seward et al., 2002) (see figure in Seward chapter).

A prospective study of the incidence of varicella in 11 day-care centers in North Carolina between 1995–1999, indicated a similar decrease in the incidence of varicella due to vaccination. A case control analysis of this population indicated vaccine effectiveness of 83% (Clements et al., 1999). In a further analysis of this population, the rate of varicella vaccine coverage increased from 4.4% in 1995 to 63.1% in 1999. The incidence of varicella per 1000 person–months fell from 16.74 in July 1996 to 1.53 cases in December 1999. Because the decrease in varicella disease exceeded the increase in vaccination rate over the period studied, the investigators proposed that herd immunity had occurred (Clements, et al., 2001).

Considerations of vaccine use

In the United States, contraindications to varicella vaccine include pregnancy, allergy to vaccine components, and immunodeficiency. It is recommended that children receiving doses of steroids of over 2 mg/kg per day of prednisone or its equivalent NOT be immunized unless this medication can be discontinued for at least 3 months before vaccination. There are currently no programs for immunization of children with underlying leukemia because of potential safety concerns. On the other hand, studies of children with infection with human immunodeficiency virus (HIV) have indicated that it is safe to immunize them as long as their CD4 lymphocytes exceed 25% of their total lymphocytes in their peripheral blood. Two doses of vaccine are given to HIV-infected children, 4–8 weeks apart (Levin et al., 2001). The CDC has supported this recommendation (Centers for Disease Control 1999). Children undergoing renal transplantation have been safely immunized in French studies. These children have had protection against varicella and also have had a decreased incidence of zoster, compared to similar children who experienced natural varicella (Broyer and Boudailliez, 1985a, b; Broyer et al., 1997).

Because transmission of the vaccine virus to others is rare, healthy persons who have close contact with susceptible individuals who are at high risk to develop severe varicella are recommended to be immunized. This includes, for example, healthy children whose pregnant mothers are susceptible to varicella, and children whose varicella-susceptible siblings have malignant diseases for which they are being treated.

While the major thrust of vaccine use in the United States is in young children who have not been exposed to the virus, the vaccine often provides protection to susceptibles who have already been exposed. That post-exposure vaccination can be successful was best demonstrated in studies in Japan in the 1970s and 1980s (Asano et al., 1977, 1982). In these studies, family members who were exposed to varicella were immunized within 3 days and the disease was largely prevented. Vaccination was also used successfully to control an outbreak of varicella in a shelter for homeless families that was experiencing an epidemic of chickenpox (Watson et al., 2000).

The vaccine has been shown to be cost effective in a number of studies in the United States and abroad (Lieu et al., 1994; Beutels et al., 1996; Burnham et al., 1998; Coudeville et al., 1999; Diez Domingo et al., 1999; Brisson and Edmunds, 2002). In general this is a vaccine that is geared for use in developed countries, where it is not uncommon for children to be cared for out of the home as both parents are employed, or in single parent households where there is only one breadwinner.

Persistent questions regarding varicella vaccine

While ideally a vaccine should induce protection of close to 100% against a given disease, breakthrough cases of chickenpox have consistently been reported despite the administration of varicella vaccine, an observation first made in the early clinical trials involving leukemic children (Gershon et al., 1984a, b). The rate at which breakthrough varicella has occurred has varied from study to study. There are a myriad of possible explanations for the phenomenon. One obvious one is that not even natural varicella induces total immunity in every individual. Second cases of natural varicella are well recognized to occur (Gershon et al., 1984a, b; Junker et al., 1989, 1991). It is unrealistic to expect a viral vaccine to provide better protection than the natural illness itself. Another indication that complete immunity to VZV may never be quite achievable is the existence of zoster, which is due to reactivation of latent VZV in persons with partial immunity. Unless a vaccine that does not induce latent infection is developed and widely used, herd immunity will be required to control diseases due to VZV in addition to personal immunity from the vaccine itself.

There is now general agreement that varicella vaccine is both safe and effective. A number of important questions about the vaccine have been raised recently. None of these uncertainties preclude the use of varicella vaccine, but all need further exploration. The remainder of this chapter will address these issues.

Does immunity to varicella wane with time after immunization?

There are two types of vaccine failure, which have been termed primary and secondary. Primary vaccine failure, commonly called a “no take,” is said to occur when there is no measurable immune response to a vaccine that was administered and the person remains susceptible to the immunizing product. Persons who received varicella vaccine and developed full blown infections which are severe have probably experienced this phenomenon. In the Merck-Columbia postmarketing study, there were 11 reports of severe varicella despite immunization (Sharrar et al., 2000). How often primary vaccine failure occurs is unknown, but it should be recalled that even with the very sensitive gp ELISA antibody test, the seroconversion rate in healthy children was 97%, not 100%. Considering that about 4 million children are immunized annually in the United States, there would be expected to be over 100 000 children annually who might have primary vaccine failure. This might be true for other vaccines as well and underscores the need for strong herd immunity in protection against infections after vaccination.

Secondary vaccine failure is said to occur when an immune response brought about by vaccination decreases with time, leaving the vaccinee with varying degrees of susceptibility to the disease. At present, there is little evidence for secondary vaccine failure due to waning of immunity to VZV after immunization of healthy children, but subtle degrees of waning immunity may be difficult to identify. An extremely high degree of persistence of antibodies and cellular immunity to VZV have been reported for as long as 20 years after vaccination, in Japanese and American studies (Asano et al., 1994; Arvin and Gershon, 1996; Ampofo et al., 2002). Moreover, studies in over 400 vaccinated adults indicate that there is no increase in the incidence or severity of breakthrough varicella with time, with up to 20 years of follow-up (Ampofo et al., 2002). Were immunity to be waning, one would expect that breakthrough disease would become more frequent and more severe with time after vaccination, but this has not been observed.

Nevertheless there are hints that the current vaccine strategy in the U.S. may need some adjustment to provide better protection, especially to young children. It is disquieting that about 10% of children may develop a modified form of varicella despite vaccination, and in some studies the rate has been even higher. In four studies, the breakthrough rate of varicella in children followed for up to 10 years after immunization, ranged between 18%–34% (Clements et al., 1995, 1999; Johnson et al., 1997; Takayama et al., 1997). This breakthrough varicella may occur months to years after immunization, and it is caused by wild type VZV (LaRussa et al., 2000). It may be so mild that it is misdiagnosed clinically as insect bites or hives. It occurs mainly in individuals who have low VZV antibody levels following immunization.

A number of outbreaks of varicella in vaccinated young children have been reported in the United States (Dworkin et al., 2002; Galil et al., 2002a, b; Gershon, 2002). Some of these cases may have resulted from secondary vaccine failure. In addition, there are other possibilities to explain these outbreaks. The vaccine is labile, and improper storage may account for primary vaccine failure in some children. Children with asthma may have less ability to mount a protective immune response, possibly related to medications such as steroids (Izurieta et al., 1997; Shapiro and LaRussa, 1997). Currently, a CDC study to examine the seroconversion rate to VZV in vaccinated asthmatic children, as determined by FAMA, is underway in the United States, which should provide an answer to this question. In two reports, children vaccinated when they were less than 15 months old had higher rates of breakthrough varicella than those immunized when they were older (Dworkin et al., 2002; Galil et al., 2002a, b). When varicella vaccine is administered with an interval of less than one month after another live vaccine has been given, the incidence of breakthrough varicella increases (Centers for Disease Control, 2001) (Table 70.2).

Table 70.2

Factors associated with vaccine failure/breakthrough disease.

One report of an outbreak of chickenpox in a day-care center in New Hampshire, in which the rate of vaccination in attendees was high is especially compelling with regard to the possibility of secondary vaccine failure (Galil et al., 2002a, b). In this outbreak, the effectiveness of the vaccine was only 44%, much lower than in any previous report. In this study, 25/88 (28.4%) of children developed varicella in a 6-week period. It seems likely that the index case, whose varicella was quite extensive, had experienced primary vaccine failure. In the other involved children, the only factor that was associated with vaccine failure was an interval of greater than 3 years since vaccination. However, the children involved were very young, and it may be that the age at vaccination combined with the interval of time after immunization also played a role in predisposing them to breakthrough varicella. Continued investigations will be necessary to further understand whether waning immunity is a significant factor in breakthrough disease and how frequently it might occur, but it seems to be a real possibility. A follow up of the study conducted in private practices in New Haven has indicated that vaccine efficacy decreases with time, from 97% in year 1 to 72% in year 6 (Vazquez et al., 2003), which confirms and extends the above observations of Galil et al. (2002a, b).

It may be that a second dose of varicella vaccine given routinely will alleviate potential problems of primary and secondary vaccine failure (Gershon, 2002). (Table 70.3) One possible way in which this could be accomplished in a practical manner is to administer routinely two doses of vaccine as measles, mumps, rubella, varicella (MMRV). Developing an immunogenic formulation of the varicella component of MMRV has proven to be a difficult task. Even a formulation of very high titered VZV (40 000 pfu) did not produce significantly higher titers of VZV antibodies, although it appeared to be safe (Shinefield, et al., 2002). However, MMR and varicella vaccine may be administered safely together, and many children receive the two vaccine formulations at the same time although in separate syringes at different body sites (White, 1996).

Table 70.3

Factors associated with successful vaccination.

It should be emphasized that breakthrough varicella is almost always a mild infection. Reports of varicella of normal severity in vaccines are few and probably represent mostly episodes of primary vaccine failure (Sharrar et al., 2000). Zoster may be more of a concern although it appears that zoster is more common after natural than vaccine infection (see below). If skin lesions of varicella predispose to latency, as has been suggested by experimental evidence (Chen et al., 2003), then it would be important to try to prevent breakthrough infection in order to minimize the chance of developing zoster.

Varicella-susceptible adults may be safely immunized against varicella. Two doses are utilized, 4–8 weeks apart. Adults manifest lower seroconversion rates after one dose of vaccine than children, and therefore two doses are routinely administered. As in children, adverse effects are minimal and protection is high (Gershon, et al., 1988; 1990; Ampofo et al., 2002).

Serologic testing following immunization is usually discouraged because VZV antibody tests are both insensitive and results may be non-specific. Whether adults with no history of varicella should have serologic testing prior to immunization or simply be given two doses of vaccine if they have no history of past varicella remains moot. Inadvertent administration of vaccine to persons with immunity to varicella is not harmful (Gershon et al., 2002).

Zoster: effects and potential effects on its incidence in the vaccine era

Although use of varicella vaccine is now contraindicated in immunocompromised individuals, early vaccine studies often involved these children because they were at high risk of developing severe varicella. (Table 70.4) In these vaccinees, the incidence of zoster was shown to be lower than after natural infection (Hardy et al., 1991; Arvin and Gershon, 1996). Thus, there is every reason to predict that vaccination would also be protective against zoster in healthy children. Although the data are of necessity not controlled, the existing information since 1995 to the present strongly suggests that this is the case. Although healthy vaccinees have developed zoster, less than 50 known cases have been reported after distribution of over 40 million doses of vaccine between 1995 and 2002 (White, 1996; Sharrar et al., 2000; Galea et al., 2002). The rate of zoster after vaccination is roughly 20 times less the expected rate for that age group (Gershon et al., 2002).

Table 70.4

A comparison of the reported percentage of immunocompromised patients developing zoster who were vaccinated and those who experienced natural infection.

Recently several studies have addressed the question of whether exposure to varicella is protective against zoster, because it is known that zoster is associated with a low cell-mediated immune response to VZV. It was found that in vaccinated leukemic children, both household exposure and additional doses of varicella vaccine correlated with greater protection against zoster than a single dose of vaccine alone (Gershon et al., 1996a, b). A case-control study has shown that following natural varicella, there is a lower incidence of zoster in individuals who have exposures to children with VZV infections in comparison to those who do not (Thomas et al., 2002). Based on such data, using computer modeling, a theoretical calculation of the incidence of zoster in a highly vaccinated population has been made. This model predicts an epidemic of zoster with accompanying significant mortality in countries where varicella vaccination is routine (Brisson et al., 2002). These observations, even though theoretical, have led to reluctance to use varicella vaccine routinely in some countries. It is therefore important to put the possibility into perspective.

The reported incidence of zoster in healthy individuals aged 40–50 in developed countries ranges between 2–4 cases per 1000 person–years of observation (Hope-Simpson, 1965; Donahue et al., 1995). It was calculated that the rate of zoster would double in countries where routine vaccination is being carried out (Brisson et al., 2002). This would lead to an incidence of 4–8 cases per 1000 person–years of observation in this age group. The incidence of zoster per 1000 person–years of observation in other high risk groups has been reported to be as follows: vaccinated leukemics 8, unvaccinated leukemics 25, adults with AIDS 50, children with AIDS 300 (Gershon et al., 1996a, b). Thus the projected increase in the incidence of zoster based on computer modeling might double but even this is unlikely to represent an epidemic. Moreover, the mortality of zoster appears to be less than that from varicella, the primary infection, and thus the validity of an increasing incidence of zoster leading to significantly increased mortality must be questioned (Feldman et al., 1973; 1975; Whitley et al. 1982a,b; Shepp et al., 1988). Finally, as yet, no actual increase in the incidence of zoster has been observed in the United States although the CDC is collecting epidemiologic data on the issue. Should an increase in zoster be recognized, however, it can logically be approached by immunization to prevent zoster, as described below.

Vaccination to prevent zoster in the elderly

It is estimated that about 20% of individuals who have had natural varicella will develop zoster during their lifetime, usually if they become immunocompromised or elderly. After age 50, the incidence of zoster climbs steadily with each advancing decade. While mortality from zoster is rare, morbidity from this infection remains a significant medical problem. The risk of developing the severe and painful complication of post-herpetic neuralgia (PHN) also increases with increasing age. It has been recognized for years that zoster occurs when the cell-mediated immune (CMI) response falls to below a critical level, and with advancing age, fewer and fewer people maintain a positive CMI response to VZV, although their antibody titers remain intact or may even increase (Arvin et al., 1978; Berger et al., 1981; Gershon and Steinberg, 1981; Burke et al., 1982; Hardy et al., 1991).

In attempts to explore whether vaccination may be used to boost immunity to VZV and possibly be used to prevent zoster, at least 8 clinical trials have been performed by investigators in the United States and Europe. These trials have determined that it is possible to boost CMI responses safely in many, although not all, elderly subjects. Varying doses of vaccine from roughly 1000 to 12 000 pfu have been employed. Some of these studies employed controls and others did not; in each, the subjects and medical personnel was aware of whom had received which vaccine. While no firm conclusions can be made from these studies, it appeared that vaccination seemed to modify zoster. All observed cases of zoster were mild in these otherwise healthy adults (Levin, 2001).

Based on these apparently successful open label studies, a large double blind placebo controlled study of immunization of healthy individuals over the age of 60 is currently being carried out. This study has now enrolled approximately 30 000 subjects and the observational period is still in progress. After a 3-year follow-up interval, the code will be broken and the data will be analyzed. At present, no results from this study are available, but there should be some published information by 2005. The vaccine employed is the live attenuated product, at a dose of about 20 000 pfu, which is roughly ten times the dose that is administered to healthy children (Levin, 2001) (see update below).

Use of inactivated varicella vaccine in patients at high risk to develop zoster

As in the studies described above to try to prevent zoster in elderly individuals, these studies were undertaken to try to boost the CMI response to VZV in highly immunocompromised patients who are at even greater risk to develop zoster than elderly patients. Because of the possibility of inducing another serious VZV infection with the live vaccine itself, however, an inactivated formulation of the vaccine was utilized. In an early controlled study, three doses of heat-inactivated vaccine were administered to a heterogeneous group of 75 patients; the incidence of zoster remained unchanged but the illness appeared to have been modified (Redman et al., 1997). In a second, more successful clinical trial, 4 doses were employed, including one given a month before transplantation, and the subject population was more homogeneous and included only patients with lymphoma who had undergone autologous stem cell transplantation (Hata et al., 2002). A dose of 6115 pfu of heat-inactivated VZV was administered, which was well tolerated although induration, erythema, or pain occurred after 10% of the doses. The rate of zoster was significantly decreased in vaccines compared to controls. Zoster occurred in 17/56 (30%) of the evaluable unvaccinated control patients and in only 7/53 (13%) vaccinees. Protection correlated with reconstitution of CD4 T-cell immunity to VZV. Because all the patients who developed zoster received antiviral therapy for their illness, it was not possible to compare the severity of zoster in the vaccines and controls. While this vaccine remains experimental, it holds promise for eventual prevention of zoster in immunocompromised patients. It also suggests an approach that might successfully prevent infections with other herpesviruses in the immunocompromised (Hata et al., 2002).

Recent developments

There are two recent changes in policy with regard to recommendations for VZV vaccine use in the United States. They involve a CDC mandated second dose of varicella vaccine for all children, and the use of the newly licensed by the FDA of combined measles-mumps-rubella-varicella (MMRV) vaccine. An additional development concerns vaccination of healthy older adults against zoster. Recently it was demonstrated that zoster can be prevented by immunization of healthy individuals over the age of 60 years with a different formulation of the Oka vaccine VZV strain that contains over 10 times the dose of virus as the monovalent varicella vaccine.

As has been mentioned, by 2002, numerous outbreaks of varicella were being observed in immunized children in day care facilities and schools in the United States. Vaccine efficacy rates were calculated to vary from 85% to as low as 44%.(Galil et al., 2002b) One study showed that it appeared that the vaccine failure rate after 1 dose of vaccine might be as high as 20%, which alone could account for apparent breakthrough disease. In 2006, a study of the seroconversion against VZV of 16 month old children vaccinated in a practice setting at Vanderbilt University in 2004, indicated a seroconversion rate of 76% (FAMA ≥ 1:4) 16 weeks after 1 dose of Varivax (Michalek, Gershon et al., personal communication). As part of a study conducted by Merck study (Kuter et al., 2004), roughly 1000 children received a second dose of varicella vaccine 3 months after the first dose. A similar number of children were followed for the same interval but received only 1 dose of vaccine. In these children who received 2 doses, the seroconversion rate 6 weeks after the second dose increased to 99.5%, and the geometric mean titer (GMT) to 141.5, indicating a marked booster response after the second dose. In this study, the gp ELISA assay was used to assess humoral immunity. In October, 2006, the FDA approved the use of the combined vaccine MMRV for use in the United States. Marked boosting of humoral immunity following a second dose of MMRV was also observed (Shinefield et al., 2005a,b). Boosting against VZV was about 10 times greater than boosting against the MMR components, in which it was only about 2 times greater. Importantly, as part of the Merck study (Kuter et al., 2004), protection against varicella over 10 years of follow up was significantly higher after 2 doses of vaccine than 1 dose, 94% vs 98% respectively.

Due to the costs, inconvenience, and transmission of wild-type VZV associated with the numerous outbreaks of varicella, as well as the consistently observed boosting of both humoral and cell mediated immunity after a second dose of vaccine, the ACIP mandated a second routine dose of varicella vaccine for infants and children, with catch up programs, in June 2006. For harmonization with MMR vaccine, MMRV will usually be given at 12–15 months of age with a second dose at 4–6 years of age. Details concerning this recommendation should become available on the CDC website in the near future. As yet this information is unpublished.

Without a second dose of vaccine it was predicted that there would be an accumulation of vaccinated children destined to become varicella-susceptible young adults, potentially at high risk to develop severe varicella. This would especially be liable to occur in the setting of less opportunity for boosting of immunity due to less exposure to cases of varicella. In addition, it had been found by the CDC that outbreak control with a second dose was expensive and almost impossible to implement. While it is uncertain that there will be complete protection against varicella after 2 routine doses of varicella vaccine, it is projected that the numbers of breakthrough cases will decrease significantly, with a subsequent decrease in transmission of the virus, and a decrease in outbreaks.

Monovalent varicella vaccine contains a dose of about 1350 plaque forming units (pfu) of virus, but MMRV contains about ten times this amount. The increased dose of varicella vaccine in MMRV was required in order to reach an acceptable seroconversion against VZV. It is hypothesized that the measles component in MMRV may suppress the immune response to VZV. This dose of virus in MMRV is similar to the dose of vaccine used to prevent zoster.

In 2005, it was shown in a double-blind placebo-controlled study that vaccination of healthy adults over age 60 years resulted in significant protection against zoster and that in preventing zoster, postherpetic neuralgia was also prevented (Oxman et al., 2005). In vaccinees aged 60–69 years, the vaccine was 64% effective in protection against zoster. Although the vaccine was less effective in preventing zoster in vaccinees aged 70–79 years (41%), it was 55% protective against PHN in this age group. Many questions about the use of this vaccine remain, such as the duration of immunity, but thus far the vaccine appears to be safe and effective when used in this manner. Currently the decisions are being made as to exactly how this vaccine should be used in the elderly population; the outcome should be known in the fall of 2006 (see CDC website for further information).

Conclusions

Despite the controversial introduction, varicella vaccines represent the first truly successful preventive measure against VZV. Although the approach of routine vaccine regimens for children may require some adjustment, the vaccine safely prevents most cases of clinical varicella, which saves lives, hospitalizations, and resources. Recipients of live vaccine are also at decreased risk to develop zoster. The promise of prevention of zoster in individuals who already have latent infection with the wild type virus due to past natural infection with VZV is a potential goal that is likely to be accomplished with either live or inactivated vaccine or both. A new era in herpesvirus virology is well underway.

References

• Ampofo K., Saiman L., Russa, Steinberg S., Annunziato P., Gershon A. Persistence of immunity to live attenuated varicella vaccine in healthy adults. Clin. Infect. Dis. 2002;34(6):774–779. [PubMed: 11830801]
• Arvin A., Gershon A. Live attenuated varicella vaccine. Annu. Rev. Microbiol. 1996;50:59–100. [PubMed: 8905076]
• Arvin A. M., Pollard R. B., Rasmussen L., Metigan T. Selective impairment in lymphocyte reactivity to varicella-zoster antigen among untreated lymphoma patients. J. Infect. Dis. 1978;137:531–540. [PubMed: 207782]
• Asano Y. 1996Varicella vaccine: the Japanese experience J. Infect. Dis. 174S310–S313. [PubMed: 8896537]
• Asano Y., Nakayama H., Yasaki T., et al. Protection against varicella in family contacts by immediate inoculation with live varicella vaccine. Pediatrics. 1977;59:3–7. [PubMed: 190583]
• Asano Y., Hirose S., Iwayama S., Miyata, Yazaki T., Takahashi M. Protective effect of immediate inoculation of a live varicella vaccine in household contacts in relation to the viral dose and interval between exposure and vaccination. Biken J. 1982;25:43–45. [PubMed: 6289799]
• Asano Y., Suga S., Yoshikawa T., et al. Experience and reason: twenty year follow up of protective immunity of the Oka live varicella vaccine. Pediatrics. 1994;94:524–526. [PubMed: 7936864]
• Berger R., Florent G., Just M. ‘Decrease of the lympho-proliferative response to varicella-zoster virus antigen in the aged. Infect. Immunol. 1981;32:24–27. [PMC free article: PMC350580] [PubMed: 6163722]
• Beutels P., Clara R., Tormans G., Vandoorsalaer E., Damme 1996Costs and benefits of routine varicella vaccination in German children J. Infect. Dis. 174S335–S341. [PubMed: 8896542]
• Bogger-Goren S., Baba K., Husley P., Yabuuchi H., Takahashi M., Ogra P. Antibody response to varicella-zoster virus after natural or vaccine-induced infection. J. Infect. Dis. 1982;146:260–265. [PubMed: 6286790]
• Brisson M., Edmunds W. J. 2002The cost-effectiveness of varicella vaccination in Canada Vaccine 20(7–8), 1113–1125. [PubMed: 11803072]
• Brisson M., Gay N., Do W. J., Andrews N. J. Exposure to varicella boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox. Vaccine. 2002;20:2500–2507. [PubMed: 12057605]
• Broyer M., Boudailliez B. Prevention of varicella infection in renal transplanted children by previous immunization with a live attenuated varicella vaccine. Transpl. Proc. 1985a;17:151–152.
• Broyer M., Boudailliez B. 1985bVaricella vaccine in children with chronic renal insufficiency Postgrad. Med J. 61 (S4), 103–106. [PubMed: 3014466]
• Broyer M., Tete M. T., Guest G., Gugnadoux M. F., Rouzioux C. Varicella and zoster in children after kidney transplantation: long term results of vaccination. Pediatrics. 1997;99:35–39. [PubMed: 8989334]
• Burke B. L., Steele R., Beard O. W., Woods J. S., Cain T. D., Marmer D. J., W., 1982Immune responses to varicella-zoster in the aged Arch. Intern. Med. 142291–293. [PubMed: 6277260]
• Burnham B. R., Wells T. S., Riddle J. R. A cost–benefit analysis of a routine varicella vaccination program for United States Air Force Academy cadets. Milit. Med. 1998;163(9):631–634. [PubMed: 9753992]
• Centers for Disease Control (1996Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP) Morb. Mortal. Wkly Rep. 451–36. [PubMed: 8668119]
• Centers for Disease Control (1999Prevention of varicella. Update Morb. Mortal. Wkly. Rep. 481–6.
• Centers for Disease Control (2001Simultaneous administration of varicella vaccine and other recommended childhood vaccines – United States, 1995–1999 Morb. Mortal. Wkly. Rep. 501058–1061. [PubMed: 11808928]
• Chen J., Gershon A., Silverstein S. J., Li Z. S., Lung P., Gershon M. D. 2003Latent and lytic infection of isolated guinea pig enteric and dorsal root ganglia by varicella zoster virus J. Med. Virol. 70S71–S78. [PubMed: 12627492]
• Clements D., Moreira S. P., Coplan P., Bland C., Walter E. Postlicensure study of varicella vaccine effectiveness in a day-care setting. Pediatr. Infect. Dis. J. 1999;18:1047–1050. [PubMed: 10608622]
• Clements D. A., Armstrong C. B., Ursano A. M., Moggio M., Walter E. B., Wilfert C. M. Over five-year follow-up of Oka/Merck varicella vaccine recipients in 465 infants and adolescents. Pediatr. Infect. Dis. J. 1995;14:874–879. [PubMed: 8584315]
• Clements D. A., Zaref J. I., Bland C. L., Walter E. B., Coplan P. Partial uptake of varicella vaccine and the epidemiological effect on varicella disease in 11 day-care centers in North Carolina. Arch. Pediatr. Adolesc. Med. 2001;155:433–461. [PubMed: 11296072]
• Coudeville L., Paree F., Lebrun T., Sally J. The value of varicella vaccination in healthy children: cost–benefit analysis of the situation in France. Vaccine. 1999;17(2):142–151. [PubMed: 9987148]
• Domingo, Ridao M., Latour J., Ballester A., Morant A. 1999A cost benefit analysis of routine varicella vaccination in Spain Vaccine 17(11–12), 1306–1311. [PubMed: 10195765]
• Donahue J. G., Choo P. W., Manson J. E., Platt R. The incidence of herpes zoster. Arch. Intern. Med. 1995;155(15):1605–1609. [PubMed: 7618983]
• Dworkin M. S., Jennings C. E., Thomas-Roth J., Lang J. E., Stukenberg C., Lumpkin J. R. An outbreak of varicella among children attending preschool and elementary school in Illinois. Clin. Infect. Dis. 2002;35:102–104. [PubMed: 12060885]
• Feldman S., Hughes W. T., Kim H. Y. Herpes zoster in children with cancer. Am. J. Dis. Child. 1973;126:178–184. [PubMed: 4353308]
• Feldman S., Hughes W., Daniel C. Varicella in children with cancer: 77 cases. Pediatrics. 1975;80:388–397. [PubMed: 1088828]
• Galea, S., Sweet, A., Gershon, A., et al. (2002). The Postmarketing Safety Review of Reports of Herpes Zoster after the Administration of VARIVAXR [Varicella Virus Vaccine Live (OKA/MERCK). Fifth Annual Conference on Vaccine Research, Baltimore, MD.
• Galil K., Fair E., Mountcastle N., Britz P., Seward J. Younger age at vaccination may increase risk of varicella vaccine failure. J. Infect. Dis. 2002a;186:102–105. [PubMed: 12089668]
• Galil K., Lee B., Strine T., et al. Outbreak of varicella at a day-care center despite vaccination. N. Engl. J. Med. 2002b;347:1909–1915. [PubMed: 12477940]
• Gelb L. D., Dohner D. E., Gershon A., et al. Molecular epidemiology of live, attenuated varicella virus vaccine in children and in normal adults. J. Infect. Dis. 1987;155:633–640. [PubMed: 3029239]
• Gershon A. Varicella-zoster virus: prospects for control. Adv. Pediatr. Infect. Dis. 1995;10:93–124. [PubMed: 7718215]
• Gershon A. Varicella vaccine: are two doses better than one? N. Engl. J. Med. 2002;347:1962–1963. [PubMed: 12477947]
• Gershon A., Steinberg S. Antibody responses to varicella-zoster virus and the role of antibody in host defense. Am. J. Med. Sci. 1981;282:12–17. [PubMed: 6267940]
• White.Gershon, A., La Russa, P., and Steinberg, S. (1996a). Varicella vaccine: use in immunocompromised patients. Infectious Disease Clinics of North America, ed. Philadelphia: W. B. Saunders; 10, 583–594. [PubMed: 8856353]
• Gershon A., Russa P., Steinberg S., Lo S. H., Murevish N., Meier P., La1996bThe protective effect of immunologic boosting against zoster: an analysis in leukemic children who were vaccinated against chickenpox J. Infect. Dis. 173450–453. [PubMed: 8568309]
• Plotkin, OrensteinGershon, A., Takahashi, M., and Seward, J. (2002). Live attenuated varicella vaccine. In Vaccines, ed. , 4th edn, pp. 783–823. Philadelphia: W. B. Saunders;
• Gershon A. A. Live-attenuated varicella vaccine. Infect. Dis. Clin. N. Amer. 2001;15:65–81. [PubMed: 11301823]
• Gershon A. A., Steinberg S., Gelb L., et al. Clinical reinfection with varicella-zoster virus. J. Infect. Dis. 1984a;149:137–142. [PubMed: 6321605]
• Gershon A. A., Steinberg S., Gelb L., et al. Live attenuated varicella vaccine: efficacy for children with leukemia in remission. J. Am. Med. Assoc. 1984b;252:355–362. [PubMed: 6330386]
• Gershon A. A., Steinberg S., Russa, et al. Immunization of healthy adults with live attenuated varicella vaccine. J. Infect. Dis. 1988;158:132–137. [PubMed: 2839577]
• Gershon A. A., Steinberg S., Gelb L., et al. Live attenuated varicella vaccine: protection in healthy adults in comparison to leukemic children. J. Infect. Dis. 1990;161:661–666. [PubMed: 2156941]
• Ghaffar F., Carrick K., Rogers B. B., Margraf L. R., Krisher K., Ramillo O. Disseminated infection with varicella-zoster virus vaccine strain presenting as hepatitis in la child with adenosine deaminase deficiency. Pediatr. Infect. Dis. J. 2000;19:764–765. [PubMed: 10959752]
• Gomi Y., Imagawa T., Takahashi M., Yamanishi K. Oka varicella vaccine is distinguishable from its parental virus in DNA sequence of open reading frame 62 and its transactivation activity. J. Med. Virol. 2000;61:497–503. [PubMed: 10897069]
• Gomi Y., Imagawa T., Takahashi M., Yamanish K. Comparison of DNA sequence and transactivation activity of open reading frame 62 of Oka varicella vaccine and its parental viruses. Arch. Virol. 2001;S17:49–56. [PubMed: 11339550]
• Hardy I. B., Gershon A., Steinberg S., et al. The incidence of zoster after immunization with live attenuated varicella vaccine. A study in children with leukemia. N. Engl. J. Med. 1991;325:1545–1550. [PubMed: 1658650]
• Hata A., Asanuma H., Rinki M., et al. Use of an inactivated varicella vaccine in recipients of hematopoietic- cell transplants. N. Engl. J. Med. 2002;347(1):26–34. [PubMed: 12097537]
• Hope-Simpson R. E. The nature of herpes zoster: a long term study and a new hypothesis. Proc. Roy. Soc. Med. 1965;58:9–20. [PMC free article: PMC1898279] [PubMed: 14267505]
• Izurieta H., Strebel P., Blake P. Post-licensure effectiveness of varicella vaccine during an outbreak in a child care center. J. Am. Med. Assoc. 1997;278:1495–1498. [PubMed: 9363968]
• Johnson C., Stancin T., Fattlar D., Rome L. P., Kumar M. L. A long-term prospective study of varicella vaccine in healthy children. Pediatrics. 1997;100:761–766. [PubMed: 9346974]
• Junker A. K., Angus E., Thomas E. Recurrent varicella-zoster virus infections in apparently immunocompetent children. Pediatr. Infect. Dis. J. 1991;10:569–575. [PubMed: 1891288]
• Junker K., Avnstorp C., Neilsen C., Hansen N. Reinfection with varicella-zoster virus in immunocompromised patients. Curr. Probl. Dermatol. 1989;18:152–157. [PubMed: 2743800]
• Kramer J. M., Russa, Tsai W. C., et al. Disseminated vaccine strain varicella as the acquired immunodeficiency syndrome-defining illness in a previously undiagnosed child. Pediatrics. 2001;108(2):E39. [PubMed: 11483849]
• Kuter B., Matthews H., Shinefield H., et al. Ten year follow-up of healthy children who received one or two injections of varicella vaccine. Pediatr. Infect. Dis. J. 2004;23(2):132–137. [PubMed: 14872179]
• Russa P., Lungu O., Gershon A., Steinberg S., Silverstein S.La1992Restriction fragment length polymorphism of polymerase chain reaction products from vaccine and wild-type varicella-zoster virus isolates J. Virol. 661016–1020. [PMC free article: PMC240804] [PubMed: 1346169]
• Russa P., Steinberg S., et al. La1997Transmission of vaccine strain varicella-zoster virus from a healthy adult with vaccine-associated rash to susceptible household contacts J. Infect. Dis. 1761072–1075. [PubMed: 9333170]
• Russa P., Steinberg S., Merwice F., Gershon A.La2000Viral strain identification in varicella vaccinees with disseminated rashes Pediatr. Infect. Dis. J. 191037–1039. [PubMed: 11099082]
• Levin M. J. Use of varicella vaccines to prevent herpes zoster in older individuals. Arch. Virol. Suppl. 2001;17:151–160. [PubMed: 11339544]
• Levin M. J. Development of acyclovir resistance during chronic Oka strain varicella-zoster virus infection in an immunocompromised child. J. Infect. Dis. 2003;188:954–959. [PubMed: 14513413]
• Levin M. J., Gershon A. A., Weinberg A., et al. Immunization of HIV-infected children with varicella vaccine. J. Pediatr. 2001;139(2):305–310. [PubMed: 11487761]
• Levy O., Orange J. S., Hibberd P., et al. Disseminated varicella infection due to vaccine (Oka) strain varicella-zoster virus in a patient with a novel deficiency in natural killer cells. J. Infect. Dis. 2003;188:948–953. [PubMed: 14513412]
• Lieu T., Cochi S., Black S., et al. Cost-effectiveness of a routine varicella vaccination program for U.S. children. J. Am. Med. Assoc. 1994;271:375–381. [PubMed: 8283587]
• Loparev V. N., Argaw T., Krause P., Takayama M., Schmid S. Improved identification and differentiation of varicella-zoster virus (VZV) wild type strains and an attenuated varicella vaccine strain using a VZV open reading frame 62-based PCR. J. Clin. Micro. 2000a;38:3156–3160. [PMC free article: PMC87343] [PubMed: 10970349]
• Loparev V. N., Caustland K., Holloway B., Krause P. R., Takayama M., Schmid S., Mc2000Rapid genotyping of varicella-zoster virus vaccine and wild type strains with fluorophore-labeled hybridization probes J. Clin. Micro. 384315–4319. [PMC free article: PMC87598] [PubMed: 11101557]
• Moffat J. F., Zerboni L., Kinchington P., Grose C., Kaneshima H., Arvin A. Attenuation of the vaccine Oka strain of varicella-zoster virus and role of glycoprotein C in alphaherpesvirus virulence demonstrated in the SCID-hu mouse. J. Virol. 1998;72:965–974. [PMC free article: PMC124567] [PubMed: 9444989]
• Oxman M. N., Levin M. J., Johnson G. R., et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N. Engl. J. Med. 2005;352(22):2271–2284. [PubMed: 15930418]
• Provost P. J., Krah D. L., Kuter B. J., et al. Antibody assays suitable for assessing immune responses to live varicella vaccine. Vaccine. 1991;9:111–116. [PubMed: 1647574]
• Redman R., Nader S., Zerboni L., et al. Early reconstitution of immunity and decreased severity of herpes zoster in bone marrow transplant recipients immunized with inactivated varicella vaccine. J. Infect. Dis. 1997;176:578–585. [PubMed: 9291302]
• Ross A. H., Lencher E., Reitman G. Modification of chickenpox in family contacts by administration of gamma globulin. N. Engl. J. Med. 1962;267:369–376. [PubMed: 14494142]
• Saiman L., Russa P., Steinberg S., et al. , La2001Persistence of immunity to varicella-zoster virus vaccination among health care workers Inf. Cont. Hosp. Epidemiol. 22279–283. [PubMed: 11428437]
• Salzman M. B., Sharrar R., Steinberg S., LaRussa P. Transmission of varicella-vaccine virus from a healthy 12 month old child to his pregnant mother. J. Pediatr. 1997;131:151–154. [PubMed: 9255208]
• Seward J. F., Watson B. M., Peterson C. L., et al. Varicella disease after introduction of varicella vaccine in the United States, 1995–2000. J. Am. Med. Assoc. 2002;287(5):606–611. [PubMed: 11829699]
• Shapiro E., LaRussa P. Vaccination for varicella – just do it. J. Am. Med. Assoc. 1997;278:1529–1530. [PubMed: 9363975]
• Sharrar R. G., Russa P., Galea S., et al. , La2000The postmarketing safety profile of varicella vaccine Vaccine 19916–923. [PubMed: 11115716]
• Shepp D., Dandliker P., Meyers J. 1988Current therapy of varicella zoster virus infection in immunocompromised patients Am. J. Med. 85 (S2A), 96–98. [PubMed: 3044102]
• Shinefield H., Black S., Staehle B., et al. Vaccination with measles, mumps, and rubella vaccine and varicella vaccine: safety, tolerability, immunogenicity, persistence of antibody, and duration of protection against varicella in healthy children. Pediatr. Infect. Dis. J. 2002;21:555–561. [PubMed: 12182381]
• Shinefield H., Williams W. R., Marchant C., et al. Dose-response study of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr. Infect. Dis. J. 2005a;24(8):670–675. [PubMed: 16094218]
• Shinefield H., Black S., Digilio L., et al. Evaluation of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr. Infect. Dis. J. 2005b;24(8):665–669. [PubMed: 16094217]
• Takahashi M., Otsuka T., Okuno Y., Asano T., Yazahi T., Isomura S. Live vaccine used to prevent the spread of varicella in children in hospital. Lancet. 1974;2:1288–1290. [PubMed: 4139526]
• Takayama N., Minamitani M., Takayama M. HIgh incidence of breakthrough varicella observed in healthy Japanese lchildren immunized with live varicella vaccine (Oka strain). Acta Paediatr. Jpn. 1997;39:663–668. [PubMed: 9447754]
• Thomas S., Wheeler J., Hall A. J. Contacts with varicella or with children and protection against herpes zoster in adults: a case-control study. Lancet. 2002;360:678–682. [PubMed: 12241874]
• Tsolia M., Gershon A., Steinberg S., Gelb L. Live attenuated varicella vaccine: evidence that the virus is attenuated and the importance of skin lesions in transmission of varicella-zoster virus. J. Pediatr. 1990;116:184–189. [PubMed: 2153790]
• Varis T., Vesikari T. 1996Efficacy of high titer live attenuated varicella vaccine in healthy young children J. Infect. Dis. 174S330–S334. [PubMed: 8896541]
• Vazquez M., Russa P., Gershon A., Steinberg S., Freudigman K., Shapiro E., La2001The effectiveness of the varicella vaccine in clinical practice N. Engl. J. Med. 344955–960. [PubMed: 11274621]
• Vazquez, M., LaRussa, P., Gershon, A., et al. (2003). Effectiveness of varicella vaccine after 8 years. Infectious Disease Society of America 41 St Annual Meeting, San Diego, CA.
• Watson B., Seward J., Yang A., et al. Post exposure effectiveness of varicella vaccine. Pediatrics. 2000;105:84–88. [PubMed: 10617709]
• Weibel R., Neff B. J., Kuter B. J., et al. Live attenuated varicella virus vaccine: efficacy trial in healthy children. N. Engl. J. Med. 1984;310:1409–1415. [PubMed: 6325909]
• Weibel R., Kuter B. J., Neff B., et al. Live Oka/Merck varicella vaccine in healthy children: further clinical and laboratory assessment. J. Am. Med. Assoc. 1985;245:2435–2439. [PubMed: 2995697]
• White C. J. Clinical trials of varicella vaccine in healthy children. Infect. Dis. Clin. N. Amer. 1996;10:595–608. [PubMed: 8856354]
• White C. J. Varicella-zoster virus vaccine. Clin. Infect. Dis. 1997;24:753–763. [PubMed: 9142766]
• Whitley R., Hilty M., Haynes R., et al. Vidarabine therapy of varicella in immunosuppressed patients. J. Pediatr. 1982;101(1):125–131. [PubMed: 7045313]
• Whitley R., Soong S., Dolin R., et al. Early vidarabine to control the complications of herpes zoster in immunosuppressed patients. N. Engl. J. Med. 1982;307:971–975. [PubMed: 7110300]
• Williams V., Gershon A., Brunell P. Serologic response to varicella-zoster membrane antigens measured by indirect immunofluorescence. J. Infect. Dis. 1974;130:669–672. [PubMed: 4372275]