Two live, attenuated varicella zoster virus-containing vaccines are available in the United States for prevention o f varicella: 1) a single-antigen varicella vaccine (VARIVAX,# CONTENTS______________________________________

# Introduction
Varicella is a highly infectious disease caused by the vari cella-zoster virus (VZV). Secondary attack rates for this virus might reach 90% for susceptible household contacts. V ZV causes a systemic infection that results typically in lifetime immunity. In otherwise healthy persons, clinical illness after reexposure is rare.
In 1995, a vaccine to prevent varicella (VARIVAX, Merck & Co., Inc., Whitehouse Station, New Jersey) was licensed in the United States for use among healthy children aged >12 months, adolescents, and adults; recommendations o f the Advisory Committee on Immunization Practices (ACIP)

# M ethods
In response to increasing reports o f varicella outbreaks among highly vaccinated populations (3)(4)(5)(6), ACIP's measles-mumpsrubella and varicella (M M RV ) workgroup first met in February 2004 to review data related to varicella vaccine use in the United States since implementation of the vaccination program in 1995 and to consider recommendation options for improving control ofvaricella disease. The workgroup held monthly conference calls and met in person three times a year. The workgroup reviewed data on the impact o f the 1-dose varicella vaccination program, including data on vaccination coverage, changes in varicella epidemiology, transmission from vaccinated persons with varicella, vaccine effectiveness, immune response to vaccination, evidence of immunity, and potential risk factors for vaccine failure. Published and unpublished data related to correlates of protection, safety, immunogenicity, and efficacy' !' o f the new quadrivalent M M RV vaccine and the immunogenicity and efficacy o f a second dose of varicella vaccine also were reviewed. Costbenefit and cost-effectiveness analyses were considered, includ ing revised cost-benefit analysis of both the 1-and 2-dose programs for children compared with no vaccination program and the incremental benefit of a second dose.

# Epidemiology of Varicella

# General
V Z V is transmitted from person to person by direct con tact, inhalation of aerosols from vesicular fluid of skin lesions of acute varicella or zoster, or infected respiratory tract secre tions that also might be aerosolized. The virus enters the host through the upper-respiratory tract or the conjunctiva.
The average incubation period for varicella is 14-16 days  after exposure to rash; however, this period can vary (range: 10-21 days). The period o f contagiousness o f infected per sons is estimated to begin 1-2 days before the onset o f rash and to end when all lesions are crusted, typically 4-7 days after onset o f rash (7). Persons who have progressive varicella (i.e., development o f new lesions for >7 days) might be conta gious longer, presumably because their immune response is depressed, which allows viral replication to persist. V Z V remains dormant in sensory-nerve ganglia and might be reactivated at a later time, causing herpes zoster (HZ) (i.e., shingles), a painful vesicular rash typically appearing in a dermatomal distribution o f one or two sensory-nerve roots.
Since implementation of a universal childhood varicella vac cination program in 1995, the epidemiology and clinical char acteristics of varicella in the United States have changed, with substantial declines in morbidity and mortality attributable to varicella. No consistent changes in H Z epidemiology have been documented.
Vaccinated persons might develop modified varicella dis ease with atypical presentation. Varicella disease that develops >42 days after vaccination (i.e., breakthrough varicella) typi cally is mild, with <50 skin lesions, low or no fever, and shorter (4-6 days) duration o f illness. The rash is more likely to be predominantly maculopapular rather than vesicular. Never theless, breakthrough varicella is contagious.

# Prevaccine Era
Before the introduction of varicella vaccine in 1995, vari cella was a universal childhood disease in the United States, with peak incidence in the spring and an average annual inci dence o f 15-16 cases per 1,000 population. On the basis of data from the National Health Interview Survey (N H IS) for 1980-1990, an average o f 4 million cases were estimated to have occurred annually (annual incidence rate: 15 cases per 1,000 population) (8). Varicella was not a nationally notifi able disease when vaccine was introduced in 1995, and sur veillance data were limited. In 1994, only 28 states, the District In this rep o rt, efficacy refers to th e extent to w hich a specific intervention p roduces a beneficial result under ideal conditions.  T h e en dash in num eric ranges is used to represent inclusive years, hours, days, ages, dosages, or a sequence o f num b ered items. reporting was passive, with estimated completeness ranging from 50 years. How ever, studies using data from state and local surveys conducted during 1990-1992 and during 1994-1995 indicated that the highest incidence o f varicella occurred among preschool-aged rather than school-aged children, indicating that the disease was being acquired at earlier ages (1 0 ,1 1 ). N ation al seroprevalence data for 1988-1994 indicated that 95.5% of adults aged 20-29 years, 98.9% o f adults aged 30-39 years, and >99.6% o f adults aged >40 years were immune to V ZV (12). However, for reasons that are not well understood, the epidemiology of varicella differs between countries with tem perate and tropical climates (13)(14)(15)(16)(17)(18). In the majority o f coun tries with temperate climates, >90% of persons are infected by adolescence whereas in countries with tropical climates, a higher proportion o f infections are acquired at older ages, which results in higher susceptibility among adults (19).
Estimates of the burden of varicella hospitalization varied according to the year(s) studied, the source of data, and the definitions used for a varicella-related hospitalization (20)(21)(22)(23). Estimates were higher if varicella was listed as either a princi pal or a secondary cause o f hospitalization, in which case some incidental varicella hospitalization might have been included. During 1988-1995, an estimated 10,632 hospitalizations were attributable annually to varicella in the United States (range: 8,198-16,586) (20). Another study demonstrated an annual average o f 15,073 hospitalizations during 1993-1995, but this period might have included an epidemic year (22). Overall rates o f hospitalization for varicella during 1988-1995 ranged from 2.3 to 6.0 cases per 100,000 population. If any vari cella-related hospital discharge diagnostic code was included, rates varied between 5.0 and 7.0 cases per 100,000 popula tion (20)(21)(22)(23).
D uring 1 9 8 8 -1 9 9 5 , persons without severe im m uno compromising conditions or treatments comprised the larg est proportion (89%) o f annual varicella-related hospitaliza tions (20). Before vaccination, children aged 20 years accounted for 32% -33% (20,22). The rate o f complications from varicella was substantially higher for persons aged >20 years and for infants (i.e., children aged 20 years were 13 times more likely to be hospitalized when they had varicella than children aged 5 -9 years, and infants aged <1 year were six times more likely to be hospitalized than children aged 5-9 years (20). The most common complications of varicella that resulted in hospital izations were skin and soft tissue infections (especially inva sive group A strep to co ccal in fe c tio n s), p n eu m on ia, dehydration, and encephalitis. In 1980, an association was identified between Reye syndrome and the use of aspirin dur ing varicella or influenza-like illness; since then, Reye syn drome, which was once considered a common complication resulting from varicella infection, has become rare (24)(25)(26).
During 1970-1994, the average annual number o f deaths for which varicella was recorded as the underlying cause was 105; the overall average annual varicella mortality rate was 0.4 deaths per 1 million population. The age distribution of varicella deaths has shifted during this period. During 1970 1974, persons aged 20 years (27). Although CFRs declined substantially during this period, the risk for varicella-related death during 1990-1994 was still 25 times higher for adults than for children aged 12 months-4 years (CFR: 21.3 and 0.8 per 100,000 cases, respectively). During the same period, 89% o f varicella deaths among children and 75% of varicella deaths among adults occurred in persons without severe underlying im m uno compromising medical conditions. The most common com plication s am ong persons who died o f varicella were pneumonia, central nervous system complications (including encephalitis), secondary infection, and hemorrhagic condi tions. A recent reanalysis of varicella deaths also considered varicella when listed as a contributing cause of death in addi tion to the underlying cause studied in the previous report (28). During 1990-1994, a varicella diagnosis was listed on an aver age o f 145 death certificates per year (105 as an underlying cause and 40 as a contributing cause), with an overall annual varicella mortality rate of 0.6 deaths per 1 million population.
Varicella during pregnancy can have adverse consequences for the fetus and infant, including congenital varicella syn drome (see Prenatal and Perinatal Exposure). Reliable data on the number of cases of congenital varicella syndrome are not available. However, on the basis of age-specific varicella inci dence (from N H IS), the annual number of births, and the risk for congenital varicella syndrome (1.1% overall risk in the first 20 weeks of pregnancy), 44 cases of congenital varicella syndrome are estimated to have occurred each year in the United States during the prevaccine era (29).

# Postvaccine Era
In 1995, a varicella vaccine (VARIVAX, Merck & Co., Inc., Whitehouse Station, New Jersey) was licensed in the United States for use among healthy children aged >12 months, ado lescents, and adults. At that time, ACIP recommended routine varicella vaccination o f children aged 12-18 months, catch-up vaccination o f susceptible children aged 19 months-12 years, and vaccination of susceptible persons who have close contact with persons at high risk for serious complications (e.g., health care workers and family contacts of immunocompromised per sons) (1; Table 1). In 1999, ACIP updated the recommendations to include child care and school entry requirements, use of the vaccine after exposure and for outbreak control, use of the vac cine for certain children infected with human immunodeficiency virus (HIV), and vaccination o f adolescents and adults at high risk for exposure or transmission (2; Table 1).
During 1997-2005, national varicella vaccination coverage among children aged 19-35 months increased from 27% to 88%, with no statistically significant difference in coverage by race or ethnicity (30). In 2005, state-specific varicella vac cination coverage ranged from 69% to 96% (31). National surveillance data continue to be limited, but passive surveil lance data in certain states have documented a decline in varicella incidence.
In four states (Illinois, Michigan, Texas, and West Virginia) with adequate (>5% o f expected cases during 1990-1994) reporting to N N D S S, varicella incidence for 2004 declined 53% -88% compared with the average incidence for 1990 1994, with vaccination coverage among children aged 19-35 months ranging from 82% to 88% (32; C D C , unpublished data, 2006). During 2003During -2005, the number o f cases increased in Illinois and Texas; the biggest increase (56%) occurred in Texas (Figure 1). The number o f cases remained stable in Michigan (Figure 1) and declined minimally in West Virginia.
In 1995, along with implementation o f the national vacci nation program, C D C instituted active surveillance for vari cella in three communities (Antelope Valley, California; Travis County, Texas; and West Philadelphia, Pennsylvania) in col laboration with state and local health departments to estab lish baseline data and to monitor trends in varicella disease after introduction o f varicella vaccine. By 2000, vaccination coverage among children 19-35 months in these three com munities had reached 74% -84% , and reported total varicella cases had declined 7 1 % -8 4 % (33). Although incidence declined to the greatest extent (83% -90% ) among children aged 12 months-4 years, incidence declined in all age groups, including infants and adults, indicating the herd immunity effects o f the vaccination program. Since 2001, only two sites were funded to continue surveillance (Antelope Valley and West Philadelphia). By 2005, vaccination coverage in these two sites had increased to 90% , and the reduction in inci dence had reached 90% and 91% , respectively (34). During

# MMWR June 22, 2007
1996-2005, as vaccination coverage continued to increase, the proportion of persons with varicella who had been vacci nated increased from 2% to 56%. During 1995-2004, peak incidence for varicella cases in active surveillance sites shifted from age 3 -6 years to age 9-11 years.
After introduction o f vaccine in 1995, the number and rate of annual varicella-related hospitalizations declined. In one study o f a nationally representative sample that was conducted during 1993-2001, varicella hospitalizations declined 75% (22). In another study, the annual varicella-related hospital ization rate declined 88% during 1994-2002 (23) (Figure 2). Hospitalization rates declined 100% among infants, and sub stantial declines also were recorded in all other age groups (up to age 50 years); hospitalization rates declined 91% among children aged 20 years) (23). In the combined active surveillance area, varicella-related hospitaliza tions declined from 2.4-4.2 hospitalizations per 100,000 popu lation during 1995-1998 to 1.5 per 100,000 population in 2000 (33) and to 0.8 per 100,000 population in 2005 (34).
During 1995-2001, the number o f deaths for which vari cella was listed as the underlying cause decreased from 115 to 26 (28) (Figure 3). Since then, the number of deaths declined further; 16 deaths were reported in 2003. Age-adjusted mor tality rates decreased 66% , from an average o f 0.41 deaths per 1 million population during 1990-1994 to 0.14 during 1999 2001. The decline was observed in all age groups 50 years did not decline to the same extent; however, the validity of reported varicella deaths in this age group is low (35), and the majority o f these deaths are not considered to be caused by varicella. During 1999-2001, the average rate of mortality attributed to varicella among all racial and ethnic populations was <0.15 deaths per 1 million persons. Persons without high-risk conditions (e.g., malignan cies, HIV/acquired immunodeficiency syndrome , and other immune deficiencies) accounted for 92% of deaths attributable to varicella. The average rates of deaths for which varicella was listed as a contributing cause of death also declined during 1999-2001, compared with 1990-1994.
F IG U R E 2 . V
Despite high 1-dose vaccination coverage and the success of the vaccination program in reducing varicella morbidity and mortality, reports to C D C from active surveillance sites and from states with well-implemented vaccination programs and surveillance indicate that in certain states and in one active surveillance site, the number of reported varicella cases has remained constant or declined minimally, and outbreaks have continued to occur. During 2001-2005, outbreaks were reported in schools with high varicella vaccination coverage (range 96% -100% ) (3,4). The outbreaks were similar in cer tain respects: 1) all occurred in elementary schools, 2) vaccine effectiveness was similar (range: 72% -85% ), 3) the highest attack rates occurred among the younger students, 4) each outbreak lasted approximately 2 months, and 5) index cases occurred among vaccinated students (although their disease was mild). Overall attack rates among vaccinated children var ied (range: 11%-17%), with attack rates in certain classrooms as high as 40% . These data indicate that even in settings in which vaccination coverage was nearly universal and vaccine performed as expected, the 1-dose vaccination program could not prevent varicella outbreaks completely.

# Prenatal and Perinatal Exposure
In the prevaccine era, prenatal infection was uncommon because the majority o f women o f childbearing age were immune to V Z V (12,36). Varicella in pregnant women is associated with a risk for V Z V transmission to the fetus or newborn. Intrauterine V Z V infection might result in congeni tal varicella syndrome, neonatal varicella, or H Z during infancy or early childhood (3 7 -4 6 ). Infants who are exposed prenatally to VZV, even if asymptomatic, might have measurable varicella-specific IgM antibody during the new born period, have persistent varicella-specific IgG immunity after age 1 year without a history of postnatal varicella, or demonstrate positive lymphocyte transformation in response to V Z V antigen (37).
Congenital varicella syndrome was first recognized in 1947 (40). Congenital varicella syndrome can occur among infants born to mothers infected during the first half o f pregnancy and might be manifested by low birthweight, cutaneous scar ring, limb hypoplasia, microcephaly, cortical atrophy, chori oretinitis, cataracts, and other anomalies. In one study, incidence o f congenital varicella syndrome was calculated us ing aggregate data from nine cohort studies carried out dur ing 1986-2002 (47). Rates were 0.6% (4 o f 725) for 2-12 weeks' gestation, 1.4% (9 o f 642) for 13-28 weeks, and 0 (0 of 385) after 28 weeks.
In a prospective study o f 1,373 mothers with varicella dur ing pregnancy conducted in the United Kingdom and West Germany during 1980-1993, the highest risk (2%) for con genital varicella syndrome was observed when maternal infec tion occurred during 13-20 weeks' gestation (43). The risk was 0.4% after maternal infection during 0-12 weeks' gesta tion. No cases of congenital varicella syndrome occurred among the infants o f 366 mothers with H Z during pregnancy. Nine isolated cases involving birth defects consistent with con genital varicella syndrome have been reported after maternal varicella beyond 20 weeks' gestation (with the latest occur ring at 28 weeks) (47,48). In a prospective study, H Z occurred during infancy or early childhood in four (0.8%) of 477 infants who were exposed to V Z V during 13-24 weeks' gestation and in six (1.7%) o f 345 infants who were exposed during 25-36 weeks' gestation (43).
The onset of varicella in pregnant women from 5 days before to 2 days after delivery results in severe varicella infec tion in an estimated 17% -30% o f their newborn infants. These infants are exposed to V Z V without sufficient maternal antibody to lessen the severity of disease. The risk for neona tal death has been estimated to be 31% among infants whose mothers had onset o f rash <4 days before giving birth (45). This estimate was made on the basis of a limited number of infant deaths and might be higher than the actual risk because the study was performed before neonatal intensive care was available. In addition, certain cases were not part of prospective studies but were reported retrospectively, making the results subject to selection bias. When these cases were reevaluated subsequently by another investigator, certain infants were demonstrated to have been at higher risk for death because o f low birthweight; in at least one case, another cause o f death was probable (46). Varicella-zoster immune globulin (VZIG) has been reported to reduce incidence o f severe neo natal varicella disease (49) and therefore is indicated in such situations. Nevertheless, the risk for death among neonates who do not receive postexposure prophylaxis with V Z IG is likely to be substantially lower than was estimated previously.

# H erpes Zoster Surveillance
After primary infection, V Z V persists as a latent infection in sensory-nerve ganglia. The virus can reactivate, causing HZ. Mechanisms controlling V ZV latency are not well understood. Risk factors for H Z include aging, immunosuppression, and initial infection with varicella in utero or during early child hood (i.e., age <18 months). An estimated 15%-30% o f the general population experience H Z during their lifetimes (50,51); this proportion is likely to increase as life expectancy increases. The most common complication of H Z, particu larly in older persons, is postherpetic neuralgia (PHN), the persistence of sometimes debilitating pain weeks to months after resolution o f H Z. Life-threatening complications o f H Z also can occur; these include herpes ophthalmicus, which can lead to blindness. Another severe manifestation is dissemina tion, which might involve generalized skin eruptions, and cen tral nervous system, pulmonary, hepatic, and pancreatic com plications. D issem ination, pneum onia, and visceral involvement typically are restricted to immunocompromised persons. V Z V can be transmitted from the lesions o f patients who have H Z to susceptible contacts. Although few data are available to assess this risk, one household contact study reported that the risk for V Z V transmission from H Z was approximately 20% ofthe risk for transmission from varicella (52).
Varicella vaccination might alter the risk for H Z at the level of both the individual and the population (i.e., herd immu nity). Just as wild-type V Z V can cause wild-type H Z, attenu ated vaccine virus has the potential to become latent and later reactivate to cause vaccine virus strain (also called Oka-strain) H Z (53). Multiple studies have evaluated the risk for Oka-strain Varicella vaccination also might change the risk for H Z at the population level. With the development o f herd immu nity and reduction in the likelihood o f exposure, the varicella vaccination program prevents wild-type V Z V infection among vaccine recipients and nonvaccine recipients, eliminating the risk for wild-type H Z in these persons. Reduction in the like lihood o f wild-type varicella infection also increases the median age for acquiring varicella (although age-specific inci dence rates themselves are lower). This reduces the risk for varicella infection during early childhood (i.e., age <18 months), thereby reducing a risk factor for childhood HZ.
Exposure of persons with latent wild-type V Z V infection to persons with varicella is thought to boost specific immu nity, which might contribute to controlling reactivation of V Z V and the development o f H Z (50). Concern has been expressed that by providing fewer opportunities for varicella exposure among persons with previous wild-type varicella infection, reduction in the likelihood o f exposure might increase the risk for H Z, possibly within as few as 5 years after introduction of varicella vaccination (59 ) and reaching a vaccination coverage of >90%.
Herpes zoster is not a nationally notifiable disease in the United States, and H Z surveillance has been conducted using multiple methods, study sites, or data sources. For certain stud ies, baseline data were available before the start o f the varicella vaccination program. One study that included baseline data was a retrospective analysis o f electronic medical records from a health maintenance organization (HM O) during 1992-2002 (60). This H M O study indicated that age-adjusted incidence o f H Z remained stable during 1992-2002 as incidence of varicella decreased (60). Age-adjusted and -specific annual incidence rates of H Z fluctuated slightly over time; the ageadjusted rate was highest in 1992, at 4.1 cases per 1,000 per son-years, and was 3.

# Use of Acyclovir to Treat and Prevent Varicella
Acyclovir is a synthetic nucleoside analog that inhibits rep lication of human herpes viruses, including VZV. Since the early 1980s, intravenous acyclovir has been available to treat immunocompromised persons who have varicella. When administered within 24 hours o f onset o f rash, acyclovir has been demonstrated to be effective in reducing varicellaassociated morbidity and mortality in this population (66)(67)(68).
In 1992, the Food and D rug A dm inistration (FDA) approved the use o f oral acyclovir for the treatment o f vari cella in otherwise healthy children. This approval was made on the basis o f placebo-controlled, double-blind studies (69,70) that dem onstrated the beneficial clinical effects (i.e., a decrease in the number o f days in which new lesions appeared, the duration o f fever, and the severity o f cutaneous and systemic signs and symptoms) that occurred when acyclovir was administered within 24 hours o f rash onset. No serious adverse events occurred during the period o f drug administration. Administration o f acyclovir did not decrease transmission o f varicella or reduce the duration o f absence from school. Because few complications occurred (1% -2% ), these studies could not determine whether acyclovir had a sta tistically significant effect on disease severity among healthy children. In these studies, antibody titers after infection in children receiving acyclovir did not differ substantially from titers o f children in the control group (69,70). Clinical trials among adolescents and adults have indicated that acyclovir is well-tolerated and effective in reducing the duration and severity o f clinical illness if the drug is administered within 24 hours o f rash onset (71)(72)(73).
In 1993, AAP's Committee on Infectious Diseases published a statement regarding the use o f acyclovir (74). AAP did not consider administration o f acyclovir to healthy children to have clinical benefit sufficient to justify its routine administration; however, AAP stated that certain circumstances might justify its use. AAP recommended that oral acyclovir should be con sidered for otherwise healthy persons at increased risk for mod erate to severe varicella (e.g., persons aged >12 years, persons with chronic cutaneous or pulmonary disorders, persons receiving long-term salicylate therapy, and persons receiving short, intermittent, or aerosolized courses o f corticosteroids). Certain experts also recommend use o f oral acyclovir for secondary case-patients who live in the same households as infected children (74).
Acyclovir is classified as a Category B drug in the FD A usein-pregnancy rating. Although studies involving animals have not indicated teratogenic effects, adequate, well-controlled studies in pregnant women have not been conducted. However, a prospective registry o f acyclovir use during pregnancy that collected data on outcomes o f 596 infants whose mothers were exposed to systemic acyclovir during the first trimester o f preg nancy indicated that the rate and types o f birth defects approximated those in the general population (75). AAP has not recommended routine use o f oral acyclovir for pregnant women because the risks and benefits to the fetus and mother were unknown. However, in instances o f serious, viral mediated complications (e.g., pneumonia), AAP has recom mended that intravenous acyclovir should be considered (74).
Two nucleoside analogs, acyclovir and famciclovir, have been approved by FDA for treating H Z. If administered within 72 hours of rash onset, acyclovir has accelerated the rate of cuta neous healing and reduced the severity of acute pain in adults who have H Z (76). Oral famciclovir, when administered during the same period, has similar efficacy (77).
Acyclovir is not indicated for prophylactic use among otherwise healthy children, adolescents, or adults without evi dence o f immunity after exposure to varicella. Vaccination is the method o f choice in these situations. No studies have been conducted regarding prophylactic use o f acyclovir among immunocompromised persons; therefore, V Z IG is recom mended in these situations.

# Vaccines for Prevention of Varicella
Two live attenuated varicella virus vaccines are licensed in the United States for prevention of varicella: single-antigen varicella vaccine (VARIVAX, Merck & Co., Inc., Whitehouse Station, New Jersey) and com bination M M R V vaccine (ProQuad, Merck & Co., Inc., Whitehouse, New Jersey). Both vaccines are derived from the Oka strain of live, attenu ated VZV. The Oka strain was isolated in Japan (78) in the early 1970s from vesicular fluid in a healthy child who had natural varicella and was attenuated through sequential propa gatio n in cultures o f hum an em b ryon ic lu n g cells, embryonic guinea-pig cells, and human diploid cells (WI-38). The virus in the Oka/Merck vaccine has undergone further passage through human diploid-cell cultures (MRC-5) for a total of 31 passages.
In 1995, the single-antigen varicella vaccine was licensed in the United States for use among healthy persons aged >12 months. This vaccine is lyophilized; when reconstituted as directed in the package insert and stored at room temperature for a maximum o f 30 minutes, it contains a minimum o f 1,350 plaque forming units (PFUs) o f Oka/Merck V Z V in each 0.5 mL dose (79). Each dose also contains 12.

# Im m une Response to Vaccination
In clinical trials o f the single-antigen varicella vaccine con ducted before licensure, seroconversion was assessed using lots o f vaccine with different amounts o f PFUs and laboratory assays with different levels o f sensitivity and specificity. Using a sp ecially dev eloped , sen sitive gp-enzym e-linked immunosorbent assay (ELISA) test that is not available com mercially, seroconversion (defined by the acquisition o f any detectable varicella antibodies >0.3 gpELISA units) was observed at approximately 4 -6 weeks after vaccination with 1 dose o f varicella vaccine in approximately 97% o f 6,889 susceptible children aged 1-12 years (79). The seroconversion rate was 98% for children aged 12-15 months and 95% among those aged 5-12 years (81). Adolescents aged 13-17 years had a lower seroconversion rate (79%) after a single dose o f vac cine. A study perform ed postlicensure used fluorescent antibody to membrane antigen (FAMA) titers 16 weeks after vaccination to assess serologic response and demonstrated that 61 (76%) o f 80 healthy child vaccine recipients seroconverted (FAMA titers >1:4) after 1 dose o f single-antigen varicella vaccine (82).
Primary antibody response to the vaccine at 6 weeks post vaccination is correlated with protection against disease (83,84). In clinical trials, rates o f breakthrough disease were lower am ong children with varicella antibody titers o f >5 gpELISA units than among those with titers o f 5 gpELISA units. Later studies o f immunogenicity (85) have reported the pro portion o f vaccinated children who achieved this antibody level instead o f seroconversion. After 1 dose o f the single antigen varicella vaccine, 86% o f children had gpELISA lev els o f >5 units/m L (85). Studies performed using FAMA indicated that a titer >1:4 at 16 weeks postvaccination is cor related with protection against disease (82). O f healthy per sons with a titer o f >1:4 at 16 weeks post vaccination, <1% have had varicella after a household exposure (n = 130). In contrast, the attack rate among those with a titer o f <1:4 was 55% (n = 60).
Persistence o f antibody in children after 1 dose o f single antigen varicella vaccine was demonstrated in both short-and long-term follow-up studies. In a clinical study, the rate of antibody persistence detected by gpELISA was nearly 100% after 9 years o f follow-up for 277 children (85). Another study demonstrated that although antibody titers (detected by FAMA) might decline 12-24 months after vaccination, the median titer did not change after 1-4 years and even rose after 10 years (86). In Japan, V Z V antibodies were present in 37 (97%) o f 38 children who received varicella vaccine 7-10 years earlier (with titers comparable to those o f 29 children who had had natural varicella infection within the previous 10 years) (87) and in 100% o f 25 children when followed for as long as 20 years (i.e., antibody levels were higher than those observed 10 years earlier) (88). Interpretation o f long-term studies is complicated by at least two factors. First, asymp tomatic boosting o f vaccine-induced immunity by exposure to wild-type V Z V is likely. Because varicella vaccine is not routinely recommended in Japan, coverage o f children was estimated to be low (approximately 20%) during 1991-1993. Second, sample sizes were limited as a result o f the decrease in the number o f children followed-up with increasing time since vaccination.
The second dose o f varicella vaccine in children produced an improved immunologic response that is correlated with improved protection. A comparative study o f healthy chil dren who received 1 or 2 doses o f single-antigen varicella vac cine administered 3 months apart indicated that a second dose provided higher antibody levels as measured by the propor tion o f subjects with titers o f >5 gpELISA units and by geometric mean titers (G M Ts) and higher efficacy (85; Tables 2-4). The proportion o f subjects with antibody titers o f >5 gpELISA units in the 2-dose recipients was higher 6 weeks after the second dose than after the first dose (99.6% and 85.7% , respectively) and remained high at the end o f the 9-year follow-up period, although the difference between the two regimens narrowed (97% and 95% , respectively). G M T 6 weeks after the second dose was substantially higher than that after a single dose (142 and 12, respectively). The differ ence in GM Ts between the two regimens did not persist over 9 years o f follow-up among subjects who seroconverted after vaccination, although GM Ts in both regimens remained high by the end o f the study period. However, receipt o f a second dose decreased the rate o f breakthrough varicella significantly (3.3-fold) and increased vaccine efficacy (p<0.001). Another study that assessed the immunogenicity o f a second dose received 4-6 years after the first dose demonstrated a substan tial increase in antibody levels in the first 7-10 days in the majority o f those tested, indicating an anamnestic response.    On the day o f the second dose, G M T was 25.7, compared with 143.6 G M T 7-10 days after the second dose; 60% of recipients had at least a fourfold increase in antibody titers, and an additional 17% had at least a twofold increase (89). Three months after the second dose, G M T remained higher than on the day o f second dose (119.0 and 25.7, respectively). Among children, V Z V antibody levels and GMTs after 2 doses administered 4-6 years apart were comparable to those obtained when the 2 doses were administered 3 months apart.

# T A B L E 2. H u m o ra l a n d c e llu la r im m u n e re s p o n s e a m o n g c h ild re n a g e d 12 m o n th s -1 2 y e a rs m e a s u re d a t 6 w e e k s p o s tv a c c in a tio n , b y v a c c in e t y p e a n d v a c c in a tio n s c h e d u le -U n ite d S ta
The Am ong persons aged >13 years, multiple studies have described seroconversion rates after receipt o f the single antigen varicella vaccine (range: 72% -94% after 1 dose and 94% -99% after a second dose administered 4-8 weeks later) (79,92,93). In clinical studies, detectable antibody levels have persisted for at least 5 years in 97% o f adolescents and adults who were administered 2 doses o f vaccine 4-8 weeks apart (79). However, other studies demonstrated that 25% -31% o f adult vaccine recipients who seroconverted lost detectable antibodies (by FAMA) at multiple intervals (range: 1-11 years) after vaccination (93,94). For persons who had breakthrough disease after exposure to varicella, the severity o f illness or the attack rates did not increase over time (95).
Innate (i.e., nonspecific) and adaptive (i.e., humoral and cellular) immunity are important in the control o f primary varicella infection. The capacity to elicit cell-mediated immu nity is important for viral clearance, providing long-term protection against disease and preventing symptomatic V ZV reactivation. Studies among children and adults have indi cated that breakthrough varicella typically is mild, even among vaccine recipients without seroconversion or vaccine recipi ents who lost detectable antibody, suggesting that VZVspecific cell-mediated immunity affords protection to vaccine recipients in the absence o f a detectable antibody response (94,95). Studies o f the cellular immune response to vaccina tion among children demonstrated that immunization with 1 dose o f varicella vaccine induced VZV-specific T-cell prolif eration that was maintained in 26 (90%) o f 29 children 1 year postvaccination and in 52 (87%) o f 60 children 5 years post vaccination (96). In this study, the mean stimulation index (SI), a marker o f cell-mediated immunity, was 12.1 after 1 year and 22.1 after 5 years. D ata obtained at 1 year postvaccina tion from a subset o f children in a prelicensure study compar ing the immune response among children who received 1 and 2 doses administered 3 months apart demonstrated that the varicella-specific lymphocyte proliferation responses were sig nificantly higher for recipients o f 2 doses than for recipients o f 1 dose (mean SI: 34.7 and 23.1, respectively; p = 0.03) (97). In the study o f the 2 doses administered 4-6 years apart, results also indicated that the lymphocyte proliferation response was significantly higher at 6 weeks and 3 months after the second dose than at the same time points after the first dose (p<0.01) (89; Table 2).
Among adults, vaccine-induced VZV-specific T-cell prolif eration was maintained in 16 (94%) o f 17 subjects 1 and 5 years postvaccination (96,98). The mean SI was 9.9 after 1 year and 22.4 after 5 years.

# Correlates of Protection
For children, the varicella antibody response measured by gpELISA 6 weeks postvaccination correlates with neutraliz ing antibody level, VZV-specific T-cell proliferative responses, vaccine efficacy, and long-term protection against varicella after exposure to V Z V (83,84,99,100). A titer o f >5 gpELISA units/mL is associated with protection against disease although it should not be considered an absolute guarantee o f protec tion. Breakthrough cases have occurred among children with >5 gpELISA units/mL. A FAMA titer >1:4 at 16 weeks post vaccination also correlates with protection against disease (82). However, neither o f these antibody tests is available commer cially. The relationship between the antibody level measured at other intervals postvaccination, especially immediately prior to exposure and breakthrough disease has not been studied. No correlates o f protection have been evaluated for adults.

# Vaccine Efficacy and Vaccine Effectiveness
One-Dose Regimen

# Prelicensure Efficacy
In prelicensure studies carried out among children aged 12 months-14 years, the protective efficacy o f single-antigen varicella vaccine varied, depending on the amount o f live virus administered per dose, the exposure setting (community or household), and the quality and length o f the clinical fol low-up. The majority o f the prelicensure studies reported effi cacy o f 1 dose o f varicella vaccine within the range o f 70% -90% against any clinical disease and 95% against severe disease for 7-10 years after vaccination (81,101,102). A ran domized placebo-controlled efficacy trial was conducted among children aged 12 months-14 years, but the formula tion differed from that o f the current vaccine (17,000 PFUs per dose (103,104), with follow-up o f children through 7 years postvaccination (105). Reported efficacy was 100% at 1 year and 98% at 2 years after vaccination, and 100% and 92%, respectively, after exposures to VZV that occurred in the house hold. Although a randomized control study was not conducted for adults, the efficacy o f single-antigen varicella vaccine was determined by evaluation o f protection when adult vaccine recipients were exposed to varicella in the household. On the basis o f the reported historical attack rate o f 87% for natural varicella after household exposure among unvaccinated chil dren, estimated efficacy among adults was approximately 80% (79). The attack rate o f unvaccinated adults exposed in house holds was not studied.

# Postlicensure Efficacy and Effectiveness

# Prevention o f AH Varicella Disease
Postlicensure studies have assessed the effectiveness^ o f the single-antigen varicella vaccine under field conditions in child care, school, household, and community settings using mul tiple methods. Effectiveness frequently has been estimated against all varicella and also against moderate and severe vari cella (defined in different ways). Outbreak investigations have assessed effectiveness against clinically defined varicella. The majority o f these investigations have demonstrated vac cine effectiveness for prevention o f varicella in the same range described in prelicensure trials (70% -90%) (3)(4)(5)(6)(106)(107)(108)(109)(110)(111)(112)(113), with some lower (44%, 56%) (114,115) and some higher (100% in one o f two schools investigated) estimates (107). A
In this report, effectiveness refers to the extent to w hich a specific intervention, w h en deployed in th e field, does w h at it is in ten d ed to do for a defined pop u latio n .
retrospective cohort study in 11 childcare centers demonstrated vaccine effectiveness o f 83% for prevention o f clinically diag nosed varicella (116). In a case-control study that measured vaccine effectiveness against laboratory-confirmed varicella in a pediatric office setting during 1997-2003, vaccine effec tiveness was 85% (CI = 78% -90%) during the first four years and 87% (CI = 81% -91% ) for the entire study period (117,118). Finally, in a study o f household secondary attack rates, considered the most robust test o f vaccine performance because o f the intensity o f exposure, varicella vaccine was 79% (CI = 70% -85%) effective in preventing clinically defined varicella in exposed household contacts aged 12 m onths-14 years without a history o f varicella disease or vaccination (119). Postlicensure data on vaccine effectiveness against all disease have been summarized (Table 5).
In a randomized clinical trial conducted postlicensure that compared the efficacy o f 1 dose o f varicella vaccine with that o f 2 doses, the estimated vaccine efficacy for 1 dose for a 10-year observation period was 94.4% (CI = 92.9% -95.7% ) (85; Table 3). In the same study, the efficacy o f 1 dose of vaccine in preventing varicella after household exposure for 10 years was 90.2% (CI = 83.7% -96.7% ) (Table 4). This study did not use placebo controls and used historic data for attack rates in unvaccinated children to calculate vaccine efficacy.

# Prevention o f Moderate and Severe Varicella
Postlicensure studies assessing vaccine performance in preventing moderate and severe varicella have consistently demonstrated high effectiveness. D efinitions for disease severity have varied among studies. Certain studies have used a defined scale o f illness that included the number o f skin lesions, fever, complications, and investigator assessment of illness severity, and others have used only the number o f skin lesions, reported complications, or hospitalizations. Moderate varicella typically has been defined as either 50 500 or 250-500 lesions, and severe varicella has been defined as >500 lesions or any hospitalization or complication. In the randomized postlicensure clinical trial, severe varicella was defined as >300 lesions and fever o f >102F (38.9C ), oral equivalent. Regardless o f different definitions, multiple stud ies have demonstrated that single-antigen varicella vaccine was >95% effective in preventing combined moderate and severe disease (3)(4)(5)(6)85,106,107,(109)(110)(111)(112)(113)(115)(116)(117)(118)(119); one study demonstrated effectiveness o f 86% (114). Effectiveness was 100% against severe disease when measured separately (6,85,109,111,117,119). Postlicensure data on vaccine effec tiveness against moderate and severe varicella have been summarized (Table 5).

# T A B L E 5. S u m m a ry o f p o s tlic e n s u r e d a ta o n e ffe c tiv e n e s s o f s i n g le -a n t i g e n v a r i c e l la v a c c in e a g a in s t d is e a s e a m o n g c h ild re n a g e d 12 m o n th s -1 4 y e a rs -U n ite d S ta te s , 1 9 9 6 -2 0 0 4
A

# Two-Dose Regimen
In a randomized clinical trial o f single-antigen varicella vac cine that compared the efficacy o f 1 dose with that o f 2 doses administered 3 months apart, the estimated vaccine efficacy o f 2 doses for a 10-year observation period was 98.3% (CI = 97.3% -99.0% ), which was significantly higher than efficacy after 1 dose (p<0.001) (85; Table 5). The 2-dose regi men also was 100% efficacious against severe varicella. In the same study, the efficacy o f 2 doses o f single-antigen varicella vaccine in preventing disease after household exposure over 10 years was 96.4% (CI = 92.4% -100% ), not significantly different from 1 dose (90.2%) (p = 0.112) (Table 4). How ever, the number o f cases involving household exposure was limited.
Formal studies to evaluate the clinical efficacy o f the com bination M M RV vaccine have not been performed. Efficacy o f the individual components was established previously in clinical studies with the single-antigen vaccines.

# Breakthrough Disease
Breakthrough disease is defined as a case o f infection with wild-type V ZV occurring >42 days after vaccination. In clini cal trials, varicella disease was substantially less severe among vaccinated persons than among unvaccinated persons, who usually have fever and several hundred vesicular lesions (120). In cases o f breakthrough disease, the median number o f skin lesions is com m only <50 (9 9 ,1 2 1 -123). In addition, compared with unvaccinated persons, vaccine recipients have had fewer vesicular lesions (lesions more commonly are atypi cal, with papules that do not progress to vesicles), shorter duration o f illness, and lower incidence o f fever.
Multiple postlicensure investigations also have demonstrated that the majority o f breakthrough varicella cases are signifi cantly milder than cases among unvaccinated children (p<0.05) (3,5,(107)(108)(109)(110)(111)(112)(113)(114)(116)(117)(118)124). However, approximately 2 5% -30% o f breakthrough cases are not mild, with clinical features more similar to those in unvaccinated children (124). Since 1999, when varicella deaths became nationally notifiable, two deaths from breakthrough varicella disease have been reported to C D C ; one o f a girl aged 9 years with a history o f asthma who was receiving steroids when she had the breakthrough infection, and the other o f a girl aged 7 years with a history of malignant ependymoma who also was under steroid therapy at the time o f her death (C D C , unpublished data, 2006).

# One-Dose Regimen
In clinical trials, 1,114 children aged 1-12 years received 1 dose o f single-antigen varicella vaccine containing 2,900 9,000 PFUs o f attenuated virus per dose and were actively followed for up to 10 years postvaccination (79). Among a subset o f 95 vaccine recipients with household exposure to varicella, eight (8%) reported a mild form o f varicella (10-34 lesions).
In a randomized clinical trial that compared the efficacy of 1 dose o f vaccine to that o f 2 doses during a 10-year observa tion period, the cumulative rate o f breakthrough varicella among children who received 1 dose was 7.3% (85). Break through cases occurred annually in 0.2% -2.3% o f recipients o f 1 dose o f vaccine. Cases occurred throughout the observa tion period, but the majority were reported 2-5 years after vaccination (Figure 4). O f 57 children with breakthrough cases, 13 (23%) had >50 lesions.
In cross-sectional studies, the attack rate for breakthrough disease has ranged between 11% and 17% (and as high as 40% in certain classrooms) in outbreak investigations (3 ) and 15% in household settings (119).

# Two-Dose Regimen Data Among Children
In a randomized clinical trial that compared the efficacy o f 1 dose o f vaccine with that o f 2 doses, the cumulative rate of breakthrough varicella during a 10-year observation period was 3.3-fold lower among children who received 2 doses than that among children who received 1 dose (2.2% and 7.3, respectively; p50 lesions. The proportion o f children with >50 lesions did not differ between the 1-dose and 2-dose regimens (p = 0.5).

# Breakthrough Infections Among Adolescents and Adults
In postlicensure studies o f adolescents and adults who received 2 doses, 40 (9%) cases o f breakthrough varicella occurred among 461 vaccine recipients who were followed for 8 weeks-11.8 years (mean: 3.3 years) after vaccination (95), and 12 (10%) cases occurred among 120 vaccine recipi ents who were followed for 1 m onth-20.6 years (mean: 4.6 years) (94). One prelicensure study o f persons who had received 2 doses o f vaccine reported that 12 (8%) breakthrough cases had occurred among 152 vaccine recipients who were followed for 5-66 months (mean: 30 months) postvaccina tion (93).

# Contagiousness
Prelicensure clinical trials reported the rate o f disease trans mission from vaccinated persons with varicella cases to their vaccinated siblings. In 10 trials that were conducted during 1981-1989, breakthrough infections occurred in 114 (5.3%) o f 2,163 vaccinated children during the 1-8 year follow-up period o f active surveillance, and secondary transmission oc curred to 11 (12.2%) o f their 90 vaccinated siblings (121). Illness was mild in both index and secondary case-patients. Household transmission from a vaccinated child with break through disease to a susceptible adult (one o f whom died) have been reported (C D C , unpublished data, 2006). One study examined secondary attack rates from vaccinated and unvaccinated persons with varicella to both vaccinated and unvaccinated households contacts aged 12 months-14 years (119). This study demonstrated that vaccinated persons with varicella with 50 lesions were as contagious as unvaccinated persons with varicella (119). Vaccinated per sons with varicella tend to have milder disease, and, although they are less contagious than unvaccinated persons with vari cella, they might not receive a diagnosis and be isolated. As a result, they might have more opportunities to infect others in community settings, thereby further contributing to V ZV transmission. Vaccinated persons with varicella also have been index case-patients in varicella outbreaks (3,4,115).

# Risk Factors for Vaccine Failure
Potential risk factors for vaccine failure have been identified in studies o f vaccine effectiveness during outbreak investiga tions and other specially designed studies (5,(108)(109)(110)(113)(114)(115)118,125). In outbreak investigations, the low number of cases limits the ability o f researchers to conduct multivariate analyses and examine the independent effect o f each risk fac tor for vaccine failure. An increased risk for breakthrough dis ease has been noted with decreasing age at vaccination, with a threefold increase in breakthrough disease risk for children vaccinated at age 3, >5, or >5 years) was associated with an increased risk for breakthrough disease (relative risk  = 2.6, 6.7, and 2.6, respectively) (5,114,115). However, age at vaccination and time since vaccination are highly cor related, and their independent association with the risk for breakthrough disease has been assessed in only one outbreak investigation (113). A retrospective cohort study that adjusted for other potential risk factors demonstrated an increased risk for breakthrough disease for children vaccinated at age 15 months (99%) (p = 0.01) (118). However, the difference in the overall effectiveness between children vaccinated at these ages was not statistically significant for subsequent years (8 years o f follow-up) (81% and 88%, respectively; p = 0.17). Active surveillance data collected during 1995-2004 from a sentinel population o f 350,000 persons were analyzed to determine whether the severity and annual incidence o f break through varicella cases increased with time since vaccination (126). Children vaccinated >5 years previously were 2.6 times more likely to have moderate and severe breakthrough Multiple other studies that examined possible reasons for lower vaccine effectiveness did not find age at vaccination (3)(4)(5)111,114) or time since vaccination (3,110,111) to be associated with vaccine failure. An ongoing study is examin ing these factors and risk for vaccine failure (127). After 8 years o f active follow-up o f 7,449 children vaccinated at age 12-23 months, results do not indicate an increased risk for break through disease among children vaccinated at age 12-14 months compared with those vaccinated at age 15-23 months. Moreover, a test for trend revealed no change in the rate of reported breakthrough disease for each additional month of age at vaccination (127).
Two outbreak investigations noted an increased risk for breakthrough disease in children with asthma and eczema (109,113). In these investigations, the use o f steroids to treat asthma or eczema was not studied. Steroids have been associ ated previously with severe varicella in unvaccinated persons (128)(129)(130). Only one retrospective cohort study controlled simultaneously for the effect o f multiple risk factors, includ ing the use o f steroids, and this study demonstrated no asso ciation o f risk for breakthrough disease with asthma or eczema (125). However, this study documented an increased risk for breakthrough disease if the child had received a prescription o f oral steroids (considered a proxy for taking oral steroids when exposed to varicella) within 3 months o f breakthrough disease (adjusted RR  = 2.4; CI = 1.3%-4.4%) and when varicella vaccination was administered within 28 days o f M M R vaccine (aRR = 3.1; CI = 1.5%-6.4%).

# Evidence of Im m unity
ACIP has approved criteria for evidence o f immunity to varicella (Box). Only doses ofvaricella vaccines for which writ ten documentation o f the date o f administration is presented should be considered valid. Neither a self-reported dose nor a history o f vaccination provided by a parent is, by itself, con sidered adequate evidence o f immunity. Persons who lack docu mentation o f adequate vaccination or other evidence o f immunity should be vaccinated.
Historically, self-reporting o f varicella disease by adults or by parents for their children has been considered valid evi dence o f immunity. The predictive value o f a self-reported positive disease history was extremely high in adults in the prevaccine era although data on positive predictive value are lacking in parental reports regarding their children (131)(132)(133).

# Simultaneous Adm inistration of Vaccines
Single-antigen varicella vaccine is well-tolerated and effec tive in healthy children aged >12 months when administered simultaneously with M M R vaccine either at separate sites and with separate syringes or separately >4 weeks apart. The num ber and types o f adverse events occurring in children who have received VARIVAX and M M RII concurrently have not dif fered from those in children who have been administered the vaccines at different visits (79,135). D ata concerning the effect o f simultaneous administration o f VARIVAX with vac cines containing various combinations o f M M R, diphtheria and tetanus toxoids and pertussis (D TP), and Haemophilus influenzae type b (Hib) have not been published (79). A ran domized study o f 694 subjects determined that the immune response to M M R, varicella, and Hib vaccines administered concurrently with a fourth dose o f pneumococal conjugate vaccine (PCV7) was not inferior to that o f those vaccines when administered without PCV7; the percentage o f subjects who seroconverted was >90% for all antigens for both groups (136).
Concomitant administration o f the combination M M RV vaccine with other vaccines also has been assessed. In a clini cal trial involving 1,913 healthy children aged 12-15 months, three groups were compared (137). One group received con comitantly administered (at separate sites) M M RV vaccine, Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Absorbed (DTaP), Hib conjugate (meningococcal protein conjugate) vaccine, and hepatitis B (recombinant) (Hep B) vaccine. The second group received M M RV vaccine at the initial visit, followed by DTaP, Hib, and Hep B vac cines administered concomitantly 6 weeks later. The third group received M M R and varicella vaccines concomitantly followed 6 weeks later by DTaP, Hib, and Hep B vaccines. Seroconversion rates and antibody titers were comparable for the measles, mumps, rubella, and varicella components for the first two groups. No immunologic data were reported for the third group. The Hib and Hep B seroconversion rates for the two groups that received those vaccines also were comparable.
Data are absent or limited for the concomitant use o f MMRV vaccine with inactivated polio, pneum ococal conjugate, influenza, and hepatitis A vaccines. Simultaneous administra tion o f the majority o f widely used live and inactivated vac cines has produced seroconversion rates and rates o f adverse reactions similar to those observed when the vaccines are administered separately. Therefore, single-antigen and com bination M M RV vaccines may be administered simultaneously with other vaccines recommended for children aged 12-15 months and those aged 4 -6 years. Simultaneous administra tion is particularly important when health-care providers anticipate that, because o f certain factors (e.g., previously missed vaccination opportunities), a child might not return for subsequent vaccination.

# Economic Analysis of Vaccination
A cost-effectiveness analysis was performed before initia tion o f the varicella vaccination program in the United States (138). The results o f the study indicated a savings o f $5.40 for each dollar spent on routine vaccination o f preschool-aged children when direct and indirect costs were considered. When only direct medical costs were considered, the benefit-cost ratio was 0.9:1.0. Benefit-cost ratios were only slightly lower when lower estimates o f the short-and long-term effectiveness of the vaccine were used.
A recent analysis was performed that used current estimates o f morbidity and mortality (20,28,33) and current direct and indirect costs (ACIP, unpublished presentation, 2006). The model considered that the second dose will reduce varicella disease residual after the first dose by 79% . From a societal perspective, both 1-dose and 2-dose vaccination programs are cost saving compared with no program. The vaccine program cost was estimated at $320 million for 1 dose and $538 mil lion for 2 doses. The savings from varicella disease prevented were estimated at approximately $1.3 billion for the 1-dose program and approximately $1.4 billion for the 2-dose pro gram. Compared with the 1-dose program, the incremental cost for the second dose was estimated to be $96,000 per qual ity-adjusted life year (QALY) saved. I f benefits from prevent ing group A streptococcus infections and H Z am ong vaccinated persons are added, incremental costs per QALY saved are $91,000 and $17,000, respectively. Because o f the uncertainty o f the modeled predictions o f an increase in H Z among persons with a history o f varicella and the fact that no consistent trends demonstrate an increase in H Z attributable to the varicella vaccination program in the United States, H Z among persons with a history o f varicella was not included in the model.

# MMWR June 22, 2007

# Storage, H andling, and Transportation of Varicella Vaccines
Single-antigen varicella and combination M M RV vaccines have similar but not identical distribution, handling, and stor age requirements (79,80). For potency to be maintained, the lyophilized varicella vaccines must be stored frozen at an aver age temperature o f 5F (-15C) or colder. Household freezers manufactured since the mid-1980s are designed to maintain temperatures from -4F (-20C) to 5F (-15C). When tested, VARIVAX has remained stable in frost-free freezers. Freezers that reliably maintain an average temperature o f <5F (<-15C) and that have a separate sealed freezer door are acceptable for storing VARIVAX and ProQuad. Health-care providers may use stand-alone freezers or the freezer compartment o f refrig erator-freezer combinations, provided that the freezer com partment has its own separate, sealed, and insulated exterior door. Units with an internal freezer door are not acceptable. Temperatures should be documented at the beginning and end o f each day. Providers should document the required tem perature in a newly purchased unit for a minimum o f 1 week before using it to store vaccine and routinely thereafter. When varicella vaccines are stored in the freezer compartment o f a combined refrigerator-freezer, temperatures in both compart ments should be monitored carefully. Setting the thermostat low enough for storage o f varicella-containing vaccines might inadvertently expose refrigerated vaccines to freezing tempera tures. Refrigerators with ice compartments that either are not tightly enclosed or are enclosed with unsealed, uninsulated doors (e.g., small, dormitory-style refrigerators) are not acceptable for the storage o f varicella vaccines.
Diluent should be stored separately either at room tempera ture or in the refrigerator. Vaccines should be reconstituted according to the directions in the package insert and only with the diluent supplied with the vaccine, which does not contain preservative or other antiviral substances that could inactivate the vaccine virus. Once reconstituted, vaccine should be used immediately to minimize loss o f potency. Vaccine should be discarded if not used within 30 minutes after reconstitution.

# Handling and Transportation of Varicella Vaccines Within Off-Site Clinics
When an immunization session is being held at a site dis tant from the freezer in which the vaccine is stored, the num ber o f vaccine vials needed for the immunization session should be packed in either a vaccine shipping container (as received from the manufacturer) or in an insulated cooler, with an adequate quantity o f dry ice (i.e., a minimum o f 6 lbs per box) to preserve potency. When placed in a suitable container, dry ice will maintain a temperature o f <5F (<-15C). Dry ice should remain in the container upon arrival at the clinic site. If no dry ice remains when the container is opened at the receiving site, the manufacturer (Merck and Company, Inc.) should be contacted for guidance (telephone: 1-800-982 7482). If dry ice is available at the receiving site, it may be used to store vaccine. Thermometers or temperature indica tors cannot be used in a container with dry ice. Diluent should not be transported on dry ice.
If dry ice is not available, only single-antigen varicella vac cine may be transported, with frozen packs to keep the tem peratures between 3 6F -4 6F ( 2C -8C ) . T ran sport temperatures should be monitored, and a temperature indi cator or thermometer should be placed in the container and checked on arrival. The container should be kept closed as much as possible during the immunization session; tempera tures should be checked and recorded hourly. If the tempera ture rem ains betw een 3 6F -4 6F ( 2C -8C ) , the single-antigen varicella vaccine may be used for up to 72 hours after its removal from the freezer. The date and time should be marked on the vaccine vial. Single-antigen varicella vac cine stored at refrigerated temperatures for any period o f time may not be refrozen for future use.
Transportation and storage o f combination M M RV vaccine at temperatures between 36F-46F (2C -8C ) is not permis sible for any length o f time. In contrast to single-antigen vari cella vaccine, combination M M RV vaccine must be maintained at temperatures o f <5F (<-15C) until the time o f reconstitu tion and administration. This difference in vaccine storage tem peratures must be considered when planning off-site clinics. For this reason, transportation o f M M RV vaccine to off-site clinics is not advised. If any concerns arise regarding the storage o f single-antigen varicella or combination MMRV vaccines, the manufacturer should be contacted for guidance.

# Minimizing Wastage of Vaccine
Vaccine wastage can be minimized by accurately determin ing the number o f doses needed for a given patient popula tion. To ensure maximal vaccine potency, smaller shipments o f vaccine should be ordered more frequently (preferably at least once every 3 months). Single-antigen varicella vaccine should not be distributed to providers who do not have the capacity to store it properly in a freezer until it is used. Trans portation o f varicella vaccine should be kept to a minimum to prevent loss o f potency. Off-site clinic sites should receive only such amounts o f vaccine as they can use within a short time (72 hours if storing single-antigen varicella vaccine at refrig erated temperatures).

# Adverse Events A fter Vaccination
Because adverse events after vaccination might continue to be caused by wild-type V Z V even as varicella disease declines, health-care providers should obtain event-appropriate clini cal specimens (e.g., cerebrospinal fluid for encephalitis, bron chial lavage or lung biopsy for pneumonia) for laboratory evaluation, including strain identification. Information regard ing strain identification is available from Merck's V Z V Iden tification Program (telephone: 1-800-652-6372) or from C D C 's National Varicella Reference Laboratory (telephone: 4 0 4 -6 3 9 -0 0 6 6 ; e-mail: vzvlab@cdc.gov) or at . cdc.gov/nip/diseases/varicella/surv/default.htm. Commercial laboratories do not have the capability for strain identification.
The National Vaccine Injury Act o f 1986 requires physi cians and other health-care providers who administer vaccines to maintain permanent immunization records and to report occurrences o f adverse events for selected vaccines, including varicella vaccines. Serious adverse events (i.e., all events requiring medical attention) suspected to have been caused by varicella vaccines should be reported to the Vaccine Adverse Event Reporting System (VAERS). Forms and instruc tion s are available at h ttp s c u re .v a e rs.o rg / vaersDataEntryintro.htm , in the FD A D rug Bulletin at , or from the 24-hour VAERS information recording at 1-800 822-7967.

# Prelicensure Single-Antigen Varicella Vaccine
Single-antigen varicella vaccine was well-tolerated when administered to >11,000 healthy children, adolescents, and adults during prelicensure clinical trials. In a double-blind, placebo-controlled study among 914 susceptible healthy chil dren aged 12 m onths-14 years, the only statistically signifi cant (p<0.05) adverse events reported that were more common among vaccine recipients than among placebo recipients were pain and redness at the injection site (103). This study also described the presence o f unspecific rash among 2% o f pla cebo and 4% o f vaccine recipients occurring within 43 days o f vaccination. O f the 28 reported rashes, 10 (36%) were examined by a physician; among those that were examined, four o f the seven noninjection site rashes in vaccine recipients were judged to be varicella-like, compared with none o f the rashes in the placebo recipients.
In a study comparing the safety o f 1 dose o f single-antigen varicella vaccine with that o f 2 doses administered 3 months apart, no serious adverse events related to vaccination were reported among approximately 2,000 healthy subjects aged 12 m onths-12 years who were followed for 42 days after each injection. The 2-dose vaccine regimen was generally welltolerated, and its safety profile was comparable to that o f the 1-dose regimen. Incidence o f injection site com plaints observed <3 days after vaccination was slightly higher after dose 2 (25.4%) than after dose 1 (21.7%). Incidence o f sys temic clinical complaints was lower after dose 2; fever inci dence from days 7-21 was 7% after dose 1 and 4% after dose 2 (p = 0.009), and varicelliform rash incidence after dose 1 was 3%, compared with 1% after dose 2 (p = 0.008), with peak occurrence 8-21 days after vaccination (139).
In uncontrolled trials o f persons aged >13 years , approxi mately 1,600 vaccine recipients who received 1 dose o f single antigen varicella vaccine and 955 who received 2 doses of vaccine were monitored for 42 days for adverse events (79). After the first and second doses, 24.4% and 32.5% o f vaccine recipients, respectively, had complaints regarding the injec tion site. Varicella-like rash at the injection site occurred in 3% o f vaccine recipients after the first injection and in 1% after the second. A nonlocalized rash occurred in 5.5% of vaccine recipients after the first injection and in 0.9% o f vac cine recipients after the second, at a peak o f 7-21 and 0-23 days postvaccination, respectively.

# Combination MMRV Vaccine
In clinical trials, combination M M RV vaccine was admin istered to 4,497 children aged 12-23 months without con comitant administration with other vaccines (80). The safety profile of the first dose was compared with the safety o f MMRII vaccine and VARIVAX administered concomitantly at sepa rate injection sites. The follow-up period was 42 days post vaccination. Systemic vaccine-related adverse events were reported at a statistically significantly greater rate in persons who received M M RV vaccine than in persons who received the two vaccines administered concomitantly at separate injection sites: fever (>102F  oral equivalent), (21.5% and 14.9%, respectively), and measles-like rash (3.0% and 2.1% , respectively). Both fever and measles-like rash usu ally occurred within 5-12 days after the vaccination, were of short duration, and resolved with no long-term sequelae. Pain, tenderness, and soreness at the injection site were reported at a statistically significantly lower rate in persons who received To demonstrate that M M RV vaccine could be administered as a second dose, a study was conducted involving 799 chil dren aged 4 -6 years who had received primary doses o f MMRII and VARIVAX vaccines, either concomitantly or not, at age >12 months and >1 month before study enrollment (91).

# Postlicensure
During March 1, 1995-December 31, 2005, a total o f 47.7 million doses o f varicella vaccine were distributed in the United States, and 25,306 adverse events that occurred after varicella vaccine administration were reported to VAERS, 1,276 (5%) o f which were classified as serious. The overall adverse event reporting rate was 52.7 cases per 100,000 doses distributed. The rate o f reporting o f serious adverse events was 2.6 per 100,000 doses distributed. H alf o f all adverse events reported occurred am ong children aged 1 2-23 months (VAERS, unpublished data, 2006).
N ot all adverse events that occur after vaccination are reported, and many reports describe events that might have been caused by confounding or unrelated factors (e.g., medi cations and other diseases). Because varicella disease contin ues to occur, wild-type virus might account for certain reported events. For serious adverse events for which background inci dence data are known, VAERS reporting rates are lower than expected after natural varicella or than background rates of disease in the community. Inherent limitations o f passive safety surveillance impede comparing adverse event rates after vac cination reported to VAERS with those from complications after natural disease. Nevertheless, the magnitude o f these dif ferences suggests that serious adverse events occur at a substantially lower rate after vaccination than after natural disease. This assumption is corroborated by the substantial decline in the number o f severe complications, hospitaliza tions, and deaths related to varicella that have been reported since implementation o f the varicella vaccination program (22,23,28).
Similar to the prelicensure experience, postlicensure safety surveillance data after administration o f single-antigen vari cella vaccine indicated that rash, fever, and injection-site reac tions were the most frequently reported adverse events (140,141). Using these reports from passive surveillance of adverse events during the first 4 years o f the vaccination pro gram, when wild-type V Z V was still circulating widely, poly merase chain reaction (PCR) analysis confirmed that the majority o f rash events occurring within 42 days o f vaccina tion were caused primarily by wild-type varicella-zoster virus. Rashes from the wild-type virus occurred a median o f 8 days after vaccination (range: 1-24 days), whereas rashes from the vaccine strain occurred a median o f 21 days after vaccination (range: 5-42 days) (140).
As part o f postmarketing evaluation o f the short-term safety o f VARIVAX, 89,753 vaccinated adults and children were identified from automated clinical databases o f hospitals, emergency room visits, and clinic visits during April 1995-December 1996 (56). Out o f all potential adverse events iden tified, no consistent time association or clustering o f any events was noted during the exposure follow-up period. No cases o f ataxia or encephalitis were identified after receipt o f varicella vaccine in this group o f vaccine recipients. In the prevaccine era, among children aged <15 years, acute cerebellar ataxia was estimated to occur at a rate o f one in 4,000 varicella cases, and varicella encephalitis without ataxia was estimated to occur at one in 33,000 varicella cases (142).
Severe complications that are laboratory-confirmed to be caused by vaccine virus strain are rare and include pneumonia (140), hepatitis (143), severe disseminated varicella infection (140,141,144,145), and secondary transmission from five vaccine recipients (140,(146)(147)(148). Except for the secondary tran sm issio n cases, these cases all occu rred in immunocompromised patients or in persons who had other serious medical conditions that were undiagnosed at the time o f vaccination.
Although other serious adverse events have been reported, vaccine strain involvement was not laboratory-confirmed. Thrombocytopenia (140,141,149) and acute cerebellar ataxia (140,141,150) have been described as potentially associated with single-antigen varicella vaccine. Two children had acute hemiparesis diagnosed after varicella vaccination (one at 5 days and the other at 3 weeks) (151). In both cases, unilateral infarction o f the basal ganglia and internal capsule was noted; this distribution is consistent with varicella angiopathy. Urti caria after varicella vaccine has been associated with gelatin allergy (152). Recurrent papular urticaria has been reported to be potentially associated with varicella vaccination (153). However, available data regarding the potential adverse events after varicella vaccination are insufficient to determine a causal association. The quality o f reported information varies widely, and simultaneous administration with other vaccines (especially M M R) might confound attribution.
Herpes Zoster. Similar to wild-type VZV, vaccine virus can establish latent infection and subsequently reactivate, causing H Z disease in vaccine recipients. Before vaccine licensure, studies in children with leukemia had demonstrated a much lower rate o f H Z in vaccinated children compared with those (age and protocol matched) with previous varicella (54). Cases o f H Z in healthy vaccine recipients have been confirmed to be caused by both vaccine virus and wild-type virus, suggesting that certain H Z cases in vaccine recipients might result from antecedent natural varicella infection that might not have been detected by the patient or from infection after vaccination (140). A single case has been reported o f a child who received a diagnosis of neuroblastoma and had severe chronic zoster attributed to vac cine virus strain that with time became drug resistant (145). A large postlicensure safety study performed through surveys con ducted every 6 months and validated by medical chart review in the first 9 years o f a 15-year follow-up study o f >7,000 en rolled children vaccinated with single-antigen varicella vaccine at age 12-24 months estimated H Z disease incidence to be 22 per 100,000 person-years (CI = 13-37) as reported by parents (Steven Black, M D , Northern California Kaiser Permanente Medical Care Program, unpublished presentation, 2005). The incidence o f H Z was 30 per 100,000 person-years among healthy children aged 5-9 years (154) and 46 per 100,000 per son-years for those aged <14 years (64). However, these rates are drawn from different populations and based on different methodologies. In addition, a proportion o f children in these age groups would not have experienced varicella disease; those rates are likely to underestimate rates in a cohort o f children all infected with wild-type VZV, making direct comparison difficult with a vaccinated cohort.

# Transmission of Vaccine Virus
Results from prelicensure vaccine trials o f the single antigen varicella vaccine suggest that transmission o f varicella vaccine virus from healthy persons to susceptible contacts is rare. This risk was assessed in siblings o f healthy vaccinated children who themselves received placebo (103). Six (1%) o f 439 placebo recipients seroconverted without rash; the vacci nated siblings o f these six children also did not develop rash. Serologic data suggested that three o f these six seroconverters received vaccine mistakenly in lieu o f their siblings. In a smaller study, immunocompromised siblings o f healthy children receiving varicella vaccine were evaluated clinically and by test ing for humoral or cell-mediated immune responses (155). No evidence was demonstrated o f vaccine virus transmission to any o f 30 immunocompromised siblings from 37 healthy children receiving varicella vaccine.
Accumulated data from postlicensure surveillance activities suggest that the risk for transmission o f varicella vaccine virus from healthy persons to susceptible contacts is low. With >55 million doses ofVARIVAX distributed since licensure, trans mission from immunocompetent persons after vaccination has been documented by PC R analysis from only five persons, resulting in six secondary infections, all o f them mild (140,(146)(147)(148). Three episodes involved transmission from healthy children aged 1 year to healthy household contacts, including a sibling aged 4 months, a father, and a pregnant mother. In the latter episode, the mother chose to terminate the pregnancy, but fetal tissue tested subsequently by PC R was negative for varicella vaccine virus (147). The children in these episodes had 2, 12, and 30 lesions, respectively. A fourth episode involved transmission from an immunocompetent adolescent who was a resident in an institution for chroni cally disabled children. The adolescent had >500 lesions after vaccination, and vaccine virus was transmitted to another immunocompetent resident o f the institution and to a health care worker, both o f whom had histories o f varicella (146). The fifth episode represented a tertiary spread from a healthy sibling contact o f a vaccinee with leukemia (148). Rashes for both healthy siblings were mild (i.e., 40 and 11 lesions, respectively), and vaccine virus was isolated from all three casepatients. The third sibling had rash 18 days after the onset of the secondary case-patient and 33 days after rash onset in the vaccinated leukemic child. In addition to these five episodes, one child has been reported to have transmitted vaccine virus from H Z that occurred 5 months after varicella vaccination; 2 weeks later, a mild varicella-like rash from which vaccine varicella virus was isolated occurred in the child's vaccinated brother (156).
Although varicella vaccine is not recommended for chil dren with cellular immune deficiencies, the experience from prelicensure vaccine trials involving children with leukemia is instructive. Data from a study o f varicella vaccination in chil dren with leukemia indicated that varicella virus vaccine trans mission occurred in 15 (17%) o f 88 healthy, susceptible siblings o f leukemic vaccine recipients; the rash was mild in

# Sum m ary of Rationale for Varicella Vaccination
Varicella vaccine is an effective prevention tool for decreas ing the burden attributable to varicella disease and its compli cations in the United States. In the prevaccine era, varicella was a childhood disease with >90% o f the 4 million cases, two thirds o f approximately 11,000 hospitalizations, and approximately half o f 100-150 annual deaths occurring among persons aged 12 months, and the combination M M RV vaccine is licensed for use in healthy children aged 12 m on ths-12 years. Prelicensure and postlicensure studies have demonstrated that 1 dose o f single antigen varicella vaccine is approximately 85% effective in preventing varicella. Breakthrough varicella disease that occurs after vaccination frequently is mild and modified. Varicella vaccine is >95% effective in preventing severe vari cella disease. Since implementation o f the varicella vaccina tion program in 1995, varicella incidence, hospitalizations, and deaths have declined substantially. M M RV was licensed on the basis o f immunological noninferiority to its vaccine antigenic components. Initial varicella vaccine policy recom mendations were for 1 dose o f varicella vaccine for children aged 12 months-12 years and 2 doses, 4-8 weeks apart, for persons aged >13 years. In June 2006, ACIP approved a rou tine 2-dose recommendation for children. The first dose should be administered at age 12-15 months and the second dose at age 4-6 years.
The rationale for the second dose o f varicella vaccine for children is to further decrease varicella disease and its compli cations in the United States. Despite the successes o f the 1-dose vaccination program in children, vaccine effectiveness o f 85% has not been sufficient to prevent varicella outbreaks, which, although less than in the prevaccine era, have contin ued to occur in highly vaccinated school populations. Break through varicella is contagious. Studies o f the immune re sponse after 1 and 2 doses o f varicella vaccine demonstrate a greater-than-tenfold boost in GM Ts when measured 6 weeks after the second varicella vaccine dose. A higher proportion (>99% ) o f children achieve an antibody response o f >5 gpELISA units after the second dose compared with 7 6 % -85% o f children after a single dose o f varicella vaccine. The second dose o f varicella vaccine is expected to provide im proved protection to the 15% -20% o f children who do not respond adequately to the first dose. D ata from a randomized clinical trial conducted postlicensure indicated that vaccine efficacy after 2 doses o f single-antigen varicella vaccine in chil dren (98.3%; CI = 97.3% -99.0% ) was significantly higher than that after a single dose (94.4%; CI =92.9% -95.7% ). The risk for breakthrough disease was 3.3-fold lower among children who received 2 doses than it was among children who received 1 dose. How this increase in vaccine efficacy (typically higher than observed under field conditions) will translate into vaccine effectiveness under conditions o f com munity use will be an important area o f study.
The recommended ages for routine first (at age 12-15 months) and second (at age 4 -6 years) doses o f varicella vac cine are harmonized with the recommendations for M M R vaccine use and intended to limit the period when children have no varicella antibody. The recommended age for the second dose is supported by the current epidemiology o f varicella, with low incidence and few outbreaks among pre school-aged children and higher incidence and more outbreaks among elementary-school-aged children. However, the sec ond dose may be administered at an earlier age, provided that the interval between the first and second doses is 3 months. The recommendation for the minimum interval between doses is made on the basis o f the design o f the studies evaluating 2 doses among children aged 12 months-12 years. M M RV vaccine may be used to vaccinate children against measles, mumps, rubella, and varicella simultaneously. Because the risk for transmission can be high among students in schools, col leges, and other postsecondary educational institutions, stu dents without evidence o f immunity should receive 2 doses o f varicella vaccine. All children and adolescents who received 1 dose o f varicella vaccine previously should receive a second dose.
Varicella disease is more severe and its complications more frequent among adolescents and adults. The recommenda tion for vaccination o f all adolescents and adults without evidence o f immunity will provide protection in these age gro u p s. B ecau se v aricella m ight be m ore severe in immunocompromised persons who might not be eligible for vaccination, and because o f the risk o f V Z V transmission in health-care settings, H C P must be vaccinated. Varicella dis ease during the first two trimesters o f pregnancy might infect the fetus and result in congenital varicella syndrome. There fore, routine antenatal screening for evidence o f immunity and postpartum vaccination for those without evidence of immunity now is recommended.

# Recommendations for the Use of Varicella Vaccines
Two 0.5-m L doses o f varicella vaccine administered subcu taneously are recommended for children aged >12 months, adolescents, and adults without evidence o f immunity. For children aged 12 m onths-12 years, the recommended mini mum interval between the two doses is 3 months. However, if the second dose was administered >28 days after the first dose, the second dose is considered valid and need not be repeated.

# Routine Vaccination Persons Aged 12 M onths-12 Years

# Preschool-Aged Children
All healthy children should receive their first dose o f vari cella-containing vaccine routinely at age 12-15 months.

# School-Aged Children
A second dose o f varicella vaccine is recommended routinely for all children aged 4 -6 years (i.e., before entering prekindergarten, kindergarten, or first grade). However, it may be administered at an earlier age provided that the interval between the first and second dose is >3 months.
Because o f the risk for transmission o f V Z V in schools, all children entering school should have received 2 doses o f vari cella-containing vaccine or have other evidence o f immunity to varicella (see Evidence o f Immunity).

# Persons Aged > 1 3 Years
Persons aged >13 years without evidence o f varicella immu nity should receive two 0.5-mL doses o f single-antigen vari cella vaccine administered subcutaneously, 4 -8 weeks apart. If >8 weeks elapse after the first dose, the second dose may be administered without restarting the schedule. Only single antigen varicella vaccine may be used for vaccination o f per sons in this age group. M M RV is not licensed for use among persons aged >13 years.

# School-Aged Children, College Students, and Students in Other Postsecondary Educational Institutions
All students should be assessed for varicella immunity, and those without evidence o f immunity should routinely receive 2 doses o f single-antigen varicella vaccine 4 -8 weeks apart. The risk for transmission o f varicella among school-aged chil dren, college students, and students in other postsecondary educational institutions can be high because o f high contact rates.

# Other Adults
All healthy adults should be assessed for varicella immu nity, and those who do not have evidence o f immunity should receive 2 doses o f single-antigen varicella vaccine 4 -8 weeks apart. Adults who might be at increased risk for exposure or transmission and who do not have evidence o f immunity sh ould receive special con sideration for vaccin ation , including 1) HCP, 2) household contacts o f im m uno compromised persons, 3) persons who live or work in envi ronments in which transmission ofV Z V is likely (e.g., teachers, day-care employees, residents and staff in institutional set tings), 4) persons who live or work in environments in which transmission has been reported (e.g., college students, inmates and staff members o f correctional institutions, and military personnel), 5) nonpregnant women o f childbearing age, 6) adolescents and adults living in households with children, and 7) international travelers.

# Second Dose Catch-Up Vaccination
To improve individual protection against varicella and to have a more rapid impact on school outbreaks, second dose catch-up varicella vaccination is recommended for children, adolescents, and adults who previously received 1 dose. The recommended minimum interval between the first dose and the catch-up second dose is 3 months for children aged 13 years. However, the catch-up second dose may be administered at any interval longer than the minimum recommended interval. Catch-up

# MMWR
June 22, 2007 vaccination may be implemented during routine health-care provider visits and through school-and college-entry require ments.
As part o f comprehensive health services for all adolescents, ACIP, AAP, and AAFP recommend a health maintenance visit at age 11-12 years. This visit also should serve as an immuni zation visit to evaluate vaccination status and administer nec essary vaccinations (158). Physicians should use this and other routine visits to ensure that all children without evidence of varicella immunity have received 2 doses o f varicella vaccine.

# Requirements for Entry to Child Care, School, College, and Other Postsecondary Educational Institutions
Child care and school entry requirements for varicella immunity have been recommended previously (2). In 2005, ACIP recommended expanding the requirements to cover stu dents in all grade levels. Official health agencies should take necessary steps, including developing and enforcing school immunization requirements, to ensure that students at all grade levels (including college) and children in child care centers are protected against varicella and other vaccine-preventable diseases (157).

# Prenatal Assessment and Postpartum Vaccination
Prenatal assessment o f women for evidence o f varicella immunity is recommended. Birth before 1980 is not consid ered evidence o f immunity for pregnant women because of potential severe consequences ofvaricella infection during preg nancy, including infection o f the fetus. Upon completion or termination o f their pregnancies, women who do not have evidence o f varicella immunity should receive the first dose of vaccine before discharge from the health-care facility. The sec ond dose should be administered 4 -8 weeks later, which coincides with the postpartum visit (6-8 weeks after deliv ery). For women who gave birth, the second dose should be administered at the postpartum visit. Women should be coun seled to avoid conception for 1 month after each dose o f vari cella vaccine. Health-care settings in which completion or termination o f pregnancy occurs should use standing orders to ensure the administration o f varicella vaccine to women without evidence o f immunity.

# Special Considerations for Vaccination

# Vaccination of HIV-Infected Persons
HIV-infected children with C D 4+ T-lymphocyte percent age >15% should be considered for vaccination with the single antigen varicella vaccine. Varicella vaccine was recommended previously for HIV-infected children in C D C clinical and immunologic categories N1 and A1 with age-specific C D 4+ T-lymphocyte percentage >25% (2). Limited data from a clini cal trial in which 2 doses o f single-antigen varicella vaccine were administered 3 months apart to 37 HIV-infected chil dren (C D C clinical categories N , A, or B and immunologic category 2 ) aged 1-8 years indicated that the vaccine was well-tolerated and that >80% o f subjects had detectable V Z V specific immune response (either antibody or cell immune response or both) at 1 year after immunization (159). These children were no less likely to have an antibody response to the vari cella vaccine than were subjects who were less affected immu nologically by H IV infection. Because children infected with H IV are at increased risk for morbidity from varicella and H Z (i.e., shingles) compared with healthy children, ACIP rec ommends that, after weighing potential risks and benefits, single-antigen varicella vaccine should be considered for HIVinfected children with C D 4+ T-lymphocyte percentages >15%. Eligible children should receive 2 doses o f single-antigen vari cella vaccine 3 months apart. Because persons with impaired cellular immunity are potentially at greater risk for complica tions after vaccination with a live vaccine, these vaccine recipients should be encouraged to return for evaluation if they experience a postvaccination varicella-like rash. D ata are not available regarding safety, immunogenicity, or efficacy of M M RV vaccine in HIV-infected children, M M RV vaccine should not be administered as a substitute for the single antigen varicella vaccine when vaccinating these children. The titer o f Oka/Merck V Z V is higher in combination M M RV vaccine than in single-antigen varicella vaccine. Recommen dations for vaccination o f HIV-infected children with measles, mumps, or rubella vaccines have been published previously (160).
D ata on use o f varicella vaccine in HIV-infected adoles cents and adults are lacking. However, on the basis o f expert opinion, the safety o f varicella vaccine in HIV-infected per sons aged >8 years with comparable levels o f immune func tion (CD4+T-lymphocyte count >200 cells/^L) is likely to be similar to that o f children aged 200 cells/^L in these age groups. I f vaccination o f HIV-infected persons results in clinical disease, the use o f acyclovir might modify the severity o f disease.

# Situations in Which Some Degree of Immunodeficiency Might be Present
Persons with impaired humoral immunity may be vacci nated. No data have been published concerning whether per sons without evidence o f immunity receiving only inhaled, nasal, or topical doses o f steroids can be vaccinated safely. However, clinical experience suggests that vaccination is welltolerated among these persons. Persons without evidence of immunity who are receiving systemic steroids for certain con d itio n s (e.g ., asth m a) and who are not otherw ise immunocompromised may be vaccinated if they are receiving 2 mg/kg prednisone) for >2 weeks may be vaccinated once steroid therapy has been discontinued for >1 month, in accordance with the general recommendations for the use o f live-virus vaccines (157).
Vaccination o f leukemic children who are in remission and who do not have evidence o f immunity to varicella should be undertaken only with expert guidance and with the availabil ity o f antiviral therapy should complications ensue. Patients with leukemia, lymphoma, or other malignancies whose dis ease is in remission and whose chemotherapy has been termi nated for at least 3 months can receive live-virus vaccines (157). When immunizing persons in whom some degree o f immu nodeficiency might be present, only single-antigen varicella vaccine should be used.

# Vaccination of Household Contacts of Immunocompromised Persons
Immunocompromised persons are at high risk for serious varicella infections. Severe disease occurs in approximately 30% o f such persons with primary infection. Because varicella vac cine now is recommended for all healthy children and adults w ithout evidence o f im m unity, household contacts o f immunocompromised persons should be vaccinated routinely. A lth o u gh the risk for exposure to w ild V Z V for immunocompromised persons now is lower than it was pre viously, vaccine should be offered to child and adult house hold con tacts w ith ou t evidence o f im m u n ity o f immunocompromised persons. Vaccination o f household con tacts provides protection for immunocompromised persons by decreasing the likelihood that wild-type V ZV will be introduced into the household. Vaccination o f household con tacts o f immunocompromised persons theoretically might pose a m in im al risk for tran sm issio n o f vaccine virus to immunocompromised persons, although in one study, no evi dence o f transmission o f vaccine virus was demonstrated after vaccination o f 37 healthy siblings o f 30 children with malig nancy (155). No cases have been documented o f transmission o f vaccine virus to immunocompromised persons in the postlicensure period in the United States, with >55 million doses o f vaccine distributed. Other data indicate that disease caused by vaccine virus in immunocompromised persons is milder than wild-type disease and can be treated with acyclovir (148,159). The benefits o f vaccinating susceptible household contacts o f im m unocom prom ised persons outweigh the extremely low potential risk for transmission o f vaccine virus to immunocompromised contacts. Vaccine recipients in whom vaccine-related rash occurs, particularly H C P and household contacts o f immunocompromised persons, should avoid con tact with susceptible persons who are at high risk for severe complications. If a susceptible, immunocompromised person is inadvertently exposed to a person who has a vaccine-related rash, postexposure prophylaxis with V Z IG is not needed because disease associated with this type o f virus is expected to be mild.

# Nursing Mothers
Postpartum vaccination o f women without evidence o f im munity need not be delayed because o f breastfeeding. Women who have received varicella vaccination postpartum may con tinue to breastfeed. The majority o f live vaccines are not asso ciated with virus secretion in breast milk (157). A study involving 12 women who received single-antigen varicella vac cine while breastfeeding indicated no evidence ofV Z V D N A June 22, 2007 either in 217 breast milk samples collected or in infants tested after both vaccine doses (162). No infants seroconverted. Another study did not detect varicella gene sequences in the postvaccination breast milk samples (163). Therefore, single antigen varicella vaccine should be administered to nursing mothers without evidence o f immunity. Combination MMRV vaccine is not licensed for use among persons aged >13 years.

# H ealth -C are Personnel
N osocom ial transm ission o f V Z V is well-recognized (131,(164)(165)(166)(167)(168)(169)(170)(171)(172)(173), and guidelines for the prevention o f nosoco mial V Z V infection and for infection control in H C P have been published (174,175). Sources o f nosocomial exposure have included patients, hospital staff, and visitors (e.g., the children o f hospital employees) who are infected with vari cella or H Z. In hospitals, airborne transmission o f V Z V has been demonstrated when varicella has occurred in susceptible persons who had no direct contact with the index casepatient (176)(177)(178)(179)(180).
To prevent disease and nosocomial spread o f VZV, health care institutions should ensure that all H C P have evidence of immunity to varicella. Birth before 1980 is not considered evidence o f immunity for H C P because o f the possibility of nosocomial transmission to high-risk patients. In health-care institutions, serologic screening before vaccination o f person nel who have a negative or uncertain history o f varicella and who are unvaccinated is likely to be cost effective. Institutions may elect to test all H C P regardless o f disease history because a small proportion o f persons with a positive history o f disease might be susceptible.
Routine testing for varicella immunity after 2 doses o f vac cine is not recommended for the management o f vaccinated HCP. Available commercial assays are not sensitive enough to detect antibody after vaccination in all instances. Sensitive tests have indicated that 99% o f adults develop antibodies after the second dose. However, seroconversion does not always result in full protection against disease, and no data regarding correlates o f protection are available for adults.
H C P who have received 2 doses o f vaccine and who are exposed to V Z V should be monitored daily during days 10 21 after exposure through the employee health program or by an infection control nurse to determine clinical status (i.e., daily screen for fever, skin lesions, and systemic symptoms). Persons with varicella might be infectious up to 2 days before rash onset. In addition, H C P should be instructed to report fever, headache, or other constitutional symptoms and any atypical skin lesions immediately. H C P should be placed on sick leave immediately if symptoms occur. Health-care insti tutions should establish protocols and recommendations for screening and vaccinating H C P and for management o f H CP after exposures in the work place.
H C P who have received 1 dose o f vaccine and who are exposed to V Z V should receive the second dose with single antigen varicella vaccine within 3-5 days after exposure to rash (provided 4 weeks have elapsed after the first dose). After vaccination, management is similar to that o f 2-dose vaccine recipients.
Unvaccinated H C P who have no other evidence o f immu nity who are exposed to V Z V are potentially infective from days 10-21 after exposure and should be furloughed during this period. They should receive postexposure vaccination as soon as possible. Vaccination within 3-5 days o f exposure to rash might modify the disease if infection occurred. Vaccina tion >5 days postexposure still is indicated because it induces protection against subsequent exposures (if the current exposure did not cause infection).
The risk for transmission o f vaccine virus from vaccine recipients in whom varicella-like rash occurs after vaccination is low and has been documented after exposures in house holds and long-term care facilities (140,(146)(147)(148). No cases have been documented after vaccination o f HCP. The ben efits o f vaccinating H C P without evidence o f immunity out weigh this extremely low potential risk. As a safeguard, institutions should consider precautions for personnel in whom rash occurs after vaccination. H C P in whom a vaccine-related rash occurs should avoid contact with persons without evidence o f immunity who are at risk for severe disease and complications until all lesions resolve (i.e., are crusted over or fade away) or no new lesions appear within a 24-hour period.

# Varicella IgG Antibody Testing
The tests most widely used to detect varicella IgG antibody after natural varicella infection among H C P are latex aggluti nation (LA) and ELISA. A commercially available LA test using latex particles coated with V Z V glycoprotein antigens can be completed in 15 minutes and does not require special equip ment (181). The sensitivity and specificity o f the LA test are comparable to those o f FAMA in detecting antibody response after natural varicella infection. The LA test generally is more sensitive than commercial ELISAs. The LA test has detected antibody for up to 11 years after varicella vaccination (182). However, for the purpose o f screening H C P for varicella sus ceptibility, a less sensitive and more specific commercial ELISA should be considered. A recent report indicated that the LA test can produce false-positive results, particularly when only a single concentration o f serum is evaluated (183); this led to documented cases o f false-positive results in H C P who conse quently remained unvaccinated and subsequently contracted varicella.

# Vaccination for O u tb rea k Control
Varicella vaccination is recommended for outbreak control. Persons who do not have adequate evidence ofimmunity should receive their first or second dose as appropriate. Additionally, in outbreaks among preschool-aged children, 2-dose vaccination is recommended for optimal protection, and children vacci nated with 1 dose should receive their second dose provided 3 months have elapsed since the first dose. State and local health departments may advise exposed persons who do not have evi dence o f immunity to contact their health-care providers for vaccination, or they may offer vaccination through the health department or school (or other institutions) vaccination clin ics. Although outbreak control efforts optimally should be imple mented as soon as an outbreak is identified, vaccination should be offered even if the outbreak is identified late. Varicella out breaks in certain settings (e.g., child care facilities, schools, or institutions) can last as long as 4-5 months. Thus, offering vac cine during an outbreak might provide protection to persons not yet exposed and shorten the duration of the outbreak (184). Persons receiving either their first or second dose as part o f the outbreak control program may be readmitted to school imme diately. Those vaccinated with the first dose as part o f outbreak control measures should be scheduled for the second dose as age appropriate. Persons who are unvaccinated and without other evidence o f immunity who do not receive vaccine should be excluded from institutions in which the outbreak is occurring until 21 days after the onset o f rash in the last case o f varicella. In addition, for school-aged persons covered by the 2-dose school vaccination requirements, exclusion during an outbreak is rec ommended for those vaccine recipients who had received the first dose before the outbreak but not the second as part o f the oubtreak control program. Persons at increased risk for severe varicella who have contraindications to vaccination should receive V ZIG within 96 hours o f exposure.

# Contraindications General
Adequate treatment provisions for anaphylactic reactions, including epinephrine injection (1:1000), should be available for immediate use should an anaphylactic reaction occur. Before administering a vaccine, health-care providers should obtain the vaccine recipient's vaccination history and deter mine whether the individual had any previous reactions to any vaccine including VARIVAX, ProQuad or any measles, mumps, or rubella containing vaccines.

# Allergy to Vaccine Components
The administration o f live varicella-containing vaccines rarely results in hypersensitivity. The information in the pack age insert should be reviewed carefully before vaccine is administered. Vaccination is contraindicated for persons who have a history o f anaphylactic reaction to any component o f the vaccine, including gelatin. Single-antigen varicella vaccine does not contain preservatives or egg protein; these substances have caused hypersensitive reactions to other vaccines. For the combination M M RV vaccine, live measles and live mumps vaccines are produced in chick embryo culture. However, among persons who are allergic to eggs, the risk for serious allergic reactions after administration o f measles-or mumpscontaining vaccines is low. Because skin testing with vaccine is not predictive o f allergic reaction to vaccination, skin test ing is not required before administering combination M M RV vaccine to persons who are allergic to eggs (160). The major ity o f anaphylactic reactions to measles-and m um pscontaining vaccines are associated not with hypersensitivity to egg antigens but with other vaccine components. Neither single-antigen varicella nor combination M M RV vaccines should be administered to persons who have a history o f ana phylactic reaction to neomycin. However, neomycin allergy usually is manifested as a contact dermatitis, which is a delayedtype immune response rather than anaphylaxis. For persons who experience such a response, the adverse reaction, if any, would appear as an erythematous, pruritic nodule or papule present 48-96 hours after vaccination. A history o f contact dermatitis to neomycin is not a contraindication to receiving varicella vaccines. Varicella vaccines should not be administered to persons receiving high-dose systemic immunosuppressive therapy, including persons on oral steroids >2 mg/kg o f body weight or a total o f >20 mg/day o f prednisone or equivalent for per sons who weigh >10 kg, when administered for >2 weeks. Such persons are more susceptible to infections than healthy persons. Administration o f varicella vaccines can result in a more extensive vaccine-associated rash or disseminated dis ease in persons receiving immunosuppressive doses o f corti costeroids (185). This contraindication does not apply to persons who are receiving inhaled, nasal, or topical corticos teroids or low-dose corticosteroids as are used commonly for asthma prophylaxis or for corticosteroid-replacement therapy (see Situations in Which Some Degree o f Immunodeficiency Might Be Present).

# Altered Immunity

# Pregnancy
Because the effects o f the varicella virus vaccine on the fetus are unknown, pregnant women should not be vaccinated. N onpregnant women who are vaccinated should avoid becoming pregnant for 1 month after each injection. For per sons without evidence o f immunity, having a pregnant house hold member is not a contraindication to vaccination.
If a pregnant woman is vaccinated or becomes pregnant within 1 month o f vaccination, she should be counseled about potential effects on the fetus. Wild-type varicella poses a low risk to the fetus (see Prenatal and Perinatal Exposure). Because the virulence o f the attenuated virus used in the vac cine is less than that o f the wild-type virus, the risk to the fetus, if any, should be even lower. In 1995, Merck and Co., Inc., in collaboration with C D C , established the VARIVAX Pregnancy Registry to monitor the maternal-fetal outcomes o f pregnant women who were inadvertently administered varicella vaccine 3 months before or at any time during preg nancy (to report, call: 1-800-986-8999) (186). During the first 10 years o f the pregnancy registry no cases o f congenital varicella syndrome or birth defects compatible with congeni tal varicella syndrome have been documented (187,188). Among 131 live-born infants o f prospectively reported serone gative women (82 o f whom were born to mothers vaccinated during the highest risk period ), no birth defects consistent with congeni tal varicella syndrome have been documented (prevalence rate = 0; CI = 0-6.7% ), and three major birth defects were reported (prevalence rate = 2.3%; CI = 0.5% -6.7%). The rate o f occurrence o f major birth defects from prospective reports in the registry was similar to the rate reported in the general U.S. population (3.2%), and the defects indicated no specific pattern or target organ. Although the study results do not exclude the possibility o f risk for women who received inad vertent varicella vaccination before or during pregnancy, the potential risk, if any, is low.

# Precautions Illness
Vaccination o f persons who have acute severe illness, including untreated, active tuberculosis, should be postponed until recovery. The decision to delay vaccination depends on the severity o f symptoms and on the etiology o f the disease. No data are available regarding whether either single-antigen varicella or combination M M RV vaccines exacerbate tuber culosis. Live attenuated measles, mumps, and rubella virus vaccines administered individually might result in a tempo rary depression o f tuberculin skin sensitivity. Therefore, if a tuberculin test is to be performed, it should be administered either any time before, simultaneously with, or at least 4 -6 weeks after combination M M RV vaccine. However, tubercu lin skin testing is not a prerequisite for vaccination with single antigen varicella or combination M M RV vaccines.
Varicella vaccines may be administered to children without evidence o f immunity who have mild illnesses, with or with out low-grade fever (e.g., diarrhea or upper-respiratory infec tion) (189). Physicians should be alert to the vaccine-associated temperature elevations that might occur predominantly in the second week after vaccination, especially with combination MMRV vaccine. Studies suggest that failure to vaccinate chil dren with minor illnesses can impede vaccination efforts (190).

# Thrombocytopenia

# Recent Administration of Blood, Plasma, or Immune Globulin
Although passively acquired antibody is known to interfere with response to measles and rubella vaccines (191), the effect o f the adm inistration o f immune globulin (IG) on the response to varicella virus vaccine is unknown. The duration o f interference with the response to measles vaccination is doserelated and ranges from 3-11 months. Because o f the poten tial inhibition o f the response to varicella vaccination by passively transferred antibodies, varicella vaccines should not be administered for the same intervals as measles vaccine (3 -1 1 m on th s, d ep en d in g on the dosage) after administration o f blood (except washed red blood cells), plasma, or IG. Suggested intervals between administration of antibody-containing products for different indications and varicella vaccine have been published previously (157). In addition, persons who received a varicella vaccine should not be administered an antibody-containing product for 2 weeks after vaccination unless the benefits exceed those o f vaccina tion. In such cases, the vaccine recipient should either be revaccinated or tested for immunity at the appropriate inter vals, depending on the dose received, and then revaccinated if seronegative.

# Use of Salicylates
No adverse events associated with the use o f salicylates after varicella vaccination have been reported; however, the vaccine manufacturer recommends that vaccine recipients avoid using salicylates for 6 weeks after receiving varicella vaccines because o f the association between aspirin use and Reye syn drome after varicella. Vaccination with subsequent close moni toring should be considered for children who have rheumatoid arthritis or other conditions requiring therapeutic aspirin. The risk for serious complications associated with aspirin is likely to be greater in children in whom natural varicella develops than it is in children who receive the vaccine containing attenuated VZV. N o association has been docum ented between Reye syndrome and analgesics or antipyretics that do not contain salicylic acid.

# Postexposure Prophylaxis

# Healthy Persons
Prelicensure data from the United States and Japan on vari cella exposures in children from household, hospital, and com munity settings indicate that single-antigen varicella vaccine is effective in preventing illness or modifying varicella severity if administered to unvaccinated children within 3 days, and possibly up to 5 days, o f exposure to rash (78,101,192). Vac cination within 3 days o f exposure to rash was >90% effective in preventing varicella whereas vaccination within 5 days o f exposure to rash was approximately 70% effective in prevent ing varicella and 100% effective in modifying severe disease (101,192). Limited postlicensure studies also have demon strated that varicella vaccine is highly effective in either pre venting or modifying disease if administered within 3 days o f exposure (193,194). Varicella vaccine is recommended for postexposure administration for unvaccinated persons with out other evidence o f immunity. If exposure to V Z V does not cause infection, postexposure vaccination should induce pro tection against subsequent exposures. If the exposure results in infection, no evidence indicates that administration o f single-antigen varicella vaccine during the presymptomatic or prodromal stage o f illness increases the risk for vaccineassociated adverse events. No data are available regarding the potential benefit o f administering a second dose to 1-dose vaccine recipients after exposure. However, administration o f a second dose should be considered for persons who have pre viously received 1 dose to bring them up-to-date. Studies on postexposure use o f varicella vaccine have been conducted exclusively in children. A higher proportion o f adults do not respond to the first dose o f varicella vaccine. Nevertheless, postexposure vaccination should be offered to adults without evidence o f immunity. Although postexposure use o f varicella vaccine has potential applications in hospital settings, vacci nation is recommended routinely for all H C P without evi dence o f immunity and is the preferred method for preventing varicella in health-care settings (195). Preferably, H CP should be vaccinated when they begin employment. No data are avail able on the use o f co m b in atio n M M R V raccine for postexposure prophylaxis.  (197,198). In a study o f immunocompromised children who were adm inistered V Z IG within 96 hours o f exposure, approximately one in five exposures resulted in clinical vari cella, and one in 20 resulted in subclinical disease (198). The severity o f clinical varicella (evaluated by percentage o f patients with >100 lesions or complications) was lower than expected on the basis o f historic controls. The V Z IG product currently used in the United States, VariZIGTM (Cangene Corporation, W innipeg, Canada), is available under an Investigational New D rug Application Expanded Access protocol (available at / cber/infosheets/mphvzig020806.htm). A request for licensure in the United States might be submitted to FD A in the future. VariZIG is a lyophilized presentation which, when properly reconstituted, is approximately a 5% solution o f IgG that can be administered intramuscularly (199). VariZIG can be obtained 24 hours a day from the sole authorized U.S. distributor (FFF Enterprises, Temecula, California) at 1-800 843-7477 or online at .

# Persons Without Evidence of Immunity

# Administration of VZIG
V Z IG provides maximum benefit when administered as soon as possible after exposure, but it might be effective if administered as late as 96 hours after exposure. The effective ness o f V Z IG when administered >96 hours after initial exposure has not been evaluated. The duration o f protection provided after administration ofV Z IG is unknown, but pro tection should last at least one half-life o f the IG (i.e., approximately 3 weeks). Susceptible persons at high risk for whom varicella vaccination is contraindicated and who are again exposed >3 weeks after receiving a dose ofV Z IG should receive another full dose ofV Z IG . Patients receiving monthly high-dose immune globulin intravenous (IGIV) (>400 mg/ kg) are likely to be protected and probably do not require V Z IG if the last dose o f IG IV was administered 28 days. This should be taken into account after exposures when V Z IG is administered.

# Dosage
VariZIG is supplied in 125-U vials. The recommended dose is 125 units/10 kg o f body weight, up to a maximum o f 625 units (five vials). The minimum dose is 125 U. The human IgG content is 60-200 mg per 125 units dose o f VariZIG.

# Indications for the Use of VZIG for Postexposure Prophylaxis
The decision to administer V Z IG depends on three factors: 1) whether the patient lacks evidence o f immunity, 2) whether the exposure is likely to result in infection, and 3) whether the patient is at greater risk for complications than the general population.
Both healthy and immunocompromised children and adults who have verified positive histories ofvaricella (except for bonemarrow transplant recipients) may be considered immune (see Evidence o f Immunity). The association between positive his tories o f varicella in bone-marrow donors and susceptibility to varicella in recipients after transplants has not been studied adequately. Thus, persons who receive bone-marrow trans plants should be considered nonimmune, regardless o f previ ous history o f varicella disease or varicella vaccination in themselves or in their donors. Bone-marrow recipients in whom varicella or H Z develops after transplantation should subsequently be considered immune.
V Z IG is not indicated for persons who received 2 doses o f varicella vaccine and became imm unocom prom ised as a result o f disease or treatment later in life. These persons should be monitored closely; if disease occurs, treatment with acyclovir should be instituted at the earliest signs or symptoms. For patients without evidence o f immunity and on steroid therapy doses >2 mg/kg o f body weight or a total o f 20 mg/day of prednisone or equivalent, VariZIG is indicated.

# Types of Exposure
Certain types o f exposure can place persons without evi dence o f immunity at risk for varicella. Direct contact expo sure is defined as face-to-face contact with an infectious person while indoors. The duration o f face-to-face contact that war rants administration o f V Z IG is not certain. However, the contact should not be transient. Certain experts suggest a con tact o f >5 minutes as constituting significant exposure for this purpose, whereas others define close contact as >1 hour (200). Substantial exposure for hospital contacts consists o f sharing the same hospital room with an infectious patient or direct, face-to-face contact with an infectious person (e.g., HCP). Brief contacts with an infectious person (e.g., contact with x-ray technicians or housekeeping personnel) are less likely than more prolonged contacts to result in V Z V transmission.
Persons with continuous exposure to household members who have varicella or disseminated H Z are at greatest risk for infection. Varicella occurs in approximately 85% (range: 65% -100%) o f susceptible household contacts exposed to VZV. Localized H Z is much less infectious than varicella or dis seminated H Z (52). Transmission from localized H Z is more likely after close contact, such as in household settings. Physi cians may consider recommending postexposure prophylaxis with V Z IG in such circumstances. After household exposure to varicella, attack rates among immunocompromised chil dren who were administered V Z IG were up to 60% (197). No comparative data are available for immunocompromised children without evidence o f immunity who were not admin istered V Z IG . However, the incidence o f severe disease (defined as >100 skin lesions) was less than that predicted from the natural history o f disease in normal children (27% and 87%, respectively), and the incidence o f pneumonia was less than that described in children with neoplasm (6% and 25% , respectively) (201). The risk for varicella after close con tact (e.g., contact with playmates) or hospital exposure is esti mated to be approximately 20% o f the risk occurring from household exposure.
The attack rate in healthy neonates who were exposed in utero within 7 days o f delivery and who received V Z IG after birth was 62% , which does not differ substantially from rates reported for neonates who were similarly exposed but not treated with V Z IG (49). However, the occurrence o f compli cations and fatal outcomes was substantially lower for neo nates who were treated with V Z IG than for those who were not.
In a study o f pregnant women without immunity to VZV who were exposed to varicella and administered V ZIG , the infection rate was 30%. This is substantially lower than the expected rate o f >70% in unimmunized women exposed to varicella (199,202).

# Recommendations for the Use of VZIG
The following patient groups are at risk for severe disease and complications from varicella and should receive V ZIG : Immunocompromised patients. V Z IG is used primarily for passive immunization o f immunocompromised persons without evidence o f immunity after direct exposure to vari cella or disseminated H Z patients, including persons who 1) have primary and acquired immune-deficiency disorders, 2) have neoplastic diseases, and 3) are receiving immunosup pressive treatment. Patients receiving monthly high-dose IGIV (>400 mg/kg) are likely to be protected and probably do not require V Z IG if the last dose o f IG IV was administered <3 weeks before exposure (200).
Neonates whose mothers have signs and symptoms of varicella around the time o f delivery. V Z IG is indicated for neonates whose mothers have signs and symptoms o f varicella from 5 days before to 2 days after delivery. V Z IG is not neces sary for neonates whose mothers have signs and symptoms of varicella more than 5 days before delivery, because those infants should be protected from severe varicella by transpla centally acquired maternal antibody. No evidence suggests that infants born to mothers in whom varicella occurs >48 hours after delivery are at increased risk for serious complications (e.g., pneumonia or death).
Premature neonates exposed postnatally. Transmission of varicella in the hospital nursery is rare because the majority of neonates are protected by maternal antibody. Premature infants who have substantial postnatal exposure should be evaluated on an individual basis. The risk for complications o f postnatally acquired varicella in premature infants is unknown. However, because the immune system o f prema ture infants is not fully developed, administration o f V Z IG to premature infants born at >28 weeks o f gestation who are exposed during the neonatal period and whose mothers do not have evidence o f immunity is indicated. Premature infants born at 28 weeks o f gestation to immune mothers have enough acquired maternal antibody to protect them from severe disease and complications. Although infants are at higher risk than older children for serious and fatal complications, the risk for healthy, full-term infants who have varicella after postnatal exposure is substan tially less than that for infants whose mothers were infected 5 days before to 2 days after delivery. V Z IG is not recom mended for healthy, full-term infants who are exposed post natally, even if their mothers have no history o f varicella infection.
Pregnant women. Because pregnant women might be at higher risk for severe varicella and complications (37,42,203), V Z IG should be strongly considered for pregnant women without evidence o f immunity who have been exposed. Administration o f V Z IG to these women has not been found to prevent viremia, fetal infection, congenital varicella syn drome, or neonatal varicella. Thus, the primary indication for V Z IG in pregnant women is to prevent complications of varicella in the mother rather than to protect the fetus. Neonates born to mothers who have signs and symptoms o f MMWR June 22, 2007 varicella from 5 days before to 2 days after delivery should receive V Z IG , regardless o f whether the mother received V ZIG .

# Interval Between Administration of VZIG and Varicella Vaccine
Any patient who receives V Z IG to prevent varicella should receive varicella vaccine subsequently, provided the vaccine is not contraindicated. Varicella vaccination should be delayed until 5 months after V Z IG administration. Varicella vaccine is not needed if the patient has varicella after administration o f V ZIG .

# Antiviral Therapy
Because V Z IG might prolong the incubation period by >1 week, any patient who receives V Z IG should be observed closely for signs or symptoms o f varicella for 28 days after exposure. Antiviral therapy should be instituted immediately if signs or symptoms o f varicella disease occur. The route and duration o f antiviral therapy should be determined by spe cific host factors, extent o f infection, and initial response to therapy. Information regarding how to obtain VariZIG is avail able at  ww .cdc.gov/m m wr/preview/m m w rhtm l/ m m5508a5.htm (204).