INTRODUCTION — Varicella-zoster virus (VZV) is one of eight herpesviruses known to cause human infection and is found worldwide. Primary infection with varicella causes chickenpox in susceptible hosts. While most healthy children have self-limited infection with primary varicella, the incidence of hospitalization and even mortality in selected groups is significant. Varicella can cause significant complications, such as soft tissue infection, pneumonia, hepatitis, and encephalitis. Patients at increased risk of complications include adults, pregnant women, and immunosuppressed hosts.

The introduction of the varicella vaccine in 1995 in the United States was a major advance, which led to a marked decline in morbidity and mortality associated with this infection. The efficacy and safety of the varicella vaccine will be reviewed here. The major clinical manifestations and complications of chickenpox and herpes zoster, the management of VZV infection in neonates, and the prevention of varicella after exposure are discussed separately. (See "Clinical features of varicella-zoster virus infection: Chickenpox" and "Clinical manifestations of varicella-zoster virus infection: Herpes zoster" and "Varicella-zoster infection in the newborn" and "Post-exposure prophylaxis against varicella-zoster virus infection".)

VACCINE FORMULATIONS — Varicella vaccine is composed of the Oka strain of live, attenuated VZV [1]. Two live, attenuated varicella-zoster virus-vaccines are licensed in the United States for the prevention of chickenpox [1]:

• A single-antigen varicella vaccine (VARIVAX, Merck)
• A combination measles, mumps, rubella, and varicella vaccine (ProQuad, Merck). This formulation is licensed for use in persons aged 12 months to 12 years and was created to decrease the number of injections and to increase compliance. Because of production problems at its manufacturer, this formulation is currently not available [2].

EVIDENCE OF IMMUNITY — Evidence of immunity to varicella in adults includes any of the following:

• Documentation of two doses of varicella vaccine at least four weeks apart
• Laboratory confirmation of prior exposure to varicella infection
• History of prior varicella infection or herpes zoster infection
• Birth in the US before 1980

Persons born before 1980 are considered immune since the prevalence of disease was previously so high. However, in high-risk groups (eg, in health care providers or pregnant women) age alone does not constitute immunity; these risk groups should have serologic testing or a history of prior disease or vaccination.

VACCINE RECOMMENDATIONS — Below are guidelines regarding the use of varicella vaccine in various subgroups (table 1).

Children — Varicella vaccination is recommended for all children between 12 and 15 months of age without evidence of immunity. In 2006, the Advisory Committee on Immunization Practices (ACIP) recommended the addition of a routine second dose of varicella vaccine at age four to six years (table 2) [1,3,4].

These recommendations were made because of varicella outbreaks that have continued to occur among school-aged children vaccinated with a single dose [5]. Varicella is usually less severe in vaccinated individuals, but these children can still transmit the virus to a susceptible host [6].

All susceptible children aged 19 months to 13 years should be fully vaccinated (with two doses) by their 13th birthday [1]. The recommended minimum interval between the first dose and the "catch-up" second dose is three months for children aged <12 years and four weeks for persons aged >13 years [1].

Adolescents and adults — Routine vaccination for all healthy persons aged >13 years is recommended for those without evidence of immunity [1,4,7]. Two doses of single-antigen varicella vaccine should be given four to eight weeks apart. Varicella vaccine is highly recommended in VZV-seronegative adults with ongoing risk of exposure (eg, day care employees, health care workers), those who are household contacts of immunosuppressed hosts, and in women of childbearing age [8].

A second dose of varicella vaccine is recommended for adolescents and adults who had previously received only one dose [1,4,8]. The recommended minimum interval between the first dose and the "catch-up" second dose is four weeks for persons aged >13 years [1].

"Catch-up" vaccination is important in preventing outbreaks among susceptible individuals. Vaccination requirements for entry into middle school, high school, and college have been helpful in attaining high rates of complete immunization [1,9].

Pregnancy — Vaccination is not recommended in women who are pregnant or might become pregnant within four weeks of receiving the vaccine. However, the Advisory Committee on Immunization Practices (ACIP) recommends that pregnant women, without evidence of VZV-specific immunity, should receive the first dose of varicella vaccine upon completion or termination of pregnancy and before discharge from the health care facility. The second dose should be administered four to eight weeks after the first dose [8].

Prevention of varicella during pregnancy is discussed in detail elsewhere. (See "Varicella-zoster virus infection in pregnancy".)

Immunosuppressed hosts — Since varicella vaccine is a live attenuated virus preparation, it is generally contraindicated for immunocompromised hosts, including those receiving immunosuppressive medications (eg, systemic steroids greater than 2 mg/kg body weight per day or a total of 20 mg prednisone per day) and those with hematologic malignancies (eg, leukemia, lymphoma) [1,10,11]. Varicella vaccine should also not be given to persons who have a family history of hereditary immunodeficiency until the immunocompetence of the potential vaccinee is determined (table 1) [1]. VZV-susceptible household contacts of susceptible HIV-infected persons should be vaccinated to prevent acquisition of chickenpox and potential transmission to their HIV-infected contacts [12].

Varicella can be a severe disease when it occurs in immunocompromised children, in spite of antiviral therapy. Clinical trials of varicella vaccine administration to immunocompromised children suggest that immunization may be an option once immune suppression is reduced [13]. The vaccine-induced response is usually partially or fully protective in these settings. Important caveats regarding these patient subgroups are discussed in detail below.

Children with leukemia — The varicella vaccine was shown to be efficacious in children with leukemia in remission. The most frequent reaction to the vaccine in patients with leukemia is a mild to moderate varicella-like rash (approximately 200 lesions) which occurs in approximately 5 percent of children who have completed chemotherapy before vaccination and in 40 percent of patients on maintenance chemotherapy [14].

However, immunization in this patient group should only be undertaken with expert guidance and consultation [1]. If a decision is made to vaccinate, the single antigen preparation (Varivax) should be used. (See 'Vaccine formulations' above.)

HIV-infected children — Varicella can be a severe illness in HIV-infected children [15]. Varicella vaccine has been demonstrated to be safe [16] and immunogenic in asymptomatic HIV-infected children with CD4 percentages of 25 percent or more [17,18]. A subsequent study evaluated the safety and efficacy of varicella vaccine in children with a history of severe immunosuppression who had achieved immune reconstitution (n = 17) and in those with moderate symptoms and CD4 percentages >15 percent (n = 37) [19]. Regardless of immunologic category, 79 percent of HIV-infected vaccine recipients developed VZV-specific antibody and/or cell-mediated immunity 60 days after the immunization series. A multivariate analysis indicated that detectable HIV viremia at baseline correlated with a lower likelihood of immunization response.

The authors concluded that the recommendations for varicella vaccine in HIV-infected children should be similar to measles vaccine. Both the CDC and ACIP guidelines recommended that single-antigen varicella vaccine should be administered to HIV-infected children with a CD4+ T lymphocyte percentage of >15 percent [4,12].

HIV-infected adults — Although data on the use of varicella vaccine are lacking, most experts feel that adult patients with clinically stable HIV infection and a CD4 count >200 cells/microL would have comparable immunity to the HIV-infected children described above. The CDC and the ACIP have recommended that single-antigen varicella vaccine may be considered in VZV-seronegative HIV-infected adolescents or adults with a CD4 count >200 cells/microL; two doses should be administered three months apart [1,4].

We feel that more data are needed on the safety of varicella vaccination in VZV-seronegative adults with HIV infection and varying degrees of immunocompromise. We suggest varicella vaccination in those individuals with a CD4 count >350 cells/microL. Decisions about immunization in those individuals with CD4 cell count <350/microL should be made on an individual basis after discussion of potential risks and benefits with the patient.

If vaccination results in disease because of vaccine virus, therapy with acyclovir is recommended [12].

EFFICACY — Multiple studies in different countries have demonstrated the efficacy of varicella vaccination [20-24].

Outside the United States — The most extensive use of varicella vaccine has been in the United States and Canada, where it is universally recommended. However, the use of varicella vaccine is expanding in Europe, Australia, Latin America, and Asia [25,26].

A report from Japan evaluated over 1.39 million subjects who had been vaccinated from 1987 to 1993 [27]. The following results were noted:

• Clinical symptoms were reported in 580 of 8429 vaccinees (7 percent), and seroconversion was documented in 2347 of 2565 (92 percent).
• Evidence of humoral and cellular immunity to VZV persisted in 26 vaccine recipients for >20 years.
• Despite 100 documented contacts with varicella patients, only two vaccinees (2 percent) developed breakthrough varicella with mild clinical features within 12 months of vaccination.

Within the United States — A review of postlicensure data included 17 studies on varicella vaccine efficacy before exposure and two small studies on efficacy after exposure [6]. The majority of estimates assessed protection against clinically diagnosed varicella, with most of the studies defining severity of illness by the number of skin lesions and incidence of complications or hospitalization. The following results were reported:

• One dose of varicella vaccine was 85 percent effective (median; range, response rate to 100 percent) in preventing all varicella infections and 100 percent effective in preventing severe disease.
• Although the two studies of post-exposure prophylaxis included small numbers of patients, varicella vaccine appeared to have significant efficacy: overall prevention of infection was 42 to 95 percent while prevention of severe disease was 88 to 100 percent. Similar data were observed in a prospective observational study of 42 susceptible children immunized within 36 hours following exposure to varicella in a homeless shelter [28].

In summary, the post-licensure experience with varicella vaccine has demonstrated that one dose is usually 80 to 90 percent effective in preventing clinically diagnosed or laboratory-confirmed varicella and exhibits 95 to 100 percent effectiveness in preventing severe disease.

BREAKTHROUGH VARICELLA

Definition — "Breakthrough varicella" or "mild varicella-like syndrome" (MVLS) refers to infection after exposure to wild-type virus in those who have been previously vaccinated. Most studies have noted MVLS occurring in <1 to 3 percent of vaccinated children each year after vaccination [29-31].

Most documented cases of varicella in vaccinated children are mild [32]. Patients with breakthrough varicella may have a maculopapular rash rather than a vesicular rash. Breakthrough varicella generally results in fewer than 50 lesions and no fever compared with a median of 300 lesions and fever in more than 90 percent of unvaccinated children [29-31]. However, breakthrough varicella is still a matter of concern since infected children can transmit varicella to others [33].

Primary vaccine failure — Breakthrough varicella may arise from primary or secondary vaccine failure. "Primary vaccine failure" refers to the failure to mount a protective immune response to a dose of vaccine, whereas "secondary vaccine failure" refers to the gradual loss of immunity after initial vaccine response (see 'Waning of immunity' below.

In an effort to determine the etiology of "breakthrough varicella", serum samples from healthy children immunized against varicella were tested for evidence of seroconversion using a highly sensitive and specific assay used in research laboratories (ie, fluorescent antibody to membrane antigen testing; FAMA) [34]. Of 148 vaccinees, only 113 (76 percent) seroconverted and 24 percent had no detectable VZV antibodies after one dose of vaccine. These data strongly contrast with earlier reported seroconversion rates of 86 to 96 percent by other commercial antibody testing methods (eg, gpELISA).

These data suggest that many cases of varicella in immunized children may result from primary vaccine failure. Some experts have advocated that vaccine immunogenicity should be reassessed by directly comparing results of gpELISA and FAMA testing [33]. Another explanation for the lower seroconversion rates may be related to the absence of circulating wild-type virus, which may have previously boosted immunity in patients with asymptomatic infection [35].

Potential risk factors for primary vaccine failure include younger age at vaccination, steroid use, or receipt of other vaccines prior to varicella vaccination [6,36,37]. However, in a study of more than 7500 children who were immunized against varicella, no difference in the rate of breakthrough varicella was found between children vaccinated at <15 months of age and those vaccinated at ≥15 months of age.

Waning of immunity — Among patients who initially attained a primary vaccine response, breakthrough varicella may reflect an intrinsic waning of immunity over time [38-43]. Several postlicensure studies have indicated that levels of protective efficacy fall from 97 to 84 percent eight years after immunization, consistent with waning immunity [38,39]. This observation raises the theoretical concern that previously vaccinated persons could be at increased risk of acquiring varicella infection later in life, when the risk of serious complications is greater.

Loss of immunity against varicella infection is suggested by a large observational database among persons who received one dose of vaccine. The Varicella Active Surveillance Project was established in California in 1995 to enhance community surveillance for varicella cases occurring >42 days after immunization and to determine their relationship with varicella vaccine status [44]. The study was significant for the following results:

• After one decade (1995 to 2004) of active surveillance data from a sentinel population of 350,000 subjects, a total of 11,356 subjects developed varicella, of whom 1080 (9.5 percent) had breakthrough disease.
• Children between the ages of 8 and 12 years who had been vaccinated at least five years previously were more likely to have moderate or severe disease than those who had been vaccinated less than five years previously (risk ratio, 2.6; 95% CI 1.2-5.8).
• The annual rate of breakthrough varicella significantly increased with the time since vaccination.

Cases of breakthrough disease have led to the adoption of a second dose of varicella vaccine for children between the ages of four and six years and "catch-up" doses for adults [45]. Studies of patients who have received two doses of varicella vaccine demonstrate geometric mean titers that are 12 times higher with two doses of vaccine compared with one; these levels approximate those seen after natural disease [35]. Although long-term follow-up of antibody levels are not yet possible with MMRV vaccine, early data suggest similar seroconversion rates at one year of follow-up [46]. (See 'Vaccine recommendations' above.)

Secondary attack rates — Breakthrough varicella is a concern since these vaccinated patients can still transmit infection to other susceptible individuals.

In a surveillance study of more than 320,000 individuals in Los Angeles county, secondary attack rates were analyzed within households according to disease history and vaccination status [41]. A total of 6316 varicella cases were reported. The following findings were noted among susceptible young contacts (1 to 14 years of age):

• Overall, vaccinated patients (eg, those with breakthrough varicella) were half as contagious as unvaccinated patients; exposure to vaccinated patients with varicella was associated with much lower secondary attack rates compared with unvaccinated patients (15 versus 72 percent).
• However, the contagiousness of vaccinated patients also varied with the number of varicella-associated lesions. For example, the secondary attack rate was similar between vaccinated patients and unvaccinated patients if the vaccinated patient had >50 lesions.
• Vaccine effectiveness for the prevention of all disease was 79 percent overall, 92 percent for moderate disease (50 to 500 lesions), and 100 percent for severe disease.

These data support the observation that varicella vaccine decreases disease severity and decreases the risk of transmission, even in those with breakthrough disease.

TRANSMISSION OF VACCINE VIRUS

From healthy individuals to immunosuppressed hosts — There is a theoretical risk of viral transmission from health care providers or family members who were immunized with a live attenuated vaccine to an immunosuppressed patient. However, a review of the literature revealed no major risk of transmission associated with any live attenuated vaccine [47]. Transmission of vaccine virus from healthy children to other susceptible contacts is uncommon and only described in a few case reports [1,48,49]. Thus, healthy household contacts of immunosuppressed patients can receive varicella vaccine since the risk of transmission is low [50].

The American Academy of Pediatrics, the CDC, and the ACIP do not recommend any specific precautions except in the event that the vaccine recipient develops skin lesions; in this case, physical contact should be avoided until the rash has resolved [47].

From immunosuppressed hosts to healthy contacts — In contrast, in a study of 88 susceptible siblings of children with leukemia who developed a rash after varicella immunization, evidence of transmission occurred in 15 siblings (17 percent) [51]. As noted above, persons who develop a rash after immunization should refrain from contact of other susceptible persons.

Immunization in this patient group should only be undertaken with expert guidance and consultation (see 'Vaccine recommendations' above.

ADVERSE EVENTS — The ten-year safety profile of more than 55 million doses of administered varicella vaccine has demonstrated that immunization is generally well tolerated [52]. Worldwide, there were 16,683 reports voluntarily submitted to Merck as part of a global postmarketing surveillance program for an overall reporting rate of 3.4 reports/100,000 doses of vaccine distributed. In the United States, data from the Vaccine Adverse Events Reporting System from 1995 to 2005 continue to suggest that serious events are rare (2.6/100,000 doses administered) [53].

Serious adverse events suspected to have been caused by varicella vaccines should be reported to the Vaccine Adverse Event Reporting System (VAERS). Forms and instructions are available at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm, in the FDA Drug Bulletin at http://www.fda.gov/medwatch, or from the 24-hour VAERS information recording at 1-800 822-7967.

Adverse events reported in association with varicella vaccine are listed below.

Injection site reactions — Pain and erythema at the injection site and fever have been the most common adverse events reported with vaccine compared with placebo [52,54].

Rash — Out of the 16,683 case reports, there were 3192 reports of rashes, half of which were vesicular in nature [52]. The probable origin of vesicular lesions appears related to the timing of the rash in relationship to vaccine administration, as determined by polymerase chain reaction (PCR) analysis of vesicular fluid samples. Rashes that occurred within the first two weeks after vaccination (median of eight days) were related to wild-type VZV; vaccine-derived virus was generally isolated from rashes that occurred 15 to 42 days after vaccination (median 21 days).

Febrile seizures — In the pre-marketing data of ProQuad, there was a signal of a possible increase of febrile seizures associated with this vaccine. At the time of licensure, the manufacturer began a prospective study in 31,000 children 12 to 60 months of age to evaluate the risk of febrile seizures compared with historical matched controls who received MMR and varicella vaccines administered separately at two different sites. The study suggested that ProQuad was associated with an increased risk of febrile seizures occurring 5 to 12 days after vaccination compared with controls (5 per 10,000 vaccinations versus 2 per 10,000 vaccinations, respectively). Data from the CDC also confirmed this observation; the risk of febrile seizures was documented to be 9 per 10,000 vaccinations with ProQuad versus 4 per 10,000 vaccinations with separate immunizations [55].

In February 2008, the Federal Drug Administration (FDA) changed the labeling for the ProQuad formulation to reflect this increased risk. However, the indications for ProQuad have not changed reflecting the overall good prognosis of febrile seizures, the low incidence of this complication and the overall benefit of vaccine in preventing the morbidity and mortality associated with varicella infection. Following this observation, the ACIP removed its preference for administering combination MMRV vaccine over separate injections of MMR and varicella vaccines [55].

Disseminated vaccine virus — Disseminated vaccine virus was identified in six immunocompromised patients and one patient with Down syndrome [52]. Vaccination of persons receiving immunosuppressive therapy or with primary or acquired immunodeficiencies is contraindicated. (See 'Vaccine recommendations' above.)

Meningitis — Three laboratory-confirmed cases of meningitis caused by a VZV strain in the Oka/Merck vaccine have been reported in children, including an immunocompetent child [56].

RISK OF VACCINE-ASSOCIATED ZOSTER — Since the licensure of varicella vaccine, theoretical concerns were raised regarding two main issues:

• Immunization might lead to an increased risk of vaccine-associated herpes zoster, particularly in immunocompromised children.
• Widespread varicella immunization in childhood may increase the incidence of herpes zoster in the general population due to decreased circulation of wild-type virus and a decline in T-cell immunity.

Studies monitoring herpes zoster incidence have shown inconsistent findings; two suggest no change while another shows an increase in incidence [57]. Further studies are needed to define the risk of this infection. (See "Epidemiology and pathogenesis of varicella-zoster virus infection: Herpes zoster", section on Varicella vaccine.)

VACCINE PROGRAMS IN THE UNITED STATES — The National Immunization Survey (NIS) is an ongoing 50-state survey that provides estimates of vaccination coverage among children aged 19 to 35 months in the United States. The CDC initiated the NIS in 1994 to monitor vaccination coverage of children during the first two years of life.

Between 1997 and 2005, national varicella vaccination coverage among children 19 to 35 months of age increased from 26 to 88 percent [58]. By the start of the 2006-2007 school year, 46 states (92 percent) and the District of Columbia (DC) had implemented entry requirements for varicella vaccination. Implementation of day care and school entry requirements for varicella vaccination has led to high rates of coverage among children in the United States [1].

Impact on health care utilization — Varicella remains the leading cause of vaccine-preventable deaths in children living in the United States. Prior to the introduction of vaccine, four million cases occurred annually in the United States, resulting in 10,000 hospitalizations and 100 deaths [59]. Vaccination has had a positive impact on health care expenditures:

• A study using retrospective population-based data that included enrollees (children and adults) from 100 health insurance plans from 1994 to 2002 demonstrated that the total estimated direct medical expenditures for varicella hospitalizations and ambulatory visits declined by 74 percent [60].
• Data from the Varicella Active Surveillance Project (VASP) were used to compare rates of hospital admissions for varicella-related illnesses from 1995 to 2005 [61]. Rates of hospitalization per 100,000 population decreased significantly from 2.54 (95% CI 2.1-3.0) in the early vaccination period to 0.6 (95% CI 0.4-1.0) in the late vaccination period.

Vaccination strategies and cost-effectiveness — A decision-tree analysis found that compared with no vaccination, the one-dose and the two-dose program of varicella immunization were both estimated to be cost-effective from the societal perspective [62].

The specific population of immigrant and refugee adults remains preferentially susceptible to primary varicella infection compared with adults from industrialized nations [63-66]. A cost-effectiveness analysis was conducted in a cohort of 1480 adult immigrants and refugees from six disparate geographic regions who relocated to Canada to determine the optimal vaccination strategy for this patient population [66]. Four vaccination strategies were compared with no intervention; the strategies evaluated were:

• Vaccination of all individuals
• Serologic testing of all individuals followed by vaccination of those who were seronegative
• Vaccination of an individual with a negative or uncertain history of varicella
• Serologic testing of only those individuals with a negative or uncertain history of varicella followed by vaccination of those who were seronegative

The optimum strategy identified was targeted serologic testing in immigrants without a self-reported history of varicella, followed by vaccination in those confirmed to be susceptible. Such an approach would prevent an estimated 37 percent of varicella cases.

ZOSTER VACCINE — Issues related to zoster vaccine in prevention of herpes zoster infection are described separately. (See "Prevention of varicella-zoster virus infection".)

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Childhood immunizations" and "Patient information: Immunizations for infants and children age 0 to 6 years".) We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.

SUMMARY AND RECOMMENDATIONS

• For all children who are less than 13 years of age, we recommend varicella immunization as suggested by the Advisory Committee on Immunization Practices (Grade 1A). Two doses should be administered instead of a single dose to decrease the risk of breakthrough varicella. (See 'Vaccine recommendations' above and 'Efficacy' above.)

• For all healthy persons >13 years of age without evidence of immunity, we recommend routine varicella vaccination, as suggested by the Advisory Committee on Immunization Practices (Grade 1A). Two doses should be administered instead of a single dose to decrease the risk of breakthrough varicella. Adolescents and adults who had previously received only one dose of varicella vaccine should receive a "catch-up" dose.
• Evidence of immunity can include documentation of serologic status, history of vaccination, birth before 1980, or prior illness. (See 'Evidence of immunity' above.)

• Immunization is particularly important for health care providers and in those who are household contacts of immunosuppressed hosts. (See 'Vaccine recommendations' above.)

• Vaccination should be deferred in women who are pregnant or might become pregnant within four weeks of receiving the vaccine. (See 'Vaccine recommendations' above.)

• Varicella vaccine is not generally recommended in patients with immunodeficiency (eg, transplant recipients). However, varicella vaccine has been demonstrated to be safe and effective in certain subgroups of HIV-infected patients with relatively preserved immune function. In HIV-infected children, we suggest varicella vaccine for those with a CD4+ T lymphocyte percentage >15 percent (Grade 2B).
• More data are needed on the safety of varicella vaccination in VZV-seronegative adults with HIV infection and varying degrees of immunocompromise. We suggest varicella vaccination in those individuals with a CD4 count >350 cells/microL (Grade 2C). Decisions about immunization in those individuals with CD4 cell count <350/microL should be made on an individual basis after discussion of potential risks and benefits with the patient.
• Breakthrough varicella refers to infection after exposure to wild-type virus in those who have been previously vaccinated. This can occur due to lack of response to vaccine or waning of immunity over time in individuals who had a primary vaccine response. Breakthrough varicella is usually a mild disease. (See 'Breakthrough varicella' above.)

• The risk of transmission of vaccine virus is generally low, but can occur in contacts of patients with vesicular skin lesions; physical contact should be avoided until the rash has resolved. (See 'Transmission of vaccine virus' above.)

• The ten-year safety profile of more than 55 million doses of administered varicella vaccine has demonstrated that immunization is generally well tolerated; rash and febrile seizures have been reported. Due to the association of febrile seizures and the quadrivalent vaccine containing measles, mumps, rubella and varicella antigens, the quadrivalent vaccine is no longer the preferred vehicle for immunization for varicella. (See 'Adverse events' above.)