Varicella Virus Vaccine Live

[Section Outline]

Past and Current Considerations Regarding Varicella Vaccine Recommendations
Risks of Varicella Exposure and Infection
Serologic Testing and Evaluation of Susceptibility
Primary Immunization
Postexposure Vaccination and Outbreak Control

Varicella virus vaccine live is used to stimulate active immunity to varicella (chickenpox).1,27,82,92 Varicella virus vaccine live is commercially available as a single-antigen vaccine (Varivax^®) for use in adults, adolescents, and children 12 months of age or older1 and as a fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad^®) for use in children 12 months through 12 years of age.125 MMRV (ProQuad^®) contains the same potency of measles, mumps, and rubella antigens as commercially available measles, mumps, and rubella virus vaccine live (MMR) and contains a slightly higher potency of varicella antigen than the single-antigen varicella vaccine (Varivax^®).27,125,128

The US Public Health Service Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the Infectious Diseases Society of America (IDSA) recommend universal immunization against varicella with 2 doses of a vaccine containing varicella virus vaccine live for all susceptible, healthy children 12 months through 12 years of age unless the vaccine is contraindicated.27,100,71,137 The ACIP, AAP, AAFP, IDSA, American College of Obstetricians and Gynecologists (ACOG), and American College of Physicians (ACP) also recommend universal immunization against varicella with 2 doses of varicella virus vaccine live for all adolescents and adults 13 years of age or older without evidence of immunity, unless the vaccine is contraindicated.27,71,89,100,114,129,137 These experts state that special consideration should be given to use of varicella virus vaccine live in susceptible adults who have close contact with individuals who are at high risk for severe varicella (e.g., health-care personnel and family contacts of immunocompromised individuals) and susceptible adults and adolescents who are at high risk for exposure or transmission of the disease (e.g., teachers of young children, child-care employees, residents and staff members of institutional settings including correctional institutions, college students, military personnel, those living in households with children, non-pregnant women of childbearing age, international travelers).27,82,92,93,114,129 Varicella virus vaccine live also has been used for postexposure vaccination† in susceptible individuals and for outbreak prevention and control in certain settings.27,100,115,116,126

The ACIP states that individuals have evidence of immunity to varicella if there is written documentation of age-appropriate vaccination (one vaccine dose in preschool children 12 months of age or older or 2 doses in school-aged children, adolescents, and adults), they were born in the US before 1980 (US birth before 1980 should not be considered evidence of immunity for health-care providers and pregnant women), they have a history of herpes zoster based on a diagnosis by a health-care provider, or there is laboratory evidence of immunity or laboratory confirmation of varicella infection.27,129 In addition, the ACIP states that individuals with a history of typical varicella disease based on a diagnosis or verification of such history by any health-care provider (e.g., school or occupational clinic nurse, nurse practitioner, physician assistant, clinician) can be considered to have evidence of immunity to varicella.27,129 For those reporting a history of or presenting with atypical and/or mild varicella , health-care providers should seek either an epidemiologic link to a typical varicella case (e.g., case occurred in the context of an outbreak or patient had household exposure to varicella in the previous 3 weeks) or evidence of laboratory confirmation performed at the time of acute disease;27,129 when such documentation is lacking, individuals should not be considered as having a valid history of varicella since other diseases may mimic mild, atypical varicella.27

Past and Current Considerations Regarding Varicella Vaccine Recommendations

The ACIP, AAP, AAFP, and IDSA first recommended universal immunization against varicella in all healthy, susceptible children in the US in 1996; however, there has been some controversy hindering implementation of this recommendation.5,12,14,16,24,27,32,36,37,38,41,57,61,77,88,92,114 Results of several studies evaluating the short-term benefits and costs related to use of varicella virus vaccine live indicate that universal immunization of healthy children is cost-effective.21,22,23 These studies evaluated both direct medical costs related to varicella and indirect costs related to work-loss of the parents of children with varicella.21,22,23 However, some clinicians have expressed concerns about routine use of the vaccine in healthy children, partly because long-term efficacy and duration of protection against varicella have not been determined and because long-term epidemiologic effects of widespread use of the vaccine are unclear.12,14,16,24,32,36,37,38,41,57,61,63,77,97

It has been suggested that universal immunization of healthy children could increase the incidence of varicella in susceptible, healthy adolescents and adults.16,21,24,38,57,61,77 For example, if immunity to varicella eventually wanes in immunized children who received primary immunization against varicella, there is a theoretical possibility that varicella infections will occur in these individuals later in life.16,32,57,77 Widespread (but not universal) use of varicella virus vaccine live could result in an increased incidence of varicella infections in adults who were not vaccinated as children and were not previously exposed to natural varicella infection.21,24,32,57,77 Such a shift in age distribution to older individuals could increase the overall morbidity associated with varicella since the disease generally is more severe in adults than in children.24,32,61,77,100 This concern has now been addressed with recommendations that emphasize use of varicella virus vaccine live in susceptible older children, adolescents, and adults, in addition to universal immunization of younger children.24,92,94 Beginning in June 2005, the ACIP expanded their varicella vaccination recommendations to promote wider use of the vaccine in adolescents and adults.27,127 Vaccination with 2 doses of varicella virus vaccine live is now recommended for adolescents and adults 13 years of age or older who do not have evidence of immunity to varicella.27,71,129 In addition, to prevent herpes zoster (also known as shingles or zoster) caused by reactivation of varicella zoster virus (VZV) infection, the ACIP recommends that all adults 60 years of age or older receive a single dose of zostervaccine live (Zostavax^®)), unless the vaccine is contraindicated.129,131

Another concern expressed by some clinicians is that additional long-term studies are needed to evaluate the effects of universal varicella immunization on the incidence of subsequent herpes zoster.21,24,32,37,38,39,77 Theoretically, individuals who receive varicella virus vaccine live and have breakthrough varicella infections caused by wild-type virus could harbor both virus types and be at risk for reactivation and herpes zoster associated with either type.24,40 (See Cautions: Latent Infections and Herpes Zoster.)

Long-term studies, including 15-year follow-up of children following administration of varicella virus vaccine live, have been initiated.63,85 The US Centers for Disease Control and Prevention (CDC) encourages all state public health agencies to continue ongoing surveillance for varicella incidence and hospitalization and death rates; investigation of all varicella-related deaths; and establishment of reporting systems for varicella cases in schools, day-care centers, health-care provider offices, and hospitals.92

Risks of Varicella Exposure and Infection

Varicella occurs most frequently in susceptible children, usually in those younger than 10 years of age,1,14,27,64,100 but has been reported with increasing frequency in susceptible adolescents and adults.59,60,80,92,100 Prior to licensure of varicella virus vaccine live (i.e., prior to 1995), approximately 4 million cases of varicella occurred annually in the US,1,27,64,92,137 with peak incidence during late winter and early spring and an average annual incidence of 15-16 cases per 1000.27,100 Age-specific incidence data for that time period indicate that more than 90% of reported cases occurred in individuals younger than 15 years of age with 33 and 44% of cases in children 1-4 and 5-9 years of age, respectively.27,137 Since 1995, when varicella virus vaccine live became commercially available, there have been substantial decreases in the incidence of varicella and varicella-associated hospitalizations in the US in all age groups, especially in children 1-9 years of age.112,138 The number of hospitalizations and deaths from varicella have decreased more than 90% in the US since 1996.138 Adults who immigrate to the US from tropical areas where natural exposure to the heat-labile virus is unlikely are at particular risk of infection in the US.11,27,100,137

Varicella is highly communicable, and the secondary infection rate in healthy, susceptible individuals exposed through household contact generally is 80-90%.1,6,8,27 Although less than 5% of varicella cases in the US occur in adults older than 20 years of age, 55% of varicella-related deaths occur in this age group.92 Varicella is associated with severe maternal93 and congenital1,9,15,25,27,31,93 (See Cautions: Pregnancy, Fertility, and Lactation) morbidity and mortality, with approximately 10-20% of infected pregnant women developing varicella pneumonia that has a maternal mortality rate as high as 40%.93

Serologic Testing and Evaluation of Susceptibility

Prevaccination serologic testing is not required before administration of varicella virus vaccine live since the vaccine is well tolerated by immune individuals100 and a prior history of chickenpox is not a contraindication to the vaccine.138 Prevaccination serologic testing is not warranted in children 12 months through 12 years of age without a history of chickenpox since the majority of these children are susceptible.138

Routine postvaccination serologic testing to confirm seroconversion following administration of varicella virus vaccine live in otherwise healthy children, adolescents, or adults is not routinely recommended because of the high rate of seroconversion in these individuals94,100 and because commercially available assays lack sensitivity to detect vaccine-induced immunity and may give false-negative results.27,137,138

In health-care institutions, prevaccination serologic screening of personnel who have a negative or uncertain history of varicella may be cost-effective.27,113 However, the ACIP and Hospital Infection Control Practices Advisory Committee (HICPAC) state that routine postvaccination testing of health-care personnel probably is not recommended.27,113 (See Health-care Personnel under Uses: Primary Immunization.)

Ideally, individuals 12 months of age and older who are scheduled to undergo solid organ transplantation should be tested for serologic evidence of varicella immunity and, if susceptible, should receive varicella vaccine at least 1 month prior to the procedure.104

Levels of anti-varicella zoster virus antibodies (anti-VZV) that protect against varicella infection have not been identified and seroconversion following administration of varicella virus vaccine live generally is defined as acquisition of any detectable level of anti-VZV antibodies.1,27,52 Although varicella is unlikely to develop in individuals who have detectable anti-VZV antibodies, breakthrough varicella infections can occur despite seroconversion and presence of such antibodies.5,27,42,73,75,77,81

Many different serologic tests have been used to determine the presence or absence of anti-VZV and these tests differ in sensitivity and specificity, time required to obtain results, and availability.11,15,27,42,100 While fluorescent antimembrane antibody assay (FAMA), indirect fluorescent antibody (IFA), neutralization (N), and radioimmunoassay (RIA) are sensitive tests, they are time consuming and not usually appropriate for general diagnostic laboratories.11,15,27,42 The tests most widely used are latex agglutination (LA) and enzyme-linked immunosorbent assay (ELISA).27 The commercially available LA test uses latex particles coated with VZV glycoprotein antigens and is a sensitive and specific test requiring only 15 minutes for completion; however, the LA test is less effective for detecting antibody following vaccination than for detecting antibody response following natural varicella infection and can yield false-positive results.27,137,138 The commercially available ELISA test is less sensitive, but more specific, than the LA test and should be considered when screening health-care providers for varicella susceptibility.27

Primary Immunization

Children 12 Months through 12 Years of Age

The ACIP, AAP, AAFP, IDSA, and other clinicians recommend that all healthy, susceptible children 12 months through 12 years of age without evidence of immunity receive 2 doses of a vaccine containing varicella virus vaccine live.27,71,92,100,114,137 Vaccines containing varicella virus vaccine live are not recommended in children younger than 12 months of age since safety and efficacy in this age group have not been fully evaluated.1,27,71,94 (See Cautions: Pediatric Precautions.)

The ACIP, AAP, and AAFP state that the first dose of a vaccine containing varicella virus vaccine live should be administered at 12 through 15 months of age and the second dose at 4 through 6 years of age (i.e., before the child begins kindergarten or first grade).27,71,137 The second dose of a vaccine containing varicella virus vaccine live may be administered prior to 4 years of age, provided at least 3 months have elapsed since the first dose was given and both doses are administered at 12 months of age or older;27,71,137 however, if a second dose was administered at least 28 days following the first dose, the second dose does not need to be repeated.71,137 The first dose of a vaccine containing varicella virus vaccine live ideally should be administered on or after the first birthday as soon as the child becomes eligible for vaccination.128

To ensure immunization of all children, the ACIP, AAP, AAFP, and other clinicians recommend that the immunization status of children 11-12 years of age be evaluated during routine health maintenance visits and that catch-up vaccination be given to any previously unvaccinated child without a reliable history of natural varicella infection.27,129,137 In children younger than 13 years of age, the catch-up second dose of varicella virus vaccine live should be administered at least 3 months after the initial dose;27,71,137 however, if a second dose was administered at least 28 days following the first dose, the second dose does not need to be repeated.27,71,129 In previously unvaccinated children 13 through 18 years of age, 2 doses of single-antigen varicella virus vaccine live should be given at least 4 weeks apart.71,129,137

Primary immunization against varicella can be integrated with primary immunization against measles, mumps, rubella, diphtheria, tetanus, pertussis, Haemophilus influenzae type b (Hib), hepatitis A, hepatitis B, human papillomavirus (HPV), influenza, pneumococcal disease, meningococcal disease, and poliomyelitis.27,71,100,119,120 (See Drug Interactions: Vaccines.)

Fixed-combination Vaccine Containing Varicella Vaccine and Other Antigens

When there are no contraindications to any of the individual components, the commercially available fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) can be used instead of the single-antigen varicella virus vaccine live for primary immunization in children 12 months through 12 years of age when the first dose of MMR and first dose of varicella virus vaccine live are both indicated or when a second dose of MMR and a first or second dose of varicella virus vaccine live are both indicated.27,125,128,137,145

The ACIP, AAP, and AAFP state that use of a combination vaccine generally is preferred over separate injections of the equivalent component vaccines.71 However, although use of MMRV (ProQuad^®) reduces the number of required injections when both vaccines are indicated during a single health-care visit,27,128 there is some evidence that the relative risk for febrile seizures in infants 12 through 23 months of age may be higher with the fixed-combination vaccine than that reported when a dose of single-antigen varicella virus vaccine live (Varivax^®) and a dose of MMR are given concomitantly.125,136,145 (See Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

When the first dose of MMR and first dose of varicella virus vaccine live are indicated in infants and children 12 through 47 months of age, the ACIP states that providers considering use of MMRV (ProQuad^®) should advise the parent or caregiver about the benefits and risks associated with the fixed-combination vaccine compared with the individual component vaccines.145 Although MMRV (ProQuad^®) results in 1 less injection, it is associated with a higher risk for fever and febrile seizures on days 5 through 12 after the first dose in children 12 through 23 months of age (i.e., about 1 extra febrile seizure for every 2300-2600 doses of ProQuad^®).145 The ACIP states that if providers face any barriers to clearly communicating these benefits and risks (e.g., language barrier), then MMR and varicella virus vaccine live should be administered instead of MMRV (ProQuad^®).145 When the first dose of MMR and first dose of varicella virus vaccine live are indicated in children 48 months of age or older and when second doses are indicated in those 15 months through 12 years of age, the ACIP states that use of MMRV (ProQuad^®) generally is preferred over separate injections of the component vaccines;145 considerations should include provider assessment (e.g., number of injections, vaccine availability, likelihood of improved coverage, likelihood of patient return, storage and cost considerations), patient preference, and potential for adverse effects.145

Safety and efficacy of MMRV (ProQuad^®) have not been established in individuals with human immunodeficiency virus (HIV) infection†.27,144 Therefore, pending further accumulation of data, the fixed-combination vaccine should not be used in HIV-infected individuals.27,144 (See HIV-infected Individuals under Primary Immunization: Individuals with Altered Immunocompetence and Their Household Contacts, in Uses).

Clinical studies in healthy children 12-23 months of age indicate that those who received a single dose of MMRV (ProQuad^®) developed antibody levels against measles, mumps, rubella, and varicella that were similar to levels attained in children who received a single dose of MMR and a single dose of varicella virus vaccine live concomitantly at separate sites.128

Adults and Adolescents 13 Years of Age or Older

The ACIP, AAP, AAFP, IDSA, ACOG, and ACP recommend that all healthy, susceptible adults and adolescents 13 of age or older without evidence of immunity to varicella receive primary immunization with 2 doses of varicella virus vaccine live given 4-8 weeks apart.27,71,89,92,100,114,129 Safety and efficacy of the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) have not been established in adults and adolescents 13 years of age or older and should not be used in this age group.27,125

Previously, it was recommended that primary immunization against varicella virus vaccine live be considered only for susceptible adults at high risk for exposure or transmission of varicella.27,82,92,93,100 However, beginning in June 2005, the ACIP began recommending universal immunization with varicella virus vaccine live for all healthy, susceptible, nonpregnant adolescents and adults 13-49 years of age unless the vaccine is contraindicated.27,129,137 Currently, the ACIP, AAFP, ACOG, and ACP recommend primary immunization against varicella for all adults, unless contraindicated.27,129 Primary immunization with 2 doses of varicella virus vaccine live is especially important in susceptible adults who have close contact with individuals at high risk for severe varicella (e.g., health-care personnel and family contacts of immunocompromised individuals) and those who are at high risk for exposure or transmission of varicella (e.g., teachers of young children, child-care personnel, residents and staff in institutional settings such as correctional institutions, college students, military personnel, adolescents and adults living in households with children, nonpregnant women of childbearing age, international travelers).27,82,92,100,129 (See Individuals with Altered Immunocompetence and their Household Contacts and see Health-Care Personnel under Uses: Primary Immunization.) To facilitate vaccination of susceptible adolescents and adults, varicella virus vaccine live should be offered during routine health-care visits.127

Varicella virus vaccine live should not be used in women who are pregnant or might become pregnant within 4 weeks of receiving the vaccine.27,100,129,137 (See Cautions: Pregnancy, Fertility, and Lactation.) The ACIP, AAFP, and ACOG recommend that all pregnant women be assessed for evidence of varicella immunity and those without such evidence should receive a dose of monovalent varicella virus vaccine live administered after delivery or termination of pregnancy (before discharge) and a second dose administered 4-8 weeks after the first dose (at a postpartum or other health-care visit).27,100,127,129,137 The ACIP and AAP recommend the use of standing orders to ensure administration of the vaccine in health-care settings where completion or termination of pregnancy occur.100,127

For adults 60 years of age or older, the ACIP recommends that all adults in this age group receive a single dose of zoster vaccine live, unless the vaccine is contraindicated.129,131 The varicella antigen contained in commercially available zoster vaccine live (Zostavax^®) is the same as that contained in varicella virus vaccine live (Varivax^®)); however, zoster vaccine live is about 14 times more potent than varicella virus vaccine live.1,133,137 The dose of zoster vaccine live is used to boost active immunity to VZV in adults 60 years of age or older and prevent herpes zoster (also known as shingles or zoster) caused by reactivation of VZV infection.131,133

Internationally Adopted Children and Other Immigrants

Individuals seeking an immigrant visa for permanent US residency must provide proof of age-appropriate vaccination according to the US Recommended Childhood and Adolescent Immunization Schedules or the US Recommended Adult Schedule.26,112 Although this vaccination requirement applies to all immigrant infants and children entering the US, internationally adopted children younger than 11 years of age are exempt from the overseas vaccination requirements; however, adoptive parents are required to sign a waiver indicating their intention to comply with the vaccination requirements within 30 days after the infant or child arrives in the US.112 The CDC states that more than 90% of newly arrived internationally adopted children need catch-up vaccinations to meet the US Recommended Immunization Schedules.112

The fact that immunization schedules of other countries may differ from US schedules (e.g., different recommended vaccines, recommended ages of administration, and/or number and timing of vaccine doses) also should be considered.26 Vaccines administered outside the US can generally be accepted as valid if the administration schedule was similar to that recommended in the US childhood and adolescent immunization schedules.26 Only written vaccination records should be considered as evidence of previous vaccination since such records are more likely to accurately predict protection if the vaccines administered, intervals between doses, and child's age at the time of vaccination are similar to US recommendations; however, the extent to which an internationally adopted child's immunization record reflects their protection against disease is unclear and it is possible there may be transcription errors in such records (e.g., single-antigen vaccine may have been administered although a multiple-antigen vaccine was recorded).26 Although vaccines with inadequate potency have been produced in other countries, most vaccines used worldwide are immunogenic and produced with adequate quality control standards.26

When the immune status of an internationally adopted child is uncertain, health-care providers can either repeat vaccinations (since this usually is safe and avoids the need to obtain and interpret serologic tests) and/or use selective serologic testing to determine the need for immunizations (helps avoid unnecessary injections).26,112 Because varicella virus vaccine live is not available in the majority of countries, especially developing countries, all internationally adopted children who lack reliable evidence of varicella immunity should be vaccinated using an age-appropriate regimen of varicella virus vaccine live according to the US recommended immunization schedule.26 Although serologic testing can be done to verify immunization status in children older than 12 months of age, such testing prior to vaccination is not recommended in children younger than 12 years of age coming from tropical countries, unless there is a history of the disease.112

Individuals with Altered Immunocompetence and Their Household Contacts

Varicella virus vaccine live, like most other live viral vaccines, generally is contraindicated in children, adolescents, and adults with altered immunocompetence, including those with primary immunodeficiencies (e.g., cellular immune deficiency, hypogammaglobulinemia, dysgammaglobulinemia), blood dyscrasias, leukemia, lymphomas of any type or any other malignant neoplasms affecting the bone marrow or lymphatic system, HIV infection, and individuals receiving immunosuppressive therapy (e.g., corticosteroids, antineoplastic agents, radiation).1,26,54,70,92,100

Because individuals with altered immunocompetence are at high risk for serious varicella infections, vaccination of their susceptible, healthy household contacts is recommended since such a strategy provides protection for the immunocompromised individual by decreasing the likelihood that wild-type varicella virus will be introduced into the household.27,143,144 While vaccination of household contacts of immunocompromised individuals theoretically results in a risk of transmission of vaccine virus to the immunocompromised individual, the risk appears to be minimal and the benefits of vaccinating susceptible household contacts outweigh the potential risk for transmission of vaccine virus to immunocompromised contacts.27,100 However, if the healthy household contact develops a varicelliform rash following vaccination, they probably should avoid contact with the immunocompromised, susceptible individual.27,100,137 If inadvertent contact does occur, use of varicella zoster immune globulin (VZIG) for postexposure prophylaxis in the immunocompromised individual probably is unnecessary since transmission of vaccine virus is rare and disease associated with this type of transmission is expected to be mild if it occurs.27 However, some experts recommend that use of acyclovir should be considered in immunocompromised individuals (e.g., HIV-infected individuals) who develop skin lesions possibly related to vaccine virus after contact with a recipient of varicella virus vaccine live.100,143

HIV-infected Individuals

Safety and efficacy of varicella virus vaccine live have not been established in children, adolescents, or adults with HIV infection†.1,27,125 However, because HIV-infected individuals are at increased risk for morbidity from varicella and herpes zoster, the ACIP, AAP, CDC, National Institutes of Health (NIH), HIV Medicine Association of the Infectious Diseases Society of America (IDSA), Pediatric Infectious Diseases Society, and others state that use of single-antigen varicella virus vaccine live can be considered in selected HIV-infected individuals who are asymptomatic or mildly symptomatic.27,100,137,143,144 These experts suggest that, after weighing risks and benefits, use of the single-antigen varicella vaccine should be considered in HIV-infected† children 1-8 years of age with age-specific CD4⁺ T-cell percentages of at least 15% 27,137,144 and may be considered in HIV-infected† adults, adolescents, and children older than 8 years of age with CD4⁺ T-cell counts of 200/mm³ or greater.27,129,143,144 Other HIV-infected children, adolescents, or adults who are more severely immunocompromised should not receive varicella virus vaccine live.1,27,129,143,144

Routine screening for HIV prior to administration of varicella virus vaccine live is unnecessary.70,100,137 If varicella virus vaccine live is used in an HIV-infected individual†, the possibility that such individuals may be at increased risk for complications after vaccination with a live virus should be considered since they have impaired cellular immunity.27,100 Because individuals with impaired cellular immunity are potentially at greater risk for complications after vaccination with a live vaccine, HIV-infected children and their caregivers should be encouraged to consult their clinician if the child develops a postvaccination varicella-like rash.100 If an HIV-infected individual is inadvertently vaccinated and varicella develops, appropriate antiviral therapy (e.g., acyclovir) may modify the severity of the disease.27,137,143

Children and Adolescents with Acute Lymphocytic Leukemia

Although monovalent varicella virus vaccine live was used in the past under an investigational protocol in certain children and adolescents with acute lymphocytic (lymphoblastic) leukemia (ALL)† in remission,27,52,100,137 this protocol has been terminated.100 The ACIP and AAP state that varicella virus vaccine live should not be used routinely in susceptible children with leukemia and use of the vaccine in leukemic children in remission who do not have evidence of immunity to varicella should only be undertaken with expert guidance and only if antiviral therapy is available in case complications occur.27,100,137 ACIP states that use of live virus vaccines can be considered in patients with leukemia or other malignancies if the disease is in remission and chemotherapy was terminated at least 3 months prior to vaccination.26,27,137

Transplant Recipients

Information regarding use of varicella virus vaccine live in hematopoietic stem cell transplant (HSCT) or bone marrow transplant (BMT) recipients or patients who have undergone solid organ transplantation (e.g., kidney or liver transplantation) is limited.100

Ideally, individuals 12 months of age or older who are scheduled to undergo solid organ transplantation should be tested for serologic evidence of immunity to varicella and, if susceptible, should receive varicella virus vaccine live at least 1 month prior to the procedure.100,104 Although some solid organ transplant recipients have received live virus vaccines (e.g., MMR, varicella virus vaccine live) after transplantation (e.g., at least 6 months after transplantation, when minimal immunosuppressive agents were being given, when there were no recent episodes of organ rejection), but data are too limited to recommend general use of the vaccines in this population.100 The AAP recommends that serum antibody concentrations should be measured in all solid organ transplant recipients 1 year or longer after transplantation and appropriate vaccines administered if indicated.100

The AAP states that varicella virus vaccine live is contraindicated in HSCT recipients during the first 24 months after transplantation and that use of the vaccine in HSCT patients should be restricted to research protocols in which the vaccine may be considered 24 months or longer after HSCT in those presumed to be immunocompetent.100

Health-care Personnel

The ACIP and HICPAC state that all health-care personnel should ensure that they are immune to varicella and recommend that susceptible personnel receive primary immunization with 2 doses of varicella virus vaccine live as soon as possible.27,113 Immunization of susceptible personnel protects the worker following varicella exposure in the workplace and also may help reduce nosocomial transmission of VZV;11 this is particularly important for health-care personnel who have close contact with individuals who are at high risk for serious complications from varicella.27,113 Sources of nosocomial infections include patients, hospital staff, and visitors (e.g., children of hospital employees) who have varicella or herpes zoster;27,113 airborne transmission of the virus in hospitals has resulted in varicella infection in susceptible individuals who had no direct contact with the index case patient.27,113

In health-care institutions, serologic screening of personnel who have a negative or uncertain history of varicella is likely to be cost-effective.27,113 However, while varicella is unlikely to develop in individuals who have detectable anti-VZV, seroconversion does not always result in full protection and varicella has occurred in health-care personnel who had previous evidence of seroconversion.27,73,81 The ACIP and HICPAC state that routine testing of health-care personnel for varicella immunity following administration of 2 doses of varicella virus vaccine live probably is not necessary,27 but that testing vaccinees for seropositivity immediately after exposure to VZV is a potentially effective strategy for identifying those who remain at risk for varicella.113 The ACIP states that health-care personnel who have received 2 doses of varicella virus vaccine and who are exposed to varicella should be monitored through the employee health program or by an infection control nurse daily during days 10-21 after exposure to determine clinical status (i.e., screen daily for fever, skin lesions, and systemic symptoms).27 The ACIP and HICPAC state that health-care workers who remain susceptible may be furloughed or, alternatively, such individuals can be monitored daily to determine clinical status and then furloughed at the onset of manifestations of varicella.27,113 Institutional guidelines are needed for the management of exposed health-care workers who have received varicella virus vaccine live but do not have detectable antibody and for health-care personnel who develop clinical varicella.27,113

Only health-care personnel who are immune to varicella (i.e., have a positive history of varicella infection, have serologic evidence of immunity, or have received varicella virus vaccine live) should care for patients who have confirmed or suspected VZV infection.27,113 Strategies that have been used to manage clusters of VZV infection in hospitals have included isolating varicella patients and susceptible patients who have been exposed to the virus; controlling air flow; daily screening of all exposed, susceptible personnel for skin lesions, fever, and systemic symptoms; and furloughing exposed, susceptible personnel or temporarily reassigning them to locations remote from patient-care areas.27,113 However, policies of furloughing exposed, susceptible health-care personnel are disruptive (these individuals are potentially infective for 9-21 days after exposure) and costly27,81,113 and may be inadequate for preventing spread of the infection in the hospital setting.81 Although postexposure use of varicella virus vaccine live can be considered for unvaccinated health-care personnel who lack documented immunity at the time of exposure to varicella,113 preexposure vaccination is the preferred method for preventing varicella in health-care settings.27 While varicella zoster immune globulin (VZIG) can be used for postexposure prophylaxis in health-care personnel, VZIG does not necessarily prevent varicella, may prolong the incubation period by 1 week or more, and is costly.27,113 In addition, the only VZIG preparation available for use in the US (VariZIG^®; Cangene) must be obtained through an investigational new drug (IND) protocol under an expanded access program.134,135 For patients who have been exposed to varicella and who are at increased risk for severe disease and complications, this VZIG preparation can be obtained by contacting FFF Enterprises (the sole authorized US distributor) at 800-843-7477 (available 24-hours daily).134,135

Travelers

The CDC and ACIP recommend primary immunization with varicella virus vaccine live in susceptible travelers.27,112 Varicella occurs throughout the world.112,138 Although vaccination against varicella is not a requirement for entry into any country (including the US), the CDC states that individuals traveling or living abroad should ensure that they are immune.112 Unless the vaccine is contraindicated, the CDC and ACIP recommend that susceptible adults, adolescents, and children 12 months of age or older receive primary immunization with varicella virus vaccine live prior to international travel.27,112

Postexposure Vaccination and Outbreak Control

The ACIP and AAP recommend postexposure vaccination in susceptible children, adolescents, and adults following exposure to varicella, unless contraindicated.27,100,138 There is some evidence that varicella virus vaccine live may be effective in preventing varicella or modifying severity of the disease if given within 3 days, and possibly up to 5 days, after exposure.27,100,112,115,116,138 In a limited study in healthy siblings of children with varicella, administration of a single dose of vaccine (approximately 4350 units of the Oka/Merck strain of live, attenuated virus) within 3 days after the onset of rash in the index case appeared to prevent infection in 90% of susceptible siblings.11

If the exposure does not cause infection, postexposure vaccination should induce protection against subsequent exposure.100,138 If the exposure results in infection, no evidence indicates that administration of varicella virus vaccine live during the presymptomatic or prodromal stage of illness increases the risk for vaccine-associated adverse effects or more severe natural disease.100 Although postexposure use of varicella virus vaccine live can be considered for unvaccinated health-care personnel who lack documented immunity at the time of exposure to varicella,113 preexposure vaccination is the preferred method for preventing varicella in health-care settings.27,138 (See Health-care Personnel under Uses: Primary Immunization.)

When varicella virus vaccine live cannot be used (e.g., pregnant women, neonates, immunocompromised individuals) and postexposure prophylaxis is considered necessary, passive immunization with VZIG within 96 hours of exposure is recommended to prevent or reduce the severity of varicella.15,27,100,138,143,144 The only VZIG preparation available for use in the US (VariZIG^®; Cangene) must be obtained through an investigational new drug (IND) protocol under an expanded access program.134,135 For patients who have been exposed to varicella and who are at increased risk for severe disease and complications (e.g., pregnant women, neonates, immunocompromised individuals), this VZIG preparation can be obtained by contacting FFF Enterprises (the sole authorized US distributor) at 800-843-7477 (available 24 hours daily).134,135 Varicella virus vaccine live should not be administered concomitantly with VZIG.1 (See Drug Interactions: Immune Globulins.) If VZIG is not available for postexposure prophylaxis, immune globulin IV (IGIV) can be used.100 If varicella develops despite passive immunization, therapies that reduce disease severity and complications (e.g., acyclovir) may be beneficial.27,92,143

Varicella virus vaccine live can be used in the prevention and control of varicella outbreaks (e.g., in child-care facilities, schools, institutions).27,138 Varicella outbreaks can persist for up to 4-6 months.27,138 During varicella outbreaks, the ACIP and AAP recommend a second dose of varicella virus vaccine live for those who previously received only a single dose, provided the age-appropriate time interval has elapsed since the first dose (i.e., 3 months for children 12 months through 12 years of age, at least 4 weeks for adults and adolescents 13 years of age and older).27,100,138

Dosage and Administration ⬆ ⬇

[Section Outline]

Reconstitution and Administration
Dosage

Reconstitution and Administration

Varicella virus vaccine live (Varivax^®) and the fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad^®) are administered by subcutaneous injection.1,125 These vaccines should not be given intravascularly.1,125

Although some clinicians state that inadvertent IM† administration of varicella virus vaccine live does not necessitate revaccination,26,30,100 this route of administration is not recommended.1,125

The preferred site for subcutaneous injection of Varivax^® or MMRV (ProQuad^®) is the outer aspect of the upper deltoid; injections also can be given into the anterolateral thigh.1,26,125 For children 1 year of age and older, adolescents, and adults, the upper-outer triceps area usually is preferred.26 To ensure appropriate delivery, subcutaneous injections should be made at a 45° angle using a 5/8-inch, 23- to 25-gauge needle.26 Prior to injection, care should be taken to ensure that the needle is not in a blood vessel.1,26

When multiple vaccines are administered during a single health-care visit, each vaccine should be given with a different syringe and at different injection sites.26 Injection sites should be separated by at least 1 inch (if anatomically feasible) to allow appropriate attribution of any local adverse effects that may occur.26,100 If multiple vaccines must be given into a single limb, the deltoid may be used in older children and adults, but the anterolateral thigh is preferred in infants and younger children.26

Since syncope may occur following vaccination, vaccinees should be observed for approximately 15 minutes after the vaccine dose is administered.26 If syncope occurs, the patient should be observed until symptoms resolve.26 Syncope after vaccination occurs most frequently in adolescents and young adults.26

Varicella virus vaccine live should not be administered concomitantly with varicella zoster immune globulin (VZIG).1 (See Drug Interactions: Immune Globulins.)

Varivax®

Varicella virus vaccine live (Varivax^®) is reconstituted by adding 0.7 mL of the diluent provided by the manufacturer to the vial of lyophilized vaccine and gently agitating the vial.1 Only the diluent supplied by the manufacturer should be used to reconstitute the vaccine.1 Varicella virus vaccine live should be reconstituted and administered using sterile syringes and needles that are free of preservatives, antiseptics, and detergents, since these substances may inactivate live viral vaccines.1 The reconstituted vaccine should be inspected visually for particulate matter and discoloration whenever solution and container permit.1

To minimize loss of potency and ensure an adequate immunizing dose, varicella virus vaccine live should be administered immediately following reconstitution and any reconstituted vaccine not used within 30 minutes should be discarded.1 (See Chemistry and Stability: Stability.)

MMRV (ProQuad®)

MMRV (ProQuad^®) is reconstituted by adding the entire volume of diluent provided by the manufacturer to the vial of lyophilized vaccine and gently agitating the vial.125 Only the diluent supplied by the manufacturer should be used to reconstitute the fixed-combination vaccine.125 The vaccine should be reconstituted and administered using sterile syringes and needles that are free of preservatives, antiseptics, and detergents, since these substances may inactivate live viral vaccines.125 The reconstituted vaccine should be inspected visually for particulate matter and discoloration whenever solution and container permit.125

To minimize loss of potency and ensure an adequate immunizing dose, MMRV (ProQuad^®) should be administered immediately following reconstitution and any reconstituted vaccine not used within 30 minutes should be discarded.125

Dosage

Single-antigen varicella virus vaccine live (Varivax^®) and the fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad^®) are administered in 0.5-mL doses.1,26,125

When the single-antigen varicella vaccine (Varivax^®) is administered within 30 minutes following reconstitution as specified, each 0.5-mL dose contains at least 1350 plaque-forming units (PFU) of Oka/Merck varicella virus (approximately 3.13 log₁₀ PFU).1 (See Chemistry and Stability: Stability.)

When the fixed-combination vaccine (MMRV; ProQuad^®) is reconstituted as specified, each 0.5-mL dose contains the same potency of measles, mumps, and rubella antigens as measles, mumps, and rubella virus vaccine live (MMR) and at least 3.99 log₁₀ PFU of Oka/Merck varicella virus.125

Children 12 Months Through 12 Years of Age

Varivax®

For routine primary immunization in healthy children 12 months through 12 years of age, a 2-dose regimen of varicella virus vaccine live is used.1,27,71,100,137

For routine childhood immunization, the US Public Health Service Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP) recommend administration of the first dose at 12 through 15 months of age and the second dose at 4 through 6 years of age (i.e., before the child begins kindergarten or the first grade).27,71,100 The second dose may be administered prior to age 4-6 years, provided at least 3 months have elapsed since the first dose was given and both doses are administered at 12 months of age or older;1,27,71,137 however, if a second dose was administered at least 28 days following the first dose, the second dose does not need to be repeated.27,71,137

Catch-up vaccination is recommended during routine preventive care visits for children without a reliable history of varicella or in those who have not previously received 2 doses of a vaccine containing varicella virus vaccine live.27,71,100,137 Children who previously received one dose should receive a second dose, preferably at least 3 months after the first dose and children who have not received any doses of the vaccine should receive 2 doses given at least 3 months apart; however, if a second dose was administered at least 28 days following the first dose, the second dose does not need to be repeated.1,27,71,100,137

MMRV (ProQuad®)

For routine primary immunization in healthy children 12 months through 12 years of age, MMRV (ProQuad^®) is given as a 0.5-mL dose.125,128

MMRV (ProQuad^®) may be used when simultaneous administration of the first or second dose of varicella virus vaccine live and the first or second dose of measles, mumps, and rubella virus vaccine live (MMR) are both indicated in a child 12 months through 12 years of age and there are no contraindications to any of the antigens.125,128 When considering use in infants and children 12 through 47 months of age, the ACIP states that providers should advise the parent or caregiver about the benefits and risks associated with MMRV (ProQuad^®) compared with the individual component vaccines.145 (See Fixed-combination Vaccine Containing Varicella Vaccine and Other Antigens under Primary Immunization: Children 12 Months through 12 Years of Age, in Uses.)

At least 1 month should elapse between a dose of a measles-containing vaccine (e.g., MMR) and a dose of MMRV (ProQuad^®) and preferably at least 3 months should elapse between a dose of a varicella-containing vaccine (e.g., Varivax^®) and a dose of MMRV (ProQuad^®); however, if a second dose of a varicella-containing vaccine was administered at least 28 days following the first dose, the second dose does not need to be repeated.71,125,128

Adults and Adolescents 13 Years of Age or Older

Varivax®

For routine primary immunization in adults and adolescents 13 years of age or older, 2 doses of varicella virus vaccine live should be given 4-8 weeks apart.1,11,27,71,80,82,89,100,129,137 A longer interval between the first and second dose does not necessitate a third dose, but may leave the individual susceptible for the intervening months.27,100

Catch-up vaccination is recommended during routine preventive care visits for adolescents and adults without a reliable history of varicella who have not previously received 2 doses of a vaccine containing varicella virus vaccine live.1,71,129 Adolescents and adults who previously received one dose should receive a second dose given at least 4 weeks after the first dose.1,27,71,129,137 Adolescents and adults who have not received the vaccine should receive 2 doses given 4-8 weeks apart.1,27,71

HIV-infected Individuals

Varivax®

When varicella virus vaccine live is used in selected children 12 months through 12 years of age who have human immunodeficiency virus (HIV) infection† and are asymptomatic or only mildly symptomatic with CD4+ T-lymphocyte percentages of at least 15%, the ACIP, AAP, Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), HIV Medicine Association of the Infectious Diseases Society of America (IDSA), and Pediatric Infectious Diseases Society recommend that 2 doses of the vaccine be given at least 3 months apart.27,127,144

If varicella virus vaccine live is used in HIV-infected adults, adolescents, and children older than 8 years of age with CD4⁺ T-cell counts of 200/mm³ or greater, the ACIP, AAP, NIH, CDC, and HIV Medicine Association of the IDSA recommend that 2 doses of the single-antigen vaccine be given at least 3 months apart.27,137,143,144

Other HIV-infected children, adolescents, or adults who are more severely immunocompromised should not receive varicella vaccine.1,27,143,144 (See HIV-infected Individuals under Primary Immunization: Individuals with Altered Immunocompetence and Their Household Contacts, in Uses.)

MMRV (ProQuad®)

Data are not available on the safety, immunogenicity, or efficacy of MMRV; ProQuad^®) in HIV-infected children and the ACIP and other experts state that the fixed-combination vaccine should not be administered as a substitute for the component vaccines when vaccinating HIV-infected children.27,125,137,144

Postexposure Vaccination and Outbreak Control

If varicella virus vaccine live is used for postexposure prophylaxis† of varicella in susceptible children 12 months of age and older and adults, the vaccine should be given within 3-5 days after the exposure.27,100,112,126

However, if varicella zoster immune globulin (VZIG) or immune globulin IV (IGIV) is used for postexposure prophylaxis of varicella in susceptible individuals, varicella virus vaccine live should not be administered for at least 5-8 months following the immune globulin.27,126 (See Drug Interactions: Immune Globulins.) Varicella virus vaccine live is not necessary in patients who develop varicella following exposure.27,126

If varicella virus vaccine live is used for outbreak control during a varicella outbreak, the ACIP and AAP recommend that individuals who previously received a single dose of varicella virus vaccine live should receive a second dose of the vaccine if resources permit such a strategy and if the appropriate interval has elapsed since the first vaccine dose (i.e., at least 3 months in children 12 months through 12 years of age and at least 4 weeks in adults and adolescents 13 years of age or older).27,100,138

Additional Doses or Revaccination

The duration of protection following primary immunization with 2 doses of varicella virus vaccine live has not been fully established to date.1,27,35,77,100 Although immunity may wane as the time since primary immunization with varicella virus vaccine increases,122,123 there is some evidence from long-term efficacy studies that protection against varicella may last for at least 5-10 years after administration of a single dose of the vaccine.1,4,9,19,27,65,66,86,100,137 (See Pharmacology: Extent and Duration of Immunity.)

Cautions ⬆ ⬇

[Section Outline]

Local Effects
Systemic Effects
Breakthrough Varicella Infections
Latent Infections and Herpes Zoster
Transmission of Vaccine Virus
Precautions and Contraindications
Pediatric Precautions
Geriatric Precautions
Mutagenicity and Carcinogenicity
Pregnancy, Fertility, and Lactation

Varicella virus vaccine live generally is well tolerated in healthy children, adolescents, and adults.1,9,27,30,42,43,44,45,46,47,75,80 In a placebo-controlled trial in healthy children and adolescents, pain and erythema at the injection site were the only adverse reactions that occurred more frequently in vaccine recipients than in placebo recipients.1,27,43 Administration of varicella virus vaccine live to individuals with serologic evidence of varicella zoster virus (VZV) antibodies (anti-VZV) elicited by previous vaccination or natural infection does not appear to be associated with a clinically important increase in the incidence of adverse effects compared with administration in susceptible individuals.43,45,100

The fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad^®) generally is well tolerated.125 Adverse effects reported with the fixed-combination vaccine are similar to those reported when varicella virus vaccine live and the fixed combination of measles, mumps, and rubella virus vaccine live (MMR) are administered concurrently at separate sites.125 In clinical studies in healthy children 12-23 months of age, fever (38.9°C or higher) and measles-like rash were the only adverse effects that occurred more frequently in those who received MMRV (ProQuad^®) compared with those who received MMR and varicella virus vaccine live at separate sites.125 In children who received a second dose of MMRV (ProQuad^®), the incidence of adverse effects reported after the second dose was similar to or lower than that reported with the first dose.125 (See Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Local Effects

The most frequent adverse effects of varicella virus vaccine live are local reactions including pain, soreness, swelling, and erythema.1,9,11,27,30,42,43,44,45,47,80 Pruritus, hematoma, induration, or stiffness also has been reported.1,27 These adverse local reactions generally occur within the first 48 hours following vaccination and are more common in adolescents and adults than in children.1,3,9,45 Local effects may persist for several days following vaccination, particularly following a second dose.45

In healthy children 12 months through 12 years of age who received a single dose of varicella virus vaccine live, adverse local effects (e.g., pain/soreness, swelling and/or erythema, rash, pruritus, hematoma, induration, stiffness) were reported in 2-29% of vaccinees.1,3,9,27,42,44 When a 2-dose regimen was used in children, the incidence of injection site reactions (usually erythema and swelling) observed in the first 4 days following vaccination was slightly higher after the second dose (overall incidence 25.4%) than after the first dose (overall incidence 21.7%).1

In healthy adults and adolescents 13 years of age or older who received a 2-dose regimen of varicella virus vaccine live, adverse local effects occurred in 10-25% following the initial dose1,3,11,27,45,47,80 and in 27-47% following the second dose.1,27,45,80

In addition to the more common local effects, a varicella-like maculopapular or papulovesicular rash composed of only a few lesions or vesicles (median: 2-5) has occurred at the injection site in 1-12% of healthy children, adolescents, or adults who received varicella virus vaccine live.1,27,30,42,75,80 The varicelliform rash at the injection site generally occurs 6-30 days after vaccination.1,27,30,42 In adults and adolescents 13 years of age or older, the varicelliform rash occurs at a peak of 6-20 days following the first dose of vaccine and 0-6 days following the second dose.1,27 While vaccine virus generally is not present in the lesions,11,14,15 the virus has been isolated occasionally and theoretically could be transmitted.1,8,9,10,11,14,20,42,45,54 (See Cautions: Transmission of Vaccine Virus.) A more generalized rash also can occur.1 (See Cautions: Systemic Effects.)

Systemic Effects

Febrile Reactions

In healthy children 12 months through 12 years of age who received a single dose of varicella virus vaccine live, fever (38.3°C or higher) occurred in 12-31% during the first 42 days following the dose.1,3,27,30,42 In a placebo-controlled study using a vaccine similar to the vaccine commercially available for use in the US, the incidence of fever was the same in children who received the vaccine and in those who received placebo.43 Although a causal relationship was not established, febrile seizures have occurred rarely (less than 0.1%) in children who received varicella virus vaccine live.1 Febrile seizures also have been reported with the fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad^®).125 (See Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

In healthy adults and adolescents 13 years of age or older who received a 2-dose regimen of varicella virus vaccine live, fever (37.7°C or higher) occurred during the first 42 days following vaccination in up to 10% after the first or second dose.1,9,11,27,47,80

Rash

A generalized varicella-like maculopapular or papulovesicular rash occurs in 4-10% of healthy children who receive a dose of varicella virus vaccine live at 12 months through 12 years of a 1,3,14,27,30,42,43,44,75 the rash generally is mild,3,14 composed of 1-30 vesicles, appears 5-41 days after administration of the vaccine, and persists for 2-8 days.1,3,14,30,42,44

In healthy adults and adolescents 13 years of age or older, varicella-like rash occurred in 1-8% and appears within 35 days after a dose of varicella virus vaccine live.1,11,27,45,47,80 The rash generally is mild, composed of a median of 5-6 vesicles (range: 1-47 vesicles), lasts for a median of 4-8 days (range: 1-21 days), and occurs more frequently after the first dose than after the second dose.1,80 Although a generalized, typical varicelliform rash may develop,1,3,11,30,42,43 the rash also can be difficult to distinguish from other rashes14,20 and occasionally may resemble mosquito bites.20

Sensitivity Reactions

Adverse effects that appear to be hypersensitivity reactions to varicella virus vaccine live have been reported rarely, including anaphylaxis,1,27 rash,1,27 urticaria,1 hypersensitivity vasculitis,105 erythema multiforme,1,27 and Stevens-Johnson syndrome.1

Varicella virus vaccine live contains hydrolyzed gelatin as a stabilizer,1,27 which may stimulate hypersensitivity reactions in some individuals.27,106 At least 2 healthy adults who had immediate reactions (i.e., wheezing and dyspnea with or without urticaria) within 15 minutes after receiving varicella virus vaccine live (vaccine type not identified) were found to have IgE antibodies to bovine gelatin.106 While IgE antibodies specific to gelatin were not found in 2 adults with nonimmediate reactions to the vaccine (i.e., erythema and swelling at the injection site), it has been suggested that these reactions may have been related to a cell-mediated immune response to gelatin since gelatin-specific T-cell responses (detected by in vitro lymphocyte proliferation assay and an assay for antigen-specific IL-2 responsiveness) have been found in individuals with nonimmediate-type reactions to live viral vaccines that contain gelatin.106 (See Sensitivity Reactions under Cautions: Precautions and Contraindications.)

Other Adverse Systemic Effects

Other adverse systemic effects that have been reported in 1% or more of healthy children, adolescents, or adults receiving varicella virus vaccine live and may or may not be related to the vaccine include upper respiratory illness, cough, irritability/nervousness, fatigue, disturbed sleep, diarrhea, loss of appetite, nausea, vomiting, otitis, diaper rash/contact rash, headache, teething, malaise, abdominal pain, other rash, ocular complaints, chills, lymphadenopathy, myalgia, lower respiratory illness, stiff neck, heat rash/prickly heat, arthralgia, eczema/dry skin/dermatitis, cold/canker sore, constipation, and pruritus.1,80 Although a causal relationship has not been established, pneumonia, pneumonitis, encephalitis, and ataxia have been reported rarely following administration of varicella virus vaccine live.1,27 In addition, Henoch-Schönlein purpura, secondary bacterial infections of skin and soft tissue (including impetigo and cellulitis), pharyngitis, thrombocytopenia (including immune thrombocytopenic purpura), dizziness, nonfebrile seizures, aseptic meningitis, Guillain-Barré syndrome, transverse myelitis, Bell's palsy, and paresthesia have been reported during postmarketing surveillance.1

Breakthrough Varicella Infections

Although varicella virus vaccine live is effective in promoting immunity to varicella in most individuals, breakthrough varicella infections may occur following exposure to wild-type virus in children or adults who have seroconverted following vaccination.1,5,9,11,13,16,17,18,20,24,27,42,44,47,48,52,53,55,75,77,122,123 These infections (i.e., wild-type VZV infection occurring more than 42 days after vaccination) generally are milder than those reported in unvaccinated individuals and are associated with a low rate of fever and rapid recovery.1,13,16,17,24,27,42,47,48,52,75,77,100,137

In studies using live, attenuated varicella vaccines containing 1000-9000 units per dose, breakthrough infections have occurred in up to 4% of healthy children or adolescents within 8 years following vaccination1,13,42 and in 7-9% of immunosuppressed children, including those with acute lymphoblastic leukemia (ALL).52,53 In one study in children and adolescents 12 months to 17 years of age who received varicella vaccine virus live containing 950-3265 units per dose, breakthrough infections occurred in about 19% within 10 years.75 Most cases of breakthrough varicella are much milder than infections reported in unvaccinated individuals.1,13,16,17,24,27,42,47,48,52,75,77 Breakthrough infections generally involve less than 100 vesicles and are associated with a low rate of fever and with rapid recovery.1,13,16,17,27,47,48,75,77 In one study of an outbreak of varicella at a US day-care center, the efficacy of the vaccine in preventing disease of any severity in immunized children following exposure to an index case with breakthrough varicella infection was only 44% but was 86% in preventing moderate or severe disease;122,123 the risk of breakthrough infection was greatest in children who had been vaccinated 3 or more years prior to the outbreak.

The rate of breakthrough infections in healthy adults who receive the vaccine is higher, and these infections may occur in as many as 31% of adults.11 Although breakthrough varicella infections in adults generally involve less than 50 vesicles,1,11,27,100,137 some infections may be associated with 50-300 vesicles or more.1,11

Breakthrough infections may occur despite seroconversion and evidence of anti-VZV.5,27,42,75,77 However, there appears to be an inverse relationship between antibody levels and development of breakthrough varicella infections, and individuals with higher antibody levels 6 weeks after vaccination have lower rates of breakthrough disease.75 In children, the varicella antibody response measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) 6 weeks postvaccination correlates with neutralizing antibody levels, VZV-specific T-cell proliferative responses, vaccine efficacy, and long-term protection against varicella after exposure to VZV.27 Results of some clinical trials indicate that the incidence of breakthrough infections is lower in children with postvaccination antibody titers of 5 units or greater measured by gpELISA than in children with lower postvaccination antibody titers.27,77

The rate of disease transmission from vaccinees who develop breakthrough varicella infections appears to be low in children, but has not been studied in adults.27 Data from studies conducted in 1981-1989 indicate that breakthrough infections occurred in about 5% of vaccinated children 1-8 years following vaccination and resulted in secondary transmission to about 12% of their vaccinated siblings.27 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that vaccinated individuals with less than 50 varicella lesions were only one third as contagious as unvaccinated individuals with varicella.27 However, vaccinated individuals who had more than 50 varicella lesions were as contagious as unvaccinated individuals with varicella.27,137 Vaccinated individuals with varicella tend to have milder disease, and, although they are less contagious than unvaccinated persons with varicella, they might not receive a diagnosis and be isolated; therefore, these individuals might have more opportunities to infect others in community settings and contribute to VZV transmission.27

Latent Infections and Herpes Zoster

Primary immunization with varicella virus vaccine live does not necessarily ensure protection against latent infection or reactivation of latent infections in those previously infected with natural wild-type VZV.8,9,27,42,49,50,74,137 Herpes zoster has been reported rarely in immunocompromised children and healthy children, adolescents, and adults who received primary immunization with varicella virus vaccine live.1,8,9,42,47,49,50,51,52,55,74 Herpes zoster in vaccinated individuals may be caused by vaccine virus or by wild-type virus.1,8,9,27,49,74,137 There is no evidence to date that latent vaccine virus infections are any more likely to reactivate than latent infections caused by wild-type virus.8,55

Most cases of herpes zoster reported to date have occurred 3-5 years after vaccination and were mild without sequelae.1,9,50,74 The manufacturer states that 9454 healthy children 12 months to 12 years of age and 1648 adolescents and adults have received Varivax^® in clinical trials and that the calculated incidence of herpes zoster has been 18.8 cases per 100,000 person years for children (8 cases during 42,556 person years) and 18.5 cases per 100,000 person years for adolescents and adults (1 case during 5410 person years).1 According to data from one study in children who received single-antigen varicella vaccine, the rate of herpes zoster after vaccination was 22 per 100,000 person years in those 12-24 months age, 30 per 100,000 person years in those 5-9 years of age, and 47 per 100,000 person years for those younger than 14 years of age.27 Cases of herpes zoster in healthy vaccine recipients have been confirmed to be caused by both vaccine virus and wild-type virus, suggesting that some herpes zoster cases in vaccinees might result from antecedent natural varicella infection that might not have been detected by the patient or from infection after vaccination.27

Although further study is needed, waning cell-mediated immunity to VZV may predispose to reactivation of the virus.6,9,74,137 The long-term effect of primary immunization with varicella virus vaccine live on the incidence of subsequent herpes zoster, particularly in vaccinees exposed to natural varicella, is unknown.1,9,21,24,32,37,38,39,78 Although further long-term study is needed, the reported rate of herpes zoster in vaccine recipients appears to be considerably lower than that reported in population-based studies in healthy children who have had natural varicella.1,8,11,27,42,74,137 In children with ALL†, herpes zoster appears to occur less frequently in those who have received varicella virus vaccine live than in those who have had natural varicella infection.11,49,55,78

Transmission of Vaccine Virus

Varicella live vaccines (Varivax^® and MMRV [ProQuad^®]) contain live, attenuated virus.1,8,11,27,45,54,125 Transmission of vaccine virus may occur rarely between vaccinees and susceptible contacts.1,125 Vaccine virus has been isolated from vesicular fluid obtained from individuals who developed a varicelliform rash following primary immunization with varicella virus vaccine live,1,8,9,10,11,14,20,42,45,54,79 and individuals who receive the vaccine can transmit the vaccine virus to susceptible close contacts.1,8,11,45,54 The risk for transmission of vaccine virus to susceptible close contacts appears to be minimal following vaccination of healthy children or adults,9,11,20,27,45,47,79 but may be increased if the vaccine recipient develops a varicelliform rash following vaccination and/or the vaccine recipient is immunocompromised.10,27,40 Transmission of vaccine virus from vaccinees without a varicella-like rash has been reported, but not confirmed.1

Transmission of vaccine virus to susceptible siblings following administration of the vaccine to children with leukemia in remission has been documented.9,10,20,27,52,54,55,58 Data from studies in children with leukemia who developed varicelliform rash after receiving varicella virus vaccine live indicate that the vaccine virus was transmitted to 14-17% of their healthy, susceptible siblings within 1 month.10,27,55 In one family, tertiary transmission to a second healthy sibling occurred, with rash developing 18 days after onset of rash in the secondary case and 33 days after onset of rash in the leukemic child; vaccine virus was isolated from all 3 siblings and the rash in the healthy siblings was mild (11 and 40 lesions).27

Postmarketing surveillance suggests that transmission of vaccine virus from healthy vaccinees who develop a varicelliform rash to healthy, susceptible contacts occurs only rarely.1,27 There have been at least 5 documented cases of transmission of vaccine virus from immunocompetent vaccinated individuals to susceptible contacts; all reported cases resulted in mild disease without complications.27 In one documented case, vaccine virus was transmitted from a healthy child to his pregnant mother.27,108 The child received varicella virus vaccine live at 12 months of age and developed a varicelliform rash (approximately 30 lesions) 24 days later; the mother developed varicella (approximately 100 lesions) 16 days after the child's rash was evident.108 Results of in vitro testing confirmed that the rash in both the child and his mother was caused by vaccine virus.108 The mother elected to terminate the pregnancy, and fetal tissue tested by PCR was negative for varicella vaccine virus.27

Vaccine-related contact infections reported to date generally have been mild or subclinical, indicating that the vaccine virus remains attenuated when transmitted.8,10,54 While the risk of transmission appears to be minimal when the vaccine recipient does not develop a varicelliform rash, vaccine recipients should attempt to avoid close contact with high-risk individuals (e.g., immunocompromised individuals, pregnant women without a documented history of varicella or laboratory evidence of prior infection, and neonates of such susceptible pregnant women) for up to 6 weeks following vaccination, whenever possible.1,125 If contact with high-risk individuals is unavoidable, the potential risk of transmission of vaccine virus should be weighed against the risk of acquiring and transmitting natural varicella virus.1,125

Vaccinees who develop a rash should avoid contact with susceptible, immunocompromised individuals until the rash resolves.10,27,54 If contact inadvertently occurs, postexposure prophylaxis with varicella zoster immune globulin (VZIG) is unnecessary since transmission is rare and contact infections generally are mild.27,94

Precautions and Contraindications

Varicella virus vaccine live and the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) are contraindicated in individuals who are hypersensitive to the vaccines or any component in the formulations, including gelatin.1,27,125 (See Sensitivity Reactions under Cautions: Precautions and Contraindications.)

The patient and/or the patient's parent or guardian should be informed of the benefits and risks of immunization with varicella virus vaccine live or MMRV (ProQuad^®) and should be provided with a copy of the appropriate Vaccine Information Statement (available at the CDC website [Web]).1,125,140 Patients and/or the patient's parent or guardian also should be instructed to report any severe or unusual adverse reactions to their health-care provider.1,140 Clinicians or individuals can report any adverse reactions that occur following vaccination to VAERS at 800-822-7967 or [Web].1,125,137,140

Sensitivity Reactions

Prior to administration, the recipient and/or parent or guardian should be questioned concerning reactions to previous doses of varicella virus vaccine or similar preparations.1,27,125 Epinephrine should be readily available for immediate treatment of an anaphylactic reaction if such a reaction should occur.1,27,125

Because varicella virus vaccine live and MMRV (ProQuad^®) contain trace amounts of neomycin, the vaccines are contraindicated in individuals who have had an anaphylactic reaction to topically or systemically administered neomycin.1,26,27,125 Neomycin allergy usually is characterized by a delayed-type (cell-mediated) hypersensitivity reaction, such as contact dermatitis (e.g., characterized by an erythematous, pruritic nodule or papule) occurring within 48-96 hours.26,27,125 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) state that vaccines containing trace amounts of neomycin should not be used in individuals with a history of anaphylactic reaction to neomycin, but use of such vaccines may be considered in those with a history of a delayed-type hypersensitivity reaction to neomycin if benefits of vaccination outweigh risks.26,27,125

The possibility of an allergic reaction to hydrolyzed gelatin, which is present in varicella virus vaccine live and MMRV (ProQuad^®) as a stabilizer, should be considered.26,27,100,106,125 Although skin testing for gelatin sensitivity before administering a gelatin-containing vaccine such as varicella virus vaccine live can be considered, there are no specific protocols for this purpose.26,100 Because gelatin used in vaccines manufactured in the US usually is derived from porcine sources, and food gelatin may be derived solely from bovine sources, a negative food history does not exclude the possibility of a reaction to the gelatin contained the vaccine.100

Individuals with Altered Immunocompetence

Varicella virus vaccine live and MMRV (ProQuad^®) generally are contraindicated in individuals with primary immunodeficiencies (e.g., cellular immune deficiency, hypogammaglobulinemia, dysgammaglobulinemia) and in individuals with suppressed immune responses resulting from acquired immunodeficiency syndrome (AIDS) or other clinical manifestations of human immunodeficiency virus (HIV) infection, blood dyscrasias, leukemia, lymphomas of any type, or any other malignant neoplasms affecting the bone marrow or lymphatic systems.1,27,70,100,125,137,143,144 (See Individuals with Altered Immunocompetence and Their Household Contacts under Uses: Primary Immunization.) The vaccines also generally are contraindicated in individuals with a family history of congenital or hereditary immunodeficiency in a first-degree relative (e.g., parents and siblings), unless the immune competence of the potential vaccine recipient has been clinically substantiated or verified by a laboratory.1,20,27,125,137

Varicella virus vaccine live and MMRV (ProQuad^®) are contraindicated in individuals in whom immunologic responses have been suppressed because of immunosuppressive therapy (e.g., corticosteroids, antineoplastic agents, radiation therapy).1,26,27,70,125 Use of the vaccine in individuals receiving corticosteroid dosages that are immunosuppressive can result in a more extensive vaccine-associated rash or disseminated disease.1,26,125 (See Drug Interactions: Immunosuppressive Agents.)

Contact with High-risk Individuals

The fact that recipients of varicella virus vaccine live and MMRV (ProQuad^®) may be capable of transmitting the vaccine viruses to close, susceptible contacts should be considered.1,9,10,11,20,125 It is recommended that vaccine recipients avoid close association with susceptible high-risk individuals for up to 6 weeks following vaccination, whenever possible.1,125 High-risk individuals include immunocompromised individuals, pregnant women without a documented history of varicella or laboratory evidence of prior infection, and neonates of such susceptible pregnant women.1,93,125 In circumstances when contact with high-risk individuals is unavoidable, the potential risk of transmission of vaccine virus should be weighed against the risk of acquiring and transmitting natural varicella virus.1,125 Vaccine recipients who develop a varicelliform rash should avoid contact with immunocompromised, susceptible individuals until the rash resolves.27 The American Academy of Pediatrics (AAP) and other clinicians state that if contact inadvertently occurs, use of varicella zoster immune globulin (VZIG) for postexposure prophylaxis is unnecessary since transmission is rare and contact infections generally are mild.27,94 However, some experts recommend that use of acyclovir be considered in immunocompromised individuals who develop skin lesions possibly related to vaccine virus after contact with a recipient of varicella virus vaccine live.100 The role of VZIG or acyclovir as prophylaxis for high-risk individuals exposed to vaccinated individuals with lesions will be difficult to evaluate given the rarity of transmission of vaccine virus.100

Concomitant Illness

The decision whether to administer or delay administration of varicella virus vaccine live or MMRV (ProQuad^®) in an individual with a current or recent acute illness depends largely on the severity of symptoms and etiology of the illness.26,27 The manufacturer states that the vaccines are contraindicated in individuals with any febrile respiratory illness or other active febrile infection.1,125 ACIP and AAP state that minor acute illness, such as mild upper respiratory infection (with or without fever) or mild diarrhea, does not preclude vaccination.26,27,100 However, vaccination of individuals with moderate or severe acute illness (with or without fever) generally should be deferred until they have recovered from the acute phase of the illness.26,27 This precaution avoids superimposing adverse effects of the vaccine on the underlying illness or mistakenly concluding that a manifestation of the underlying illness resulted from vaccination.26

Known history of varicella disease is not a contraindication to varicella vaccination.112

The manufacturer states that varicella virus vaccine live and MMRV (ProQuad^®) are contraindicated in individuals with active untreated tuberculosis.1,125 The ACIP states that, although no data exist regarding whether either varicella or varicella virus vaccine live exacerbates tuberculosis, vaccination is not recommended for individuals with untreated, active tuberculosis.27 However, tuberculin skin testing is not a prerequisite for administration of varicella virus vaccine live.27,100

Thrombocytopenia

Thrombocytopenia has been reported after administration of varicella virus vaccine live or measles, mumps, and rubella virus vaccine live (MMR); thrombocytopenia has worsened in those with preexisting thrombocytopenia and may worsen with subsequent doses.27,125

The manufacturer of MMRV (ProQuad^®) states that potential benefits and risks should be evaluated before considering use of the vaccine in patients who develop thrombocytopenia or had worsening of thrombocytopenia with a previous dose.125 Serologic testing for antibody to MMR should be considered to determine whether additional doses should be given.125

Use of Fixed Combinations

Whenever the fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad^®) is used, the contraindications and precautions related to each antigen should be considered.125

For complete information on adverse effects and precautions and contraindications related to measles, mumps, and rubella antigens (including hypersensitivity to eggs), see Cautions in the individual monographs on Measles Virus Vaccine Live, Mumps Virus Vaccine Live, and Rubella Virus Vaccine Live in 80:12.

There is some evidence that the relative risk for febrile seizures in children 12-60 months of age after a dose of MMRV (ProQuad^®) is higher than that reported when a dose of monovalent varicella virus vaccine live (Varivax^®) and a dose of MMR are given concomitantly.125,136 Interim results from a postmarketing observational study in children 12-60 months of age (99% were 12-23 months of age) indicate that the relative risk for febrile seizures 5-12 days after a dose of MMRV (ProQuad^®) is 2.3 times higher than in historic, age- and gender-matched controls who received a dose of varicella virus vaccine live (Varivax^®) and a dose of MMR concomitantly.136 (See Fixed-combination Vaccine Containing Varicella Vaccine and Other Antigens under Primary Immunization: Children 12 months through 12 Years of Age, in Uses.)

The manufacturer recommends that MMRV (ProQuad^®) be used with caution in individuals with a history of cerebral injury, personal or family history of seizures, or any other condition in which fever-induced stress should be avoided.125 The ACIP states that a personal or family (i.e., sibling, parent) history of seizures is a precaution for use of MMRV (ProQuad^®).145 Studies suggest that children with a personal or family history of febrile seizures or family history of epilepsy are at increased risk for febrile seizures compared with children who do not have such histories.145 ACIP states that the risks of using MMRV (ProQuad^®) in children with a personal or family history of seizures generally outweigh the benefits and such children should receive a dose of MMR and a dose of varicella virus vaccine live.145

Data are not available regarding safety and efficacy of MMRV (ProQuad^®) in HIV-infected individuals†.27,144 The ACIP, AAP, Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), HIV Medicine Association of the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society state that the fixed-combination vaccine should not be used in HIV-infected individuals.27,144 When vaccination against varicella is indicated in HIV-infected individuals, monovalent varicella virus vaccine live (Varivax^®) should be used.27,137,143,144 (See HIV-infected Individuals under Primary Immunization: Individuals with Altered Immunocompetence and Their Household Contacts, in Uses.)

MMRV (ProQuad^®) contains albumin human.125 Since albumin is prepared from pooled human plasma, it is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and HIV infection, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).125,141

Limitations of Vaccine Effectiveness

Varicella virus vaccine live (Varivax^®) and MMRV (ProQuad^®) may not protect all individuals from varicella.1,27,125

Safety and efficacy of varicella virus vaccine live (Varivax^®) or MMRV (ProQuad^®) for postexposure prophylaxis have not been established and it is not known whether administration of varicella vaccine immediately after exposure to natural varicella virus will prevent illness.1,27,125 However, the single-antigen varicella vaccine has been used for postexposure vaccination† in susceptible individuals and for outbreak prevention and control in certain settings.27,100,115,116,126 (See Uses: Postexposure Vaccination and Outbreak Control.)

Improper Storage and Handling

Improper storage or handling of vaccines may result in loss of vaccine potency26,139 and reduced immune response in vaccinees.26

Single-antigen varicella vaccine (Varivax^®) or MMRV (ProQuad^®) that has been mishandled or has not been stored at the recommended temperature should not be administered.1,26,125,139 (See Chemistry and Stability: Stability.)

The lyophilized varicella virus vaccine live should be protected from light at all times1,125,139 since exposure to light may inactivate the vaccine virus.125,139

All vaccines should be inspected upon delivery and monitored during storage to ensure that the appropriate temperature is maintained.26 If there are concerns about mishandling, the manufacturer or state or local health departments should be contacted for guidance on whether the vaccine is usable.26,139

Reconstituted vaccine should be discarded if not used within 30 minutes and should not be frozen.1,125,139 (See Chemistry and Stability: Stability.)

Pediatric Precautions

Safety and efficacy of varicella virus vaccine live (Varivax^®) in children younger than 12 months of age have not been established, and use of the vaccine in this age group is not recommended.1,27,94 Transplacental antibodies to VZV reportedly persist for no more than 6-8 months after delivery44 and should not interfere with the immunologic response to varicella virus vaccine live if vaccines containing the antigen are administered to children at 12 months of age or older.44,100

A few clinicians have suggested that consideration can be given to administering Varivax^® to children as young as of 6 months age† as a means of decreasing the risk of transmission of wild-type varicella infection to high-risk household members (e.g., individuals with altered immunocompetence, pregnant woman without a documented history of varicella or laboratory evidence of prior infection).94 However, such use is not included in current ACIP or AAP recommendations for the vaccine.27

Safety and efficacy of the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) have not been established in children younger than 12 months of age or in children or adolescents 13 years of age or older.125

Geriatric Precautions

Clinical studies of varicella virus vaccine live (Varivax^®) did not include sufficient numbers of seronegative adults 65 years of age and older to determine whether geriatric adults respond differently than younger individuals.1 Other reported clinical experience has not identified differences in responses between geriatric and younger individuals.1

The fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) is not indicated in adults, including geriatric adults.125

Mutagenicity and Carcinogenicity

The mutagenic and carcinogenic potential of varicella virus vaccine live (Varivax^®) or the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) have not been evaluated.1,125

Pregnancy, Fertility, and Lactation

Pregnancy

Varicella virus vaccine live and the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) are contraindicated in pregnant women,1,26,27,100,125,129 and pregnancy should be avoided for 1-3 months following vaccination.1,26,27,100,125,129,137,140 Natural varicella infection during pregnancy, especially during the first 2 trimesters, has been associated with congenital varicella syndrome which may result in spontaneous abortion, fetal death, or congenital abnormalities.1,9,15,25,27,31,93 Animal reproduction studies have not been performed to date with varicella virus vaccine live or MMRV (ProQuad^®),1,125 and it is not known if the vaccines can cause fetal harm when administered to pregnant women or can affect fertility.1,27,125

On theoretical grounds, live attenuated vaccines generally are avoided in pregnant women or those likely to become pregnant within 3 months of vaccination.26,94 Reasonable precautions should be taken to preclude vaccination of pregnant women, including asking postpubertal women if they are pregnant, excluding those who state that they are, informing the others of the theoretical risks to the fetus, and explaining the importance of not becoming pregnant for 1-3 months after vaccination.89,94,140 Although the manufacturer recommends that pregnancy be avoided for 3 months after administration of live viral vaccines,1,26,125 the ACIP26,27 and AAP100 have stated that pregnancy should be avoided for at least 1 month following administration of varicella virus vaccine live.27,129 The ACIP suggests that if a woman is pregnant when vaccinated or becomes pregnant within 1 month of vaccination, she should be counseled concerning potential effects on the fetus.26,27 Because the virulence of the attenuated varicella virus used in the vaccine is less than that of the wild-type virus, the ACIP suggests that the risk to the fetus, if any, should be lower than that following natural varicella infection and in most circumstances a decision to terminate a pregnancy should not be based on whether varicella virus vaccine live was administered during pregnancy.26,27

The manufacturer, in collaboration with the US Centers for Disease Control and Prevention (CDC), has established a registry to monitor pregnancy outcomes in women who inadvertently receive a vaccine containing varicella virus vaccine live during pregnancy or any time during the 3 months prior to pregnancy, and clinicians and health-care providers are encouraged to register such patients at 800-986-8999.1,27,72,100,125

The ACIP and AAP state that the presence of a pregnant woman in a household does not contraindicate use of varicella virus vaccine live in other household members.26,27,100,137 Vaccination of the susceptible household member will likely protect the susceptible pregnant woman from exposure to wild-type VZV.96,100 If varicella virus vaccine live is administered to a household member and the recipient develops a varicelliform rash, contact with the susceptible pregnant woman should be avoided if possible.95,103 Vaccine virus has been transmitted from a healthy 12-month-old child who developed a varicelliform rash following vaccination to his pregnant mother.108 (See Cautions: Transmission of Vaccine Virus.) After elective abortion, no virus was detected in the fetal tissue.108

The ACIP, American Academy of Family Physicians (AAFP), and American College of Obstetricians and Gynecologists (ACOG) recommend that all pregnant women be assessed for evidence of varicella immunity and those without such evidence should receive a dose of monovalent varicella virus vaccine live administered after delivery or termination of pregnancy (before discharge) and a second dose administered 4-8 weeks after the first dose (at a postpartum or other health-care visit).27,100,127,129,137

Lactation

It is not known whether attenuated varicella virus contained in varicella virus vaccine live is distributed into milk following subcutaneous administration.1,27,100 Because some viruses are distributed into milk, the manufacturer states that the vaccine should be used with caution in nursing women.1 Although organisms contained in live vaccines multiply within the body and some may be distributed into milk following immunization of the mother (e.g., rubella virus vaccine live), there is no evidence that this occurs with varicella vaccine and no evidence that it would adversely affect a nursing infant.26,27,100 The ACIP and AAP state that use of monovalent varicella virus vaccine live in susceptible nursing women may be considered,26,27,100,137 especially if the risk for exposure to natural infection is high.100

Drug Interactions ⬆ ⬇

[Section Outline]

Antiviral Agents
Blood Products
Immune Globulins
Immunosuppressive Agents
Vaccines
Salicylates

Antiviral Agents

Because antiviral agents active against herpesviruses (e.g., acyclovir, famciclovir, valacyclovir) may reduce efficacy of varicella virus vaccine live, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) recommends that these antiviral agents be discontinued at least 24 hours before administration of vaccines containing varicella virus vaccine live, if possible.26

Blood Products

Blood products (e.g., whole blood, packed red blood cells [RBCs], plasma) may interfere with the immune response to certain live virus vaccines (e.g., measles virus vaccine live); therefore, these live vaccines should not be administered simultaneously with or for specified intervals before or after administration of these preparations.1 Although specific studies evaluating possible interference with the immune response to varicella virus vaccine live have not been performed, use of the vaccine generally should be deferred following administration of blood products.1,26,27,125

The ACIP recommends that administration of varicella virus vaccine live should be deferred for at least 3 months following administration of RBCs (with adenine-saline added), for at least 6 months following administration of administration of packed RBCs or whole blood, and for at least 7 months following administration of plasma or platelet products. However, because of the importance of postpartum vaccination in women without evidence of varicella immunity, vaccination of such women should not be delayed because they received a blood product.26 If simultaneous administration of varicella virus vaccine live and a blood product or administration at less than the recommended interval is deemed necessary, the fact that vaccine-induced immunity may be compromised should be considered and, unless there is serologic evidence of an adequate antibody response to the live virus vaccine, an additional dose of vaccine should be administered at the specified interval.26

The fact that revaccination may be necessary in individuals who receive a blood product shortly after varicella virus vaccine live also should be considered.26 After receiving varicella virus vaccine live, vaccinees should avoid blood products for 2 weeks; if use of a blood product is considered necessary during this period, a repeat vaccine dose should be given after the recommended interval unless serologic testing is feasible and indicates a response to the vaccine was attained.27

Immune Globulins

Antibodies contained in immune globulin preparations (e.g., immune globulin, cytomegalovirus immune globulin, hepatitis B immune globulin, rabies immune globulin [RIG], tetanus immune globulin [TIG], varicella zoster immune globulin [VZIG]) may interfere with the immune response to certain live virus vaccines (e.g., measles virus vaccine live) and these vaccines should not be administered simultaneously with or for specified intervals before or after administration of these preparations.1,26,27,125 Although specific studies evaluating possible interference with the immune response to varicella virus vaccine live have not been performed, use of the vaccine generally should be deferred following administration of immune globulin.1,26,27,100

The ACIP recommends that administration of varicella virus vaccine live should be deferred for at least 3 months following administration of TIG, hepatitis B immune globulin (HBIG), or IGIM used for postexposure prophylaxis of hepatitis A virus (HAV); for at least 4 months following administration of RIG; for at least 5 months following administration of IGIM used for measles prophylaxis in immunocompetent individuals; for at least 6 months following administration of cytomegalovirus immune globulin IV (CMV-IGIV), or IGIM for measles prophylaxis in immunocompromised individuals; for at least 8 months following administration of IGIV for replacement therapy of immunodeficiencies; for at least 8-10 months following administration of IGIV for the treatment of idiopathic thrombocytopenic purpura (ITP); or for at least 11 months following administration of IGIV for Kawasaki syndrome.26 The ACIP also recommends that administration of varicella virus vaccine live be deferred for at least 5-8 months after administration of VZIG or IGIV for postexposure prophylaxis of severe varicella.26,27,126 If simultaneous administration of varicella virus vaccine live and one of these immune globulin preparations or administration at less than the recommended interval is deemed necessary, the fact that vaccine-induced immunity may be compromised should be considered and, unless there is serologic evidence of an adequate antibody response to the live virus vaccine, an additional dose of vaccine should be administered at the specified interval.26 If administered simultaneously, the live virus vaccine and immune globulin should be administered at separate sites anatomically remote from each other.26

Specific studies are not available evaluating whether passively acquired antibodies from Rho(D) immune globulin interfere with the immune response to varicella virus vaccine live.26 Because of the importance of postpartum varicella vaccination in women who do not have evidence of varicella immunity, vaccination of such women should not be delayed because they received Rho(D) immune globulin.26

The fact that revaccination may be necessary in individuals who receive an immune globulin preparation shortly after varicella virus vaccine live also should be considered.26 In general, vaccine virus replication and stimulation of immunity occur within 7-14 days after administration of a live virus vaccine.26 Therefore, if the interval between administration of varicella virus vaccine live and subsequent administration of one of these preparations is less than 14 days, an additional dose of vaccine should be given after the appropriate interval previously specified, unless serologic testing indicates that an adequate antibody response to the vaccine occurred.26 An additional dose of vaccine generally is unnecessary if the interval between vaccination and administration of the immune globulin is longer than 2 weeks.26

Immunosuppressive Agents

Individuals receiving immunosuppressive agents (e.g., corticotropin, corticosteroid, alkylating agents, antimetabolites, radiation therapy) may have a diminished immunologic response to live vaccines such as varicella virus vaccine live, and replication of the virus may be potentiated.1,26,27,70 Administration of varicella virus vaccine live or the fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad^®) generally should be deferred until immunosuppressive therapy is discontinued since these individuals are more susceptible to infections than healthy individuals and more extensive vaccine-associated rash or disseminated disease can occur.1,27,125,137

While no data have been published concerning whether susceptible children who are receiving steroids by oral inhalation can be vaccinated safely, the ACIP states that the consensus of most experts based on clinical experience is that vaccination of these children is safe.27 Short-term (less than 2 weeks), low- to moderate-dose systemic corticosteroid therapy; long-term, alternate-day systemic corticosteroid therapy using low to moderate doses of short-acting drugs; topical corticosteroid therapy (e.g., nasal, cutaneous, ophthalmic); or intra-articular, bursal, or tendon injections with corticosteroids should not be immunosuppressive in usual dosages and do not necessarily contraindicate administration of live viral vaccines.26,63,70 However, use of live viral vaccines generally is contraindicated in patients receiving high doses of systemic corticosteroids or when systemic immunosuppression occurs with prolonged topical corticosteroid therapy.26,70 Varicella virus vaccine live, therefore, may be administered to susceptible children who are receiving topical corticosteroids or systemic corticosteroid for certain conditions (e.g., asthma, Addison's disease) and who are not otherwise immunocompromised if they are receiving such therapy in a daily dosage equivalent to less than 2 mg/kg or 20 mg of oral prednisone given for less than 2 weeks.26,137 The ACIP recommends that serologic testing be done 6 weeks following vaccination of these children, and those who have not seroconverted should be revaccinated.27

The optimum interval between discontinuance of immunosuppressive therapy and subsequent administration of a live viral vaccine has not been determined.26,137 Although the ACIP recommends that live viral vaccines generally not be administered for at least 3 months after immunosuppressive therapy is discontinued in patients who received high-dose systemic corticosteroids (i.e., daily dosage equivalent to or greater than 2 mg/kg or 20 mg of oral prednisone) for 2 weeks or longer,26,63,70 the ACIP and American Academy of Pediatrics (AAP) suggest that delaying administration of varicella virus vaccine live for at least 1 month after high-dose immunosuppressive therapy is discontinued probably is sufficient.26,27,100,137

Individuals with leukemia who have not received chemotherapy for at least 3 months generally can receive a live viral vaccine.27,70 However, vaccination of leukemic children who are in remission and who do not have evidence of immunity to varicella should be undertaken only with expert guidance and with the availability of antiviral therapy should complications ensue.27,100

The manufacturer of the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) states that the vaccine may be used in individuals receiving topical corticosteroids or low-dose corticosteroids for asthma prophylaxis or replacement therapy (e.g., for Addison's disease).125

Vaccines

Although specific studies may not be available evaluating concurrent administration of varicella virus vaccine live with each antigen, simultaneous administration with other age-appropriate vaccines, including live virus vaccines, toxoids, or inactivated or recombinant vaccines, during the same health-care visit is not expected to affect immunologic responses or adverse reactions to any of the preparations.26,27,100,121

Immunization with varicella virus vaccine live can be integrated with immunization against diphtheria, tetanus, pertussis, hepatitis A, hepatitis B, human papillomavirus (HPV), influenza, poliovirus, measles, mumps, rubella, rotavirus, meningococcal disease, pneumococcal disease, and rotavirus.26,27,100,121 However, unless combination vaccines appropriate for the age and vaccination status of the recipient are used, each parenteral vaccine should be administered using a different syringe and different injection site.26,27,100,121

Inactivated Vaccines and Toxoids

Diphtheria and Tetanus Toxoids and Pertussis Vaccines

Varicella virus vaccine live may be administered concurrently with diphtheria and tetanus toxoids and acellular pertussis vaccines adsorbed (DTaP).26,27,100,121 Although specific studies are not available, the ACIP and AAP state that there is no reason to suspect that simultaneous administration of varicella virus vaccine live will affect the immune response to these other antigens and that, when necessary, varicella virus vaccine live may be given concurrently with or at any interval before or after these vaccines.26,27,100 Results of a retrospective cohort study that used data from the Vaccine Safety Datalink (VSD) project and included children 12 months of age or older who were vaccinated during January 1995 to December 1999 indicate that administration of varicella virus vaccine live less than 30 days after MMR results in a 2.5-fold increase in the incidence of breakthrough varicella infections.121

The manufacturer states that data are insufficient to date to recommend concurrent administration of the fixed-combination vaccine containing measles, mumps, and rubella virus vaccine live (MMR) and varicella virus vaccine live (MMRV; ProQuad^®) with DTaP.125

Inactivated Vaccines

Varicella virus vaccine live may be administered concurrently with haemophilus b conjugate (Hib) vaccines or hepatitis B vaccine (recombinant).27,100,121 Although specific studies are not available, the ACIP and AAP state that there is no reason to suspect that simultaneous administration of varicella virus vaccine live will affect the immune response to these other vaccines and that, when necessary, varicella virus vaccine live may be given concurrently with or at any interval before or after these vaccines.27,100 The manufacturer of the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) states that the vaccine may be administered concurrently with Hib conjugate (meningococcal protein conjugate) and hepatitis B vaccine.125 MMRV (ProQuad^®) has been administered concomitantly with Hib vaccine and hepatitis B vaccine at separate injection sites and seroconversion rates and antibody titers for measles, mumps, rubella, varicella, anti-PRP, and hepatitis B were comparable with results obtained when the vaccines were administered 6 weeks apart.125

Varicella virus vaccine live may be administered concurrently with poliovirus vaccine inactivated (IPV).26,27,100,121 The manufacturer states that data are not available to date regarding concurrent administration of the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) with IPV.125

Since parenteral influenza virus vaccines are inactivated vaccines, interactions with live vaccines such as varicella vaccine are unlikely.26 Parenteral influenza virus vaccine inactivated may be administered simultaneously with (using different syringes and different injection sites) or at any interval before or after varicella virus vaccine live.26

Although specific studies are not available, pneumococcal vaccines are inactivated vaccines and interactions with varicella virus vaccine live are not expected.26,119,120 Varicella virus vaccine live may be administered concurrently with (using different syringes and different injection sites) or at any interval before or after pneumococcal vaccine.26,27,100,121 Data are not available to date regarding concurrent administration of the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) with pneumococcal 7-valent conjugate vaccine.125

Live Vaccines

Measles, Mumps, and Rubella Virus Vaccine Live

Varicella virus vaccine live may be administered concurrently with MMR at a different site using a separate syringe.1,5,7,26,27,87,100 Results of studies in healthy children 12-36 months of age indicate that seroconversion rates, antibody responses, and adverse effects reported with simultaneous administration of the vaccines are similar to those reported when the vaccines are administered 6 weeks apart.1,76

Because there is a theoretical concern that the immune response to one live viral vaccine may be impaired if administered within 1 month of another, the AAP and ACIP recommend that varicella virus vaccine live and MMR be administered at least 1 month apart if they are not administered simultaneously.26,27,100 There is some evidence that administration of varicella virus vaccine live less than 30 days after MMR decreases the effectiveness of the varicella vaccine.26,121 Results of a retrospective cohort study that used data from the Vaccine Safety Datalink (VSD) project and included children 12 months of age or older who were vaccinated during January 1995 to December 1999 indicate that administration of varicella virus vaccine live less than 30 days after MMR results in a 2.5-fold increase in the incidence of breakthrough varicella infections.121

There is evidence that the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) is safe and effective in healthy children 12 months through 12 years of age.28,29,76,90,125 Studies using MMRV (ProQuad^®) in healthy children 1-6 years of age indicate that the antibody responses to measles, mumps, rubella, and varicella antigens following a single dose of the fixed-combination vaccine are similar to those obtained after a single dose of MMR and a single dose of Varivax^®.90 However, there is some evidence that the relative risk for febrile seizures in infants may be higher with the fixed-combination vaccine than that reported when a dose of single-antigen varicella virus vaccine live (Varivax^®) and a dose of MMR are given concomitantly.125,136 (See Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Intranasal Live Influenza Virus Vaccines

Studies using seasonal influenza virus vaccine live intranasal (FluMist^®) indicate that simultaneous administration with varicella virus vaccine live in children 12-15 months of age did not interfere with the immune response to either vaccine and did not increase the frequency of adverse effects.142 If influenza virus vaccine live intranasal and varicella virus vaccine live are not given simultaneously, they should be given at least 4 weeks apart, if possible.26

Other Live Vaccines

Although data are limited regarding simultaneous administration of varicella virus vaccine live and live vaccines other than MMR, the ACIP states that there is no evidence to date that parenterally administered live vaccines interfere with the immune response to other live vaccines (e.g., rotavirus vaccine live oral, typhoid vaccine live oral, yellow fever virus vaccine live) and these vaccines may be administered concurrently.26 The ACIP and AAP state that some live oral vaccines (e.g., rotavirus vaccine live oral, typhoid vaccine live oral, poliovirus vaccine live oral [OPV; no longer commercially available in the US]) can be administered simultaneously with or at any interval before or after live parenteral vaccines.26,100

If varicella virus vaccine live and intranasal or other parenteral live vaccines are not administered on the same day, they should be administered at least 4 weeks (i.e., 28 days) apart to minimize the potential for interference.26,100

Salicylates

The manufacturer recommends that individuals who receive varicella virus vaccine live or the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®) avoid use of salicylates for 6 weeks following vaccination.1,100,125 This precaution is based on the fact that Reye's syndrome has been reported in children and adolescents who received salicylates during natural varicella infection.1,100,125 However, an association between Reye's syndrome, administration of varicella virus vaccine live, and use of salicylates has not been established, and the syndrome has not been reported to date in recipients of the vaccine.1,27,42,100 For children who are receiving long-term salicylate therapy, the AAP suggests that the theoretical risks associated with the vaccine be weighed against the known risks of the wild-type virus.100 The ACIP states that, since the risk for serious salicylate-associated complications is likely to be greater in children in whom natural varicella disease develops than in children who receive the vaccine containing attenuated virus, children who have rheumatoid arthritis or other conditions requiring therapeutic salicylate therapy probably should receive varicella virus vaccine live in conjunction with subsequent close monitoring.27

Other Information ⬆ ⬇

[Section Outline]

Tuberculin
Varicella Zoster Virus and Infection
Response to Varicella Virus Vaccine Live
Extent and Duration of Immunity
Chemistry
Stability

Laboratory Test Interferences

Tuberculin

The effect of varicella virus vaccine live, if any, on tuberculin testing has not been determined.26,100 Since measles virus vaccine live has been reported to temporarily suppress tuberculin skin sensitivity, the US Centers for Disease Control and Prevention (CDC) states that until additional information is available, tuberculin tests (if required) should be administered before, simultaneously with, or 4-6 weeks after administration of varicella virus vaccine live or the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad^®).100,125 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that vaccination with varicella virus vaccine live should not be delayed based only on a theoretical concern about a possible interaction with tuberculin skin testing.26

Pharmacology

Varicella virus vaccine live stimulates active immunity to varicella (chickenpox).1,4,8,9,65,67 Varicella vaccines commercially available for use in the US contains live, attenuated varicella zoster virus (VZV) of the Oka/Merck strain.1,27,42,100 This vaccine virus differs slightly from wild-type VZV circulating in the US and can be identified by distinctive DNA restrictive endonuclease cleavage patterns.5,8,9,33,35 Although further study is needed, it has been theorized that there may be antigenic differences between the vaccine and wild-type VZV since the immune responses elicited by varicella virus vaccine live are not identical to those elicited by the wild-type virus.8,65,67,94

Varicella virus vaccine live can induce both humoral and cell-mediated responses in vaccinees;1,4,8,9,65,67 however, the role and relative contribution of each type of response to long-term immunity against varicella has not been fully determined.1,8,9,53,67 Efficacy of varicella virus vaccine live in preventing varicella infection varies depending on the age and immunocompetence of the vaccinee.11,54,65 In some individuals, especially healthy adults and immunocompromised children, the vaccine provides partial immunity and modification of subsequent varicella infection rather than complete protection.5,8,11,13,24,41,65

Varicella Zoster Virus and Infection

Varicella (chickenpox) and herpes zoster (shingles, zoster) are distinct clinical entities caused by the same virus, VZV, a member of the family Herpesviridae.8,100,138 Varicella is the primary infection.6,8,33,100,138 During varicella, the virus invades sensory neurons and becomes latent in sensory nerve ganglia, establishing a source of potential secondary infection.6,8,27,33,41,100,137,138 Herpes zoster, the secondary infection, results from reactivation of the latent virus.6,8,27,33,41 Natural varicella infection elicits development of specific antibodies and cell-mediated immunity and generally confers lifelong protection against subsequent varicella infection.6,27,41,138 However, in 10-20% of individuals, especially older adults and immunocompromised individuals, reactivation of the latent virus and subsequent herpes zoster (shingles) occurs, with the incidence increasing with age in adults.6,27,34,137,138

In otherwise healthy children, varicella usually is an acute, self-limited disease characterized by fever, malaise, and a generalized vesicular rash consisting of 250-500 lesions.1,6,9,11,14,27,41,64,75,100,137,138 In neonates, adolescents, adults, and immunocompromised individuals, varicella may be a more serious illness associated with a greater number of lesions and an increased risk of complications (e.g., pneumonia, encephalitis, glomerulonephritis, bacterial superinfection including necrotizing fasciitis).6,9,11,15,27,34,41,64,75,80,89,91,94,100,137,138 Adults are more likely to acquire varicella pneumonia or varicella encephalitis than otherwise healthy children; pneumonia is the principal cause of death among adults with varicella.6,9,11,64,100

Before licensure of varicella virus vaccine live (i.e., prior to 1995), an average of 4 million cases of varicella and 100-150 varicella-associated deaths were reported each year in the US.6,27,64,137 The rate of complications, including varicella-related death, is greatest in immunocompromised individuals and individuals who contract varicella when they are younger than 1 year of age or older than 15 years of age.6,89,92,138 Varicella-related fatality rates are reported to be 1 per 100,000 cases in children 1-14 years of age, 2.7 per 100,000 cases in adolescents and young adults 15-19 years of age, and 25.2 per 100,000 cases in adults 30-49 years of age.138 During the first 4 months of 1997, state health departments reported 3 varicella-related fatalities (varicella pneumonia and/or varicella encephalitis) in young adult women who were infected by exposure to unvaccinated preschool-aged children with typical cases of varicella; 2 of these women were previously in good health and contracted the disease through household exposure and the other woman had Crohn's disease.92 The most common complications of varicella that resulted in hospitalizations were skin and soft tissue infections (especially invasive group A streptococcal infections), pneumonia, dehydration, and encephalitis.27

Varicella is highly contagious and the secondary infection rate in healthy, susceptible individuals exposed through household contact generally is 80-90%.6,8,27,137 The disease is transmitted person-to-person through airborne respiratory droplet infection or direct contact, droplet, or aerosol from vesicular fluid of skin vesicles, which contain high titers of anti-VZV.6,8,27,41,137,138 Varicella virus enters the host through the upper respiratory tract or the conjunctiva.27,100,137,138 Individuals with varicella are most contagious 1 or 2 days before the onset of rash and shortly after its onset, but continue to be contagious for 4-7 days after its onset when vesicles have dried and crusted.6,27,100,137,138 Following exposure to the disease or virus, the incubation period in healthy individuals averages about 14-16 days (range: 9-21 days).6,27,100,138 In immunocompromised individuals, the incubation period may be shorter6,100 and these individuals may be contagious for a longer period of time, presumably because their immune system is depressed allowing viral replication to persist.27,100 The incubation period may be prolonged (up to 28 days) in individuals who receive varicella zoster immune globulin (VZIG) of IGIV for postexposure prophylaxis.100,126,138 In utero infections can occur, and fetal infections occurring during the first and second trimesters may result in congenital varicella disease.100 Infants born to mothers with active varicella at the time of delivery may develop the disease within the first 2 weeks of life; the usual interval from onset of rash in the mother to disease onset in the neonate is 9-15 days.100

Response to Varicella Virus Vaccine Live

The immunologic response to varicella virus vaccine live has been evaluated using various live, attenuated vaccines containing Oka/Biken, Oka/RIT, or Oka/Merck strains in potencies ranging from 200-9000 units.9,11,67,68,69,75,101 The humoral and cell-mediated immune responses elicited by varicella virus vaccine live appear to be less than those elicited by natural infection with wild-type VZV.65,67 It has been suggested that potency of varicella virus vaccine live may affect both the seroconversion rate and the duration of immune response following vaccination; doses with a higher potency may induce greater immunologic responses and provide longer-lasting immunity.11,68,69,75,94

Levels of specific antibodies that protect against varicella infection have not been defined and the acquisition of any detectable level of antibodies against VZV generally has been used to indicate seroconversion in individuals who receive varicella virus vaccine live.1,27,52 The manufacturer states that seroconversion is based on an optical density (OD) cutoff, corresponding approximately to a lower limit of 0.6 glycoprotein enzyme-linked immunosorbent assay (gpELISA) units/mL.1 There is some evidence that breakthrough varicella infections occur in substantially fewer children who have geometric mean antibody titers of 5 units or greater (measured by gpELISA) following receipt of varicella virus vaccine live than in those who have gpELISA titers less than 5 units.27

In healthy children 12 months to 12 years of age, the seroconversion rate is 98% after a single dose of varicella vaccine and 100% after a second vaccine dose given 3 months after the first dose.101 In those 13 years of age and older, the seroconversion rate is 75-94% after a single dose and 99% after a second dose.1 Although administration of a second dose of vaccine for primary immunization in healthy adults increases the seroconversion rate, there is no evidence that the second dose affects the duration of protection against varicella.8,9 In a study that evaluated varicella virus vaccine live in healthy children 12 months to 12 years of age, a single dose (containing the Oka/Merck strain in a potency of 2900-9000 units) resulted in a seroconversion rate of 98% and geometric mean antibody titers (measured by gpELISA) of 11.4 and 19.5 at 6 weeks and 1 year, respectively, after the dose.101 Children who received a second dose of the vaccine 3 months after the first dose had a seroconversion rate of 100% and geometric mean antibody titers of 145.1 and 31.2 at 6 weeks and 1 year, respectively.101

Varicella virus vaccine live is less immunogenic in healthy adolescents and adults than in healthy children,5,8,9,11,65,80 and there is some evidence that antibody titers induced by the vaccine are inversely related to the age of the vaccine recipient.80 In a study in adolescents and adults 13-49 years of age, the geometric mean titer of antibody measured by gpELISA 4 weeks after the second dose of varicella virus vaccine live was 23-30 in those 13-19 years of age, 10-18 in those 20-29 years of age, and 11-14 in those 30-49 years of age.80 In all age groups, antibody titers were higher in those who received the second dose 8 weeks after the initial dose than in those who received the second dose 4 weeks after the initial dose.80 Many healthy adults who do not seroconvert after a single dose of varicella virus vaccine live do so after a second dose.9,11,27

In immunosuppressed children, including children with acute lymphocytic (lymphoblastic) leukemia (ALL) in remission, solid tumors, or renal insufficiency, the seroconversion rate following administration of a single dose of live, attenuated varicella virus vaccine containing 550-4000 units is 87-95%,9,52,53,55 and the seroconversion rate following administration of a second dose of vaccine is 95-98%.9,53,55

Extent and Duration of Immunity

Continued long-term studies are necessary to determine the extent and duration of protection against varicella provided by primary immunization with 1 or 2 doses of varicella virus vaccine live.1,8,9,19,24,35,77,80 Seroconversion following administration of varicella virus vaccine live does not result in complete protection in all individuals, and breakthrough varicella infections may occur in some children or adults who seroconverted following vaccination and are subsequently exposed to wild-type virus.1,4,5,8,27,42,65,75,80 Approximately 2-4% of healthy children, 7-9% of children with ALL, and 31% of healthy adults who initially seroconvert following primary vaccination with varicella virus vaccine live develop breakthrough varicella infections as a result of exposure to natural, wild-type virus following close contact with an individual with varicella.4,8,9,11,13,42,52,53 In one study in healthy children 12 months to 17 years of age, 19% of vaccinated children had breakthrough infections during a 10-year follow-up period and the breakthrough rate averaged 3% per year.27,75 In both healthy children and children with ALL, breakthrough varicella infections usually occur during the first 1-2 years following vaccination.4,9,13 These breakthrough varicella infections in vaccinated individuals generally are less severe than natural varicella infections occurring in unvaccinated, susceptible individuals.1,9,13,16,17,27,42,47,48,52,75,100 (See Cautions: Breakthrough Varicella Infections.)

In healthy children who receive the vaccine at 12 months through 12 years of age, immunity to varicella may persist at least 5-10 years.4,9,19,65,66,86 Although up to about 30% of healthy adults or children with ALL become seronegative 1 year after vaccination, it has been suggested that some of these individuals may have residual immunity (e.g., cell-mediated immunity) that is not detected with serologic tests for antibody.65,86 Further study is needed to assess the rate of protection against serious complications of varicella infection in adults (e.g., encephalitis, hepatitis, pneumonitis) or protection against congenital varicella syndrome during pregnancy.1

Subsequent exposure to natural wild-type varicella infection appears to boost anti-VZV levels in vaccinated individuals, even in individuals who do not develop clinical symptoms of breakthrough infection.1,8,9,11,12,24,27,77 This boosting theoretically could contribute to long-term protection against the disease,1,8,9,11,12,24 and it is possible that varicella immunity may wane in some individuals in highly vaccinated populations because of a lack of exposure to natural varicella.1 The duration of protection against varicella in vaccinated individuals in the absence of such wild-type boosting is unknown.1,11,24,35,77

Chemistry and Stability

Chemistry

Varicella virus vaccine live is commercially available in the US as a single-antigen vaccine (Varivax^®)1 and in a fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad^®).125 When reconstituted as directed with the diluent provided by the manufacturer, Varivax^® occurs as a clear, colorless to pale yellow liquid1 and MMRV (ProQuad^®) occurs as a clear, pale yellow to light pink liquid.125

Varicella virus vaccine live available for use in the US is a lyophilized preparation of live, attenuated varicella zoster virus (VZV) of the Oka/Merck strain.1,27,42 This vaccine is similar, but not identical, to varicella vaccines available in Japan and other countries that contain Oka/Biken or Oka/RIT strains of VZV.8,11,15,42,45 The vaccine commercially available for use in the US, like other live, attenuated varicella vaccines, is derived from the same strain of virus originally isolated in 1970 from a Japanese child with natural (wild-type) varicella infection.1,8,11,13,27,35,42,45 The virus was isolated in human embryonic lung cells and attenuated by serial passage in several different cell lines at different temperatures.1,8,11,13,27,35,42,45 The Oka/Merck strain contained in the US vaccine is attenuated by multiple passages through human embryonic lung cell cultures, embryonic guinea pig cell cultures, the WI-38 strain of human diploid cell cultures, and the MRC-5 strain of human diploid cell cultures (free of adventitious agents).1 The attenuated virus is suspended in a medium containing sucrose, phosphate, glutamate, and hydrolyzed gelatin and then lyophilized.1

Vaccine containing varicella virus vaccine live commercially available for use in the US meets standards established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration. Potency of the varicella component of the vaccines is expressed in terms of plaque-forming units (PFU) of OKA/Merck virus.1,125

Following reconstitution with the diluent provided by the manufacturer and storage at room temperature (20-25°C) for 30 minutes, each 0.5-mL dose of Varivax^® contains at least 1350 units of Oka/Merck varicella virus (approximately 3.13 log₁₀ PFU),1,27,128,137 approximately 25 mg of sucrose, 12.5 mg of hydrolyzed gelatin, 3.2 mg of sodium chloride, 0.5 mg of monosodium glutamate, 0.45 mg of sodium phosphate dibasic, 0.08 mg of potassium phosphate monobasic, and 0.08 mg of potassium chloride and may contain residual components of MRC-5 cells (including DNA and protein) and trace quantities of sodium phosphate monobasic, edetate disodium (EDTA), neomycin, and fetal bovine serum.1

Following reconstitution with the diluent provided by the manufacturer, each 0.5-mL dose of MMRV (ProQuad^®) contains the same potency of measles, mumps, and rubella antigens as measles, mumps, and rubella virus vaccine live (MMR), at least 3.99 log₁₀ PFU of Oka/Merck varicella virus, no more than 21 mg of sucrose, 11 mg of hydrolyzed gelatin, 2.4 mg sodium chloride, 1.8 mg sorbitol, 0.4 mg monosodium glutamate, 72 mcg of potassium phosphate monobasic, 60 mcg of potassium chloride, and 36 mcg of potassium phosphate dibasic and may contain residual components of MRC-5 cells (including DNA and protein) and less than 16 mcg of neomycin, 0.5 mcg bovine calf serum, and other buffer and media ingredients.27,125,128

The vaccines do not contain thimerosal or any other preservatives.1,125

Stability

Varicella virus vaccine live is thermolabile and requires particular care to preserve its potency.1,35,56,125

To ensure that there is no loss of potency during shipment from the manufacturer, the lyophilized single-antigen vaccine (Varivax^®) and the lyophilized fixed-combination vaccine (MMRV; ProQuad^®) must be maintained frozen at a temperature of -15°C or colder until delivery.1,26,27,125

After delivery from the manufacturer, lyophilized Varivax^® or lyophilized MMRV (ProQuad^®) must be kept frozen at -15°C or colder and protected from light; any freezer (e.g., chest, frost-free) that reliably maintains an average temperature of -15°C or colder and has a separate sealed freezer door is acceptable.1,125,139 Refrigerators with ice compartments that are either not tightly enclosed or enclosed with unsealed, uninsulated doors (e.g., small, dormitory-style refrigerators) usually do not meet temperature requirements.27,94 The diluent provided by the manufacturer should be stored separately, either at room temperature (20-25°C) or in a refrigerator1,125,139 and should not be frozen.1,139 Varivax^® retains a potency of at least 1500 units for at least 24 months when stored in a frost-free freezer with an average temperature of -15°C or colder.1

Because varicella virus vaccine live is thermolabile, planning for appropriate handling and storage is necessary if varicella immunization sessions will be held at a site distant from the freezer in which vials of the vaccine are stored.27 The number of vials of lyophilized Varivax^® vaccine required for the immunization session should be transferred in a suitable container (e.g., the original shipping container or a comparable container with a properly fitted lid) using an adequate quantity of solid carbon dioxide (dry ice)27,139 and should be delivered within 2 days.139

Prior to reconstitution, Varivax^® or MMRV (ProQuad^®) may be stored for up to 72 continuous hours at 2-8°C.1,27,125 Therefore, when optimal handling conditions are not feasible (e.g., because of the location of the freezer storage area, distance to the immunization clinic site, concern for security of the room where vaccines are administered, unavailability of dry ice), potency of varicella virus vaccine live can be maintained if vials containing unreconstituted vaccine are stored for a maximum of 72 hours at a temperature of 2-8°C.1,27,139 However, a temperature recording device should be included in the transport container to ensure that the temperature is no warmer than 2-8°C.27 Any vials of lyophilized Varivax^® or MMRV (ProQuad^®) stored at 2-8°C should be discarded if not used within 72 hours after removal from freezer storage.1,27,125,139 For information regarding vaccine stability under conditions other than those recommended, contact the manufacturer at 800-637-2590.1,125,139

Following reconstitution, potency of varicella virus vaccine live decreases rapidly at room temperature, although viral antigen content remains the same regardless of length of storage.56 In one stability study using a live, attenuated varicella vaccine containing the Oka/Merck strain of virus, the vaccine had an initial potency of 1770 units immediately following reconstitution; following storage at room temperature, the reconstituted vaccine had a potency of 400-500 or 80-160 units at 6 or 24 hours, respectively.56 To minimize loss of potency and ensure an adequate immunizing dose, reconstituted Varivax^® or reconstituted MMRV (ProQuad^®) should be used immediately and any unused vaccine discarded if not used within 30 minutes.1,125 Reconstituted Varivax^® or MMRV (ProQuad^®) should not be frozen.1,125

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Varicella Virus Vaccine Live

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for subcutaneous use	1350 plaque-forming units (PFU) per 0.5 mL	Varivax^®	Merck

Measles, Mumps, Rubella and Varicella Virus Vaccine Live (MMRV)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for subcutaneous use	Measles Virus Vaccine Live (More Attenuated Enders' Line) ≥3 log ₁₀ tissue culture infective dose 50% (TCID₅₀), Mumps Virus Vaccine Live (Jeryl Lynn [B level] Strain) ≥4.3 log ₁₀ TCID₅₀, Rubella Virus Vaccine Live (Wistar RA 27/3 Strain) ≥3 log ₁₀ TCID₅₀, and Varicella Virus Vaccine Live (Oka/Merck Strain) ≥3.99 log ₁₀ plaque-forming units (PFU) per 0.5 mL	ProQuad^®	Merck

AHFS^® Drug Information. © Copyright, 1959-2024, Selected Revisions August 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

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section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

Varicella Virus Vaccine Live

Measles, Mumps, Rubella and Varicella Virus Vaccine Live (MMRV)

Copyright ⬆ ⬇

References ⬆