Varicella Virus Vaccine Live

Suspected adverse events after administration of any vaccine may be reported to Vaccine Adverse Events Reporting System (VAERS), 1-800-822-7967

>10%

Injection site swelling/rash/pruritus/erythema (20%)

Fever >102°F [39°C] (15%)

Postmarketing Reports

Body as a whole: Anaphylaxis (including anaphylactic shock) and related phenomena such as angioneurotic edema, facial edema, and peripheral edema

Eye disorders: Necrotizing retinitis (in immunocompromised individuals)

Hemic and lymphatic system: Aplastic anemia; thrombocytopenia (including ITP)

Infections and infestations: Varicella (vaccine strain)

Nervous/psychiatric: Encephalitis; cerebrovascular accident; transverse myelitis; Guillain-Barré syndrome; Bell palsy; ataxia; nonfebrile seizures; aseptic meningitis; dizziness; paresthesia

Respiratory: Pharyngitis; pneumonia/pneumonitis

Skin: Stevens-Johnson syndrome; erythema multiforme; Henoch-Schönlein purpura; secondary bacterial infections of skin and soft tissue, including impetigo and cellulitis; herpes zoster

You should not receive this vaccine if you are allergic to gelatin, neomycin (Mycifradin, Neo-Fradin, Neo-Tab), or if you have ever had a life-threatening allergic reaction to any vaccine containing varicella.

You should also not receive this vaccine if you have:

• active tuberculosis infection that is not being treated;
• a history of Guillain-Barré syndrome;
• a chronic disease such as asthma or other breathing disorder, diabetes, kidney disease, or blood cell disorder such as anemia;
• if you or someone in your household has severe immune suppression caused by disease (such as cancer, HIV, or AIDS), or by receiving certain medicines such as steroids, chemotherapy or radiation;
• if you are under 18 years old and have recently taken aspirin or other similar medicines such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others;
• if you have recently received a stem cell transplant; or
• if you are pregnant.

Before receiving varicella virus (Chickenpox) vaccine, talk to your doctor if you have:

• thrombocytopenia purpura (easy bruising or bleeding);
• active tuberculosis infection; or
• if you have received an immune globulin or other blood product within the past year.

You can still receive a vaccine if you have a cold or fever. In the case of a more severe illness with a fever or any type of infection, wait until you get better before receiving this vaccine.

Avoid becoming pregnant for at least 3 months after receiving a varicella vaccine.

Do not receive this vaccine without telling your doctor if you are breast-feeding a baby.

Live, attenuated virus vaccine.1 27 137 Varicella virus vaccine live contains varicella zoster virus (VZV) of the Oka/Merck strain1 27 and is used to stimulate active immunity to varicella (chickenpox).1 27 Commercially available in the US as a monovalent vaccine (Varivax) and a fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad).1 125 Other varicella vaccines may be available in other countries (e.g., Oka/Biken vaccine).8 11 15 27 45

Prevention of Varicella (Chickenpox) Infection

Prevention of varicella (chickenpox) in adults, adolescents, and children ≥12 months of age.1 27 71 82 89 92 100 114 129 137

Varicella is caused by primary infection with varicella zoster virus (VZV).1 6 9 11 14 27 41 64 75 137 138 In otherwise healthy children, varicella usually is an acute, self-limited disease characterized by fever, malaise, and a generalized vesicular rash consisting of 200–500 lesions.1 6 9 11 14 27 41 64 75 137 138 In neonates, adolescents, adults, and immunocompromised individuals, it 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 94 137 138 In the past, there were an average of 4 million cases of varicella and 100–150 varicella-associated deaths each year in the US.6 27 64 137 Since 1995, when varicella vaccine 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 decreased >90% in the US since 1996.138

USPHS Advisory Committee on Immunization Practices (ACIP), AAP, and American Academy of Family Physicians (AAFP) recommend that all susceptible children 12 months through 12 years of age be vaccinated against varicella, unless the vaccine is contraindicated.27 71 100 137 (See Contraindications under Cautions.)

ACIP, AAP, AAFP, American College of Obstetricians and Gynecologists (ACOG), and American College of Physicians (ACP) recommend that all susceptible adults and adolescents ≥13 years of age be vaccinated against varicella, unless contraindicated.27 71 89 100 114 129 (See Contraindications under Cautions.)

For internationally adopted children whose immune status is uncertain, vaccinations can be repeated or serologic tests performed to confirm immunity.26 Because varicella vaccine is not available in the majority of countries, especially developing countries, all internationally adopted children without reliable evidence of varicella immunity should be vaccinated according to the US recommended immunization schedule.26 112 (See Dosage and Administration.) Although serologic testing to verify immunization status in children >12 months of age is available, such testing prior to vaccination is not recommended in children <12 years of age coming from tropical countries, unless there is a history of the disease.112

The fixed-combination vaccine containing measles, mumps, and rubella virus vaccine live (MMR) and varicella virus vaccine live (MMRV; ProQuad) may be used instead of the monovalent varicella vaccine in children 12 months through 12 years of age when a dose of MMR and a dose of varicella vaccine is indicated in this age group.27 125 136 137 145 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 MMRV (ProQuad) than when a dose of Varivax and a dose of MMR are given concomitantly.125 136 145 (See Use of Fixed Combinations under Cautions.)

ACIP states that evidence of varicella immunity includes documentation of age-appropriate vaccination against varicella, laboratory evidence of immunity or laboratory confirmation of prior varicella, birth in the US before 1980 (except pregnant women, immunocompromised individuals, health-care personnel), diagnosis or verification of history of varicella by health-care provider, or diagnosis or verification of history of herpes zoster (shingles, zoster) by health-care provider.27 Individuals without such evidence should be considered susceptible to varicella.27

Preexposure Vaccination Against Varicella Infection in High-risk Groups

Health-care personnel should ensure that they are immune to varicella, especially those who have close contact with individuals at high risk for serious complications from varicella.27 113 ACIP and the Hospital Infection Control Practices Advisory Committee of the US Public Health Service (HICPAC) recommend vaccination against varicella in all susceptible health-care personnel.27 113 This protects the worker following varicella exposure in the workplace and also may help reduce nosocomial transmission of VZV.11 27

Travelers should be vaccinated against varicella.27 112 Varicella occurs worldwide.112 138 Although vaccination against varicella is not a requirement for entry into any country (including the US), CDC states that individuals traveling or living abroad should ensure that they are immune.112

Certain immunocompromised individuals at risk of severe complications from varicella may benefit from vaccination against the disease.27 52 100 137 143 144 However, varicella vaccine generally is contraindicated in adults, adolescents, and children who are immunocompromised†.1 54 70 100 137 (See Individuals with Altered Immunocompetence under Cautions.)

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 recommend that vaccination against varicella be considered for certain HIV-infected individuals†, especially those who are asymptomatic or only mildly symptomatic.27 100 137 143 144 These experts state that, after weighing risks and benefits, use of monovalent varicella vaccine should be considered in HIV-infected children 1–8 years of age with age-specific CD4+ T-cell percentages ≥15%27 137 144 and may be considered in HIV-infected adults, adolescents, and children >8 years of age with CD4+ T-cell counts ≥200/mm3.27 143 144 Other HIV-infected adults, adolescents, or children who are more severely immunocompromised should not receive varicella vaccine.1 27 143 144 (See Individuals with Altered Immunocompetence under Cautions.)

Although monovalent varicella vaccine was previously used under an investigational protocol in certain children and adolescents with acute lymphocytic (lymphoblastic) leukemia (ALL)† in remission,27 52 100 this protocol has been terminated.100 The ACIP and AAP state that varicella vaccine 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 (See Individuals with Altered Immunocompetence under Cautions.)

Postexposure Vaccination Against Varicella Infection and Outbreak Control

Postexposure vaccination in susceptible adults, adolescents, or children with recent exposure to varicella, unless contraindicated.27 100 138

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

May prevent varicella or modify severity of the disease if given within 3 days, and possibly up to 5 days, after exposure.27 100 112 115 116 138

If the exposure does not cause infection, postexposure vaccination should provide protection against subsequent exposure.27 100 138 If the exposure results in infection, vaccination during the presymptomatic or prodromal stage of varicella does not appear to increase risk for vaccine-associated adverse effects or cause more severe natural disease.27 100 138

During varicella outbreaks, ACIP recommends a second dose of varicella vaccine 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).27 138

In hospital settings, consider postexposure vaccination for unvaccinated health-care personnel who have no evidence of immunity at the time of varicella exposure.27 113 138 Preexposure vaccination is the preferred method for preventing varicella in health-care settings.27 138

When varicella vaccine cannot be used (e.g., pregnant women, neonates, immunocompromised individuals) and postexposure prophylaxis is considered necessary, passive immunization with varicella zoster immune globulin (VZIG) is recommended to prevent or reduce severity of varicella.15 27 100 138 143 144 The only VZIG preparation currently available for use in the US (VariZIG; Cangene) must be obtained through an investigational new drug (IND) expanded access protocol from the distributor (FFF Enterprises at 800-843-7477).134 135 If VZIG is not available for postexposure prophylaxis, immune globulin IV (IGIV) can be used.100

Live Vaccines

Varicella vaccine is a live, attenuated virus vaccine.1 26 27 137 Some oral live 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 varicella vaccine.26 100 However, because of theoretical concerns that the immune response to intranasal live vaccines or other parenteral live virus vaccines might be impaired if given within 28–30 days of another live virus vaccine, if varicella vaccine and these 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 (See Specific Drugs and Laboratory Tests under Interactions.)

Inactivated Vaccines and Toxoids

Varicella vaccine may be administered simultaneously with (using different syringes and different injection sites) or at any interval before or after inactivated vaccines, recombinant vaccines, polysaccharide vaccines, or toxoids.26 27 100 121 137 (See Specific Drugs and Laboratory Tests under Interactions.)

Specific Drugs and Laboratory Tests

• Varicella vaccine available for use in the US is a lyophilized preparation of live, attenuated VZV of the Oka/Merck strain.1 27 42 It 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

• Commercially available in the US as a monovalent vaccine (Varivax)) and a fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad).125 The varicella antigen contained in these vaccines is identical, but MMRV has a higher titer of the antigen than the monovalent vaccine.27

• Varicella vaccine induces active immunity to VZV.1 4 8 9 65 67

• VZV causes varicella (chickenpox) and herpes zoster (shingles, zoster).8 138 During varicella (the primary infection), VZV invades sensory neurons and becomes latent in sensory nerve ganglia, establishing a source of potential secondary infection.6 8 27 33 41 138 In some individuals (especially older adults and immunocompromised individuals), reactivation of VZV results in herpes zoster.6 8 27 33 41 138

• Varicella is highly contagious; the secondary infection rate is 80–90% in healthy, susceptible individuals exposed through household contact.6 8 27 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 VZV.6 8 27 41

• Following exposure to the disease or virus, the incubation period in otherwise healthy individuals averages about 14–16 days (range: 9–21 days).6 27 100 138 In utero infections can occur; fetal infections occurring during the first and second trimesters may result in congenital varicella disease.100 138 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

• Natural varicella infection elicits development of specific antibodies and cell-mediated immunity and generally confers lifelong protection against subsequent varicella infection.6 27 41

• The vaccine virus differs slightly from wild-type VZV circulating in the US;5 8 9 33 35 immune responses elicited by the vaccine are not identical to those elicited by the wild-type virus.8 65 67 94

• Efficacy of varicella vaccine in preventing varicella infection varies depending on 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

• In healthy children 12 months through 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 first dose.101 In those ≥13 years of age, seroconversion rate is 75–94% after a single dose and 99% after a second dose.1

• Varicella vaccine is less immunogenic in healthy adolescents and adults than in healthy children.1 5 8 9 11 65 80 Many healthy adults who do not seroconvert after a single dose of varicella vaccine do so after a second dose.9 11 27 There is no evidence that the second dose affects the duration of protection against varicella.8 9

• 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 vaccine concomitantly at separate sites.128

• Levels of anti-VZV antibodies that protect against varicella infection have not been defined and any detectable level of anti-VZV antibodies after vaccination generally has been used to indicate seroconversion.1 27 52

• Seroconversion 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 (See Breakthrough Varicella Infections under Cautions.)

• Prior to administration of each vaccine dose, provide a copy of the appropriate CDC Vaccine Information Statement (VIS) to the patient or patient’s legal representative as required by the National Childhood Vaccine Injury Act (VISs are available at ).1 125 140

• Advise patient and/or patient’s parent or guardian of the risks and benefits of vaccination with varicella vaccine.1 125

• Importance of receiving the complete immunization series (2 doses) to ensure highest level of protection against varicella.1

• Advise patient that Varivax and MMRV (ProQuad) may not provide protection in all vaccinees.1 125

• Advise patient they should not receive Varivax and MMRV (ProQuad) if they have had a life-threatening allergic reaction to a previous dose or are allergic to ingredients of the vaccine (e.g., gelatin, neomycin).1 125 140

• Advise patient of the theoretical risk of transmitting the vaccine virus to varicella-susceptible individuals, including pregnant women who have not had chickenpox.1

• Advise patient they should not receive varicella vaccine if they have a disease that weakens the immune system (e.g., cancer, HIV/AIDS) or are receiving treatment that may weaken the immune system (e.g., cancer treatment with radiation or drugs, corticosteroids).1 140

• Importance of contacting clinician if a hypersensitivity reaction (difficulty breathing, hoarseness, wheezing, hives, paleness, weakness, fast heart beat, dizziness) or other moderate or severe reaction (high fever, behavior changes) occurs following a dose of varicella vaccine.1 140 Clinicians or individuals can report any adverse reactions that occurs following vaccination to Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or .1 125 137 140

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 125 Importance of avoiding salicylates for 6 weeks after vaccination.125

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 125 140 Advise women to avoid pregnancy for 1–3 months following a dose of Varivax and MMRV (ProQuad).1 27 125 140 Report any exposure to varicella vaccine that occurs during pregnancy to the pregnancy registry at 800-986-8999.1 27 72 125

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

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 is a highly communicable disease in children, adolescents, and adults caused by the varicella-zoster virus. The disease usually consists of 300 to 500 maculopapular and/or vesicular lesions accompanied by a fever (oral temperature >/=100°F) in up to 70% of individuals. Approximately 3.5 million cases of varicella occurred annually from 1980-1994 in the United States with the peak incidence occurring in children five to nine years of age. The incidence rate of chickenpox in the total population was 8.3-9.1% per year in children 1-9 years of age before licensure of VARIVAX. The attack rate of natural varicella following household exposure among healthy susceptible children was shown to be 87% in unvaccinated populations. Although it is generally a benign, self-limiting disease, varicella may be associated with serious complications (e.g., bacterial superinfection, pneumonia, encephalitis, Reye's Syndrome), and/or death.

Evaluation of Clinical Efficacy Afforded by VARIVAX

Clinical Data in Children

In combined clinical trials of VARIVAX at doses ranging from 1,000-17,000 PFU, the majority of subjects who received VARIVAX and were exposed to wild-type virus were either completely protected from chickenpox or developed a milder form (for clinical description see below) of the disease. The protective efficacy of VARIVAX was evaluated in three different ways: 1) by comparing chickenpox rates in vaccinees versus historical controls, 2) by assessment of protection from disease following household exposure, and 3) by a placebo-controlled, double-blind clinical trial.

In early clinical trials, a total of 4240 children 1 to 12 years of age received 1000-1625 PFU of attenuated virus per dose of VARIVAX and have been followed for up to nine years post single-dose vaccination. In this group there was considerable variation in chickenpox rates among studies and study sites, and much of the reported data was acquired by passive follow-up. It was observed that 0.3%-3.8% of vaccinees per year reported chickenpox (called breakthrough cases). This represents an approximate 83% (95% confidence interval [CI], 82%, 84%) decrease from the age-adjusted expected incidence rates in susceptible subjects over this same period. In those who developed breakthrough chickenpox postvaccination, the majority experienced mild disease (median of the maximum number of lesions <50). In one study, a total of 47% (27/58) of breakthrough cases had <50 lesions compared with 8% (7/92) in unvaccinated individuals, and 7% (4/58) of breakthrough cases had >300 lesions compared with 50% (46/92) in unvaccinated individuals.

Among a subset of vaccinees who were actively followed in these early trials for up to nine years postvaccination, 179 individuals had household exposure to chickenpox. There were no reports of breakthrough chickenpox in 84% (150/179) of exposed children, while 16% (29/179) reported a mild form of chickenpox (38% [11/29] of the cases with a maximum total number of <50 lesions; no individuals with >300 lesions). This represents an 81% reduction in the expected number of varicella cases utilizing the historical attack rate of 87% following household exposure to chickenpox in unvaccinated individuals in the calculation of efficacy.

In later clinical trials with the current vaccine, a total of 1164 children 1 to 12 years of age received 2900-9000 PFU of attenuated virus per dose of VARIVAX and have been actively followed for up to six years post single-dose vaccination. It was observed that 0.2%-2.4% of vaccinees per year reported breakthrough chickenpox for up to six years post single-dose vaccination. This represents an approximate 93% (95% CI, 92%, 95%) decrease from the age-adjusted expected incidence rates in susceptible subjects over the same period. In those who developed breakthrough chickenpox postvaccination, the majority experienced mild disease with the median of the maximum total number of lesions <50. The severity of reported breakthrough chickenpox, as measured by number of lesions and maximum temperature, appeared not to increase with time since vaccination.

Among a subset of vaccinees who were actively followed in these later trials for up to five years postvaccination, 64 individuals were exposed to an unvaccinated individual with wild-type chickenpox in a household setting. There were no reports of breakthrough chickenpox in 91% (58/64) of exposed children, while 9% (6/64) reported a mild form of chickenpox (maximum total number of lesions <50, ranging from 6 to 40 lesions). This represents an 89% reduction in the expected number of varicella cases utilizing the historical attack rate of 87% following household exposure to chickenpox in unvaccinated individuals in the calculation of efficacy.

Although no placebo-controlled trial was carried out with VARIVAX using the current vaccine, a placebo-controlled trial was conducted using a formulation containing 17,000 PFU per dose. In this trial, a single dose of VARIVAX protected 96-100% of children against chickenpox over a two-year period. The study enrolled healthy individuals 1 to 14 years of age (n=491 vaccine, n=465 placebo). In the first year, 8.5% of placebo recipients contracted chickenpox, while no vaccine recipient did, for a calculated protection rate of 100% during the first varicella season. In the second year, when only a subset of individuals agreed to remain in the blinded study (n=163 vaccine, n=161 placebo), 96% protective efficacy was calculated for the vaccine group as compared to placebo.

There are insufficient data to assess the rate of protection against the complications of chickenpox (e.g., encephalitis, hepatitis, pneumonia) in children.

Clinical Data in Adolescents and Adults

In early clinical trials, a total of 796 adolescents and adults received 905-1230 PFU of attenuated virus per dose of VARIVAX and have been followed for up to six years following 2-dose vaccination. A total of 50 clinical varicella cases were reported >42 days following 2-dose vaccination. Based on passive follow-up, the annual chickenpox breakthrough event rate ranged from <0.1% to 1.9%. The median of the maximum total number of lesions ranged from 15 to 42 per year.

Although no placebo-controlled trial was carried out in adolescents and adults, the protective efficacy of VARIVAX was determined by evaluation of protection when vaccinees received 2 doses of VARIVAX 4 or 8 weeks apart and were subsequently exposed to chickenpox in a household setting. Among the subset of vaccinees who were actively followed in these early trials for up to six years, 76 individuals had household exposure to chickenpox. There were no reports of breakthrough chickenpox in 83% (63/76) of exposed vaccinees, while 17% (13/76) reported a mild form of chickenpox. Among 13 vaccinated individuals who developed breakthrough chickenpox after a household exposure, 62% (8/13) of the cases reported maximum total number of lesions <50, while no individual reported >75 lesions. The attack rate of unvaccinated adults exposed to a single contact in a household has not been previously studied. Utilizing the previously reported historical attack rate of 87% for natural varicella following household exposure to chickenpox among unvaccinated children in the calculation of efficacy, this represents an approximate 80% reduction in the expected number of cases in the household setting.

In later clinical trials, a total of 220 adolescents and adults received 3315-9000 PFU of attenuated virus per dose of VARIVAX and have been actively followed for up to six years following 2-dose vaccination. A total of 3 clinical varicella cases were reported >42 days following 2-dose vaccination. Two cases reported <50 lesions and none reported >75. The annual chickenpox breakthrough event rate ranged from 0% to 1.2%. Among the subset of vaccinees who were actively followed in these later trials for up to five years, 16 individuals were exposed to an unvaccinated individual with wild-type chickenpox in a household setting. There were no reports of breakthrough chickenpox among the exposed vaccinees.

There are insufficient data to assess the rate of protection of VARIVAX against the serious complications of chickenpox in adults (e.g., encephalitis, hepatitis, pneumonitis) and during pregnancy (congenital varicella syndrome).

Immunogenicity of VARIVAX

Clinical trials with several formulations of the vaccine containing attenuated virus ranging from 1000 to 17,000 PFU per dose have demonstrated that VARIVAX induces detectable immune responses in a high proportion of individuals and is generally well tolerated in healthy individuals ranging from 12 months to 55 years of age.

Seroconversion as defined by the acquisition of any detectable varicella antibodies (gpELISA >0.3, a highly sensitive assay which is not commercially available) was observed in 97% of vaccinees at approximately 4-6 weeks postvaccination in 6889 susceptible children 12 months to 12 years of age. Rates of breakthrough disease were significantly lower among children with varicella antibody titers >/=5 compared to children with titers <5. Titers >/=5 were induced in approximately 76% of children vaccinated with a single dose of vaccine at 1000-17,000 PFU per dose. In a multicenter study involving susceptible adolescents and adults 13 years of age and older, two doses of VARIVAX administered four to eight weeks apart induced a seroconversion rate (gpELISA >0.3) of approximately 75% in 539 individuals four weeks after the first dose and of 99% in 479 individuals four weeks after the second dose. The average antibody response in vaccinees who received the second dose eight weeks after the first dose was higher than that in those, who received the second dose four weeks after the first dose. In another multicenter study involving adolescents and adults, two doses of VARIVAX administered eight weeks apart induced a seroconversion rate (gpELISA >0.3) of 94% in 142 individuals six weeks after the first dose and 99% in 122 individuals six weeks after the second dose.

VARIVAX also induces cell-mediated immune responses in vaccinees. The relative contributions of humoral immunity and cell-mediated immunity to protection from chickenpox are unknown.

Persistence of Immune Response

In clinical studies involving healthy children who received 1 dose of vaccine, detectable varicella antibodies (gpELISA >0.6 units) were present in 99.0% (3886/3926) at 1 year, 99.3% (1555/1566) at 2 years, 98.6% (1106/1122) at 3 years, and 99.4% (1168/1175) at 4 years, 99.2% (737/743) at 5 years, 100% (142/142) at 6 years, 97.4% (38/39) at 7 years, 100% (34/34) at 8 years, and 100% (16/16) at 10 years postvaccination.

In clinical studies involving healthy adolescents and adults who received 2 doses of vaccine, detectable varicella antibodies (gpELISA >0.6 units) were present in 97.9% (568/580) at 1 year, 97.1% (34/35) at 2 years, 100% (144/144) at 3 years, 97.0% (98/101) at 4 years, 97.4% (76/78) at 5 years, and 100% (34/34) at 6 years postvaccination.

A boost in antibody levels has been observed in vaccinees following exposure to natural varicella which could account for the apparent long-term persistence of antibody levels after vaccination in these studies. The duration of protection from varicella obtained using VARIVAX in the absence of wild-type boosting is unknown. VARIVAX also induces cell-mediated immune responses in vaccinees. The relative contributions of humoral immunity and cell-mediated immunity to protection from chickenpox are unknown.

Transmission

In the placebo-controlled trial, transmission of vaccine virus was assessed in household settings (during the 8-week postvaccination period) in 416 susceptible placebo recipients who were household contacts of 445 vaccine recipients. Of the 416 placebo recipients, three developed chickenpox and seroconverted, nine reported a varicella-like rash and did not seroconvert, and six had no rash but seroconverted. If vaccine virus transmission occurred, it did so at a very low rate and possibly without recognizable clinical disease in contacts. These cases may represent either natural varicella from community contacts or a low incidence of transmission of vaccine virus from vaccinated contacts (see PRECAUTIONS, Transmission ). Postmarketing experience suggests that transmission of vaccine virus may occur rarely between healthy vaccinees who develop a varicella-like rash and healthy susceptible contacts. Transmission of vaccine virus from vaccinees without a varicella-like rash has been reported but has not been confirmed.

Herpes Zoster

Overall, 9454 healthy children (12 months to 12 years of age) and 1648 adolescents and adults (13 years of age and older) have been vaccinated with Oka/Merck live attenuated varicella vaccine in clinical trials. Eight cases of herpes zoster have been reported in children during 42,556 person years of follow-up in clinical trials, resulting in a calculated incidence of at least 18.8 cases per 100,000 person years. The completeness of this reporting has not been determined. One case of herpes zoster has been reported in the adolescent and adult age group during 5410 person years of follow-up in clinical trials resulting in a calculated incidence of 18.5 cases per 100,000 person years.

All nine cases were mild and without sequelae. Two cultures (one child and one adult) obtained from vesicles were positive for wild-type varicella zoster virus as confirmed by restriction endonuclease analysis. The long-term effect of VARIVAX on the incidence of herpes zoster, particularly in those vaccinees exposed to natural varicella, is unknown at present.

In children, the reported rate of zoster in vaccine recipients appears not to exceed that previously determined in a population-based study of healthy children who had experienced natural varicella. The incidence of zoster in adults who have had natural varicella infection is higher than that in children.

Reye's Syndrome

Reye's Syndrome has occurred in children and adolescents following natural varicella infection, the majority of whom had received salicylates. In clinical studies in healthy children and adolescents in the United States, physicians advised varicella vaccine recipients not to use salicylates for six weeks after vaccination. There were no reports of Reye's Syndrome in varicella vaccine recipients during these studies.

Studies with Other Vaccines

In combined clinical studies involving 1080 children 12 to 36 months of age, 653 received VARIVAX and M-M-R * II (Measles, Mumps, and Rubella Virus Vaccine Live) concomitantly at separate sites and 427 received the vaccines six weeks apart. Seroconversion rates and antibody levels were comparable between the two groups at approximately six weeks post-vaccination to each of the virus vaccine components. No differences were noted in adverse reactions reported in those who received VARIVAX concomitantly with M-M-R II at separate sites and those who received VARIVAX and M-M-R II at different times (see PRECAUTIONS , Drug Interactions , Use with Other Vaccines ).

In a clinical study involving 318 children 12 months to 42 months of age, 160 received an investigational vaccine (a formulation combining measles, mumps, rubella, and varicella in one syringe) concomitantly with booster doses of DTaP (diphtheria, tetanus, acellular pertussis) and OPV (oral poliovirus vaccine) while 144 received M-M-R II concomitantly with booster doses of DTaP and OPV followed by VARIVAX 6 weeks later. At six weeks postvaccination, seroconversion rates for measles, mumps, rubella, and varicella and the percentage of vaccinees whose titers were boosted for diphtheria, tetanus, pertussis, and polio were comparable between the two groups, but anti-varicella levels were decreased when the investigational vaccine containing varicella was administered concomitantly with DTaP. No clinically significant differences were noted in adverse reactions between the two groups.

In another clinical study involving 307 children 12 to 18 months of age, 150 received an investigational vaccine (a formulation combining measles, mumps, rubella, and varicella in one syringe) concomitantly with a booster dose of PedvaxHIB * [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] while 130 received M-M-R II concomitantly with a booster dose of PedvaxHIB followed by VARIVAX 6 weeks later. At six weeks postvaccination, seroconversion rates for measles, mumps, rubella, and varicella, and geometric mean titers for PedvaxHIB were comparable between the two groups, but anti-varicella levels were decreased when the investigational vaccine containing varicella was administered concomitantly with PedvaxHIB. No clinically significant differences in adverse reactions were seen between the two groups.

In a clinical study involving 609 children 12 to 23 months of age, 305 received VARIVAX, M-M-R II, and TETRAMUNE ** ( Haemophilus influenzae type b, diphtheria, tetanus, and pertussis vaccines) concomitantly at separate sites, and 304 received M-M-R II and TETRAMUNE concomitantly at separate sites, followed by VARIVAX 6 weeks later. At six weeks postvaccination, seroconversion rates for measles, mumps, rubella and varicella were similar between the two groups. Postvaccination GMTs for all antigens were similar in both treatment groups except for varicella, which was lower when VARIVAX was administered concomitantly with M-M-R II and TETRAMUNE, but within the range of GMTs seen in previous clinical experience when VARIVAX was administered alone. At 1 year postvaccination, GMTs for measles, mumps, rubella, varicella and Haemophilus influenzae type b were similar between the two groups. All three vaccines were well tolerated regardless of whether they were administered concomitantly at separate sites or 6 weeks apart. There were no clinically important differences in reaction rates when the three vaccines were administered concomitantly versus 6 weeks apart.

In a clinical study involving 822 children 12 to 15 months of age, 410 received COMVAX * [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) vaccine], M-M-R II, and VARIVAX concomitantly at separate sites, and 412 received COMVAX followed by M-M-R II and VARIVAX given concomitantly at separate sites, 6 weeks later. At six weeks postvaccination, the immune responses for the subjects who received the concomitant injections of COMVAX, M-M-R II, and VARIVAX were similar to those of the subjects who received COMVAX followed 6 weeks later by M-M-R II and VARIVAX with respect to all antigens administered. All three vaccines were generally well tolerated regardless of whether they were administered concomitantly at separate sites or 6 weeks apart. There were no clinically important differences in reaction rates when the three vaccines were administered concomitantly versus 6 weeks apart.

VARIVAX is recommended for subcutaneous administration. However, during clinical trials, some children received VARIVAX intramuscularly resulting in seroconversion rates similar to those in children who received the vaccine by the subcutaneous route. Persistence of antibody and efficacy in those receiving intramuscular injections have not been defined.