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Pharmacology: Varicella: 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 to 1994 in the United States with the peak incidence occurring in children five to nine years of age. The incidence rate of varicella was 8.3 to 9.1% per year in children 1 to 9 years of age. The attack rate of wild-type varicella following household exposure among healthy susceptible children was shown to be 87%. Although it is generally a benign, self-limiting disease, varicella may be associated with serious complications (e.g., bacterial superinfection, pneumonia, encephalitis, Reye syndrome), and/or death.
Clinical Studies: Evaluation of Clinical Efficacy Afforded by VARIVAX Refrigerated: The protective efficacy of varicella virus vaccine live (Oka/Merck) [hereafter referred to as varicella vaccine (Oka/Merck)] was established by: a placebo-controlled, double-blind clinical trial, comparing varicella rates in vaccinees versus historical controls, and assessing protection from disease following household exposure.
Clinical Data in Children: One-Dose Regimen in Children: Although no placebo-controlled trial was carried out with refrigerator-stable varicella vaccine (Oka/Merck), a placebo-controlled trial was conducted using a prior formulation containing 17,000 PFU per dose. In this trial, a single dose of varicella vaccine (Oka/Merck) protected 96 to 100% of children against varicella 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 varicella, 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 with placebo.
In early clinical trials, a total of 4240 children 1 to 12 years of age received 1000 to 1625 PFU of attenuated virus per dose of varicella vaccine (Oka/Merck) and have been followed for up to nine years post single-dose vaccination. In this group, there was considerable variation in varicella rates among studies and study sites, and much of the reported data was acquired by passive follow-up. It was observed that 0.3 to 3.8% of vaccinees per year reported varicella (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 varicella 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 varicella. There were no reports of breakthrough varicella in 84% (150/179) of exposed children, while 16% (29/179) reported a mild form of varicella (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 varicella in unvaccinated individuals in the calculation of efficacy.
In later clinical trials, a total of 1114 children 1 to 12 years of age received 2900 to 9000 PFU of attenuated virus per dose of varicella vaccine (Oka/Merck) and have been actively followed for up to 10 years post single-dose vaccination. It was observed that 0.2 to 2.3% of vaccinees per year reported breakthrough varicella for up to 10 years post single-dose vaccination. This represents an estimated efficacy 94% (95% CI, 93%, 96%) compared with the age-adjusted expected incidence rates in susceptible subjects over the same period. In those who developed breakthrough varicella postvaccination, the majority experienced mild disease with the median of the maximum total number of lesions <50. The severity of reported breakthrough varicella, 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 10 years postvaccination, 95 individuals were exposed to an unvaccinated individual with wild-type varicella in a household setting. There were no reports of breakthrough varicella in 92% (87/95) of exposed children, while 8% (8/95) reported a mild form of varicella (maximum total number of lesions <50; observed range, 10 to 34). This represents an estimated efficacy of 90% (95% CI, 82%, 96%) based on the historical attack rate of 87% following household exposure to varicella in unvaccinated individuals in the calculation of efficacy.
Two-Dose Regimen in Children: In a clinical trial, a total of 2216 children 12 months to 12 years of age with a negative history of varicella were randomized to receive either 1 dose of varicella vaccine (Oka/Merck) (n=1114) or 2 doses of varicella vaccine (Oka/Merck) (n=1102) given 3 months apart. Subjects were actively followed for varicella, any varicella-like illness, or herpes zoster and any exposures to varicella or herpes zoster on an annual basis for 10 years after vaccination. Persistence of varicella-zoster vaccine (VZV) antibody was measured annually for 9 years. Most cases of varicella reported in recipients of 1 dose or 2 doses of vaccine were mild. The estimated vaccine efficacy for the 10-year observation period was 94% for 1 dose and 98% for 2 doses (p<0.001). This translates to a 3.4-fold lower risk of developing varicella >42 days postvaccination during the 10-year observation period in children who received 2 doses than in those who received 1 dose (2.2% vs. 7.5%, respectively).
Clinical Data in Adolescents and Adults: Although no placebo-controlled trial was carried out in adolescents and adults, the protective efficacy of varicella vaccine (Oka/Merck) was calculated by evaluation of protection when vaccinees received 2 doses of varicella vaccine (Oka/Merck) 4 or 8 weeks apart and were subsequently exposed to varicella in a household setting over 6 to 7 years. In earlier clinical trials with up to 6 years of follow-up, 13 of the 76 individuals (17%) who had household exposure to varicella, developed varicella. All of the varicella cases that were reported were generally mild with a median of 37 lesions (range 8 to 75). In later clinical trials with up to 7 years of follow-up, none of 19 individuals (0%) who had household exposure developed varicella.
The attack rate of unvaccinated adults exposed to a single contact in a household has not been previously studied. If the attack rate of 87% following household exposure in susceptible children holds true for susceptible adolescents and adults, the estimated efficacy of the vaccine in the prevention of any varicella disease would range from 80 to 100%.
There are an insufficient number of breakthrough varicella cases among vaccinated adolescents and adults to assess the rate of protection of varicella vaccine (Oka/Merck) against the serious complications of varicella (e.g., encephalitis, hepatitis, pneumonia) and during pregnancy (congenital varicella syndrome).
Immunogenicity of Varicella Vaccine (Oka/Merck): In clinical trials, varicella antibodies have been evaluated following vaccination with formulations of varicella vaccine (Oka/Merck) containing attenuated virus ranging from 1000 to 50,000 PFU per dose in healthy individuals ranging from 12 months to 55 years of age.
One-Dose Regimen in Children: In prelicensure efficacy studies, seroconversion was observed in 97% of vaccinees at approximately 4 to 6 weeks postvaccination in 6889 susceptible children 12 months to 12 years of age. Titers ≥5 gpELISA units/mL were induced in approximately 76% of children vaccinated with a single dose of vaccine at 1000 to 17,000 PFU per dose. Rates of breakthrough disease were significantly lower among children with VZV antibody titers ≥5 gpELISA units/mL compared with children with titers <5 gpELISA units/mL.
Immunogenicity of refrigerator-stable varicella vaccine (Oka/Merck) (6550 PFU per dose, n=320 and 28,400 PFU per dose, n=315) was compared with that of the licensed frozen formulation of varicella vaccine (Oka/Merck) (9189 PFU per dose, n=323) in a double-blind, randomized, multicenter study in U.S. children 12 to 23 months of age, all of whom received M-M-R-II (Measles, Mumps, and Rubella Virus Vaccine Live) concomitantly. The per-protocol analysis included all subjects with prevaccination varicella antibody titers <1.25 gpELISA units (n=267 to 276 per group); the antibody responses were comparable across the 3 treatment groups, with 6-week postvaccination varicella antibody titers ≥5 gpELISA units in 93.3%, 93.8%, and 95.1% of subjects, respectively.
Two-Dose Regimen in Children: In a multicenter study, 2216 healthy children 12 months to 12 years of age received either 1 dose of varicella vaccine (Oka/Merck) or 2 doses administered 3 months apart. The immunogenicity results are shown in the following table. (See Table 1.)
Click on icon to see table/diagram/imageThe results from this study and other studies in which a second dose of varicella vaccine (Oka/Merck) was administered 3 to 6 years after the initial dose demonstrate significant boosting of the VZV antibodies with a second dose. VZV antibody levels after 2 doses given 3 to 6 years apart are comparable to those obtained when the 2 doses are given 3 months apart.
Two-Dose Regimen in Adolescents and Adults: In a multicenter study involving susceptible adolescents and adults 13 years of age and older, two doses of varicella vaccine (Oka/Merck) administered four to eight weeks apart induced a seroconversion rate (gpELISA ≥0.6 units) 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 varicella vaccine (Oka/Merck) administered eight weeks apart induced a seroconversion rate (gpELISA ≥0.6 units) of 94% in 142 individuals six weeks after the first dose and 99% in 122 individuals six weeks after the second dose.
Varicella vaccine (Oka/Merck) also induces cell-mediated immune responses in vaccinees. The relative contributions of humoral immunity and cell-mediated immunity to protection from varicella are unknown.
Persistence of Immune Response: One-Dose Regimen in Children: In clinical studies involving healthy children who received 1 dose of vaccine, detectable VZV antibodies 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.
Two-Dose Regimen in Children: In recipients of 1 dose of varicella vaccine (Oka/Merck) over 9 years of follow-up, the geometric mean titers (GMTs) and the percent of subjects with VZV antibody titers ≥5 gpELISA units/mL generally increased. The GMTs and percent of subjects with VZV antibody titers ≥5 gpELISA units/mL in the 2-dose recipients were higher than those in the 1-dose recipients for the first year follow-up and generally comparable thereafter. The cumulative rate of VZV antibody persistence with both regimens remained very high at year 9 (99.0% for the 1-dose group and 98.8% for the 2-dose group).
Two-Dose Regimen in Adolescents and Adults: 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, 97.5% (78/80) at 5 years, and 100% (45/45) at 6 years postvaccination.
A boost in antibody levels has been observed in vaccinees following exposure to wild-type 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 varicella vaccine (Oka/Merck) in the absence of wild-type boosting is unknown. Varicella vaccine (Oka/Merck) also induces cell-mediated immune responses in vaccinees. The relative contributions of humoral immunity and cell-mediated immunity to protection from varicella are unknown.
Vaccination with VARIVAX (Refrigerated) may not result in protection of all healthy, susceptible children, adolescents, and adults.
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 varicella 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 wild-type varicella from community contacts or a low incidence of transmission of vaccine virus from vaccinated contacts. Post-marketing experience suggests that transmission of varicella vaccine virus (Oka/Merck) resulting in varicella infection including disseminated disease may occur rarely between vaccine recipients (who develop or do not develop a varicella-like rash) and contacts susceptible to varicella including healthy as well as high-risk individuals (see Transmission under PRECAUTIONS).
Herpes Zoster: Overall, 9543 healthy children (12 months to 12 years of age) and 1652 adolescents and adults (13 years of age and older) have been vaccinated with varicella vaccine (Oka/Merck) in clinical trials. Twelve cases of herpes zoster have been reported in children during 84,414 person years of follow-up in clinical trials, resulting in a calculated incidence of at least 14 cases per 100,000 person years. The completeness of this reporting has not been determined. Two cases of herpes zoster have been reported in the adolescent and adult age group during 12,372 person years of follow-up in clinical trials resulting in a calculated incidence of 16 cases per 100,000 person years.
All 14 cases of herpes zoster were mild and no sequelae were reported. 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 varicella vaccine (Oka/Merck) on the incidence of herpes zoster, particularly in those vaccinees exposed to wild-type 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 wild-type varicella. The incidence of zoster in adults who have had wild-type varicella infection is higher than that in children.
Reye Syndrome: Reye syndrome has occurred in children and adolescents following wild-type 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 syndrome in varicella vaccine recipients during these studies.
Studies with Other Vaccines: In combined clinical studies involving 1107 children 12 to 36 months of age, 680 received varicella vaccine (Oka/Merck) 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 postvaccination to each of the virus vaccine components. No differences were noted in adverse reactions reported in those who received varicella vaccine (Oka/Merck) concomitantly with M-M-R II at separate sites and those who received varicella vaccine (Oka/Merck) and M-M-R II at different times (see INTERACTIONS).
In a clinical study involving 316 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 156 received M-M-R II concomitantly with booster doses of DTaP and OPV followed by varicella vaccine (Oka/Merck) 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 306 children 12 to 18 months of age, 151 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 155 received M-M-R II concomitantly with a booster dose of PedvaxHIB followed by varicella vaccine (Oka/Merck) 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 months to 23 months of age, 305 received varicella vaccine (Oka/Merck), M-M-R II, and Haemophilus influenzae type b, diphtheria, tetanus, and pertussis combined vaccine concomitantly at separate sites and 304 received M-M-R II and Haemophilus influenzae type b, diphtheria, tetanus, and pertussis combined vaccine given concomitantly followed by varicella vaccine (Oka/Merck) 6 weeks later. At six weeks postvaccination, seroconversion rates for measles, mumps, rubella, and varicella were similar between the two groups. Compared to prevaccination GMTs, the six-week postvaccination boost in GMTs for Haemophilus influenzae type b, diphtheria, tetanus and pertussis was similar between the two groups. GMTs for all antigens were similar except for varicella which was lower when varicella vaccine (Oka/Merck) was administered concomitantly with M-M-R II and Haemophilus influenzae type b, diphtheria, tetanus, and pertussis combined vaccine but within the range of GMTs seen in previous clinical experience when varicella vaccine (Oka/Merck) 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 Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) combined vaccine, M-M-R II, and varicella vaccine (Oka/Merck) concomitantly at separate sites, and 412 received Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) combined vaccine followed by M-M-R II and varicella vaccine (Oka/Merck) given concomitantly at separate sites, 6 weeks later. At 6 weeks postvaccination, the immune responses for the subjects who received the concomitant injections of Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) combined vaccine, M-M-R II, and varicella vaccine (Oka/Merck) were similar to those of the subjects who received Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) combined vaccine followed 6 weeks later by M-M-R II and varicella vaccine (Oka/Merck) with respect to all antigens administered. All 3 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 3 vaccines were administered concomitantly versus 6 weeks apart.
VARIVAX Refrigerated is recommended for subcutaneous administration. However, during clinical trials, some children received varicella vaccine (Oka/Merck) 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.
