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Evaluation of Clinical Efficacy Afforded by VARIVAX: The following section presents clinical efficacy data on a 1-dose regimen and a 2-dose regimen in children, and a 2-dose regimen in adolescents and adults.
Clinical Data in Children: One-Dose Regimen in Children: In combined clinical trials of VARIVAX at doses ranging from 1000 to 17,000 PFU, the majority of subjects who received the vaccine and were exposed to wild-type virus were either completely protected from chickenpox or developed a milder form (for clinical description as follows) of the disease.
The protective efficacy of VARIVAX administered subcutaneously 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 to 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 to 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, a total of 1114 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 10 years post single-dose vaccination. It was observed that 0.2%-2.3% of vaccinees per year reported breakthrough chickenpox for up to 10 years post single-dose vaccination. This represents an estimated efficacy of 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 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 10 years postvaccination, 95 individuals were exposed to an unvaccinated individual with wild-type chickenpox in a household setting. There were no reports of breakthrough chickenpox in 92% (87/95) of exposed children, while 8% (8/95) reported a mild form of chickenpox (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 chickenpox in unvaccinated individuals in the calculation of efficacy.
Although no placebo-controlled trial was carried out with refrigerator-stable VARIVAX, a placebo-controlled trial was conducted using a prior formulation containing 17,000 PFU per dose. In this trial, a single dose of VARIVAX protected 96 to 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.
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 VARIVAX (n=1114) or 2 doses of VARIVAX (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 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: Two-Dose Regimen in Adolescents and Adults: In early clinical trials, a total of 796 adolescents and adults received 905 to 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 wild-type 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 to 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 50,000 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.
In an open label clinical trial 752 children 12 through 18 months of age received VARIVAX either intramuscularly (n=374) or subcutaneously (n=378), concomitantly with M-M-R II. Antibody response to varicella virus was measured by glycoprotein ELISA (gpELISA) using sera obtained 6 weeks post-vaccination. For anti-varicella virus, seroresponse rates were defined as the percentage of children seronegative at baseline who achieved antibody titers above the seroresponse threshold 6 weeks post-vaccination. The seroresponse threshold was defined as 5 gpELISA units/mL for anti-varicella virus antibodies. At baseline, 94% of enrolled children were seronegative to varicella. Seroresponse rates to varicella virus were noninferior for the intramuscular group compared to the subcutaneous group (the lower bound of the 95% confidence interval for the difference in seroresponse rates [intramuscular group minus subcutaneous group] was >-10%). The point estimates of the proportions of children achieving antibody titers above the seroresponse thresholds for varicella virus was 88.4% in the intramuscular group and 85.5% in the subcutaneous group.
The following section presents immunogenicity data on a 1-dose regimen and a 2-dose regimen in children, and a 2-dose regimen in adolescents and adults.
One-Dose Regimen in Children: Seroconversion is defined by the acquisition of any detectable VZV antibodies, based on an optical density (OD) cutoff, corresponding approximately to a lower limit of 0.6 glycoprotein enzyme-linked immunosorbent assay (gpELISA) units/mL.
The gpELISA is a highly sensitive assay that is not commercially available. 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. 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. 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.
Immunogenicity of refrigerator-stable VARIVAX (6550 PFU per dose, n=320 and 28,400 PFU per dose, n=315) was compared with that of the previously licensed formulation (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.
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.
Two-Dose Regimen in Children: In a multicenter study, healthy children 12 months to 12 years of age received either 1 dose or 2 doses of VARIVAX administered subcutaneously 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 vaccine was administered 3 to 6 years after the initial dose demonstrate significant boosting of the VZV antibody response 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, 2 doses of VARIVAX administered subcutaneously 4 to 8 weeks apart induced a seroconversion rate of approximately 75% in 539 individuals 4 weeks after the first dose and of 99% in 479 individuals 4 weeks after the second dose. The average antibody response in vaccinees who received the second dose 8 weeks after the first dose was higher than that in vaccinees who received the second dose 4 weeks after the first dose. In another multicenter study involving adolescents and adults, 2 doses of VARIVAX administered subcutaneously 8 weeks apart induced a seroconversion rate of 94% in 142 individuals 6 weeks after the first dose and 99% in 122 individuals 6 weeks after the second dose.
Persistence of Immune Response: The following section presents immune persistence data on a 1-dose regimen and a 2-dose regimen in children, and a 2-dose regimen in adolescents and adults.
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 VARIVAX administered subcutaneously over 9 years of follow-up, the geometric mean titer (GMT) 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 of 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 VARIVAX subcutaneously, detectable VZV antibodies 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 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 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.
Vaccination with refrigerator-stable VARIVAX 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 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 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, 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 VARIVAX 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 9 cases were mild and without sequelae. Two cultures (one child and one adult) obtained from vesicles were positive for wild-type VZV as confirmed by restriction endonuclease analysis. The long-term effect of VARIVAX 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 herpes 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 herpes 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 1080 children 12 to 36 months of age, 653 children received VARIVAX and M-M-R II administered subcutaneously and 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 VARIVAX concomitantly with M-M-R II at separate sites and those who received VARIVAX and M-M-R II at different times (see Drug Interactions, Use with Other Vaccines under Interactions).
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) administered subcutaneously and 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 administered subcutaneously 6 weeks later. At six weeks postvaccination, seroconversion rates for measles, mumps, rubella, and VZV and the percentage of vaccinees whose titers were boosted for diphtheria, tetanus, pertussis, and polio were comparable between the two groups, but anti-VZV 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) administered subcutaneously and 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 administered subcutaneously 6 weeks later. At six weeks postvaccination, seroconversion rates for measles, mumps, rubella, and VZV, and geometric mean titers for PedvaxHIB were comparable between the two groups, but anti-VZV 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 Haemophilus influenzae type b, diphtheria, tetanus, and pertussis combined vaccines concomitantly at separate sites, and 304 received M-M-R II and Haemophilus influenzae type b, diphtheria, tetanus, and pertussis combined vaccine concomitantly at separate sites, followed by VARIVAX 6 weeks later. At six weeks postvaccination, seroconversion rates for measles, mumps, rubella and VZV were similar between the two groups. Postvaccination GMTs for all antigens were similar in both treatment groups except for VZV, which was lower when VARIVAX 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 VARIVAX was administered alone. At 1 year postvaccination, GMTs for measles, mumps, rubella, VZV 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 VARIVAX 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 VARIVAX given concomitantly at separate sites, 6 weeks later. In this study VARIVAX was administered subcutaneously. At six weeks postvaccination, the immune responses for the subjects who received the concomitant doses of Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) combined vaccine, M-M-R II, and VARIVAX 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 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.
Refrigerator-stable VARIVAX is recommended for intramuscular or subcutaneous administration. 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 doses have not been defined.
