Chickenpox Complications May Be Serious Scientists Report At CDC Immunization Conference

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VARIVAX(R) - (Varicella Virus Vaccine Live (Oka/Merck))

Description

VARIVAX(R) (Varicella Virus Vaccine Live (Oka/Merck)) is a preparation of the Oka/Merck strain of live, attenuated varicella virus. The virus was initially obtained from a child with natural varicella, then introduced into human embryonic lung cell cultures, adapted to and propagated in embryonic guinea pig cell cultures and finally propagated in human diploid cell cultures (WI-38). Further passage of the virus for varicella vaccine was performed at Merck Research Laboratories (MRL) in human diploid cell cultures (MRC-5) that were free of adventitious agents. This live, attenuated varicella vaccine is a lyophilized preparation containing sucrose, phosphate, glutamate, and processed gelatin as stabilizers.

VARIVAX, when reconstituted as directed, is a sterile preparation for subcutaneous administration. Each 0.5 mL dose contains the following: a minimum of 1350 PFU (plaque forming units) of Oka/Merck varicella virus when reconstituted and stored at room temperature for 30 minutes, approximately 25 mg of sucrose, 12.5 mg hydrolyzed gelatin, 3.2 mg sodium chloride, 0.5 mg monosodium L-glutamate, 0.45 mg of sodium phosphate dibasic, 0.08 mg of potassium phosphate monobasic, 0.08 mg of potassium chloride; residual components of MRC-5 cells including DNA and protein; and trace quantities of sodium phosphate monobasic, EDTA, neomycin, and fetal bovine serum. The product contains no preservative.

To maintain potency, the lyophilized vaccine must be kept frozen at an average temperature of -15 degrees C (+5 degrees F) or colder and must be used before the expiration date (see HOW SUPPLIED, Stability and Storage). Storage in any freezer (e.g., chest, frost-free) that reliably maintains an average temperature of -15 degrees C (+5 degrees F) or colder and has a separate sealed freezer door is acceptable.

Clinical Pharmacology

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 3100 degrees F) in up to 70% of individuals.(12) 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.(3) The incidence rate of chickenpox is 8.3-9.1% per year in children 1-9 years of age.(4) The attack rate of natural varicella following household exposure among healthy susceptible children was shown to be 87%.(2) 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(5) 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,(5) a total of 4142 children received 1000-1625 PFU of attenuated virus per dose of VARIVAX and have been followed for up to six 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 were acquired by passive follow-up. It was observed that 2.1%-3.6% of vaccinees per year reported chickenpox (called breakthrough cases). This represents an approximate 67% (57-77%) decrease from the total number of cases expected based on attack rates in children aged 1-9 over this same period (8.3-9.1%).(4,6) In those who developed breakthrough chickenpox postvaccination, the majority experienced mild disease (median number of lesions less than 50). In one study, a total of 47% (27/58) of breakthrough cases had less than 50 lesions compared with 8% (7/92) in unvaccinated individuals, and 7% (4/58) of breakthrough cases had greater than 300 lesions compared with 50% (46/92) in unvaccinated individuals.(7) In studies of vaccinated children who contracted chickenpox after a household exposure, 57% (31/54) of the cases reported less than 50 lesions, while 1.9% (1/54) reported greater than 300 lesions with an oral temperature above 100 F.

In later clinical trials(5) with the current vaccine, a total of 1164 children received 2900-9000 PFU of attenuated virus per dose of VARIVAX and have been followed for up to three years post single-dose vaccination. It was observed that 0.2%-1.0% of vaccinees per year reported breakthrough chickenpox for up to three years post single-dose vaccination. This represents an approximate 93% decrease from the total number of cases expected based on attack rates in children aged 1-9 over this same period (8.3%-9.1%).(3,26) In those who developed breakthrough chickenpox postvaccination, the majority experienced mild disease.

Among a subset of vaccinees who were actively followed, 259 were exposed to an individual with chickenpox in a household setting. There were no reports of breakthrough chickenpox in 80% of exposed children; 20% reported a mild form of chickenpox.(5) This represents a 77% reduction in the expected number of cases when compared to the historical attack rate of varicella following household exposure to chickenpox of 87% in unvaccinated individuals.(2)

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.(4,8) 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

Although no placebo-controlled trial was carried out in adolescents and adults, efficacy 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.(5) In up to two years of active follow- up, 17 of 64 (27%) vaccinees reported breakthrough chickenpox following household exposure; of the 17 cases, 12 (71%) reported less than 50 lesions, 5 reported 50-300 lesions, and none reported greater than 300 lesions with an oral temperature above 100 F. In combined clinical studies of adolescents and adults (n=1019) who received two doses of VARIVAX and later developed breakthrough chickenpox and reported numbers of lesions (42 of 1019), 25 of 42 (60%) reported less than 50 lesions, 16 of 42 (38%) reported 50-300 lesions, and 1 of 42 (2%) reported greater than 300 lesions and an oral temperature above 100 degrees F.(5)

The attack rate of unvaccinated adults exposed to a single contact in a household has not been previously studied. When compared to the previously reported attack rate of natural varicella of 87% following household exposure among unvaccinated children, this represents an approximate 70% reduction in the expected number of cases in the household setting.(2)

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

Seroconversion as defined by the acquisition of any detectable varicella antibodies (gpELISA greater than 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 greater than or equal to 5 compared to children with titers less than 5. Titers greater than or equal to 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 greater than 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 greater than 0.3) of 94% in 142 individuals six weeks after the first dose and 99% in 122 individuals six weeks after the second dose.(5)

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

Studies in vaccinees examining chickenpox breakthrough rates over 5 years showed the lowest rates (0.2-2.9%) in the first two years postvaccination, with somewhat higher but stable rates in the third through fifth year. The severity of reported breakthrough chickenpox, as measured by number of lesions and maximum temperature, appeared not to increase with time since vaccination.(5)

In clinical studies involving healthy children who received 1 dose of vaccine, detectable varicella antibodies (gpELISA greater than 0.3) were present in 98.8% (3775/3822) at 1 year, 98.9% (1057/1069) at 2 years, 97.5% (548/562) at 3 years, and 99.5% (220/221) at 4 years postvaccination. Antibody levels were present at least one year in 97.2% (423/435) of healthy adolescents and adults who received two doses of live varicella vaccine separated by 4 to 8 weeks. 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).(4,16) Post-marketing 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.(5)

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.(5,17) 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.(5,18,19) The incidence of zoster in adults who have had natural varicella infection is higher than that in children.(20)

Reye's Syndrome

Reye's Syndrome has occurred in children and adolescents following natural varicella infection, the majority of whom had received salicylates.(21) 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(A)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 (Measles, Mumps, and Rubella Virus Vaccine Live) at separate sites and those who received VARIVAX and M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live) at different times (see PRECAUTIONS, Drug Interactions, Use with Other Vaccines).(5)

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 (Measles, Mumps, and Rubella Virus Vaccine Live) 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.(5)

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(R) (Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)) while 130 received M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live) 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.(5)

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.(22) Persistence of antibody and efficacy in those receiving intramuscular injections have not been defined.

(A) trademark of MERCK & CO., Inc. Varivax is the Merck registered trademark for Varicella Virus Vaccine Live (Oka/Merck)

CONTACT: Donna Cary of Merck & Co., 215-652-5558