Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: MSD (Pty) Ltd, 117 16 th Road, Halfway House, 1685, South Africa
A.30.2 Antigens
ONVARA is a lyophilised preparation of the Oka/Merck strain of live, attenuated varicella virus. The virus was initially obtained from a child with wild-type 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-zoster vaccine (VZV) is a lyophilised preparation containing sucrose, phosphate, glutamate, processed gelatine, and urea as stabilizers.
ONVARA induces both cell-mediated and humoral immune responses to varicella-zoster virus. The relative contributions of humoral immunity and cell-mediated immunity to protection from varicella are unknown.
In the placebo-controlled efficacy trial, transmission of vaccine virus was assessed in household settings (during the 8-week post-vaccination 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 healthy 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 Special warnings and precautions for use, Transmission). Transmission of vaccine virus from a mother who did not develop a varicella-like rash to her newborn infant has also been reported.
Overall, 9 543 healthy children (12 months to 12 years of age) and 1 652 adolescents and adults (13 years of age and older) have been vaccinated with ONVARA 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 has 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 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 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 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 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. Duration of Protection The duration of protection of ONVARA is unknown; however, long-term efficacy studies have demonstrated continued protection up to 10 years after vaccination. A boost in antibody levels has been observed in vaccinees following exposure to wild-type varicella which could account for the apparent long-term protection after vaccination in these studies.
In combined clinical trials of varicella virus vaccine live (Oka/Merck) [hereafter referred to as varicella vaccine (Oka/Merck)] at doses ranging from 1 000 to 17 000 PFU, the majority of subjects who received varicella vaccine (Oka/Merck) and were exposed to wild-type virus were either completely protected from varicella or developed a milder form of the disease.
The protective efficacy of varicella vaccine (live) (Oka/Merck strain) was evaluated in three different ways:
1) by a double-blind, placebo-controlled trial over 2 years efficacy 95 to 100%);
2) by comparing varicella rates over 7 to 9 years in vaccinees versus historical controls (efficacy 83 to 94%); and
3) by assessment of protection from disease following household exposure over 7 to 9 years (efficacy 81 to 88%)
Although no placebo-controlled trial was carried out with varicella vaccine using the current formulation of the vaccine, a placebo-controlled trial was conducted using a formulation containing 17 000 PFU per dose. In this trial, a single dose of varicella vaccine (Oka/Merck) protected 95 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=169 vaccine, n=163 placebo), 95% protective efficacy was calculated for the vaccine group as compared with placebo.
In early clinical trials, a total of 4 240 children 1 to 12 years of age received 1 000 to 1 625 PFU of attenuated virus per dose of varicella vaccine (Oka/Merck) and have been followed for up to 9 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 post-vaccination, 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 9 years post-vaccination, 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 1 114 children 1 to 12 years of age received 2 900 to 9 000 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 7 years post single-dose vaccination. This represents an approximate 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 post-vaccination, 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 7 years post-vaccination, 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.
Among 9 202 children ≤12 years of age who received 1 injection of varicella vaccine (Oka/Merck), there were 1 149 cases of breakthrough varicella (occurring more than 6 weeks post-vaccination) of which 20 (1,7%) were classified as severe (≥300 lesions and a temperature ≥37,8°C oral). Compared with the proportion of severe cases (36%) from wild-type varicella infection in unvaccinated historical controls, this represents a 95% relative reduction in the proportion of severe cases among recipients of varicella vaccine who developed breakthrough varicella.
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=1 114) or 2 doses of varicella vaccine (Oka/Merck) (n=1 102) 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).
There are an insufficient number of breakthrough varicella cases in vaccinated children to assess the rate of protection of varicella vaccine (Oka/Merck) against the serious complications of varicella (e.g., encephalitis, hepatitis, pneumonia).
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 to varicella, 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).
Clinical trials with several formulations of the vaccine containing attenuated virus ranging from 1 000 to 50 000 PFU per dose have demonstrated that varicella vaccine (Oka/Merck) induces detectable humoral 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 (based on assay cut-off that generally corresponds to 0.6 units in the gpELISA, a highly sensitive assay which is not commercially available), was observed in 98% of vaccinees at approximately 4 to 6 weeks post-vaccination in 9 610 susceptible children 12 months to 12 years of age who received doses ranging from 1 000 to 50 000 PFU. Rates of breakthrough disease were significantly lower among children with varicella antibody titres ≥5 gpELISA units compared to children with titres <5 gpELISA units. Titres ≥5 gpELISA units were induced in approximately 83% of children vaccinated with a single dose of vaccine at 1 000 to 50 000 PFU per dose. The immune response rate to varicella vaccine (Oka/Merck) (as determined by the percentage of subjects with varicella antibody titres ≥5 gpELISA units at 6 weeks post- vaccination, an approximate correlation of protection) in subjects participating in follow-up studies ranged from 72 to 98%.
Immunogenicity of refrigerator-stable varicella vaccine (Oka/Merck) (formulations containing attenuated virus ranging from 6 650 to 28 400 PFU per dose), was compared with that of the licensed frozen formulation (9 189 PFU per dose) in a double-blind, randomized, multicenter study in children 12 to 23 months of age, all of whom received M-M-R II concomitantly. The per-protocol analysis included all subjects with prevaccination varicella antibody titers <1.25 gpELISA units; the antibody responses were comparable across the 3 treatment groups, with the percentage of subjects with varicella antibody titers ≥5 gpELISA units at 6 weeks postvaccination ranging from 93 to 95%.
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 as follows:
Table 3. Summary of VZV Antibody Responses at 6 Weeks Postdose 1 and 6 Weeks Postdose 2 in Initially Seronegative Children 12 Months to 12 Years of Age (Vaccinations 3 Months Apart):
| Varicella Vaccine (Oka/Merck) 1-Dose Regimen (N=1114) | Varicella Vaccine (Oka/Merck)2- Dose Regimen (3 Months Apart) (N=1102) | ||
|---|---|---|---|
| 6 Weeks Postvaccination (n=892) | 6 Weeks Postdose 1 (n=851) | 6 Weeks Postdose 2 (n=769) | |
| Seroconversion Rate | 98.9 % | 99.5 % | 99.9 % |
| Percent with VZV Antibody Titer ≥5 gpELISA units/mL | 84.9 % | 87.3 % | 99.5 % |
| Geometric Mean Titers in gpELISA units/mL (95% CI) | 12.0 (11.2, 12.8) | 12.8 (11.9, 13.7) | 141.5 (132.3, 151.3) |
N = Number of subjects vaccinated.
n = Number of subjects included in immunogenicity analysis.
The 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.
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.
In those clinical studies involving healthy children who have been followed long-term post single-dose vaccination, detectable varicella antibodies (gpELISA ≥0.6 units) were present in 99.1% (3 092/3 120) at 1 year, 99.4% (1 382/1 391) at 2 years, 98.7% (1 032/1 046) at 3 years, 99.3% (997/1 004) at 4 years, 99.2% (727/733) at 5 years, and 100% (432/432) at 6 years post-vaccination.
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 firstyear 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).
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 post- vaccination.
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 ONVARA (Refrigerated) may not result in protection of all healthy, susceptiblechildren, adolescents, and adults.
In combined clinical studies involving 1 107 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 post-vaccination 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 (refer to section 4.5).
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 a clinical study involving 306 children 12 to 18 months of age, 151 received an investigational varicella-containing 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 OMZYTA concomitantly with a booster dose of PedvaxHIB followed by ONVARA 6 weeks later. At six weeks post-vaccination, seroconversion rates for measles, mumps, rubella, and VZV, and GMTs for PedvaxHIB were comparable between the two groups. 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 822 children 12 to 15 months of age, 410 received Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) combined vaccine, OMZYTA, and ONVARA concomitantly at separate injection sites, and 412 received Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) combined vaccine followed by OMZYTA and ONVARA given concomitantly at separate injection sites, 6 weeks later. At 6 weeks post-vaccination, 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, OMZYTA, and ONVARA were similar to those of the subjects who received COMVAX followed 6 weeks later by OMZYTA and ONVARA with respect to all antigens administered. There were no clinically important differences in reaction rates when the three vaccines were administered concomitantly versus six weeks apart.
Evaluation of pharmacokinetic properties is not required for vaccines.
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