ZOSTAVAX Powder and solvent for suspension for injection Ref.[9861] Active ingredients: Attenuated varicella-zoster virus

Pharmacotherapeutic group: Vaccines, Viral Vaccine
ATC code: J07BK02

Mechanism of action

Anyone who has been infected with VZV, including those without a clinical history of varicella, is at risk for developing zoster. This risk appears to be causally related to a decline in VZV-specific immunity. ZOSTAVAX was shown to boost VZV-specific immunity, which is thought to be the mechanism by which it protects against zoster and its complications (See Immunogenicity).

Clinical Efficacy

The protective clinical efficacy of ZOSTAVAX was demonstrated in two large, randomised, placebo controlled clinical trials where subjects received ZOSTAVAX subcutaneously (see Tables 2 and 3).

ZOSTAVAX Efficacy and Safety Trial (ZEST) in subjects 50 to 59 years of age

The ZEST study was a placebo-controlled, double-blind clinical trial in which 22,439 subjects were randomised to receive a single dose of either ZOSTAVAX or placebo and were followed for the development of zoster for a median of 1.3 years (range 0 to 2 years). Final determination of zoster cases was made by Polymerase Chain Reaction (PCR) [86%], or in the absence of virus detection, as determined by a clinical evaluation committee [14%]. ZOSTAVAX significantly decreased the incidence of zoster compared to placebo (see Table 2).

Table 2. Efficacy of ZOSTAVAX on zoster incidence compared with placebo in the ZEST trial in subjects 50 to 59 years of age*:

* The analysis was performed on the intent-to-treat (ITT) population that included all subjects randomised in the ZEST study.

Shingles Prevention Study (SPS) in Subjects 60 years of age and older

The SPS study was a placebo-controlled, double-blind clinical trial in which 38,546 subjects were randomised to receive a single dose of either ZOSTAVAX or placebo and were followed for the development of zoster for a median of 3.1 years (range 31 days to 4.9 years).

ZOSTAVAX significantly decreased the incidence of zoster compared with placebo (see Table 3).

Table 3. Efficacy of ZOSTAVAX on zoster incidence compared with placebo in the SPS in subjects 60 years of age and older*:

* The analysis was performed on the Modified Intent-To-Treat (MITT) population that included all subjects randomised in the study who were followed for at least 30 days post-vaccination and did not develop an evaluable case of zoster within the first 30 days post vaccination
^† Age strata at randomisation were 60-69 and ≥ 70 years of age

In the SPS, the reduction in zoster was seen in almost all dermatomes. Ophthalmic zoster occurred in 35 subjects vaccinated with ZOSTAVAX vs. 69 subjects who received placebo. Impaired vision occurred in 2 subjects vaccinated with ZOSTAVAX vs. 9 who received placebo.

ZOSTAVAX significantly decreased the incidence of Post-herpetic Neuralgia (PHN) compared with placebo (see Table 4). In subjects who developed zoster, ZOSTAVAX decreased the risk of subsequently developing PHN. In the vaccine group, the risk of developing PHN after zoster was 9% (27/315), while in the placebo group it was 13% (80/642). This effect was more prominent in the group of older subjects (≥70 years of age), where the risk of developing PHN after zoster was reduced to 10% in the vaccine group vs. 19% for the placebo group.

Table 4. Efficacy of ZOSTAVAX on PHN^† incidence compared with placebo in the SPS in subjects 60 years of age and older*:

^† PHN was defined as zoster-associated pain rated as ≥3 (on a 0-10 scale), persisting or appearing more than 90 days after onset of zoster rash using Zoster Brief Pain Inventory (ZBPI).
* The table is based on the Modified Intent-To-Treat (MITT) population that included all subjects randomised in the study who were followed for at least 30 days post-vaccination and did not develop an evaluable case of zoster within the first 30 days post-vaccination.
^‡ Age strata at randomisation were 60-69 and ≥70 years of age.
^§ Age-adjusted estimate based on the age strata (60-69 and ≥70 years of age) at randomisation.

ZOSTAVAX significantly reduced the zoster pain Burden of Illness (BOI) score (see Table 5).

Table 5. Reduction of the zoster-associated pain by the BOI^† score in the SPS in subjects 60 years of age and older:

^† The zoster pain BOI score is a composite score that incorporates the incidence, severity, and duration of acute and chronic zoster-associated pain over a 6 month follow-up period.
^‡ Age strata at randomisation were 60-69 and ≥70 years of age.

Prevention of HZ cases with severe pain in the entire SPS study population

ZOSTAVAX reduced the incidence of zoster with severe and long-lasting pain (severity-by-duration score >600) by 73% (95% CI: [46 to 87%]) compared with placebo (11 vs. 40 cases, respectively).

Reduction of zoster pain severity-by-duration in vaccinated individuals who developed zoster

With regard to the acute pain (pain between 0-30 days) there was no statistically significant difference between the vaccine group and the placebo group.

However, among vaccinated individuals who developed PHN, ZOSTAVAX significantly reduced PHN-associated (chronic) pain compared with placebo. In the period from 90 days after rash onset to the end of follow-up, there was a 57% reduction in the severity-by-duration score (average scores of 347 for ZOSTAVAX and 805 for placebo; p=0.016).

Overall, among vaccinated individuals who developed zoster, ZOSTAVAX significantly reduced overall acute and chronic zoster-associated pain compared with placebo. Over the 6-month (acute and chronic) follow-up period, there was a 22% reduction (p=0.008) in the severity-by-duration score and a 52% (95% CI: [7 to 74%]) reduction (from 6.2% to 3.5%) in the risk of having zoster with severe and long-lasting pain (severity-by-duration score of >600).

Zostavax persistence of protection

The persistence of protection following vaccination has been evaluated through longer-term follow-up in Short-term Persistence Substudy (STPS) and Long-term Persistence Substudy (LTPS) and supports the continued benefit of ZOSTAVAX throughout the follow-up periods studied. The STPS was initiated to accrue additional information on the persistence of vaccine efficacy for subjects who received ZOSTAVAX in SPS.

Persistence of ZOSTAVAX efficacy was studied 4 to 7 years post-vaccination in the STPS, which included 7,320 subjects previously vaccinated with ZOSTAVAX and 6,950 subjects previously vaccinated with placebo in the SPS (mean age at enrollment was 73.3 years); and 7 to 10 years postvaccination in the Long-term Persistence Substudy (LTPS), which included 6,867 subjects previously vaccinated with ZOSTAVAX (mean age at enrollment into the LTPS was 74.5 years). The median follow-up was ~1.2 years (range is one day to 2.2 years) and ~3.9 years (range is one week to 4.75 years) in STPS and LTPS, respectively. During the course of the STPS, placebo recipients were offered ZOSTAVAX, at which time they were considered to have completed the STPS. A concurrent placebo control was not available in the LTPS; data from prior placebo recipients were used to estimate vaccine efficacy.

In the STPS, there were 84 evaluable zoster cases [8.4/1,000 person-years] in the ZOSTAVAX group and 95 evaluable cases [14.0/1,000 person-years] in the placebo group. The estimated vaccine efficacy during the STPS follow-up period was 40% (95% CI: [18 to 56%]) for zoster incidence, 60% (95% CI: [-10 to 87%]) for PHN incidence and 50% (95% CI: [14 to 71%]) for zoster BOI.

In the LTPS, there were 263 evaluable zoster cases reported among 261 patients [10.3/1000 person-years]. The estimated vaccine efficacy during the LTPS follow-up period was 21% (95% CI: [11 to 30%]) for zoster incidence, 35% (95% CI: [9 to 56%]) for PHN incidence and 37% (95% CI: [27 to 46%]) for zoster BOI.

Long-term effectiveness study in individuals 50 years of age or older

In a large-scale ongoing US prospective observational cohort study of the long-term effectiveness of ZOSTAVAX, individuals 50 years of age or older at the time of vaccination are being followed for the occurrence of HZ and PHN using validated endpoints.

Out of 1,505,647 study individuals, 507,444 received ZOSTAVAX between 2007 and 2018. A total of 75,135 confirmed HZ cases and 4,954 confirmed PHN cases (>90 days of zoster-associated pain) were observed. The results showed that ZOSTAVAX is effective in reducing HZ and PHN incidence for over 8-10 years in vaccinated individuals as compared to an unvaccinated reference group.

Estimates of vaccine effectiveness (VE) against HZ by age at vaccination and average VE estimates over the first 3, 5, 8 and 10 years postvaccination are shown below (see Table 6).

Table 6. VE^† of ZOSTAVAX against HZ over the study period and on average over 3,5, 8, and 10 years by age at vaccination. 2007 to 2018:

^† VE was estimated for the first episode of herpes zoster during follow-up and was calculated as (1-hazards ratio)*100
^* Cox models adjusted for calendar time, age, sex, race/ethnic group, healthcare resource utilization (flu vaccination, number of weeks with an outpatient visit per year), co-morbid conditions (DxCG score, HCUP risk score), immunocompromise status during follow-up
^‡ VE over study period is the VE calculated over the full duration of the study (2007-2018)
^§ Average VE was calculated as the weighted average of the annual VE estimates over 3, 5, 8 and 10 years, respectively, where the weights are the proportion of the overall time period covered
^¶ Data not available
Abbreviations: VE denotes vaccine effectiveness; CI confidence interval; DxCG diagnostic cost group; HCUP healthcare cost and utilization project

Estimates of VE against PHN by age at vaccination and average VE estimates over the first 3, 5 and 8 years postvaccination are shown below (see Table 7).

Table 7. VE^† of ZOSTAVAX against postherpetic neuralgia (PHN) over the study period and on average over 3 and 5 years, by age at vaccination. 2007 to 2014:

^† VE was estimated for the first episode of herpes zoster during follow-up and was calculated as (1-hazards ratio)*100.
^* Cox models adjusted for calendar time, age, sex, race/ethnic group, healthcare resource utilization (flu vaccination, number of weeks with an outpatient visit per year), co-morbid conditions (DxCG score, HCUP risk score), immunocompromise status during follow-up
^‡ VE over study period is the VE calculated over the full duration of the study (2007-2018)
^§ Average VE was calculated as the weighted average of the annual VE estimates over 3, 5 and 8 years, respectively, where the weights are the proportion of the overall time period covered
^¶ Data not available
Abbreviations: VE denotes vaccine effectiveness; CI confidence interval; DxCG diagnostic cost group; HCUP healthcare cost and utilization project

Immunogenicity of ZOSTAVAX

Shingles Prevention Study (SPS)

Within SPS, immune responses to vaccination were evaluated in a subset of the enrolled subjects (N=1395). ZOSTAVAX elicited significantly higher VZV-specific immune responses at 6 weeks postvaccination compared with placebo.

ZOSTAVAX Efficacy and Safety Trial (ZEST)

Within ZEST, immune responses to vaccination were evaluated in a random 10% subcohort (n=1,136 for ZOSTAVAX and n=1,133 for placebo) of the subjects enrolled in the ZEST. ZOSTAVAX elicited significantly higher VZV-specific immune responses at 6 weeks post-vaccination compared with placebo.

When evaluated at 4 weeks post-vaccination, the immunogenicity of the current refrigerator-stable formulation was shown to be similar to the immunogenicity of the earlier frozen formulation of ZOSTAVAX.

Subjects who received ZOSTAVAX by SC (subcutaneous) or IM (intramuscular) route

In an open-label, randomised, controlled clinical trial, ZOSTAVAX was administered either by SC route or by IM route to 353 subjects 50 years of age or older. Subjects with severe thrombocytopenia or any other coagulation disorder were excluded. The VZV specific immune responses to ZOSTAVAX at Week 4 post-vaccination were comparable whether administered by SC or IM route.

Concomitant administration

In a double-blind, controlled clinical trial, 762 adults 50 years of age and older were randomised to receive a single dose of ZOSTAVAX administered either concomitantly (N=382) or nonconcomitantly (N=380) with inactivated split influenza vaccine. The VZV-specific immune responses to both vaccines at 4 weeks post-vaccination were similar, whether administered concomitantly or nonconcomitantly.

In a double-blind, controlled clinical trial, 473 adults, 60 years of age or older, were randomised to receive a single dose of ZOSTAVAX either concomitantly (N=237), or nonconcomitantly (N=236) with 23-valent pneumococcal polysaccharide vaccine. At four weeks post-vaccination, the VZV-specific immune responses following concomitant use were not similar to the VZV-specific immune responses following nonconcomitant administration. However in a US effectiveness cohort study of 35,025 adults ≥60 years old, no increased risk of herpes zoster was observed in individuals who received ZOSTAVAX and 23-valent pneumococcal polysaccharide vaccine concomitantly (n=16,532) as compared to individuals receiving ZOSTAVAX one month to one year after 23-valent pneumococcal polysaccharide vaccine (n=18,493) in routine practice. The adjusted hazard ratio comparing the incidence rate of HZ in the two groups was 1.04 (95% CI, 0.92, 1.16) over a median follow-up of 4.7 years. The data do not indicate that concomitant administration alters the effectiveness of ZOSTAVAX.

Subjects with a history of herpes zoster (HZ) prior to vaccination

In a double-blind, placebo-controlled, randomised clinical trial, ZOSTAVAX was administered to 100 subjects 50 years of age or older with a history of herpes zoster prior to vaccination to assess immunogenicity and safety (see section 4.8) of ZOSTAVAX. ZOSTAVAX induced a significantly higher VZV-specific immune response at 4 weeks post-vaccination, compared with placebo. VZV-specific immune responses were generally similar in subjects 50 to 59 compared to subjects ≥60 years of age.

Adults receiving additional doses/revaccination

The need for, or timing of, a booster dose with ZOSTAVAX has not yet been determined. In an open-label study, ZOSTAVAX was administered as: (1) a booster dose to 201 zoster history-negative subjects 70 years of age or older who had received a first dose approximately 10 years previously as participants in the SPS, and (2) a first dose to 199 zoster history-negative subjects 70 years of age or older. The VZV-specific immune responses to vaccine 6 weeks post-vaccination was comparable in the booster dose and first dose group.

Subjects on chronic/maintenance systemic corticosteroids

In a double-blind, placebo-controlled, randomised clinical trial, ZOSTAVAX was administered to 206 subjects 60 years of age or older who were receiving chronic/maintenance systemic corticosteroid therapy at a daily dose equivalent of 5 to 20 mg of prednisone for at least 2 weeks prior to enrollment, and 6 weeks or more following vaccination to assess the immunogenicity and safety profile of ZOSTAVAX. Compared with placebo, ZOSTAVAX induced a higher VZV-specific immune response at 6 weeks post-vaccination.

HIV-infected adults with conserved immune function

In a double-blind, placebo-controlled randomised clinical trial, ZOSTAVAX was administered to HIV-infected adults (18 years of age or older; median age 49 years) on appropriate antiretroviral therapy with conserved immune function (CD4+ T cell count ≥200 cells/µL). Although, ZOSTAVAX is indicated as a single dose regimen (see section 4.2), a two-dose regimen was used. 286 subjects received two doses and 9 subjects received only one dose. The VZV-specific immune responses following Doses 1 and 2 were similar (see section 4.3).

Immunocompromised subjects

The vaccine has not been studied in subjects with impaired immunity.

The European Medicines Agency has waived the obligation to submit the results of studies with ZOSTAVAX in all the subsets of paediatric population (see section 4.2 for information on paediatric use).