Vaccine Information: ZOSTAVAX (Page 3 of 5)

14.2 Shingles Prevention Study (SPS) in Subjects 60 Years of Age and Older

Efficacy of ZOSTAVAX was evaluated in the Shingles Prevention Study (SPS), a placebo-controlled, double-blind clinical trial in which 38,546 subjects 60 years of age or older were randomized to receive a single dose of either ZOSTAVAX (n=19,270) or placebo (n=19,276). Subjects were followed for the development of zoster for a median of 3.1 years (range 31 days to 4.90 years). The study excluded people who were immunocompromised or using corticosteroids on a regular basis, anyone with a previous history of HZ, and those with conditions that might interfere with study evaluations, including people with cognitive impairment, severe hearing loss, those who were non-ambulatory, and those whose survival was not considered to be at least 5 years. Randomization was stratified by age, 60-69 and ≥70 years of age. Suspected zoster cases were confirmed by Polymerase Chain Reaction (PCR) [93%], viral culture [1%], or in the absence of virus detection, as determined by a Clinical Evaluation Committee [6%]. Individuals in both vaccination groups who developed zoster were given famciclovir, and, as necessary, pain medications. The primary efficacy analysis included all subjects randomized in the study who were followed for at least 30 days postvaccination and did not develop an evaluable case of HZ within the first 30 days postvaccination (Modified Intent-To-Treat [MITT] analysis).

ZOSTAVAX significantly reduced the risk of developing zoster when compared with placebo (Table 5). In the SPS, vaccine efficacy for the prevention of HZ was highest for those subjects 60-69 years of age and declined with increasing age.

Table 5: Efficacy of ZOSTAVAX on HZ Incidence Compared with Placebo in the Shingles Prevention Study *
Age group (yrs.) ZOSTAVAX Placebo

Vaccine Efficacy

(95% CI)

# subjects # HZ cases Incidence rate of HZ per 1000 person-yrs. # subjects # HZ cases Incidence rate of HZ per 1000 person-yrs.
*
The analysis was performed on the Modified Intent-To-Treat (MITT) population that included all subjects randomized in the study who were followed for at least 30 days postvaccination and did not develop an evaluable case of HZ within the first 30 days postvaccination.
Age strata at randomization were 60-69 and ≥70 years of age.
Overall 19254 315 5.4 19247 642 11.1 51% (44%, 58%)
60-69 10370 122 3.9 10356 334 10.8 64% (56%, 71%)
70-79 7621 156 6.7 7559 261 11.4 41% (28%, 52%)
≥80 1263 37 9.9 1332 47 12.2 18% (-29%, 48%)

Forty-five subjects were excluded from the MITT analysis (16 in the group of subjects who received ZOSTAVAX and 29 in the group of subjects who received placebo), including 24 subjects with evaluable HZ cases that occurred in the first 30 days postvaccination (6 evaluable HZ cases in the group of subjects who received ZOSTAVAX and 18 evaluable HZ cases in the group of subjects who received placebo).

Suspected HZ cases were followed prospectively for the development of HZ-related complications. Table 6 compares the rates of PHN defined as HZ-associated pain (rated as 3 or greater on a 10-point scale by the study subject and occurring or persisting at least 90 days) following the onset of rash in evaluable cases of HZ.

Table 6: Postherpetic Neuralgia (PHN)* in the Shingles Prevention Study
Age group (yrs.) ZOSTAVAX Placebo Vaccine efficacy against PHN in subjects who develop HZ postvaccination(95% CI)
# subjects # HZ cases # PHN cases Incidence rate of PHN per 1,000 person-yrs. % HZ cases with PHN # subjects # HZ cases # PHN cases Incidence rate of PHN per 1,000 person-yrs. % HZ cases with PHN
*
PHN was defined as HZ-associated pain rated as ≥3 (on a 0-10 scale), persisting or appearing more than 90 days after onset of HZ rash using Zoster Brief Pain Inventory (ZBPI). {5}
The table is based on the Modified Intent-To-Treat (MITT) population that included all subjects randomized in the study who were followed for at least 30 days postvaccination and did not develop an evaluable case of HZ within the first 30 days postvaccination.
Age strata at randomization were 60-69 and ≥70 years of age.
§
Age-adjusted estimate based on the age strata (60-69 and ≥70 years of age) at randomization.
Overall 19254 315 27 0.5 8.6% 19247 642 80 1.4 12.5% 39%§(7%, 59%)
60-69 10370 122 8 0.3 6.6% 10356 334 23 0.7 6.9% 5% (-107%, 56%)
70-79 7621 156 12 0.5 7.7% 7559 261 45 2.0 17.2% 55%(18%, 76%)
≥80 1263 37 7 1.9 18.9% 1332 47 12 3.1 25.5% 26%(-69%, 68%)

The median duration of clinically significant pain (defined as ≥3 on a 0-10 point scale) among HZ cases in the group of subjects who received ZOSTAVAX as compared to the group of subjects who received placebo was 20 days vs. 22 days based on the confirmed HZ cases.

Overall, the benefit of ZOSTAVAX in the prevention of PHN can be primarily attributed to the effect of the vaccine on the prevention of herpes zoster. Vaccination with ZOSTAVAX in the SPS reduced the incidence of PHN in individuals 70 years of age and older who developed zoster postvaccination. Other prespecified zoster-related complications were reported less frequently in subjects who received ZOSTAVAX compared to subjects who received placebo. Among HZ cases, zoster-related complications were reported at similar rates in both vaccination groups (Table 7).

Table 7: Specific complications * of zoster among HZ cases in the Shingles Prevention Study
Complication ZOSTAVAX(N = 19270) Placebo(N = 19276)
(n = 321) % AmongZoster Cases (n = 659) % AmongZoster Cases
N=number of subjects randomizedn=number of zoster cases, including those cases occurring within 30 days postvaccination, with these data available
*
Complications reported at a frequency of ≥1% in at least one vaccination group among subjects with zoster
Allodynia 135 42.1 310 47.0
Bacterial Superinfection 3 0.9 7 1.1
Dissemination 5 1.6 11 1.7
Impaired Vision 2 0.6 9 1.4
Ophthalmic Zoster 35 10.9 69 10.5
Peripheral Nerve Palsies (motor) 5 1.6 12 1.8
Ptosis 2 0.6 9 1.4
Scarring 24 7.5 57 8.6
Sensory Loss 7 2.2 12 1.8

Visceral complications reported by fewer than 1% of subjects with zoster included 3 cases of pneumonitis and 1 case of hepatitis in the placebo group, and 1 case of meningoencephalitis in the vaccine group.

Immune responses to vaccination were evaluated in a subset of subjects enrolled in the Shingles Prevention Study (N=1,395). VZV antibody levels (Geometric Mean Titers, GMT), as measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) 6 weeks postvaccination, were increased 1.7-fold (95% CI: 1.6 to 1.8) in the group of subjects who received ZOSTAVAX compared to subjects who received placebo; the specific antibody level that correlates with protection from zoster has not been established.

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