Pharmacology: Pharmacodynamics: Herpes Zoster:
Herpes zoster (HZ), also known as shingles or simply "zoster", is a manifestation of the reactivation of VZV, which, as a primary infection, produces chickenpox (varicella). Following initial infection, the virus remains latent in the dorsal root or cranial sensory ganglia until it reactivates, producing zoster. Zoster is usually characterized by a unilateral, painful, vesicular cutaneous eruption with a dermatomal distribution.
Although the blistering rash is the most distinctive feature of zoster, the most frequently debilitating symptom is pain, which may occur during the prodrome, the acute eruptive phase and the postherpetic phase of the infection. During the acute eruptive phase, local pain has been reported to occur in up to 90% of immunocompetent individuals.
Anyone who has been infected with VZV, including those without a clinical history of varicella, is at risk for developing zoster, which is considered to be due to waning immunity to VZV. Nearly all adults (approximately 98%) in U.S. are susceptible to zoster, where an estimated 1 million cases occur annually. This number is expected to rise as the mean age group of the population increases. The incidence and severity of zoster, as well as the frequency and severity of its complications, increase markedly with age, with 2
of the cases occurring in individuals >50 years. In recent studies, the lifetime risk of zoster has been estimated to be as high as 30% in the general population. It is estimated that by 85 years, 50% of individuals will have experienced an episode of zoster.
Seventy (70) to 80% of hospitalizations for zoster occur among immunocompetent individuals. In U.S., approximately 50,000-60,000 zoster-associated hospitalizations, including 12,000-19,000 in which the primary diagnosis is zoster, occur each year.
Zoster may be associated with serious complications eg, postherpetic neuralgia (PHN), scarring, bacterial superinfection, motor neuron palsies, pneumonia, encephalitis, Ramsay Hunt syndrome, visual impairment, hearing loss and death.
Zoster-associated pain and discomfort can be prolonged and disabling and can diminish quality of life and functional capacity to a degree comparable to such debilitating diseases as congestive heart failure, myocardial infarction, type II diabetes mellitus, and major depression.
Postherpetic Neuralgia (PHN):
PHN constitutes the most common serious complication and cause of zoster-associated morbidity in the immunocompetent host. Published literature estimates the prevalence of PHN in U.S. population to be 500,000-1,000,000 cases. The frequency and severity of PHN increase with age, and may complicate 25-50% of zoster cases among patients >50 years. PHN has been described as tender, burning, throbbing, stabbing, shooting and/or sharp pain that can persist for months or even years and can also lead to emotional distress. Allodynia (pain from an innocuous stimulus) is present in at least 90% of patients with PHN and is typically described as one of the most distressing and debilitating types of pain. Several definitions of PHN are widely used in the medical community, including pain persisting >90 days after the onset of the rash.
Mechanism of Action:
The risk of developing zoster 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 Clinical Studies: Immunogenicity of Zostavax as follows.)
Clinical Studies: Evaluation of Clinical Efficacy Afforded by Zostavax:
Zostavax Efficacy and Safety Trial (ZEST) in Subject 50-59 Years: In the ZEST, a placebo-controlled, double-blind clinical trial in which 22,439 subjects 50-59 years were randomized to receive a single-dose of either Zostavax (n=11,211) or placebo (n=11,228), and were followed for the development of zoster for a median of 1.3 years (range 0-2 years). All suspected zoster cases were adjudicated by a clinical evaluation committee. 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 with placebo [30 cases (2/1000 person-years) vs 99 cases (6.6/1000 person-years), respectively; p<0.001)]. The protective efficacy of Zostavax against zoster was 69.8% [95% CI: (54.1-80.6%)].
Evaluation of Clinical Efficacy Afforded by Zostavax:
In the shingles prevention study (SPS) a placebo-controlled, double-blind clinical trial of Zostavax, 38,546 subjects ≥60 years were randomized to receive a single dose of either Zostavax (n=19,270) or placebo (n=19,276) and were followed for the development of zoster for an average of 3.1 years (1 day-4.9 years). Randomization was stratified by age, 60-69 and ≥70 years. All suspected zoster cases were adjudicated by a clinical evaluation committee. Final determination of zoster cases was made by PCR, local culture or the decision of the clinical evaluation committee, in that order. In both vaccination groups (Zostavax and placebo), subjects who developed zoster were given famciclovir and as necessary, pain medications. Severity of pain was evaluated according to a "worst pain" score on a 0-10 scale, using the zoster brief pain inventory (ZBPI), a validated questionnaire. A score of ≥3 was considered clinically significant because it correlates with significant interference with activities of daily living (ADL).
Zostavax significantly reduced the risk of developing zoster and PHN compared with placebo. In addition, Zostavax significantly reduced acute and chronic zoster-associated pain as measured by the HZ pain burden of illness (BOI) score. (See Table 1).
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Zostavax significantly decreased the incidence of zoster compared with placebo [315 (5.4/1000 person-years) vs 642 cases (11.1/1000 person-years), respectively; p<0.001]. The protective efficacy of Zostavax against zoster was 51% [95% CI: (44-58%)]. Zostavax reduced the incidence of zoster by 64% [95% CI: (56-71%)] in individuals 60-69 years and by 38% [95% CI: (25-48%)] in individuals ≥70 years. The cumulative incidence of zoster over time among vaccine recipients was also significantly reduced (p<0.001). (See Figure 1).
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Zostavax decreased the incidence of PHN compared with placebo [27 cases (0.5/1000 person-years) vs 80 cases (1.4/1000 person-years), respectively; p<0.001]. In this trial, the definition of PHN was clinically significant zoster-associated pain persisting or appearing at least 90 days after the onset of rash. The protective efficacy of Zostavax against PHN was 67% [95% CI: (48-79%)] and the reduction was similar for the 2 age groups (60-69 and ≥70 years). In addition, the efficacy of Zostavax did not change appreciably when PHN was defined using alternative cutoff times (30, 60, 120 or 182 days) for duration of pain. Zostavax significantly reduced the cumulative incidence of PHN over time compared with placebo (p<0.001). (See Figure 2).
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Zostavax reduced the HZ pain BOI score by approximately 61% [95% CI: (51-69%)], compared with placebo. Zostavax reduced the HZ pain BOI score to a similar extent for the 2 age groups (60-69 and ≥70 years). The HZ 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.
Zostavax reduced the incidence of zoster with severe and long-lasting zoster-associated pain (severity-by-duration score >600) by 73% [95% CI: (46-87%)] compared with placebo. Eleven (11) subjects vaccinated with Zostavax had severity-by-duration scores >600 compared with 40 subjects who received placebo. (See Figure 3).
Among vaccinated individuals who developed zoster, Zostavax significantly reduced zoster-associated pain compared with placebo. Over the 6-month follow-up period, there was a 22% reduction in the severity-by-duration score (average scores of 141 for Zostavax and 181 for placebo, p=0.008).
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Among vaccinated individuals who developed PHN, Zostavax significantly reduced PHN-associated 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).
To evaluate the impact of Zostavax on ADL interference associated with zoster, a combined score was calculated for each subject based on interference with general activity, mood, walking ability, normal work, relations with others, sleep and enjoyment of life. Each item was measured on a 0-10 scale (0 being no interference and 10 being maximum interference). Compared to placebo, Zostavax led to a favorable, but not statistically significant, reduction (8%) in the risk of having substantial ADL interference (defined as having a combined ADL interference score ≥2 for ≥7 days) beyond the vaccine efficacy for zoster. Among vaccinated individuals who developed zoster, Zostavax significantly reduced ADL interference compared with placebo. Over the 6-month follow-up period, there was a 31% reduction in the severity-by-duration score for combined ADL interference (average scores of 57 for Zostavax and 83 for placebo; p=0.002).
The use of antiviral drugs within 72 hrs of zoster rash onset did not have a significant effect on the efficacy of Zostavax for zoster pain or PHN incidence. The proportions of subjects using medications with analgesic effects were balanced between vaccination groups. Therefore, the use of these medications was not likely to have contributed to the reduction of zoster pain or PHN incidence.
Fewer complications were reported by subjects who received Zostavax compared with subjects who received placebo. The number of subjects with specific complications of zoster that were reported in the SPS at a frequency of ≥1% is shown in Table 2. (See Table 2).
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Visceral complications eg, pneumonitis, hepatitis, and meningoencephalitis were reported by <1% of subjects with zoster (3 cases of pneumonitis and 1 case of hepatitis in the placebo group; 1 case of meningoencephalitis in the vaccine group).
Immunogenicity of Zostavax:
Within ZEST, immune responses to vaccination were evaluated in a random 10% subcohort (n=1136 for Zostavax and n=1133 for placebo) of the subjects enrolled in the ZEST. Zostavax elicited higher VZV-specific immune responses at 6 weeks post-vaccination compared with placebo. Increases in VZV antibody level, measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were demonstrated [2.3-fold difference (95% Cl: 2.2, 2.4), geometric mean titer (GMT) of 664 vs 228 gpELISA units/mL, p<0.001].
Within the SPS, immune responses to vaccination were evaluated in a subset of the enrolled subjects (N=1395). Zostavax elicited higher VZV-specific immune responses at 6 weeks post-vaccination compared with placebo. Increases in both VZV antibody level, measured by gpELISA [1.7-fold difference, geometric mean titer (GMT) of 479 vs 288 gpELISA units/mL, p<0.001], and T-cell activity, measured by VZV interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT) assay [2.2-fold difference, geometric mean count (GMC) of 70 vs 32 spot-forming cells per million peripheral blood mononuclear cells (SFC/106
PBMCs), p<0.001] were demonstrated.
In an integrated analysis of 2 clinical trials evaluating immune response to Zostavax at 4 weeks post-vaccination, responses were generally similar in subjects 50-59 (N=389) compared to subjects ≥60 years (N=731) (GMT of 668 vs 614 gpELISA units/mL, respectively). The geometric mean fold-rise of immune response following vaccination as measured by gpELISA was 2.6-fold [95% CI: (2.4-2.9)] in subjects 50-59 years and 2.3-fold [95% CI: (2.1-2.4)] in subjects ≥60 years.
Immunogenicity following Concomitant Administration:
In a double-blind, controlled clinical trial, 762 adults ≥50 years were randomized to receive a single dose of Zostavax administered either concomitantly (N=382) or nonconcomitantly (N=380) with inactivated influenza vaccine. Subjects enrolled in the concomitant group received Zostavax and influenza vaccine on day 1 and placebo at week 4. Subjects enrolled in the nonconcomitant group received influenza vaccine and placebo on day 1 and Zostavax at week 4. The antibody 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 , were randomized to receive Zostavax and Pneumovax 23 concomitantly (N=237), or Pneumovax 23 alone followed 4 weeks later by Zostavax alone (N=236). At 4 weeks post-vaccination, the VZV antibody levels following concomitant use were significantly lower than the VZV antibody levels following nonconcomitant administration [GMTs of 338 vs 484 gpELISA units/mL, respectively; GMT ratio=0.7 [95% CI: (0.61, 0.8)]. VZV antibody levels 4 weeks post-vaccination were increased 1.9-fold [95% CI: (1.7, 2.1)]; meeting the pre-specified acceptance criterion) in the concomitant group vs 3.1-fold [95% CI: (2.8, 3.5)] in the nonconcomitant group. The GMTs for Pneumovax 23 antigens were comparable between the 2 groups. Concomitant use of Zostavax and Pneumovax 23 demonstrated a safety profile that was generally similar to that of the 2 vaccines administered nonconcomitantly.
Immunogenicity in Subjects With a History of Herpes Zoster (HZ) Prior to Vaccination:
In a double-blind, placebo-controlled, randomized clinical trial, Zostavax was administered to 100 subjects ≥50 years with a history of HZ prior to vaccination to assess immunogenicity of Zostavax. Zostavax induced a significantly higher VZV-specific immune response as measured by gpELISA at 4 weeks post-vaccination, compared with placebo [2.1-fold difference [95% CI: (1.5-2.9), p<0.001], GMT of 812 vs 393 gpELISA units/mL]. VZV antibody responses were generally similar in subjects 50-59 compared to subjects ≥60 years.
Immunogenicity in Subjects on Chronic/Maintenance Systemic Corticosteroids:
In a double-blind, placebo-controlled, randomized clinical trial, Zostavax was administered to 206 subjects ≥60 years who were receiving chronic/maintenance systemic corticosteroid therapy at a daily dose equivalent of 5-20 mg of prednisone for at least 2 weeks prior to enrollment, and >6 weeks following vaccination to assess the immunogenicity and safety profile of Zostavax. Compared with placebo, Zostavax induced a higher VZV-specific gpELISA antibody GMT at 6 weeks post-vaccination (GMT of 531.1 vs. 224.3 gpELISA units/mL, respectively). The geometric mean fold-rise of the VZV antibody response, as measured by gpELISA, from prevaccination to post-vaccination was 2.3 [95% CI: (2-2.7) in the Zostavax group compared to 1.1 (95% CI: 1-1.2) in the placebo group (see Contraindications).
The SPS Short-term Persistence Substudy (STPS):
The STPS was initiated to accrue additional information on the persistence of vaccine efficacy and to preserve a subset of subjects for the long-term persistence substudy (LTPS).The STPS included 7320 subjects previously vaccinated with Zostavax and 6950 subjects previously vaccinated with placebo in the SPS. The mean age at enrollment in STPS was 73.3 years. During the course of STPS, placebo recipients were offered Zostavax, at which time they were considered to have completed the STPS.
The STPS analyses for vaccine efficacy are based on data collected primarily 4-7 years post-vaccination in the SPS. The median follow-up in the STPS was approximately 1.2 years (range is 1 day to 2.2 years). In the STPS, there were 84 evaluable HZ cases in the Zostavax group and 95 evaluable cases in the placebo group. The estimated vaccine efficacy for HZ incidence during the STPS follow-up period was 39.6% (18.2%, 55.5%). The estimated vaccine efficacy for PHN incidence was 60.1% (-9.8%, 86.7%).The estimated vaccine efficacy for HZ BOI was 50.1% (14.1%, 71%).
There were no vaccine-related serious adverse experiences reported in the STPS.
The SPS Long-term Persistence Substudy (LTPS):
Following completion of the STPS, the open-label LTPS evaluated the duration of protection against HZ, PHN and HZ BOI of Zostavax on subjects vaccinated in the SPS. A total of 6687 subjects previously vaccinated with Zostavax in the SPS participated in the LTPS. The mean age at enrollment into LTPS was 74.5 years.
Because placebo subjects were previously offered vaccine during the STPS, a concurrent placebo control group was not available for calculation of vaccine efficacy for the LTPS. Therefore, prior placebo recipients were used as a reference group for calculating vaccine efficacy in the LTPS.
The LTPS analyses for vaccine efficacy are based on data collected primarily from year 7 through 10 following vaccination in the SPS. Median follow up during the LTPS was approximately 3.9 years (range is 1 week to 4.75 years). There were 263 evaluable HZ cases during the LTPS. The estimated vaccine efficacy for HZ incidence during the LTPS follow-up period was 21.1% (10.9%, 30.4%). The estimated vaccine efficacy for PHN incidence was 35.4% (8.8%, 55.8%). The estimated vaccine efficacy for HZ BOI was 37.3% (26.7%, 46.4%).