Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties

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*

ZOSTAVAX                                      Placebo                          Vaccine efficacy
Number      Number       Incidence        Number         Number       Incidence          (95 % CI) of          of          rate of           of             of          rate of subjects     zoster      zoster per       subjects        zoster      zoster per cases         1,000                          cases         1,000 person                                       person years                                        years
11,211         30            2.0           11,228             99          6.6              70 % (54 %, 81 %)
*The analysis was performed on the intent-to-treat (ITT) population that included all subjects randomized 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*

Age                      ZOSTAVAX                                          Placebo                          Vaccine group†                                                                                                      efficacy Number         Number         Incidence       Number         Number         Incidence         (95 % CI) of          of zoster        rate of          of          of zoster        rate of subjects         cases        zoster per      subjects         cases        zoster per 1,000                                         1,000 person                                        person years                                         years
≥ 60          19,254           315             5.4          19,247           642            11.1          51 % (44 %, 58 %)
60-69         10,370           122             3.9          10,356           334            10.8          64 % (56 %, 71 %)
≥ 70           8,884           193             7.2           8,891           308            11.5          38 % (25 %, 48 %)
70-79          7,621           156             6.7           7,559           261            11.4          41 % (28 %, 52 %)
* 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 zoster within the first 30 days post vaccination
† Age strata at randomization 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*

Age                      ZOSTAVAX                                           Placebo                       Vaccine efficacy group‡                                                                                                       (95 % CI) Number of        Number         Incidence        Number of        Number        Incidence subjects        of PHN        rate of PHN        subjects        of PHN          rate of cases         per 1,000                          cases         PHN per person years                                        1,000 person years
≥ 60          19,254            27              0.5            19,247           80             1.4               67 %§ (48 %, 79 %)
60-69         10,370            8               0.3            10,356           23             0.7                66 % (20 %, 87 %)
≥ 70           8,884            19              0.7            8,891            57             2.1                67 % (43 %, 81 %)
70-79          7,621            12              0.5            7,559            45             2.0                74 % 
(49 %, 87 %)
† 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 randomized in the study who were followed for at least 30 days postvaccination and did not develop an evaluable case of zoster 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.

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

Age                     ZOSTAVAX                                           Placebo                         Vaccine efficacy group‡                                                                                                         (95% CI) Number         Number of         Mean        Number of       Number of          Mean of            zoster           BOI         subjects         zoster            BOI subjects       confirmed         score                       confirmed          score cases                                         cases
≥ 60           19,254           315             2.21         19,247           642              5.68        61 % (51 %, 69 %) 60-69          10,370           122             1.5          10,356           334              4.33        66 % (52 %, 76 %) ≥ 70            8,884           193             3.47          8,891           308              7.78        55 % (40 %, 67 %) 70-79           7,621           156             3.04          7,559           261              7.43        59 % (43 %, 71 %) † 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 randomization 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 postvaccination 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). The median follow-up was ~ 1.2 years (range is one day to 2.2 years) in STPS. During the course of the STPS, placebo recipients were offered ZOSTAVAX, at which time they were considered to have completed the STPS.

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.

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 postvaccination compared with placebo.

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

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 postvaccination 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 postvaccination, 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 postvaccination, 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 postvaccination 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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Not applicable.