Sign Out
PHARMACOLOGY: Pharmacodynamics: Mechanism of Action: Shingrix is designed to induce antigen-specific cellular and humoral immune responses in individuals with pre-existing immunity against VZV.
Non-clinical data show that AS01B induces a local and transient activation of the innate immune system through specific molecular pathways. This facilitates the recruitment and activation of antigen presenting cells carrying gE-derived antigens in the draining lymph node, which in turn leads to the generation of gE-specific CD4+ T cells and antibodies. The adjuvant effect of AS01B is the result of interactions between MPL and QS-21 formulated in liposomes.
Pharmacodynamic Effects: 1. Efficacy of Shingrix: Efficacy against Herpes Zoster (HZ) and Post-Herpetic Neuralgia (PHN).
Two phase III, placebo-controlled, observer-blind efficacy studies of Shingrix were conducted in adults ≥ 50 years with 2 doses administered 2 months apart: Zoster-006 (ZOE-50): total vaccinated cohort (TVC) of 15,405 subjects ≥ 50 years who received at least one dose of either Shingrix (N=7,695) or placebo (N=7,710).
Zoster-022 (ZOE-70): TVC of 13,900 subjects ≥ 70 years who received at least one dose of either Shingrix (N=6,950) or placebo (N=6,950).
Two phase III, placebo-controlled, observer-blind studies evaluating Shingrix efficacy were conducted in IC adults ≥ 18 years with 2 doses administered 1-2 months apart: Zoster-002: TVC of 1,846 autologous hematopoietic stem cell transplants (aHSCT) recipients who received at least one dose of either Shingrix (N=922) or placebo (N=924) post-transplant.
Zoster-039: TVC of 562 subjects with hematologic malignancies who received at least one dose of either Shingrix (N=283) or placebo (N=279) during a cancer therapy course or after the full cancer therapy course.
Incidence of HZ and PHN cases as well as vaccine efficacy were evaluated in the modified Total Vaccinated Cohort (mTVC i.e. excluding subjects who did not receive the second dose of vaccine or who had a confirmed diagnosis of HZ within one month after the second dose).
Shingrix significantly decreased the incidence of HZ and PHN compared with placebo in: adults ≥ 50 years (Zoster-006): 6 vs. 210 HZ cases and 0 vs. 18 PHN cases; adults ≥ 70 years (pooled analysis of Zoster-006 and Zoster-022): 25 vs. 284 HZ cases and 4 vs. 36 PHN cases; adults ≥ 18 years with aHSCT (Zoster-002): 49 vs. 135 HZ cases and 1 vs. 9 PHN cases; adults ≥ 18 years with hematologic malignancies (Zoster-039): 2 vs. 14 HZ cases (PHN was not assessed as study endpoint). Vaccine efficacy was calculated post-hoc.
Vaccine efficacy results are presented in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageIn the fourth year after vaccination, the efficacy against HZ was 93.1% (95% CI: 81.2; 98.2) and 87.9% (95% CI: 73.3; 95.4) in subjects ≥ 50 years (Zoster-006) and subjects ≥ 70 years (pooled Zoster-006 and Zoster-022), respectively.
In Zoster-002, during a follow-up period starting 1 month post-dose 2 (i.e. corresponding to approximately 6 months after aHSCT) until 1 year after aHSCT, when the risk for HZ is the highest, the efficacy against HZ was 76.2% (95% CI: 61.1; 86.0).
Efficacy against other HZ-related complications: The evaluated HZ-related complications (other than PHN) were: HZ vasculitis, disseminated disease, ophthalmic disease, neurologic disease including stroke, and visceral disease.
In the pooled analysis of Zoster-006 and Zoster-022, Shingrix significantly reduced HZ-related complications by 93.7% (95% CI: 59.5; 99.9) and 91.6% (95% CI: 43.3; 99.8) in subjects ≥ 50 years (1 vs. 16 cases) and subjects ≥ 70 years (1 vs. 12 cases), respectively.
In Zoster-002, Shingrix significantly reduced HZ-related complications by 77.8% (95% CI: 19.0; 96.0) in aHSCT recipients ≥ 18 years (3 vs 13 cases).
In addition, in Zoster-002, Shingrix significantly reduced HZ-related hospitalisations by 84.7% (95% CI: 32.1; 96.6) (2 vs. 13 cases).
Effect of Shingrix on HZ-associated pain: In Zoster-022, Shingrix significantly reduced the use and the duration of HZ-associated pain medication by 39.6% (95% CI: 10.7; 64.8) and 49.3% (95% CI: 2.9; 73.5), respectively, in subjects ≥ 70 years with at least one confirmed HZ episode. The median duration of pain medication use was 30.0 and 38.0 days in the Shingrix and placebo group, respectively.
Overall there was a general trend towards less severe HZ-associated pain in subjects vaccinated with Shingrix compared to placebo.
In Zoster-002, Shingrix significantly reduced the duration of severe 'worst' HZ-associated pain by 38.5% (95% CI: 11.0; 57.6) in aHSCT recipients ≥ 18 years with at least one confirmed HZ episode.
2. Immunogenicity of Shingrix: An immunological correlate of protection has not been established; therefore the level of immune response that provides protection against HZ is unknown.
In adults ≥ 50 years, the immune responses to Shingrix were evaluated in a subset of subjects from the phase III efficacy studies Zoster-006 [humoral immunity and cell-mediated immunity (CMI)] and Zoster-022 (humoral immunity). The gE-specific immune responses (humoral and CMI) elicited by Shingrix at 1 month post-dose 2 are presented in Tables 2 and 3, respectively. (See Table 2.)
Click on icon to see table/diagram/imageAt 3 years post-dose 2, the median fold increase over baseline was 9.3 (Q1: 4.9; Q3: 19.5) in adults ≥ 50 years (Zoster-006) and 7.2 (Q1: 3.5; Q3: 14.5) in adults ≥ 70 years (pooled Zoster-006 and Zoster-022). (See Table 3.)
Click on icon to see table/diagram/imageAt 3 years post-dose 2, in Zoster-006, the median fold increase over baseline was 7.9 (Q1: 2.7; Q3: 31.6) in adults ≥ 50 years and 7.3 (Q1: 1.7; Q3: 31.6) in adults ≥ 70 years.
Data from a phase II, open-label, single group, follow-up clinical study in adults ≥ 60 years (Zoster-024) indicate that the vaccine-induced immune response (humoral and CMI) persists up to Month 72 (approximately 6 years post-dose 1 i.e. 70 months post-dose 2), following a 0, 2-month schedule (N= 119).
The median anti-gE antibody concentration was greater than 7-fold above the baseline pre-vaccination median concentration. The median frequency of gE-specific CD4[2+] T cells was greater than 3.7-fold above baseline pre-vaccination median frequency.
In IC adults ≥ 18 years, the humoral and CMI responses to Shingrix were evaluated in: one phase I/II study: Zoster-015 (HIV infected subjects); one phase II/III study: Zoster-028 (patients with solid tumors undergoing chemotherapy); three phase III studies: Zoster-002 (aHSCT recipients vaccinated post-transplant), Zoster-039 (patients with hematologic malignancies vaccinated during a cancer therapy course or after the full cancer therapy course) and Zoster-041 (renal transplant recipients on chronic immunosuppressive treatment at the time of vaccination).
The gE-specific immune responses (humoral and CMI) elicited by Shingrix at 1 month post-dose 2 in all IC populations studied are presented in Tables 4 and 5, respectively. (See Tables 4 and 5).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageAt 1 year post-dose 2, the median fold increase over baseline ranged from 2.7 to 6.5 in terms of anti-gE antibody concentration and from 2.0 to 43.6 in terms of gE-specific CD4[2+] T-cell frequencies (studies Zoster-002, Zoster-028, Zoster-039 and Zoster-041).
At 2 years post-dose 2, in Zoster-002, the median fold increase over baseline was 1.3 in terms of anti-gE antibody concentration and 50.9 in terms of gE-specific CD4[2+] T-cell frequencies.
Immunogenicity following concomitant vaccination: In four phase III, controlled, open-label clinical studies, adults ≥ 50 years of age were randomized to receive 2 doses of Shingrix 2 months apart administered either concomitantly at the first dose or non-concomitantly with unadjuvanted seasonal influenza vaccine (N=828; Zoster-004), PPV23 vaccine (N=865; Zoster-035), PCV13 vaccine (N=912; Zoster-059) or dTpa vaccine formulated with 0.3 milligrams Al3+ (N=830; Zoster-042). The vaccine response rate (in terms of anti-gE antibodies) was 95.8% (95% CI: 93.3; 97.6), 98.3% (95% CI: 96.4; 99.3), 99.1% (95% CI: 97.6; 99.7) and 97.8% (95% CI: 95.8; 99.1) following co-administration of Shingrix with the influenza, PPV23, PCV13 and dTpa vaccine respectively. The immune responses of the co-administered vaccines were unaffected, with the exception of lower geometric mean concentrations (GMCs) for one of the pertussis antigens (pertactin) when Shingrix is co-administered with the dTpa vaccine. However, these data do not suggest clinically relevant interference.
Immunogenicity in subjects with a history of HZ prior to vaccination: In a phase III, uncontrolled, open-label clinical study (Zoster-033), 96 adults ≥ 50 years of age, with a history of HZ, received 2 doses of Shingrix 2 months apart. The vaccine response rate (anti-gE antibodies) at 1 month post-vaccination was 90.2% (95% CI: 81.7; 95.7).
Immunogenicity in subjects receiving 2 doses of Shingrix 6 months apart: In a phase III, open-label clinical study (Zoster-026) where 238 subjects ≥ 50 years of age were equally randomised to receive 2 doses of Shingrix 2 or 6 months apart, the vaccine response rate (anti-gE antibodies) at 1 month post-vaccination following the 0, 6-month schedule was 96.5% (95% CI: 90.4; 99.2).
The humoral immune response (anti-gE antibodies concentration) following the 0, 6-month schedule was not inferior to the humoral immune response following the 0, 2-month schedule, as the 97.5% CI upper limit of the antibodies concentration ratio was below 1.50 [1.16 (97.5% CI: 0.98; 1.39)].
Immunogenicity in individuals previously vaccinated with live attenuated herpes zoster (HZ) vaccine: In a phase III, open-label, multicentre clinical study (Zoster-048), 430 adults ≥ 65 years of age with or without a previous history of vaccination with live attenuated HZ vaccine ≥ 5 years earlier were group-matched at a 1:1 ratio to receive 2 doses of Shingrix 2 months apart. The immune response to Shingrix was unaffected by prior vaccination with live attenuated HZ vaccine.
Pharmacokinetics: Evaluation of pharmacokinetic properties is not required for vaccines.
Clinical studies: See Pharmacodynamics as previously mentioned.
Toxicology: Preclinical Safety Data: Reproductive Toxicology: Administration of VZV gE AS01B to female rats did not indicate any harmful effects with respect to fertility, pregnancy, embryo-foetal development, parturition or postnatal development.
Treatment of male rats did not affect mating performance, fertility or early embryonic development.
Animal toxicology and/or pharmacology: Non-clinical data reveal no special hazard for humans based on conventional studies of acute and repeated dose toxicity, local tolerance and cardiovascular/respiratory safety pharmacology.
