Vaccine Information: Shingrix (Page 4 of 5)

14.4 Immunological Evaluation to Support Dosing Schedule

A measure of the immune response that confers protection against HZ is unknown. Anti-gE antibody levels were measured by anti-gE enzyme-linked immunosorbent assay (gE ELISA) and were used to support the dosing schedule.

In an open-label clinical study, 238 subjects aged 50 years and older received SHINGRIX on either a 0- and 2-month or 0- and 6-month schedule. Non-inferiority of the 0- and 6-month schedule compared with the 0- and 2-month schedule based on anti-gE ELISA GMCs 1 month after the second dose was demonstrated.

14.5 Efficacy in Immunocompromised Adults Aged 18 Years and Older

The efficacy of SHINGRIX was evaluated in one Phase 3 randomized, placebo-controlled, observer-blind clinical study in immunocompromised adults aged ≥18 years who received an auHSCT 50 to 70 days prior to Dose 1 and who were expected to receive prophylactic antiviral therapy for ≤6 months post-transplant. The efficacy of SHINGRIX was calculated post-hoc in another randomized, placebo-controlled, observer-blind study in subjects with hematologic malignancies who received Dose 1 of SHINGRIX or placebo during or within 6 months of completing immunosuppressive chemotherapy. Each of these studies was conducted in the following regions: North America, Latin America, Europe, Asia, Africa (auHSCT study only), and Australia/New Zealand.

Efficacy in Subjects Aged 18 Years and Older: auHSCT Recipients

In the auHSCT study, subjects were followed for the development of HZ and PHN for a median of 21 months (range: 0 to 49.4 months). Suspected HZ cases were followed prospectively for the development of PHN as in Studies 1 and 2.

The primary efficacy analysis population (mTVC) for the auHSCT study included 1,721 subjects who received 2 doses of either SHINGRIX or placebo and did not develop a confirmed case of HZ within 1 month after the second dose. Confirmed HZ cases were determined by either PCR (83.7%) or by a Clinical Evaluation Committee (16.3%).

Efficacy against Herpes Zoster: Compared with placebo, SHINGRIX significantly reduced the risk of developing HZ in auHSCT recipients aged 18 years and older (Table 8).

Table 8. Efficacy of SHINGRIX on Incidence of Herpes Zoster Compared with Placebo in Immunocompromised Adults Aged ≥18 Years (mTVCa)
auHSCT = Autologous, hematopoietic, stem cell transplant.N = Number of subjects included in each group; n = Number of subjects having at least 1 confirmed HZ episode; HZ = Herpes zoster; CI = Confidence Interval.a mTVC = Modified Total Vaccinated Cohort, defined as subjects who received 2 doses (0 and 1 to 2 months) of either SHINGRIX or placebo and did not develop a confirmed case of HZ within 1 month after the second dose. Follow-up was censored at the time of treatment for relapse.b NCT01610414.c Primary study endpoint was based on confirmed HZ cases in subjects aged ≥18 years.

Clinical Studies

Age Group (Years)

SHINGRIX

Placebo

% Efficacy (95% CI)

N

n

Incidence Rate of HZ per 1,000 Person-Years

N

n

Incidence Rate of HZ per 1,000 Person-Years

auHSCTb

Overall (≥18)c

870

49

30.0

851

135

94.3

68.2

(55.5, 77.6)

18-49

213

9

21.5

212

29

76.0

71.8

(38.7, 88.3)

≥50

657

40

33.0

639

106

100.9

67.3

(52.6, 77.9)

Efficacy in Subjects Aged 18 Years and Older with Hematologic Malignancies

In the study of hematologic malignancies, the mean age was 57 years. The majority of subjects were White (71%), followed by Asian (25%), Black (0.4%), and other racial groups (4%); 5% were of American Hispanic or Latino ethnicity; and 41% were female. Subjects were followed for the development of HZ for a median of 11.1 months (range: 0 to 15.6 months). PHN was not assessed as a study endpoint.

In the hematologic malignancy study, the population for the post hoc efficacy analysis included 515 subjects who received 2 doses of either SHINGRIX or placebo and did not develop a confirmed case of HZ within 1 month after the second dose. Confirmed HZ cases were determined by either PCR (81.3%) or by a Clinical Evaluation Committee (18.7%). The post hoc analysis showed SHINGRIX was 87.2% (95% CI [44.2; 98.6]) effective against development of HZ. The incidence rate of HZ per 1,000 person-years was 8.5 versus 66.2 in the SHINGRIX and placebo groups, respectively.

Additional Efficacy Endpoints Evaluated in the auHSCT Study

Efficacy against Postherpetic Neuralgia: In a descriptive analysis, including all subjects aged ≥18 years in the mTVC, 1 case of PHN was reported in the vaccine group compared with 9 cases reported in the placebo group. Vaccine efficacy against PHN was 89.3% (95% CI: [22.5; 99.8]). The benefit of SHINGRIX in the prevention of PHN can be attributed to the effect of the vaccine on the prevention of HZ.

Herpes Zoster-Associated Pain: Subjects with suspected HZ rated their “worst” HZ-associated pain on a 10-point scale. Among subjects with confirmed HZ, 37 out of 49 subjects (75.5%) receiving SHINGRIX and 120 out of 135 subjects (88.9%) receiving placebo rated their “worst” HZ-associated pain as 3 or greater. In this subset of subjects, the median duration of “worst” HZ associated pain was 14 and 24 days, among SHINGRIX and placebo recipients, respectively.

14.6 Revaccination after Vaccination with ZOSTAVAX (Zoster Vaccine Live)

In an open-label clinical study (NCT02581410), subjects aged 65 years and older, who had been previously vaccinated with ZOSTAVAX more than 5 years prior to study enrollment (n = 215) or who had never been vaccinated with ZOSTAVAX (n = 215), received 1 dose of SHINGRIX at Months 0 and 2. Subjects who had never been vaccinated with ZOSTAVAX were matched to those who had been previously vaccinated with ZOSTAVAX according to the predefined variables of age (65 to 69, 70 to 79, and ≥80 years), sex, race/ethnicity, and medical condition (immune-mediated diseases, diabetes mellitus, depression, pulmonary conditions, or heart conditions). The mean age was 71 years; 51% were female. All subjects were White and were not Hispanic or Latino.

The anti-gE antibody (Ab) concentration measured by ELISA 1 month following 2 doses of SHINGRIX in subjects who had previously been vaccinated with ZOSTAVAX was non-inferior to that of subjects who had never been vaccinated with ZOSTAVAX. The upper limit (UL) of the 95% confidence interval (CI) was 1.17 (success criterion <1.5) for the anti-gE Ab adjusted geometric mean concentration (GMC) ratio between subjects who had never been vaccinated with ZOSTAVAX and subjects who had been previously vaccinated with ZOSTAVAX. There was no evidence for interference in the immune response to SHINGRIX in subjects previously vaccinated with ZOSTAVAX.

14.7 Concomitant Administration with Other Vaccines

Concomitant Administration with Influenza Vaccine

In an open-label clinical study (NCT01954251), subjects aged 50 years and older received 1 dose each of SHINGRIX and quadrivalent influenza vaccine (FLUARIX QUADRIVALENT) at Month 0 and 1 dose of SHINGRIX at Month 2 (n = 413), or 1 dose of FLUARIX QUADRIVALENT at Month 0 and 1 dose of SHINGRIX at Months 2 and 4 (n = 415). The mean age of the population was 63 years; 52% were female. The majority of subjects were White (92%), followed by Asian (6%), and Black (2%); 0.4% were of American Hispanic or Latino ethnicity. There was no evidence for interference in the immune response to any of the antigens contained in SHINGRIX or the coadministered vaccine.

Concomitant Administration with PNEUMOVAX 23 (Pneumococcal Vaccine Polyvalent)

In an open-label clinical study (NCT02045836), subjects aged 50 years and older received 1 dose each of SHINGRIX and PNEUMOVAX 23 at Month 0 and 1 dose of SHINGRIX at Month 2 (n = 432), or 1 dose of PNEUMOVAX 23 at Month 0 and 1 dose of SHINGRIX at Months 2 and 4 (n = 433). The mean age of the population was 63 years; 60% were female. The majority of subjects were White (94%), followed by Black (2%), Asian (2%), and other racial groups (2%); 1% were of American Hispanic or Latino ethnicity.

The immune response to SHINGRIX, based on anti-gE Ab, was measured by ELISA 1 month after administration of the second dose of SHINGRIX. Immune responses to 12 of the 23 pneumococcal serotypes contained in PNEUMOVAX 23 were measured by multiplex opsonophagocytosis assay (MOPA) at 1 month after administration of the single dose of PNEUMOVAX 23. There was no evidence for interference in the immune response to the antigen contained in SHINGRIX or to the 12 evaluated antigens contained in PNEUMOVAX 23 when the two vaccines were administered concomitantly.

Concomitant Administration with PREVNAR 13 (Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein])

In an open-label clinical study (NCT03439657), subjects aged 50 years and older received 1 dose each of SHINGRIX and PREVNAR 13 at Month 0 and 1 dose of SHINGRIX at Month 2 (n = 449), or 1 dose of PREVNAR 13 at Month 0 and 1 dose of SHINGRIX at Months 2 and 4 (n = 463). The mean age of the population was 63 years; 60% were female. The majority of subjects were White (98%), followed by Black (2%); 0.4% were of American Hispanic or Latino ethnicity.

The immune response to SHINGRIX, based on anti-gE Ab, was measured by ELISA 1 month after administration of the second dose of SHINGRIX. Immune responses to the pneumococcal serotypes contained in PREVNAR 13 were measured by MOPA at 1 month after administration of the single dose of PREVNAR 13. There was no evidence for interference in the immune response to the antigens contained in SHINGRIX or PREVNAR 13 when the two vaccines were administered concomitantly.

Concomitant Administration with BOOSTRIX (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed)

In an open-label clinical study (NCT02052596), subjects aged 50 years and older received 1 dose each of SHINGRIX and BOOSTRIX at Month 0 and 1 dose of SHINGRIX at Month 2 (n = 412; concomitant administration group), or 1 dose of BOOSTRIX at Month 0 and 1 dose of SHINGRIX at Months 2 and 4 (n = 418; sequential administration group). The mean age of the population was 63 years; 54% were female. The majority of subjects were White (87%), followed by Black (11%), and other racial groups; 2% were of American Hispanic or Latino ethnicity.

The immune response to SHINGRIX, based on anti-gE Ab, was measured by ELISA 1 month after administration of the second dose of SHINGRIX. The immune response to BOOSTRIX (anti-D, anti-T, and antibodies to pertussis antigens) was measured 1 month after administration of the single dose of BOOSTRIX. Concomitant administration showed no evidence for interference in the immune response to the antigen contained in SHINGRIX or the antigens contained in BOOSTRIX, with the exception of one of the pertussis antigens (pertactin), which did not meet the non-inferiority criterion: the UL of the 95% CI for the adjusted GMC ratio (sequential administration group/concomitant administration group) for anti-pertactin antibody was 1.58 (non-inferiority criterion <1.5). The clinical significance of the reduced immune response to pertactin is unknown.

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