ADULT VACCINATION in 2010 American Geriatrics Society 2010 Annual Meeting Zoster Vaccine: Current Status and Future Prospects Michael N. Oxman, M.D. Professor of Medicine and Pathology University of California, San Diego Study Chairman, VA Cooperative Study #403: “The Shingles Prevention Study” DISCLOSURE: Michael N. Oxman, MD • No Conflict of Interest • VA Cooperative Study #403: “The Shingles Prevention Study” and its Substudies, of which Dr. Oxman is National Chairman, has been supported, in part, by grants from Merck and Company, Inc. to the VA Cooperative Studies Program, the VA San Diego Medical Research Foundation, and the VA Connecticut Research and Education Foundation • Dr. Oxman will discuss off-label uses of zoster vaccine and clearly indicate that these are off- label uses We Now Have An Effective Vaccine Against Herpes Zoster • The Same Live Attenuated Dr. Michiaki Takahashi Oka/Merck Strain of VZV Used in the Varicella Vaccine Currently Licensed in the US to Prevent Chickenpox • The Minimum Potency of the Zoster Vaccine was at least 14 Times Greater than that of Varicella Vaccine [Median = 24,600 PFU (19K-60k)] VA Cooperative Study #403: The Shingles Prevention Study Demonstrated the Efficacy of Zoster Vaccine Vaccine Efficacy for the Herpes Zoster BOI Efficacy 61.1% 65.5% 55.4% (95% CI) (51.1- 69.1) (51.5 - 75.5) (39.9 - 66.9) 8 7.78 7 6 5 5.68 4 4.33 3 3.47 2 2.21 Burden of Illness Score Illness of Burden 1 1.50 0 All Subjects Age 60–69 ≥70 n 19,247 19,254 10,356 10,370 8891 8884 Placebo Vaccine Success required a VEBOI point estimate of ≥ 47% and a lower bound of the 95 percent confidence interval >25% Zoster vaccine reduced HZ Pain Interference with ADL by ~66% (Schmader et al.), providing further evidence that the HZ BOI is a valid measure of the total adverse impact of HZ on a population of older persons ZOSTER VACCINE EFFICACY FOR HZ BOI AND INTERFERENCE ENDPOINTS HZ Burden of Illness (BOI) Score ZBPI - ADL Interference AUC ZIQ - ADL Inteference AUC 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% Relative Vaccine Efficacy (1-Vaccine/Placebo) Vaccine Efficacy for the Incidence of PHN Efficacy 66.5% 65.7% 66.8% (95% CI) (47.5 - 79.2) (20.4 - 86.7) (43.3 - 81.3) 2.5 2.0 2.13 1.5 1.38 1.0 Incidence of of PHN Incidence 0.74 0.71 (per 1000 person years) person 1000 (per 0.5 0.46 0.26 0 All Subjects Age 60–69 ≥70 n 19,247 19,254 10,356 10,370 8891 8884 Placebo Vaccine Success required a VEPHN point estimate of ≥ 62% and a lower bound of the 95 percent confidence interval >25% Vaccine Efficacy for the Incidence of Herpes Zoster Efficacy 51.3% 63.9% 37.6% (95% CI) (44.2 - 57.6) ((55.5 - 70.9)) (25.0 - 48.1) 14 12 11.5 10 11.1 10.7 8 7.2 6 5.4 4 3.9 (per 1000 person years) person 1000 (per Incidence of of zoster herpes Incidence 2 0 All Subjects Age 60–69 ≥70 n 19,247 19,254 10,356 10,370 8891 8884 Placebo Vaccine Oxman MN et al. N Engl J Med. 2005;352:2271-2284 Summary • Zoster vaccine maintains its efficacy regardless of the age of the subject – The effect in “younger” subjects is mediated mostly by preventing HZ – The effect in “older” subjects is mediated mostly by attenuating HZ Zoster vaccine was shown to be safe and well tolerated (Oxman MN et al. N Engl J Med 2005; 352:2271-2284; Simberkoff et al. Annals Internal Medicine 2010; 152: 545-552.) Safety: Mortality and SAE from Day of Vaccination to End of Study Risk Zoster Events Among Placebo Difference Vaccine All Subjects n (%) (ZV minus P) n (%) Mortality: Whole Cohort 793 (4.1%) 795 (4.1%) 0.01 (-1.2, 1.2) Age 60-69 years 218 (2.1%) 246 (2.4%) -0.80 (-2.0, 0.4) Age ≥70 years 575 (6.5%) 549 (6.2%) 0.95 (-1.2, 3.1) Possibly-related 2 (<0.1%) 3 (<0.1%) NC SAE Hospitalization† 1137 (34.0%) 1115 (34.1%) 0.1 (-8.8, 9.0) HZ-related 5 (0.2%) 6 (0.2%) -0.1 (-0.7, 0.5) † in AE Substudy Oxman M et al. N Engl J Med. 2005; 352:2271-2284; Table 4 Safety: SAE and Rashes (Day of Vaccination to Day 42 Post-Vaccination) Subjects with 1 or Zoster Placebo Risk Difference more: Vaccine (95% CI) SAE 255 (1.4%) 254 (1.4%) 0.01% (-0.2%, 0.3%) Varicella-like rash at 20 (0.1%) 7 (0.04%) 0.07% (0.02%, 0.13%)* the injection site Varicella-like rash 18 (0.1%) 14 (0.1%) 0.02% (-0.04%, 0.09%) not at injection site HZ-like rash 17 (0.1%) 36 (0.2%) -0.10% (-0.18%, -0.03%)* Rash unrelated to 595 (3.2%) 620 (3.3%) -0.13 (-0.49%, 0.23%) HZ Evaluable Case of 7 (0.04%) 24 (0.1%) -0.09% (-0.16%, -0.03%)* HZ * p<0.05 Oxman M et al. N Engl J Med. 2005;352:2271-2284; –Table 4 Safety: AE Substudy – Injection Site AE Day of Vaccination to Day 42 Post-Vaccination Subjects with one Zoster Placebo Risk Difference or more event: Vaccine And 95% CI Injection-site AE 1604 (48.3%) 539 (16.6%) 31.7% (28.3%, 32.6%)* Erythema 1188 (35.8%) 227 (7.0%) 28.8% (26.9%, 30.6%)* Pain/Tenderness 1147 (34.5%) 278 (8.5%) 26.0% (24.1%, 27.9%)* Swelling 871 (26.2%) 147 (4.5%) 21.7% (20.1%, 23.4%)* Pruritus 237 (7.1%) 33 (1.0%) 6.1% (5.2%, 7.1%) * Warmth 57 (1.7%) 11 (0.3%) 1.4% (0.9%, 1.9%)* Hematoma 53 (1.6%) 46 (1.4%) 0.2% (-0.4%, 0.8%) Rash 10 (0.3%) 3 (0.1%) 0.2% (0.0%, 0.5%) * p<0.05 Oxman M et al. N Engl J Med. 2005;352:2271-2284; – Table 4 Safety: SAE – AE Substudy vs. Non- AE Substudy (Day of Vaccination to Day 42 Post-Vaccination) Subjects Zoster Placebo Risk Difference with one Vaccine and 95%CI or more n (%) n (%) SAE Whole Cohort 255 (1.37%) 254 (1.36%) 0.01% (-0.23%, 0.25%) AE Substudy 64 (1.92%) 41 (1.26%) 0.66% (0.05%, 1.28%)* Not in AE 191 (1.25%) 213 (1.38%) -0.13% (-0.39%, 0.12%) Substudy * P<0.05 Oxman M et al. N Engl J Med. 2005;352:2271-2284 Time to First Serious Adverse Event (SAE) from Day 0 Through Day 42 for the Entire Study Population The cumulative rates of SAE are shown for the time to the first SAE within Days 0-42 post-inoculation among all persons enrolled in the study. There is no significant treatment difference within age strata: Ages 60-69, p-value for log rank is 0.41, Ages 70 and older, p-value for log rank is 0.56. Overall treatment comparison: p-value for log rank is 0.94. Comparison of age strata 60-60 vs. ≥70: p-value for log-rank test is <0.0001. (Simberkoff et al. Annals Internal Medicine 2010; 152: 545-552.) Cumulative Mortality for the Entire Study Population Number at risk: Age 60-69: P 10223 10323 10245 7231 2081 ZV 10281 10331 10239 7223 2034 Age ≥ 70: P 8692 8775 8621 6337 1942 ZV 8713 8815 8646 6415 1948 Cumulative mortality rate is shown for the time to death among all persons enrolled in the study. There is no significant treatment difference within age strata: Ages 60-69, p-value for log rank is 0.20, Ages 70 and older, p-value for log rank is 0.37. Overall treatment comparison: p-value for log rank is 0.95. Comparison of age strata 60-60 vs. ≥70: p-value for log-rank test is <0.0001. (Simberkoff et al. Annals Internal Medicine 2010; 152: 545-552.) Zoster vaccine did not cause or induce shingles During the 30 days post vaccination: • 18 cases of shingles in the Placebo group versus only 6 cases in the Vaccine group • Vaccine virus DNA was not detected in any of 919 PCR-confirmed cases of shingles • All 919 were caused by wild-type VZV (Oxman MN et al. N Engl J Med 2005; 352:2271-2284.) Zoster Vaccine is Recommended for Immunocompetent Persons ≥ 60 Years of Age -------------------------------------------------------------------------------------------------- CDC. Recommended Adult Immunization Schedule – United States, 2010. MMWR 2010; 59(1). Safety and Efficacy of Zoster Vaccine in persons ≥80 years of age Rates of Serious Adverse Events (SAE) by COSTART Body System and Pathophysiologic Diagnostic Category Occurring During Days 0-42 Post-Inoculation Among Zoster Vaccine and Placebo Recipients in the Entire Study Population Zoster Vaccine Placebo (N=19,270) (N=19,276) Risk Difference (%) Vaccine- No. of No. (Percent) No. of No. P-Value SAE of Persons SAE (Percent) of Placebo with ≥1 SAE Persons (95% CI) with ≥1 SAE No. of Persons with 18,671 18,717 Safety Follow-up SAE among All 324 255 (1.37) 320 254 (1.36) 0.01 (-0.23, 0.25) 0.94 Persons By Age: 60 - 69 years§ 135 113 (1.12) 125 101 (1.00) 0.12 (-0.17, 0.40) 0.41 70 years or older§ 189 142 (1.66) 195 153 (1.78) -0.12 (-0.51, 0.27) 0.55 70 - 80 years§§ 150 115 (1.57) 165 132 (1.80) -0.23 (-0.65, 0.19) 0.28 80 years or older§§ 39 27 (2.24) 30 21 (1.64) 0.60 (-0.49, 1.74) 0.28 § A pre-specified age stratum and analysis §§ Not a pre-specified age stratum and not a pre-specified analysis (Simberkoff et al.