ADULT VACCINATION in 2010 American Geriatrics Society 2010 Annual Meeting : 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 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 Currently Licensed in the US to Prevent • 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) Efficacy (95% CI) Vaccine Placebo

Incidence of PHN PHN of Incidence the for (per 1000 person years) 2.5 0.5 1.0 1.5 2.0 0 n Success required a VE a Success required Vaccine Efficacy Efficacy Vaccine (47.5 19,247 All Subjects 1.38 66.5% - 19,254 79.2) 0.46 of>25% the 95 confidencepercentinterval PHN (20.4 point estimate of estimate point 10,356 65.7% 0.74 Age 60–69 - 86.7) 10,370 0.26 ≥ 62% and a lower bound lower a and 62% ≥ (43.3 8891 2.13 66.8% ≥70 - 81.3) 0.71 8884 Efficacy (95% CI) Placebo Vaccine

Incidence of herpes zoster Incidenceof Herpes Zoster

(per 1000 person years) Vaccine Efficacy for the 12 14 10 2 4 6 8 0 n (44.2 All Subjects 19,247 11.1 51.3% - 19,254 Oxman MN et al. 57.6) 5.4 N Engl J Med. J Engl N ( (55.5 10,356 63.9% 10.7 Age 60–69 - 70.9) 10,370 2005;352:2271 3.9 ) - (25.0 2284 8891 11.5 37.6% ≥70 - 48.1) 8884 7.2 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. Ann Internal Med. 2010; 152: 545-552.) Zoster Vaccine Efficacy for HZ BOI by Age Group

Varicella-Zoster Vaccine Placebo (N = 19276) (N = 19270) Vaccine Efficacy for Age HZ Pain BOI Group Total Total Point Estimate † (Years) Cases Follow-Up Estimated Cases Follow- Estimated (95%) of Persons Time HZ Pain of Persons Up Time HZ Pain HZ (Person- BOI HZ (Person- BOI Years) Years)

60 to 64 54 5216 15693 1.283 153 5198 15384 3.804 0.663 (0.413, 0.806)

65 to 69 68 5154 15630 1.709 181 5158 15569 4.868 0.649 (0.460, 0.772)

70 to 74 89 4545 13830 2.734 158 4560 13814 7.082 0.614 (0.414, 0.746)

75 to 79 67 3076 9329 3.486 103 2999 9105 7.954 0.562 (0.245, 0.746)

80 and 37 1263 3721 6.089 47 1332 3864 9.780 0.377 (-0.194, 0.675) older

Zoster Vaccine Efficacy for the Incidence of PHN by Age Group

Varicella-Zoster Vaccine Placebo (N = 19270) (N = 19276) Vaccine Efficacy Age Total Estimated Total Estimated for PHN Group Cases Follow-Up Incidence Cases Follow-Up Incidence Rate Point Estimate of Subjects Time Rate of PHN of Subjects Time of PHN † (Years) (95% CI) PHN (Person- (Per 1000 PHN (Person- (Per 1000 Years) Person-Years) Years) Person-Years) 0.782 60 to 64 2 5216 15693 0.127 9 5198 15384 0.585 (-0.053, 0.977) 0.573 65 to 69 6 5154 15630 0.384 14 5158 15569 0.899 (-0.183, 0.866) 0.750 70 to 74 6 4545 13830 0.434 24 4560 13814 1.737 (0.373, 0.917) 0.721 75 to 79 6 3076 9329 0.643 21 2999 9105 2.306 (0.286, 0.908)

80 0.394 and 7 1263 3721 1.881 12 1332 3864 3.106 (-0.669, 0.798) older

Relative vs. Absolute Benefit • The Frequency and Severity of HZ and PHN increase with increasing age

• Thus even if vaccine efficacy is reduced in persons ≥80 years of age, the absolute benefit may be as great or greater than in persons 60-69 years of age Relative vs. AbsoluteRelative Benefitvs. Efficacy (95% CI) Vaccine Placebo Frequency and Severity of HZ and PHN increase with with of increase and HZ andPHNFrequency Severity Incidence of PHN (per 1000 person years) 2.5 0.5 1.0 1.5 2.0 0 n Success required a VE a Success required (47.5 19,247 All Subjects 1.38 66.5% - 19,254 79.2) 0.46 of>25% the 95 confidencepercentinterval increasing age increasing PHN (20.4 point estimate of estimate point 10,356 65.7% 0.74 Age 60–69 - 86.7) 10,370 - 0.26 0.48 ≥ 62% and a lower bound lower a and 62% ≥ (43.3 8891 2.13 66.8% ≥70 - 81.3) - 0.71 8884 1.42 - PHN Relative vs. Absolute Benefit

For example, a 33% reduction in the Incidence of PHN (i.e., from 2.13 to 1.42 cases per 1,000 persons per year) in persons ≥70 years of age is greater than a 66% reduction in the Incidence of PHN (i.e., from 0.74 to 0.26 cases per 1,000 persons per year) in persons 60-69 years of age Potential Off-Label Use of Zoster Vaccine 1. Potential use of zoster vaccine in persons <60 years of age 2. Potential use of zoster vaccine in immunocompromised persons (HIV-1 infected; TNFα inhibitors) 3. Concomitant administration of zoster vaccine and pneumococcal vaccine 1. Zoster can be a serious disease in immunocompetent persons <60 years of age Zoster Vaccine is likely to be even more effective in preventing herpes zoster in persons <60 years of age Zoster vaccine is likely to be safe and well tolerated in persons <60, although there is likely to be an increase in the frequency and severity of non-serious injection site reactions 2. Zoster is more frequent and more severe in many groups of immunocompromised patients Many Immunocompromised Patients Would Likely Benefit from Zoster Vaccine

• Patients infected with HIV-1

• Patients receiving immunosuppressive medications for chronic inflammatory diseases

• Patients receiving TNFα inhibitors The potential use of zoster vaccine in immunocompromised persons

SAFETY FACTORS • Natural History of exogenous re-infection (Second Cases of Varicella are rare, even in severely immunocompromised patients) • The Oka strain of VZV is the most attenuated of all live attenuated viral vaccines • The Oka Vaccine is sensitive to acyclovir, famciclovir and valacyclovir 3. Concomitant Use of Zoster Vaccine and Pneumococcal Vaccine A clinical trial comparing antibody responses in ≥60 year-olds given ZOSTAVAX® and PNEUMOVAX® 23 concomitantly versus 4 weeks apart, showed that VZV antibody levels following concomitant administration were significantly lower than those following non- concomitant administration. On the basis of this result, the ZOSTAVAX® Prescribing Information was revised in December 2009 to state that “ZOSTAVAX® and PNEUMOVAX® SHOULD NOT BE GIVEN CONCOMITANTLY because this resulted in reduced immunogenicity of ZOSTAVAX”

ZOSTAVAX FULL PRESCRIBING INFORMATION http/www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM132831.pdf Concomitant Use of Zoster Vaccine and and Pneumococcal Vaccine The Fallacy of Using Antibody to VZV as a Measure of Zoster Vaccine Efficacy Theoretical Basis for the Shingles Prevention Study R Edgar Hope-Simpson - 1965

• The Incidence of Herpes Zoster Increases With Increasing Age

• Because Cell-Mediated Immunity (CMI) to VZV Declines with Advancing Age

• Second Episodes of Herpes Zoster are Uncommon [≠ Herpes Simplex]

• Because an Episode of Herpes Zoster Boosts CMI to VZV, Immunizing against another episode

The nature of herpes zoster: a long-term study and a new hypothesis. Proc Royal Soc Med 1965; 58:9-20 Antibody to VZV is NOT a Proxy for Zoster Vaccine Efficacy

VZV-CMI declines with increasing age

This decline begins in early adulthood & continues with increasing age

VZV antibody does not decline with age

Levin, M., et al. JID 2008: 197 825-835 • In the Shingles Prevention Study, higher levels of cell- mediated immunity to VZV correlated with reduced severity of disease and with a lower incidence of PHN

• Higher levels of antibody to VZV did not

(Weinberg A et al, J Infect Dis 200:1068, 2009) RCF at First Visit vs. HZ Severity of Illness and Development of PHN 4

3

2 RCF Value

1

0 No PHNWeek 1 PHN

Development of PHN

(Weinberg A et al, J Infect Dis 200:1068, 2009)) CMI Substudy: Increased Antibody to VZV Correlated with Increased Herpes Zoster Severity of Illness and Increased PHN

8000

6000

4000

2000 since Rash Onset Rash since gpELISP Titer at Titer Vsist 1 gpELISP 0 0-40 41-85 86-182 183-400 > 400 Not PHN PHN 235 206 208 118 95 766 96

8000

6000

4000

2000 since Rash Onset Rash since gpELISA Titer at Week 3 0 0-40 41-85 86-182 183-400 > 400 Not PHN PHN 206 202 213 118 93 737 95 HZ Severity of Illness Score PHN

Levin, M., et al. JID 2008: 197 825-835 Consequently, it is my personal opinion that Zoster Vaccine and PNEUMOVAX® Should be Administered Concomitantly Unless a Clinically and Physiologically Relevant Measure of Immunity to Herpes Zoster (i.e., an assay of VZV-Specific CMI) Demonstrates an Inferior Response to Zoster Vaccine in Persons Who Receive the Two Vaccines Concomitantly Additional Questions Regarding Zoster Vaccine • the rationale for the ACIP recommendation to administer zoster vaccine to persons with a history of HZ?

• safety and efficacy in persons ≥80 years of age?

• the risk that recipients of zoster vaccine will transmit vaccine virus to susceptible contacts?

• the duration of zoster vaccine efficacy (need for booster dose)?

• The impact of childhood Varicella Vaccination on the incidence and severity of Herpes Zoster in adults?

• Prospects for Improved Zoster Vaccines?