1. Zoster: It’s Now a Vaccine Preventable Disease Rafael Harapz, MD, MPH, Jane Seward, MBBS, MPH, Aisha Jumaan, PhD, MPH National Center Immunization & Respiratory Diseases (proposed) Centers for Disease Control and Prevention 41st National Immunization Conference Kansas City, March 7th, 2007

2. Outline Clinical manifestations of zoster Epidemiology of zoster Zoster vaccine study Vaccine Recommendations Program implementation and surveillanceProgram implementation and surveillance

3. Clinical Manifestations of Zoster

4. Herpes Zoster Caused by reactivation of varicella zoster virusCaused by reactivation of varicella zoster virus Photo provided courtesy of Dr. Kenneth Schmader, Duke University and Durham VA Medical Centers

5. Zoster Clinical Presentation esicular rash in dermatomal distributionUnilateral vesicular rash in dermatomal distribution Dermatome: area of skin supplied by sensory nerve fibers coming from one nerve root

6. Classic Zoster Rashes: Thoracic, Lumbar Distribution T1-T2 L3-L4

7. Key symptom is pain Excruciating (e.g., like renal colic, childbirth) Aching, burning, stabbing, shock-like Associated with:   Altered or painful sensitivity to touch   Provoked by trivial stimuli like bed sheets or breeze   Exaggerated, prolonged response to pain   Unbearable itching Pain prior to rash : ~84% Some degree of pain during rash: ~89% Zoster Symptoms

8. Prolonged, sometimes incapacitating, pain after resolution of rash May persist months or even years Prevention and treatment have partial and inconsistent efficacy Negative impact on quality of life Zoster Complications Post Herpetic Neuralgia (PHN)

9. PHN: Impact on Quality of Life Physical Chronic fatigue Anorexia & weight loss Physical inactivity Insomnia Social Limits social activities Schmader KE. Clin Infect Dis2001;32(10):1481-6 Psychological Change in Anxiety Difficulty concentrating Depression Functional Interferes with activities of daily living

10. Herpes Zoster Epidemiology IncidenceIncidence –~ 3-4 per 1,000 person years –May have been increasing before availability of varicella and zoster vaccines Lifetime riskLifetime risk –~ 20% to 30% –50% of individuals living until 85 years of age Gnann J et al. N Engl J Med. 2002; Katz J et al. Clin Infect Dis. 2004; Ragozzino M et al. Medicine 1982.

11. Herpes Zoster Risk Factors Main risk factorsMain risk factors –Age –Cellular immune deficiencies Other risk factorsOther risk factors –Race –Sex –Stress –Trauma

12. Rate of zoster per 1000 per year 01020304050607080+ 11 10 9 8 7 6 5 4 3 2 1 0 Age (years) Herpes Zoster Incidence by Age Hope-Simpson RE. Proc R Soc Med 1965;58:9-20

13. Zoster Incidence, U.S., 2005 * Summary estimate of incidence from Hope-Simpson, Insinga, Olmsted, & Donahue. † Population Division, United Nations. 0 -19 20 - 29 30 - 39 40 - 49 50 - 59 60 - 69 70 - 79 ≥ 80 Age (years) Total Incidence per 1000 per year* 0.9 1.5 2.0 2.5 5.0 7.0 9.5 12.0 75 61 82 114 187 163 152 127 961 Cases per year (1000s)

14. Epidemiology of PHN in U.S. Proportion of zoster patients that develop PHN:   10% of zoster patients will have ≥90 days of pain   18% of zoster patients will have ≥30 days of pain 100 to 200 thousand new PHN cases per year

15. Risk Factors for PHN AgeAge Severity of acute painSeverity of acute pain Severity of acute rashSeverity of acute rash Painful prodromePainful prodrome Female sexFemale sex Jung BF. Neurology. 2004;62:1545-1551.

16. Kost R et al. N Engl J Med. 1996;355:32-42. Percent of patients reporting pain Age (years) 0 100 80 60 40 20 0-1920-2930-3940-4950-5960-69≥80 >1 yr <1 mo 6 - 12 mo 1 - 6 mo Prevalence and Duration of PHN Pain by Age

17. Zoster Vaccine ZOSTAVAX ®, Merck and Co., IncZOSTAVAX ®, Merck and Co., Inc Licensed by FDA in May 2006Licensed by FDA in May 2006 Live, attenuated Oka/Merck VZV vaccineLive, attenuated Oka/Merck VZV vaccine Minimum dose 19,400 PFU at expiration [varicella vaccineMinimum dose 19,400 PFU at expiration [varicella vaccine 1,350 PFU at expiration]

18. Shingles Prevention Study Randomized, double blind placebo-controlled trialRandomized, double blind placebo-controlled trial 38,546 adults ≥ 60 years at 22 study sites38,546 adults ≥ 60 years at 22 study sites Prospective, active follow up median 3.1 yearsProspective, active follow up median 3.1 years 94% cases laboratory confirmed94% cases laboratory confirmed Oxman M et al. N Engl J Med. 2005;352:2271-2284.

19. Shingles Prevention Study Study Enrollees 38,546 (59% male) Zoster vaccine 19,270 Completed study 18,359 (95.3%) 315 HZ cases Placebo 19,276 Completed study 18,357 (95.2%) 642 HZ cases 793 (4.1%) died 57 (0.3%) withdrew 61 (0.3%) lost follow up 792 (4.1%) died 75 (0.4%) withdrew 52 (0.2%) lost follow up Oxman M et al. N Engl J Med. 2005;352:2271-2284.

20. Results

21. The Shingles Prevention Study: Results Vaccine Efficacy for PHN (≥90 days) and HZ 67% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 60 - 6465 - 6970 - 7475 - 79≥80 Age at Randomization (Years) Vaccine Efficacy (%) Incidence of PHNIncidence of HZ ALL 51% 67%

22. The Shingles Prevention Study: Results Vaccine Efficacy against PHN of Varying Duration PHN Defined by Varying Duration (days) Vaccine Efficacy VE PHN (95% CI) 30 59% (47, 69) 60 60% (44, 73) 90 67% (48, 79) 120 69% (45, 83) 180 73% (42, 89)

23. Shingles Prevention Study: Results Adverse Events Appears to be safe: No pattern suggesting a causal link to serious adverse eventsNo pattern suggesting a causal link to serious adverse events No cases of HZ caused by vaccine virusNo cases of HZ caused by vaccine virus Excess of mild reactions in vaccine recipients:Excess of mild reactions in vaccine recipients: Local injection-site reactions*: Zoster Vaccine N=334548%PlaceboN=327117% *Erythema, pain, swelling, pruritis, warmth

24. FDA Licensure: May 2006 Indicated for prevention of herpes zoster in persons ≥60 yearsIndicated for prevention of herpes zoster in persons ≥60 years Not indicated for the treatment of herpes zoster or PHNNot indicated for the treatment of herpes zoster or PHN Contraindications:Contraindications:  History of anaphylaxis to vaccine components  Primary or acquired immunodeficiency states  Immunosuppressive therapy

25. Zoster Vaccine Policy Recommendations Advisory Committee Immunization Practices Recommended for adults 60 years of age and older whether or not they report a prior episode of herpes zosterRecommended for adults 60 years of age and older whether or not they report a prior episode of herpes zoster Persons with chronic medical conditions may be vaccinated unless a contraindication or precaution exists for their conditionPersons with chronic medical conditions may be vaccinated unless a contraindication or precaution exists for their condition Provisional recommendations available at http://www.cdc.gov/nip/recs/provisional_recs/zoster-11-20-06.pdfProvisional recommendations available at http://www.cdc.gov/nip/recs/provisional_recs/zoster-11-20-06.pdf http://www.cdc.gov/nip/recs/provisional_recs/zoster-11-20-06.pdf

26. Monitoring Implementation and Impact of Vaccine Program

27. Post Licensure Surveillance Vaccine Coverage - considering options for usingCoverage - considering options for using –National data sources e.g. NHIS, Medicare –Modifying NIS [NAIS] Safety – challenges with age group and co-existing medical conditionsSafety – challenges with age group and co-existing medical conditions –VAERS –VSD rapid cycle analysis –Laboratory testing and VZV strain identification (nationalVZVlab@cdc.gov) nationalVZVlab@cdc.gov

28. Post Licensure Safety Surveillance Reporting to VAERS through 1/15/07 194 reports, 2 serious194 reports, 2 serious Median age = 65 yearsMedian age = 65 years Median interval from vaccination to symptom onset = 1 dayMedian interval from vaccination to symptom onset = 1 day Injection site reactions and rashes (80%)Injection site reactions and rashes (80%)

29. Post Licensure Surveillance Disease and Vaccine Effectiveness Herpes Zoster +/- PHN National data sources e.g. NHIS, Medicare, MedStatNational data sources e.g. NHIS, Medicare, MedStat Varicella and HZ active surveillance sitesVaricella and HZ active surveillance sites Vaccine effectiveness in preventing HZ, PHN National data sources – MedicareNational data sources – Medicare Active surveillance sites: case control studyActive surveillance sites: case control study

30. Summary Herpes zoster causes considerable morbidity in elderly personsHerpes zoster causes considerable morbidity in elderly persons Herpes zoster and its complications may now be prevented or modified by vaccinationHerpes zoster and its complications may now be prevented or modified by vaccination Persons ≥ 60 years (and their health care providers) should be educated about HZ and offered vaccinePersons ≥ 60 years (and their health care providers) should be educated about HZ and offered vaccine

31. Acknowledgements Food and Drug AdministrationFood and Drug Administration Advisory Committee on Immunization Practices (ACIP)Advisory Committee on Immunization Practices (ACIP) –Herpes Zoster ACIP working group Drs Michael Oxman and Ken SchmaderDrs Michael Oxman and Ken Schmader

32. Thank You

33. Backup Slides

34. Adverse Events after Zostavax ® reported to VAERS through 01/15/07 (N=194) EventNo. % Injection site reaction 4925.3 Herpes zoster-like rash4121.1 Rash (other)3518.0 Pruritus3216.5 Fever15 7.7 Medication error13 6.7 HA13 6.7 Urticaria 9 4.6 Other (myalgia, CVA, ILI, vertigo)13 7.6

36. Vaccine Cost and Re-imbursement Wholesale acquisition price = $152Wholesale acquisition price = $152 Average wholesale price - $190.60Average wholesale price - $190.60 CDC contract price = $107.90CDC contract price = $107.90 Covered under Medicare part DCovered under Medicare part D Will be covered under prevention services by private insurersWill be covered under prevention services by private insurers Merck financial assistance programMerck financial assistance program

37. Unilateral; 1-3 adjacent dermatomes Distribution in order of frequency: – –1) thoracic – –2) lumbar, trigeminal, & cervical – –3) sacral, other cranial dermatomes Zoster Rash

38. Zoster Vaccine: Safety Study No cases of herpes zoster caused by vaccine virus among 919 PCR-confirmed cases testedNo cases of herpes zoster caused by vaccine virus among 919 PCR-confirmed cases tested Vaccine did not induce herpes zosterVaccine did not induce herpes zoster –During the 30 days postvaccination Placebo group → 18 casesPlacebo group → 18 cases Vaccine group → 6 casesVaccine group → 6 cases Oxman M et al. N Engl J Med. 2005;352:2271-2284

39. Zoster Vaccine: Safety Study Adverse event VaccinePlacebo Risk difference (95% CI) Entire study group 19,27019,276 Deaths Deaths4.1%4.1% ≥ 1 serious AE ≥ 1 serious AE1.4%1.4% AE sub study 33451115 Hospitalized Hospitalized34.0%34.1% ≥ 1 serious AE ≥ 1 serious AE1.9%1.3% 0.7 (0.1 – 1.3) ≥ 1 AE ≥ 1 AE58.1%34.4% 23.7 (21.3 – 32.6) Injection site reactions* Injection site reactions*48.3%16.6% 31.7 (28.3 – 32.6) *Erythema, pain, swelling, pruritis, warmth Oxman M et al. N Engl J Med. 2005;352:2271-2284

40. Vaccine Efficacy for the Incidence of PHN in Subjects with Herpes Zoster Efficacy 39% 5.0% 55% 26% (7%, 59%) (-107%, 56%) (18%, 76%) (-69%, 68%) (7%, 59%) (-107%, 56%) (18%, 76%) (-69%, 68%) * * *P <.001.

41. Age (detailed in next slide)   Dominant factor influencing incidence in the population Immunosuppression   Less common but influential due to magnitude of risk, e.g.: – –Following bone marrow transplant: 17-52% – –Patients with hematological malignancies: 5-14% – – HIV: risk increased 12-17 fold, and recurrences common Risk Factors for Zoster

42. The Shingles Prevention Study: Methods Double-blind, placebo-controlled, multicenter trial Collaborators: the VA system, the NIH, and Merck Enrolled 38,546 healthy subjects  60 years old Randomized: zoster vaccine vs. placebo   Attenuated VZV with titer ≥14X higher than varicella vaccine Primary efficacy endpoints:   Incidence of shingles   Burden of illness (BOI: zoster incidence X intensity X duration)   Incidence of PHN Monthly telephone follow-up to find cases and adverse events Median follow up about 3 years

43. Zoster vaccine must be kept at +5°F or colder, until reconstituted for injection - discard if excursions to warmer temperatures occur ACIP emphasizes safety monitoring & reporting of adverse events 7-13 Provisional ACIP Recommendations: October 2006 Of note, zoster vaccine is 1st live vaccine specifically for the elderly; safety monitoring will be challenging because the high rate of background medical events in older persons.

44. Number Needed to Vaccinate (NNV): Zoster Vaccine and Other Adult Vaccines Annual Incidence of Disease* 1.5 to 2.3 ¶ 8.9 † 40 †† 0.5 to 1 †† Vaccine Efficacy 67% 51% ~60% Duration of Protection 10 years 1 year 5 years NNV to Prevent 1 Case ~65 to 100** ~22** ~42 ~335 to 670 ZOSTAVAX  for PHN ≥60 years of age ZOSTAVAX  for HZ ≥60 years of age Influenza Vaccine ≥50 years of age Pneumococcal Vaccine ≥50 years of age Age at Vaccination * Incidence rate per 1000. † Summary of incidence estimates from epidemiological studies. ¶ Incidence using various PHN definitions (Olmsted County). ** Assuming vaccine efficacy from the SPS: against HZ (64% for 60 to 69 years of age, 38% for ≥70 years of age); against PHN (66% for 60 to 69 years of age, 67% for ≥70 years of age). Assuming stable efficacy over 10 years. †† Annual incidence rate in persons ≥65 years of age. Source: Kelly H et al. Vaccine 2004.

45. Evidence that varicella exposure (external boosting) can prevent zoster – –Biologically plausible – –Risk  86% in persons with ≥5 exposures to varicella – –Risk  25-30% in persons living and working with children (surrogate for varicella exposure) – –Risk  in pediatricians – –Risk  in leukemic children following household exposure – –Results of zoster vaccine trial itself: external boosting effective Methodologic flaws in individual items but together these make a strong case varicella exposure can prevent zoster, at least in theory If so, it is possible that reduced varicella circulation due to vaccine program could increase the incidence of zoster Role of Varicella Exposure on Risk of Zoster

46. Zoster Incidence by Year Interval, and Age Group, National Health Interview Survey, 1970-1994* * Jumaan, IDSA, 2003

47. Occasional consequences of rash   Secondary infections   Scarring and changes in pigmentation   Can transmit VZV to susceptible children, causing chickenpox – –Zoster perhaps 1/5 th as contagious as chickenpox Fever & regional adenopathy can occur Primary Manifestations of Zoster: Signs

48. ~ 15% of zoster cases involve the ophthalmic division of the trigeminal nerve Keratitis, conjunctivitis, scleritis, iritis, anterior uveitis, retinitis Without antiviral therapy, 50- 70% of patients with HZO develop ocular complications Can result in chronic ocular complications and reduced vision, blindness Herpes Zoster Ophthalmicus McPherson R. J Am Optom Assoc. 1997;68:527-538.

49. Post Herpetic Neuralgia (PHN) Pain persisting after herpes zoster rash resolvesPain persisting after herpes zoster rash resolves Variable definitions by time since rash onset and pain intensityVariable definitions by time since rash onset and pain intensity Estimates from antiviral trials (placebo recipients)Estimates from antiviral trials (placebo recipients) –30 days68% –60 days60% –90 days55% –180 days40% Cunningham AL, Dworkin RH. BMJ. 2000;321:778-779; Dworkin RH, Portenoy RK. Lancet. 1994;343:1648 Arani RB, et al. Stat Med 2001;20:2429-2439; Desmond RA, et al. J Pain Symptom Manage 2002;23:510-516

50. Vaccine Efficacy for the Incidence of PHN in Subjects with Herpes Zoster Efficacy 39% 5.0% 55% 26% (7%, 59%) (-107%, 56%) (18%, 76%) (-69%, 68%) (7%, 59%) (-107%, 56%) (18%, 76%) (-69%, 68%) * * *P <.001.

51. Vaccine Storage and Handling Lyophilized preparation stored frozen at -15º C (+5ºF) or colderLyophilized preparation stored frozen at -15º C (+5ºF) or colder Cannot be stored in refrigerator for any length of timeCannot be stored in refrigerator for any length of time Reconstituted with diluent providedReconstituted with diluent provided Discard if not administered within 30 minutesDiscard if not administered within 30 minutes