1. Zoster Vaccine: A New Vaccine for Preventing Herpes Zoster and Post-herpetic Neuralgia Jane Seward, MBBS, MPH Division Viral Diseases (proposed) National Center Immunization & Respiratory Diseases (proposed) Centers for Disease Control and Prevention 41st National Immunization Conference Kansas City, March 5th, 2007

2. Acknowledgements Centers for Disease Control and PreventionCenters for Disease Control and Prevention 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

3. Outline Herpes zosterHerpes zoster –Clinical manifestations and complications –Epidemiology Zoster vaccineZoster vaccine –Efficacy and safety –ACIP vaccine policy recommendations Vaccine program implementation and surveillanceVaccine program implementation and surveillance

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

6. Herpes Zoster Epidemiology IncidenceIncidence –~ 3-4 per 1,000 person years –May have been increasing before availability of varicella and zoster vaccines 750,000 to 1 million cases in U.S. annually750,000 to 1 million cases in U.S. annually 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.

7. Herpes Zoster Epidemiology Main risk factorsMain risk factors –Age –Cellular immune deficiencies Other risk factorsOther risk factors –Race –Sex –Stress –Trauma

8. 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

9. Complications Common Acute neuralgiaAcute neuralgia Postherpetic neuralgiaPostherpetic neuralgia Ocular complications of herpes zoster ophthalmicusOcular complications of herpes zoster ophthalmicus Bacterial superinfectionBacterial superinfection Uncommon DisseminationDissemination PneumonitisPneumonitis HepatitisHepatitis Encephalitis/meningitisEncephalitis/meningitis Herpetic gangrenosumHerpetic gangrenosum Motor neuropathiesMotor neuropathies MyelitisMyelitis HemiparesisHemiparesis

10. ~ 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.

11. Can be excruciating (e.g., like renal colic, childbirth)Can be excruciating (e.g., like renal colic, childbirth) Described as aching, burning, stabbing, shock-likeDescribed as aching, burning, stabbing, shock-like Continuous or paroxysmalContinuous or paroxysmal Often associated with:Often associated with:  Altered or painful sensitivity to touch (paresthesia, dysesthesia)  Provoked by trivial stimuli like bed sheets or breeze (allodynia)  Exaggerated, prolonged response to pain (hyperesthesia)  Unbearable itching Herpes Zoster Pain

12. 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

13. Risk Factors for Postherpetic Neuralgia 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.

14. 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

15. Acute and Post Herpetic Neuralgia Impact on Quality of Life PhysicalPsychological Chronic fatigueChronic fatigue Anorexia & weight lossAnorexia & weight loss Physical inactivityPhysical inactivity InsomniaInsomnia AnxietyAnxiety Difficulty concentratingDifficulty concentrating Depression, suicidal ideationDepression, suicidal ideation SocialFunctional Fewer social gatheringsFewer social gatherings Change in social roleChange in social role Interferes with activities of daily living: dressing, bathing, eating, travel, cooking, shoppingInterferes with activities of daily living: dressing, bathing, eating, travel, cooking, shopping Schmader KE. Clin Infect Dis2001;32(10):1481-6 Comparable to congestive heart failure, diabetes, and depression Comparable to congestive heart failure, diabetes, and depression

16. 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]

17. 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 Study end pointsStudy end points –Primary: Burden of illness (Sum of HZ severity of illness scores ~ pain level and duration) –Secondary: Post herpetic neuralgia (PHN) and HZ Incidence 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.

18. 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.

19. Results

20. 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%

21. 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

22. 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

23. 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

24. 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

25. 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

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

29. 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

30. 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

31. 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

32. Thank You

33. Duration of Protection?

35. 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

36. 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

37. 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)

38. 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.

39. Photo provided courtesy of Dr. Kenneth Schmader, Duke University and Durham VA Medical Centers