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Kenneth Schmader, MD Director, GRECC ACOS Geriatrics and Extended Care Durham VA Medical Center Durham, NC

Where Do We Stand with the Zoster (Shingles) Vaccine?: Clinical Implications of the CDC’s Advisory Committee on Immunization Practices (ACIP) Recent Recommendations. Kenneth Schmader, MD Director, GRECC ACOS Geriatrics and Extended Care Durham VA Medical Center Durham, NC. Objectives.

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Kenneth Schmader, MD Director, GRECC ACOS Geriatrics and Extended Care Durham VA Medical Center Durham, NC

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  1. Where Do We Stand with the Zoster (Shingles) Vaccine?: Clinical Implications of the CDC’s Advisory Committee on Immunization Practices (ACIP) Recent Recommendations Kenneth Schmader, MD Director, GRECC ACOS Geriatrics and Extended Care Durham VA Medical Center Durham, NC

  2. Objectives • Understand the burden of illness due to herpes zoster • Discuss the benefits and risks of zoster vaccination in older adults • Understand the practice implications of ACIP recommendations • Learn the latest information on immunogenicity and durability of vaccine response CDC MMWR 2008;57(05):1-30

  3. Patient Letter • “Dr. Schmader, I sure hope you can help me with this shingles pain, it is so bad it has changed my whole life. I am unable to do any of the things I used to do. I am willing to start all over if you think you can help me” Pain is the Cardinal Problem in Herpes Zoster Acute and Chronic Pain

  4. Incidence of Herpes Zoster • About1millioncasesintheUSannually • 11.8casesper1000person-yearsinadults60yearsofageandolder GnannJetal.NEnglJMed.2002;347:340-346;ThomasSLetal.LancetInfectDis2004;4:26-33;Oxmanetal.NEJM.2005;352:2271-84;SchmaderKEetal.JInfectDis2008;197:207-15

  5. Electron Micrograph of Varicella Zoster Virus Grose&Padilla. Varicella-Zoster Virus 2001, Arvin & Gershon, eds.

  6. VZV Latency and Reactivation Straus. JAMA. 1989;262:3455-3458.

  7. Age and Incidence of Herpes Zoster 12 10 8 Rate Per Thousand 6 4 2 0 10 20 30 40 50 60 70 80 90 Age Groups Hope-Simpson RE. Proc R Soc Med 1965;58:9-20 Age- specific Incidence of Zoster

  8. >1 yr 100 6 - 12 mo 1 - 6 mo 80 <1 mo 60 Patients reporting pain (%) 40 20 0 0-19 20-29 30-39 40-49 50-59 60-69 ≥79 Age (years) Prevalence and Duration of Zoster Associated Pain Increases with Age Kost R et al. N Engl J Med. 1996;355:32-42.

  9. Acute Pain in Herpes Zoster and Postherpetic Neuralgia Interferes with Functional Status and Quality of Life in Older Adults SchmaderKEetal.ClinJPain.2007;23:490-496;ChidiacCetal.ClinInfectDis.2001;33:62-69;LydickEetal.QualLifeRes.1995;4:41-45;KatzJetal.ClinInfectDis.2004;39:342-348;CoplanPMetal.JPain.2004;5:344-356;Scottetal,Vaccine2006;24:1308-16;SchmaderKE.ClinInfectDis2001;32(10):1481-6 Poorer physical, emotional, social, and role functioning Interference with basic and instrumental activities of daily living Impaired vitality, sleep and mental health

  10. Rationale for Developing and Using A Zoster Vaccine for Older Adults • Herpes zoster (HZ) is common and adversely affects quality of life among older adults • Antiviral therapy does not prevent postherpetic neuralgia (PHN), and once established, PHN is difficult to treat • Cell-mediated immunity (CMI) to varicella-zoster virus (VZV) declines with aging • Highly correlated with the increase in the incidence and severity of HZ and PHN in older persons Kost R et al. N Engl J Med1996;355:32-42.

  11. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults M.N. Oxman, M.D., M.J. Levin, M.D., G.R. Johnson, M.S., K.E. Schmader, M.D., S.E. Straus, M.D., L.D. Gelb, M.D., R.D. Arbeit, M.D., M.S. Simberkoff, M.D., A.A. Gershon, M.D., L.E. Davis, M.D., A. Weinberg, M.D., K.D. Boardman, R.Ph., H.M. Williams, R.N., M.S.N., J. Hongyuan Zhang, Ph.D., P.N. Peduzzi, Ph.D., C.E. Beisel, Ph.D., V.A. Morrison, M.D., J.C. Guatelli, M.D., P.A. Brooks, M.D., C.A. Kauffman, M.D., C.T. Pachucki, M.D., K.M. Neuzil, M.D., M.P.H., R.F. Betts, M.D., P.F. Wright, M.D., M.R. Griffin, M.D., M.P.H., P. Brunell, M.D., N.E. Soto, M.D., A.R. Marques, M.D., S.K. Keay, M.D., Ph.D., R.P. Goodman, M.D., D.J. Cotton, M.D., M.P.H., J.W. Gnann, Jr., M.D., J. Loutit, M.D., M. Holodniy, M.D., W.A. Keitel, M.D., G.E. Crawford, M.D., S.-S. Yeh, M.D., Ph.D., Z. Lobo, M.D., J.F. Toney, M.D., R.N. Greenberg, M.D., P.M. Keller, Ph.D., R. Harbecke, Ph.D., A.R. Hayward, M.D., Ph.D., M.R. Irwin, M.D., T.C. Kyriakides, Ph.D., C.Y. Chan, M.D., I.S.F. Chan, Ph.D., W.W.B. Wang, Ph.D., P.W. Annunziato, M.D., J.L. Silber, M.D., for the Shingles Prevention Study Group

  12. Live, attenuated, cell-free preparation of Oka/Merck strain VZV Attenuated by 31 passages in tissue culture (human embryonic lung fibroblasts, guinea pig embryonic cells, human diploid cells) Contains whole live virus, viral antigen and Neomycin, sucrose, gelatin, glutamate, inorganic salts Formulated to contain substantially more live virus and viral antigen than are contained in the varicella vaccine Zoster Vaccine (Oka/Merck)

  13. Shingles Prevention Study • Design: Randomized, double-blind, placebo-controlled, stratified by age, 60-69 and ≥ 70 • Setting: 22 US sites (16 VA and 6 university medical centers) • Participants: 38,546 immunocompetent adults ≥60 years old • 19,270 zoster vaccine • 19,276 placebo Oxman M et al. N Engl J Med.2005;352:2271-2284.

  14. Shingles Prevention Study • Outcomes • Burden of illness (pain severity by duration) • Incidence of PHN • Incidence of herpes zoster Oxman MN et al. N Engl J Med. 2005;352:2271-2284

  15. Shingles Prevention Study Results All Ages *BOI = pain severity by duration Oxman MN et al. N Engl J Med. 2005;352:2271-2284

  16. Adverse Events Injection Site Oxman MN et al. N Engl J Med. 2005;352:2271-2284; Simberkoff et al. Abst G-406 IDSA Annual Meeting 2008

  17. Number of Subjects with ≥1 Serious Adverse Experience (0-42 Days Postvaccination) in Overall Study Cohort http://www.fda.gov/cber/label/zosmer052506LB.pdf

  18. Effect of Zoster Vaccination on Functional Status in Older Adults • The zoster vaccine reduced HZ related interference with ADL by ~ 66% in older adults • Most of this reduction was due to vaccine efficacy at preventing HZ • HZ interference with ADL was reduced by ~ 30% in vaccine recipients who developed HZ Schmader KE et al. Abstract #859 IDSA Annual Meeting, 2006

  19. N =V/P 691/704 686/702 669/682 659/665 635/632 VZV- Specific Immune Responses by Time Since Vaccination(n = 704) N =V/P 691/704 Levin et al J Infect Dis 2008;197:825-35

  20. FDA Label Zoster Vaccine INDICATIONS AND USAGE • Indicated for prevention of herpes zoster (shingles) in individuals 60 years of age and older http://www.fda.gov/cber/label/zosmer052506LB.pdf

  21. FDA Label Zoster Vaccine CONTRAINDICATIONS • History of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine • History of primary or acquired immunodeficiency states including leukemia; lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system; or AIDS or other clinical manifestations of infection with human immunodeficiency viruses • On immunosuppressive therapy, including high-dose corticosteroids. • Active untreated tuberculosis. http://www.fda.gov/cber/label/zosmer052506LB.pdf

  22. Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control (CDC) • ACIP recommends routine vaccination of all persons aged ≥60 years with one dose of zoster vaccine. CDC MMWR 2008;57(05):1-30

  23. The zoster vaccine is on the VA National FormularyVHA health care providers can prescribe the vaccine www.pbm.va.gov/Clinical Guidance/Criteria For Use/Zoster Vaccine Criteria for Use (Rev 20080714).doc

  24. Top Five Clinical Issues and Implications • Age issues • Screening for varicella and herpes zoster • Disease considerations • Transmission of vaccine virus • Storage and administration

  25. Age Considerations • What about use of the vaccine in the “old-old” – persons ≥80 years old? • What about the use of the vaccine in persons <60 years old?

  26. Vaccine Efficacy for Incidence of PHN in Patients with Herpes Zoster 50 Efficacy(95% CI) Placebo Zoster Vaccine 40 26%(–69%, 68%) 30 55% (18%, 76%) % of Zoster Cases with Postherpetic Neuralgia 39%(7%, 59%) 25.5 20 5%(–107%, 56%) 18.9 17.2 10 12.5 7.7 8.6 6.9 6.6 0 All Subjects Age 60–69 70–79 ≥80 80 27 23 8 45 12 12 7 No. PHN Cases 642 315 334 122 261 156 47 37 No. HZ Cases http://www.fda.gov/cber/label/zosmer052506LB.pdf; Oxman MN et al. N Engl J Med. 2005;352:2271-2284

  27. Use in Persons ≥80 Years Old or Frail Older People The Issue . . . • The number of individuals over age 80 years in the trial was insufficient to determine vaccine efficacy in this age group alone. • The study was never intended to be powered for outcomes in this age group • Furthermore, few frail elderly individuals were enrolled in the trial.

  28. Use in Persons ≥80 Years Old or Frail Older People Skepticism . . . • Unknown adequacy of the immune response to the vaccine in this population • Efficacy against herpes zoster declined with increasing age • Safety data are limited • Utility in malnourished individuals or in those with limited life expectancy

  29. Use in Persons ≥80 Years Old or Frail Older People However . . . • Efficacy in reducing pain relatively preserved with increasing age, including severe PHN • Zoster vaccine was effective at reducing interference with activities of daily living • Incidence of zoster and PHN are highest in this age group, this population may derive significant benefit • reserve to withstand pain and adverse effects of potent analgesics is lower than younger individuals on average . . .Neither FDA nor ACIP specifies an upper age limit on the use of the vaccine CDC MMWR 2008;57(05):1-30

  30. Use in persons < 60 years old • Middle-aged individuals may seek the zoster vaccine • ACIP does not recommend the routine vaccination of persons < 60 years of age • Off-label prescribing in the US • Ongoing international randomized controlled trial of the zoster vaccine in persons 50-59 years old CDC MMWR 2008;57(05):1-30

  31. Ask About History of Varicella (Chickenpox) Before Vaccination? • Not necessary to take a varicella history or do serologic testing for varicella immunity before administration of zoster vaccine • Nearly all older adults in the US are VZV seropositive and latently infected regardless of the history they give regarding varicella • If known that patient is VZV seronegative, then the patient should receive a two dose regimen of the varicella vaccine CDC MMWR 2008;57(05):1-30

  32. Ask About History of Herpes Zoster Before Vaccination? • ACIP recommends the zoster vaccine for eligible persons whether or not they report a prior episode of zoster, not necessary to screen for past herpes zoster • Many older adults have past history of herpes zoster and specifically ask for the vaccine • Self-report of herpes zoster and physician diagnosis sometimes in error • Recurrent zoster occurs in 1-5% of cases • No reason that it would be unsafe CDC MMWR 2008;57(05):1-30

  33. Disease ConsiderationsHerpes Zoster and PHN • Older adults who are experiencing herpes zoster or PHN may ask for the vaccine • Zoster vaccination is not indicated to treat acute zoster or to treat PHN CDC MMWR 2008;57(05):1-30

  34. Disease ConsiderationsHIV Infection • Not specifically contraindicated for use in persons with less-advanced HIV infection • CD4+ T-lymphocyte values >200 per mm3 and/or >15% of total lymphocytes • In HIV-infected children without prior varicella and CD4+ counts as low as 15% the varicella vaccine was immunogenic and safe (Levin, 2006) • If zoster vaccination planned in an HIV infected individual with less advanced disease, check serum VZV IgG before giving the vaccine • Seronegative individuals should receive the varicella vaccine • Seropositive individuals should receive the zoster vaccine CDC MMWR 2008;57(05):1-30

  35. What About Transmission of Vaccine Virus After Zoster Vaccination? Shingles Prevention Study Potential transmission requires a vesicular rash containing vaccine virus after vaccination; if there is no vesicular rash, there is no chance for transmission *Neither vaccine virus nor wild type virus were detected by DNA PCR testing

  36. What About Transmission of Vaccine Virus After Zoster Vaccination? • No documented episodes of transmission of vaccine virus from vaccine recipients to contacts • Persons receiving zoster vaccine that have susceptible, pregnant or immune compromised contacts need not take any precautions following vaccination except in the rare situation that a rash develops, in which case standard contact precautions are adequate CDC MMWR 2008;57(05):1-30

  37. Key Points on Administration and Storage • Stored frozen at an average temperature ≤ 5°F (-15°C) • Reconstitute with diluent, give subcu. (0.65 mL) in the upper arm within 30 minutes of reconstitution • Each 0.65-mL dose contains at least 19,400 PFU of vaccine virus • 14 times the dose of varicella vaccine • Zoster vaccine can be co-administered with the inactivated influenza, tetanus-diptheria, or pneumococcal polysaccharide vaccines at different body sites • Should not be given same time as another live attenuated vaccine (e.g, varicella, BCG, polio, measles, mumps, yellow fever, rubella) • Administer at least 4 weeks before or after another live vaccine

  38. Durability of Vaccine ResponseShingles Prevention Study Oxman MN, et al. N Engl J Med. 2005;352:2271-84

  39. Durability of Vaccine ResponseSPS Persistence Substudy3.5-7.0 years post vaccination *BOI = pain severity by duration Schmader KE et al. Abstract G-409 IDSA Annual Meeting, 2008

  40. Summary • Herpes zoster is a common disease in older veterans that substantially lowers quality of life from acute and chronic pain • The zoster vaccine is immunogenic and effective in reducing the incidence of zoster and pain in older adults and is safe and well tolerated • The durability of vaccine response appears to be at least 7 years based on recent analyses GnannJetal.NEnglJMed2002;347:340-6;SchmaderKEetal.JInfectDis2008;197:207-15; LevinetalJInfectDis2008;197:825-35OxmanMNetal.NEnglJMed2005;352:2271-84; SchmaderKEetal.AbstG-409IDSAAnnualMeeting,2008

  41. SummaryKey Practice Points • Indicated for eligible persons ≥60 years old with no upper age limit • No need to screen for a history of varicella or herpes zoster before vaccination • Not for treatment of herpes zoster or PHN • Transmission of zoster vaccine virus very unlikely • No precautions for susceptible, pregnant or immune compromised contacts except in the rare situation that a rash develops, in which case standard contact precautions are adequate • Must be given within 30 minutes of reconstitution CDC MMWR 2008;57(05):1-30; Oxman MN et al. N Engl J Med. 2005;352:2271-2284

  42. Contact Information • For information about this specific presentation please contact Ken Schmader, MD, at schma001@mc.duke.edu • For any questions about the monthly GRECC Audio Conference Series please contact Tim Foley at tim.foley@va.gov or call (734) 222-4328 • For the link to the evaluation form for this conference that will confer CE credit please go to http://vaww.sites.lrn.va.gov/vacatalog/cu_detail.asp?id=25148and click the “Handout: Registration and Evaluation” link

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