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桃園縣藥師公會藥師持續教育訓練認識帶狀疱疹及預防方式台大醫院家庭醫學部主治醫師台大醫學院一般醫學科臨床助理教授蔡詩力

帶狀皰疹的病原體 Varicella Zoster Virus, VZV ( 水痘病毒 ) 的入侵

3 初識 VZV -- 水痘流行季節在冬季及早春好發年齡 :60% 個案為 3-9 歲 90% 以上民眾在 15 歲以前曾經感染過水痘絕大部份病患都不會引起併發症併發症的高危險群 : 大於 20 歲病患免疫功能不全病患

水痘的治療鑑別 : 一般 VS 重症疑慮一般處置症狀治療呼吸道皮膚營養疼痛情緒重症疑慮族群? 重症疑慮處置 IV Acyclovir -- VZV Steroid cytokine storm Vital sign

HIGH CONTAGIOUS One study showed a 75% secondary attack rate with chickenpox in susceptible household contacts. [1] More than 90% of adults have been infected although many will not remember having it or may have had subclinical infection. Most adults in Australia are at risk of developing herpes zoster. Studies have shown that about 1/3 of the population will experience herpes zoster during the course of their lifetime with the incidence increasing particularly after the age of 60 years. [2]

Varicella-Zoster Virus (VZV): Immune Response Both structural and regulatory proteins of VZV are recognized during primary varicella infection by T lymphocytes. 1 Cell-mediated (T-cell) immunity is required to maintain the balance between host and latent VZV. 1 Cell-mediated immunity is more important than humoral immunity in recovery from varicella. 2 Immunity persists following disease. 2 T-cell immunity is also aging when aging 1. Gershon AA et al. In: Vaccines. 5th ed. Elsevier; 2008:915 958. 2. Straus SE et al. In: Freedberg IM et al, eds. Fitzpatrick s Dermatology in General Medicine. 5th ed. Vol 2. McGraw-Hill; 1999:2427 2450.

VZV Memory T Cells Host Factors in Varicella-Zoster Virus (VZV) Latency and Reactivation Exogenous varicella exposure Silent reactivation? Zoster vaccination Varicella infection Herpes zoster Zoster threshold Age Reprinted with permission from Arvin A. N Engl J Med. 2005;352:2266 2267. Copyright 2005 Massachusetts Medical Society. All rights reserved.

水痘痊癒後,VZV 跑那兒去 T-cell 免疫力下降會發生的事!!! 病毒沿著神經跑到體表 Chickenpox (VZV) rash 脊隨 Skin 水痘病毒被身體免疫壓制潛伏在背根神經節 1. Opstelten et al. Herpes zoster and post herpetic neuralgia: incidence and risk indicators using a general practice research database. Family Practice. 19:5;471-475. 2002. 2. CDC Immunization. Immunization: Shingles Vaccine. www.cdc.gov/vaccines. Accessed 14 Feb 2013. 3. National Institute of Aging. Age Page: Shingles. www.nia.nih.gov/health/publication/shingles. Accessed 14 Feb 2013. 4. ShinglesInfo.com FAQ. Accessed May 2013. http://www.shinglesinfo.com/shinglesinfo/shingles-in-depth/questions-about-shingles.jsp#4

Case I 38 歲男性北部某醫學中心婦產科主治醫師小學五年級時, 水痘發作高三寒假時, 皮蛇發作症狀 -- 疼痛注意力不集中焦慮失眠 9

T-cell 免疫力下降還會發生什麼事

你得過帶狀疱疹嗎? >50 歲都可能會得帶狀疱疹帶狀疱疹 (Herpes zoster; HZ)( 俗稱皮蛇 ) 是 VZV( 水痘 - 帶狀疱疹病毒 ) 再度活化的表現症狀表現 : 延著皮節分佈的單側性疼痛性水泡性皮疹疼痛症狀可能會發生於感染的前驅期急性發疹期以及疱疹後期曾有報告指出, 在急性發疹期間, 高達 90% 會發生局部神經疼痛疼痛期 : 可長達兩年 Spinal cord Dorsal root ganglion VZV moves along the sensory nerve to the dorsal root ganglion Chickenpox (VZV) rash Skin VZV establishes latency in the dorsal root ganglion 1. Opstelten et al. Herpes zoster and post herpetic neuralgia: incidence and risk indicators using a general practice research database. Family Practice. 19:5;471-475. 2002. 2. CDC Immunization. Immunization: Shingles Vaccine. www.cdc.gov/vaccines. Accessed 14 Feb 2013. 3. National Institute of Aging. Age Page: Shingles. www.nia.nih.gov/health/publication/shingles. Accessed 14 Feb 2013. 4. ShinglesInfo.com FAQ. Accessed May 2013. http://www.shinglesinfo.com/shinglesinfo/shingles-in-depth/questions-about-shingles.jsp#4

帶狀疱疹的發生率台灣 :2000-2006 JHI. et.al. Acta Derm Venereol. 2009. 89: 612-616

年齡 - 重要因素年齡是罹患帶狀疱疹最重要的一項因素超過 50 歲後, 罹患帶狀疱疹的風險及嚴重性會大幅增加, 這是由於免疫力會隨著年齡增長而降低的緣故 - 到了 85 歲, 約有 50% 的人會出現至少一次的帶狀疱疹隨著年齡增長, 罹患帶狀疱疹的風險越高過去 50 年來, 老年人的數量已增加一倍 ; 在接下來的 50 年, 老年人增加的數量將更多有越來越多的人將達到易罹患帶狀疱疹的年齡 1. CDC. MMWR. Prevention of Herpes Zoster: Recommendations of the Advisory Committee on Immunization Practices. 2008; 57:1-30. 2. Shinglesinfo.com. FAQ. www.shinglesinfo.com/shinglesinfo/shingles-in-depth/questions-about-shingles.jsp Accessed 28 May 2013 3. Schmader, K. Herpes Zoster in Older Adults. Aging and Infectious Diseases. CID. 2001:32 1481-1486 4. Oxman, M.N. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults. N Engl J Med 2005 352:22, 2271-84. 5. National Institute of Aging. Age Page: Shingles. www.nia.nih.gov/health/publication/shingles. accessed 14 Feb 2013. 6. Population Division, DESA, United Nations. World Population Ageing: 1950-2050. Chapter II:11. 7. WHO. Ageing and Life Course. 2013 http://www.who.int/ageing/en/ Accessed on 29 May 2013.

Annual Incidence (per 1,000 person-years) 全世界罹患帶狀疱疹的年齡分布 Worldwide Shingles by Age 20 18 16 14 12 10 8 6 4 2 0 Hope-Simpson (UK) Brisson (UK) Gonzalez (France) Ultsch (Germany) Insinga (US) Yawn (US) Stein (Australia) Brisson (Canada) Jih (Taiwan) Choi (South Korea) 0 10 20 30 40 50 60 70 80 90 Age 1. Brisson M et al. Epidemiol Infect. 2001;127:305 314. 2. Choi WS et al. J Clin Virol. 2010;47:325 329. 3. Gonzalez Chiappe S et al. Vaccine. 2010;28:7933 7938. 4. Hope-Simpson RE. Proc R Soc Med. 1965;58:9 20. 5 Insinga RP et al. J Gen Intern Med. 2005;20:748 753. 6. Jih JS et al. Acta Derm Venereol. 2009;89:612 616. 7. Stein AN et al. Vaccine. 2009;27:520 529. 8. Ultsch B et al. BMC Infect Dis. 2011;11:173. 9. Yawn BP et al. Mayo Clin Proc. 2007;82:1341 1349.10. Shinglesinfo.com. FAQ. www.shinglesinfo.com/shinglesinfo/shingles-in-depth/questions-about-shingles.jsp Accessed 28 May 2013 11. Population Division, DESA, United Nations. World Population Ageing: 1950-2050. Chapter II:11. 12. Schmader, K. Herpes Zoster in Older Adults. Aging and Infectious Diseases. CID. 2001:32 1481-1486 13. Oxman, M.N. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults. N Engl J Med 2005 352:22, 2271-84.

病毒性疫苗病毒性疾病疫苗成分使用者麻疹減毒兒童腮腺炎減毒兒童德國麻疹減毒兒童水痘減毒兒童流行性感冒去活化醫護年長 B 型肝炎次蛋白新生兒高危險群 A 型肝炎去活化兒童流行區腺病毒減毒軍事人員黃熱病減毒軍事人員旅行者狂犬病去活化獸醫處理動物天花痘病毒已不需要日本腦炎去活化旅行者小兒麻痺去活化 - 沙克兒童減毒 - 沙賓兒童

18 減毒疫苗製作概念

帶狀疱疹的徵兆及症狀起初的徵兆並不明顯, 症狀往往是發癢疼痛及刺痛幾天之後會出現水泡紅疹, 通常會出現在身體或臉部的單側紅疹的出現通常伴隨 : - 焦慮 - 類流感症狀 - 從輕微到嚴重的疼痛, 包含 : 發癢灼熱感或刺痛抽痛 96% 罹患帶狀疱疹的人會感到疼痛 45% 每天都感到疼痛 42% 形容此疼痛感為可怕的或難忍受的 Phototake. Reprinted with permission. 1. Goh, CL. A retrospective study of the clinical presentation and outcome of herpes zoster in a tertiary dermatology outpatient referral clinic. International Journal of Dermatology. 1997, 36, 667-672. 2. Schmader, K. Herpes Zoster in Older Adults. Aging and Infectious Diseases. CID. 2001:32 1481-1486 3. Oxman MN. Clinical manifestations of herpes zoster. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus Virology and Clinical Management. 2000; Cambridge Press: pp.246-75. 4. Stankus et al. Management of Herpes Zoster (Shingles) and Postherpetic Neuralgia. Am Fam Physician. April 15;61(8):2437-2444 5. Katz, J. Acute Pain in Herpes Zoster and Its Impact on Health-Related Quality of Life. Clinical Infectious Diseases. 2005. 39:342-8

帶狀皰疹疼痛的原因

我們如何感到疼痛大腦組織受損時會對痛覺受器造成刺激痛覺受器會將訊號傳遞至大腦, 從而使身體產生疼痛的感覺疼痛的程度取決於受到刺激之痛覺受器的數目痛覺受器脊髓背側角神經連結疼痛的訊息從受傷部位的周邊神經中的痛覺受器, 傳到脊髓神經, 再傳達到大腦感受到疼痛的訊息

疼痛的病理機轉

帶狀疱疹如何作怪? 病毒沿著神經跑到體表 Chickenpox (VZV) rash 脊隨 Skin 水痘病毒被身體免疫壓制潛伏在背根神經節 1. Opstelten et al. Herpes zoster and post herpetic neuralgia: incidence and risk indicators using a general practice research database. Family Practice. 19:5;471-475. 2002. 2. CDC Immunization. Immunization: Shingles Vaccine. www.cdc.gov/vaccines. Accessed 14 Feb 2013. 3. National Institute of Aging. Age Page: Shingles. www.nia.nih.gov/health/publication/shingles. Accessed 14 Feb 2013. 4. ShinglesInfo.com FAQ. Accessed May 2013. http://www.shinglesinfo.com/shinglesinfo/shingles-in-depth/questions-about-shingles.jsp#4

Total pain physical Psychological Total pain Social Spiritual

疼痛評估工具 (1) 視覺同化評估表 (Visual Analogue Scale, VAS) 0 cm 10 cm 哭笑臉譜疼痛評估表 (Facial Affective Scale) 26

疼痛評估工具 (2) 疼痛分數評估表 (Numeric rating Scale) 27

軀體性痛 (somatic pain) 由於皮膚軟組織骨骼傷害而造成的疼痛病人會感到持續的刺痛銳痛或壓痛, 有固定疼痛部位, 與體神經分佈有關

臟器痛 (visceral pain) 由於臟器直接刺激痛覺神經而造成的疼痛部位一般顯較為糢糊, 常合併轉移痛 (referred pain) 若來自中空的器官阻塞, 表現為間歇性的鈍痛或絞痛 ; 若來自實質器官的包膜或腸繫膜, 則表現為銳痛或脹痛

神經病變性痛 (neuropathic pain) 由於周邊神經受損或長期受壓迫所造成常見造成原因 : 腫瘤浸潤或侵犯神經叢帶狀庖疹感染手術傷害神經病人會覺得尖銳痛燒灼痛或刺痛對傳統止痛藥的反應不佳, 但部份抗憂鬱劑 (antidepression) 或抗痙攣藥 (anticonvulsant) 可能會有幫助

Case II 77 歲女性, 國小教師退休移民台北三個月感冒症狀一天第二天, 右耳癢 + 痛, 女兒發現嘴歪歪第三天, 右耳出現小水泡 + 微微紅疹第四天住院治療 31

Patients reporting interference (%) 帶狀疱疹引起的疼痛對日常活動的影響 100 90 80 70 60 50 40 30 20 10 0 General activity Work Sleep Enjoyment of life 0 1 2 3 4 5 6 7 8 9 10 Worst pain score 1. Adapted from Lydick E, Epstein RS, et al. Neurology; 1995;45 (suppl 8):S52

帶狀疱疹的併發症 4 位病人當中就有 1 位會得到 1 種或多種併發症對某些人來說, 帶狀疱疹會導致長期的神經疼痛, 稱為帶狀疱疹後神經痛 ( Postherpetic Neuralgia, PHN) 其它的併發症包含 : 帶狀疱疹病毒眼症 (Zoster opthalmicus) 罹患帶狀疱疹的病人有 10-25% 會發生在這些人當中,50-72% 的病人會得到嚴重的眼疾及視力退化皮膚細菌感染肌肉無力留下疤痕聽力損失 1. Lang et al. Stop Shingles in its tracks. Journal Fam Pract. Oct 2009. 58;10:531-534 2. Yawn BP et al. Mayo Clin Proc. 2007;82:1341 1349. 3. CDC Harpaz, R. Prevention of Herpes Zoster. Recommendations of the ACIP. MMWR. 2008: 57: 1-30. 4. Oxman MN. Clinical manifestations of herpes zoster. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus Virology and Clinical Management. 2000; Cambridge Press: pp.246-75. 5. Pavan-Langston, D. Ophthalmic zoster: Varicella-zoster virus. Virology and Clinical Management. 2000. 276-298. 6. National Institute of Aging. Age Page: Shingles. www.nia.nih.gov/health/publication/shingles. Accessed 14 Feb 2013. 7. US National Library of Medicine. PubMed Health. Shingles. Accessed May 2013. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/pmh0001861/

Patients reporting pain (%) 帶狀疱疹引起疼痛的程度及持續性與年齡層的的關聯性 100 80 60 >1 yr 6-12 mo 1-6 mo <1 mo 40 20 0 0-19 20-29 30-39 40-49 50-59 60-69 79 Age (years) 1. Kost R et al. N Engl J Med. 1996; 355:32-42.

帶狀疱疹及帶狀疱疹後神經痛 (PHN) 對健康的衝擊生理層面疲勞缺乏食慾體重減輕行動力下降體能活動不足失眠社會層面退縮孤立社交聚會次數減少喪失獨立性社會角色的改變心理層面憂鬱焦慮情緒壓力注意力無法集中恐懼感功能層面穿著洗澡飲食行動旅行烹飪家務購物 1. Johnson, R. The impact of herpes zoster and post- herpetic neuralgia on quality of life. BMC Medicine. 2010. 8:37. 2. Katz, J. Acute Pain in Herpes Zoster and Its Impact on Health-Related Quality of Life. Clinical Infectious Diseases. 2005. 39:342-8

帶狀疱疹的治療帶狀疱疹的治療 : 通常需要全方位的治療通常是複雜的所費不貲抗病毒藥一般止痛劑局部藥物帶狀泡疹神經痛復健類固醇嗎啡類止痛劑神經疼痛控制雖然帶狀疱疹後神經痛會隨時間消除, 但仍有病患會抗拒所有的治療帶狀疱疹的抗病毒治療應在紅疹出現後 72 小時內開始, 但病患通常會拖過 72 小時後才就醫 1. Gnann JW et al. N Engl J Med. 2002;347:340 346. 2. Johnson, R. The impact of herpes zoster and post- herpetic neuralgia on quality of life. BMC Medicine. 2010. 8:37 3. Goh, CL. A retrospective study of the clinical presentation and outcome of herpes zoster in a tertiary dermatology outpatient referral clinic. International Journal of Dermatology. 1997, 36, 667-672. 4. Watson, CP. The prognosis with postherpetic neuralgia. 1991. 46 (2) 195-199. 5. CDC. Prevention of Herpes Zoster: Recommendations of the ACIP. MMWR. 2008: 57: 1-30.

疼痛的處置 The WHO analgesic ladder opioid opioid Non opioid Anticonvulsants Steroid NSAID Aspirin Acetaminophen Weak- opioid +/- Non - opioid Strong - +/- Non - +/- Adjuvant

改善皰疹疼痛肌肉麻痺雞尾酒療法非藥物治療使用冷熱療電刺激超音波藥物治療口服外用注射改善循環消炎止痛劑

Barbara P. Yawn, MD, MSc; Peter C. Wollan, PhD; Marge J. Kurland, RN; Jennifer L. St. Sauver, PhD; and Patricia Saddier, MD, PhD. Herpes Zoster Recurrences More Frequent Than Previously Reported. Mayo Clin Proc. February 2011;86(2):88-93

Shingles Prevention Study (SPS) Objectives Primary Objective To determine whether vaccination with a live attenuated varicella-zoster virus vaccine would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia (PHN, pain 3/10, 90 days after the onset of rash) Secondary Objectives To evaluate adverse events in a subpopulation of subjects To evaluate cell-mediated immunity in a subpopulation of subjects Design Randomized, multicenter (22 sites in US), double-blind, placebo-controlled study Randomization was stratified by age: 60 69 years, 70 years. 38,546 varicella history-positive, herpes zoster-negative adults 60 years of age or older Sub-studies: Immunologic (1,395); Adverse Events (AEMS) (6,616) Oxman MN et al. N Engl J Med. 2005;352:2271 2284.

Oxman MN et al. N Engl J Med. 2005;352:2271 2284. Study Design

SPS: Baseline Study Subjects Characteristics (1) Oxman MN et al. N Engl J Med. 2005;352:2271 2284.

SPS: Baseline Study Subjects Characteristics (2) Oxman MN et al. N Engl J Med. 2005;352:2271 2284.

Number of Zoster Cases SPS: Overall Efficacy of ZOSTAVAX on Zoster Incidence Compared With Placebo Overall, ZOSTAVAX significantly reduced the risk of herpes zoster in subjects 60 years of age and older. OVERALL LOWER INCIDENCE OF ZOSTER 51% (95% CI: 44 58) 642 315 Placebo (n=19,247) ZOSTAVAX (n=19,254) Oxman MN et al. N Engl J Med. 2005;352:2271 2284. CI = confidence interval; SPS = Shingles Prevention Study.

Number of Zoster Cases Number of Zoster Cases Number of Zoster Cases SPS: Efficacy of ZOSTAVAX on Zoster Incidence Compared With Placebo by Age Group (Years) Vaccine efficacy for the prevention of herpes zoster was highest in those subjects 60 to 69 years of age and declined with increasing age. 64% in subjects 60 69 yrs (95% CI: 56 71) 41% in subjects 70 79 yrs (95% CI: 28 52) 18% in subjects 80 yrs (95% CI: 29 48; NS) 334 122 261 156 47 37 Placebo ZOSTAVAX (n=10,356) (n=10,370) Placebo ZOSTAVAX (n=7,559) (n=7,621) Placebo ZOSTAVAX (n=1,332) (n=1,263) Harpaz R et al. MMWR Recomm Rep. 2008;57(RR-5):1 30 CI = confidence interval; SPS = Shingles Prevention Study.

% of Zoster Cases With PHN SPS: Postherpetic Neuralgia (PHN) in Patients 60 Years Who Developed Herpes Zoster PHN = Zoster-associated pain rated as 3 on a 10-point scale and occurring or persisting at least 90 days after rash onset. 30 Placebo ZOSTAVAX 20 39% a (95% CI: 7 59) 10 0 12.5 8.6 Number of PHN Cases 80 27 Number of HZ Cases 642 315 Overall The benefit of ZOSTAVAX in the prevention of PHN can be primarily attributed to the effect of the vaccine on the prevention of herpes zoster. Harpaz R et al. MMWR Recomm Rep. 2008;57(RR-5):1 30 HZ = herpes zoster; PHN = postherpetic neuralgia; SPS = Shingles Prevention Study. a Age-adjusted estimate based on the age strata (60 69 and 70 years of age) at randomization.

SPS Safety Profile for ZOSTAVAX in Patients 60 Years 1 The Adverse Event Monitoring Substudy (AEMS) (n=6,616) Vaccination report cards (VRCs) Vaccine-Related Injection-site and Systemic Reactions in 1% of Adults Who Received ZOSTAVAX or Placebo (Days 0-42) Adverse Reaction Erythema Solicited (%) Unsolicited (%) Pain/ Tenderness Swelling Hematoma Pruritus Warmth Headache (Systemic) ZOSTAVAX (n=3,345) Placebo (n=3,271) 35.6 34.3 26.1 1.6 7.1 0.3 1.4 6.9 8.6 4.5 1.4 1.0 0.3 0.8 Most of these adverse events (AEs) were reported as mild in intensity Overall incidence of vaccine-related injection site AEs was significantly greater with ZOSTAVAX vs. placebo (48% vs. 17%), respectively Oxman MN et al. N Engl J Med. 2005;352:2271 2284.

SPS: Immunogenicity Substudy ZOSTAVAX elicited higher varicella-zoster virus (VZV) specific antibody responses at 6 weeks after vaccination compared with placebo. 95% CI: 1.6 1.8 Harpaz R et al. MMWR Morb Mortal Wkly Rep. 2008; 57(RR-5):1 30. gpelisa = glycoprotein enzyme-linked immunosorbent assay; SPS = Shingles Prevention Study. a As measured by gpelisa.

ZOSTAVAX Efficacy and Safety Trial (ZEST) Baseline Characteristics Characteristic Sex, n (%) Male Female Age, years Mean ± SD Range Race, n (%) White Black Asian Other a ZOSTAVAX (N=11,211) 4298 (38.3) 6913 (61.7) 54.9 ± 2.8 50 to 59 10,588 (94.4) 468 (4.2) 80 (0.7) 75 (0.7) Placebo (N=11,228) 4256 (37.9) 6972 (62.1) 54.8 ± 2.8 50 to 59 10,601 (94.4) 476 (4.2) 68 (0.6) 83 (0.7) N=Number of subjects randomized n=number of subjects contributing to each category SD = standard deviation; ZEST = ZOSTAVAX Efficacy and Safety Trial. a Other includes American Indian or Alaska Native, Multiracial, Native Hawaiian, or Other Pacific Islander. Schmader KE et al., Clin Infect Dis, 2012;54:922 928.

ZEST Primary Objective Results: Incidence of Confirmed Herpes Zoster (HZ) Cases in ITT Population Efficacy of ZOSTAVAX on Incidence of HZ in Subjects 50 to 59 Years of Age n m ZOSTAVAX (N=11,211) Total Follow-Up Time (Person-Years) Estimated Incidence Rate of HZ (Per 1000 Person-Years) n m Placebo (N=11,228) Total Follow-Up Time (Person-Years) Estimated Incidence Rate of HZ (Per 1000 Person- Years) 30 11,211 15,043 1.99 99 11,228 15,010 6.60 Vaccine Efficiency With Respect to HZ Point Estimate (95% CI) 69.8% (54.1 80.6) p-value for testing the vaccine efficacy for HZ being less than 25% is <0.001. N=Number of subjects randomized. n=number of confirmed HZ cases. m=number of subjects in the intent-to-treat (ITT) population. CI = confidence interval; ZEST = ZOSTAVAX Efficacy and Safety Trial. Schmader KE et al. Efficacy, Safety, and Tolerability of Herpes Zoster Vaccine in Persons Aged 50-59 Years, Clin Infect Dis, 2012;54:922 928.

ZEST Exploratory Objective Results: Severity-by-Duration Scores of Herpes Zoster (HZ) Pain in ITT Population n m ZOSTAVAX (N=11,211) Total Follow-Up Time (Person- Years) Mean Severityby-Duration Scores HZ Pain n m Placebo (N=11,228) Total Follow-Up Time (Person- Years) Mean Severityby-Duration Scores HZ Pain 30 11,211 15,043 0.13 99 11,228 15,010 0.49 Relative Reduction in Mean HZ Pain Severity-by- Duration Score [ZOSTAVAX Placebo] Point Estimate (95% CI) 73.0% (52.7 84.6) N=Number of subjects randomized. n=number of confirmed HZ cases. m=number of subjects in the intent-to-treat (ITT) population. CI = confidence interval; ZEST = ZOSTAVAX Efficacy and Safety Trial. Schmader KE et al. Efficacy, Clin Infect Dis, 2012;54:922 928.

ZEST Analysis of Varicella-Zoster Virus gpelisa Antibody Responses Week 6 Postvaccination Random Subcohort Population End Point n ZOSTAVAX (N=1136) Estimated GMT n Placebo (N=1133) Estimated GMT Estimated GMT Ratio (95% CI) P Value GMT 1124 663.7 1125 288.8 2.3 (2.2 2.4) <0.001 N=Number of subjects vaccinated in the Random Subcohort Population. n=number of subjects who had results either at prevaccination or 6 weeks postvaccination thus contributing to the immunogenicity analysis. The specific antibody level that correlates with protection from zoster has not been established. CI = confidence interval; gpelisa = glycoprotein enzyme-linked immunosorbent assay; GMT = geometric mean titer; ZEST = ZOSTAVAX Efficacy and Safety Trial. Schmader KE et al. 48th Annual Meeting of the Infectious Diseases Society of America. Poster 1380. October 21 24, 2010, Vancouver, Canada.

ZEST Adverse Event Summary (Days 1 to 42 Postvaccination) Subjects vaccinated in population with safety follow-up ZOSTAVAX Placebo Difference (95% CI) n (%) n (%) 11,094 11,116 With one or more adverse events 8080 (72.8) 4613 (41.5) 31.3 (30.1 32.6) Injection-site 7089 (63.9) 1596 (14.4) 49.5 (48.4 50.6) Systemic 3932 (35.4) 3722 (33.5) 2.0 (0.7 3.2) With vaccine-related adverse events a 7213 (65.0) 1988 (17.9) 47.1 (46.0 48.3) Injection-site 7089 (63.9) 1596 (14.4) 49.5 (48.4 50.0) Systemic 746 (6.7) 526 (4.7) 2.0 (1.4 2.6) With serious adverse events 69 (0.6) c 61 (0.5) c 0.1 ( 0.1 0.3) Serious vaccine-related adverse events a 1 (0.0) 0 (0.0) 0.0 (0 0.1) Who died b 1 (0.0) 3 (0.0) 0.0 (0 0) The same subject may appear in different categories but is counted only once in each category. a Determined by the investigator to be possibly, probably, or definitely related to the vaccination. b All deaths were determined not vaccine-related by the investigator. c Relative risk of 1.13 (95% CI: 0.81 1.60). CI = confidence interval; ZEST = ZOSTAVAX Efficacy and Safety Trial. Schmader KE et al. Clin Infect Dis, 2012;54:922 928.

Number of HZ % of Zoster cases with PHN Summary: ZOSTAVAX is Highly Effective in Reducing the Incidence of Herpes Zoster and positive effects to Postherpetic Neuralgia * ZOSTAVAX is not indicated for prevention of PHN Number of HZ Cases Overall Incidence of Herpes Zoster (HZ) In patients 50-59 y.o. 1 70% Reduction 95%(CI: 54-80) 700 600 500 400 300 200 100 0 Overall Incidence of Herpes Zoster (HZ) In patients 60 y.o. 2 642 315 51% Reduction 95%(CI: 44-58) 15 10 5 0 Overall % of Zoster cases with Postherpetic Neuralgia (PHN) In patients who develop HZ postvaccination 60 y.o. 39% Reduction 12.5 95%(CI: 7-59) 12.1 2.55 8.6 Placebo (n=11,228) ZOSTAVAX (n=11,211) Placebo (n=19,247) ZOSTAVAX (n=19,254) Placebo (n=642)* ZOSTAVAX (n=315)* * Number of Herpes zoster cases ZOSTAVAX has demonstrated a favorable safety profile The incidence of serious adverse events (SAEs) was comparable to placebo The most common adverse event is injection site reactions ZOSTAVAX has demonstrated a significantly higher varicella-zoster virus gpelisa antibody GMT at 6 weeks post-vaccination compared with placebo 1. Schmader KE et al. Clin Infect Dis. 2012; 54: 922-928. 2. Oxman MN et al. N Engl J Med, 2005;352:2271 2284.

帶狀疱疹及其引起的併發症是可以預防的疾病衛教帶狀疱疹疾病的教育罹患帶狀疱疹的風險意識, 如年齡及併發症了解預防及治療的途徑預防施打帶狀疱疹疫苗是一項可用來降低患病的重要方式 1. National Library of Medicine. Posterherpetic Neuralgia. PubMed Health. NIH. June 28, 2011. 2. CDC Immunization. Immunization: Shingles Vaccine. www.cdc.gov/vaccines. Accessed 14 Feb 2013

帶狀疱疹疫苗的重要研究兩項重要研究評估帶狀疱疹疫苗的功效安全性預防性及減輕疼痛的效果 : 帶狀疱疹預防研究 (SPS) 38,546 位 60 歲以上 (19,270 ZOSTAVAX vs. 19,276 安慰劑 ) 的男性及女性, 無帶狀疱疹病史子研究 : 免疫製劑 (1,395); 藥物不良反應 (AEMS) (6,616) 效果及安全性測試 (ZEST) 22,439 位曾得過水痘但無帶狀疱疹病史的男性及女性年齡介於 50 至 59 歲之間 (11,211 ZOSTAVAX vs. 11,228 安慰劑 ) 1. Merck & Co. World Product Circular ZOSTAVAX. WPC-V211-ZST-R-I-072011. 2011:1-24

帶狀疱疹預防研究 (SPS) 帶狀疱疹預防研究 (SPS) 與施打安慰劑相比,ZOSTAVAX 明顯地減少罹患帶狀疱疹風險達 51% ZOSTAVAX 在預防帶狀疱疹的效果上, 對 60-69 歲間的老年人是最顯著的減少罹患風險達 64% 與施打安慰劑相比,ZOSTAVAX 降低帶狀疱疹後神經痛的整體發生率, 達到 67%, 效果令人滿意 1. Merck & Co. World Product Circular ZOSTAVAX. WPC-V211-ZST-R-I-072011. 2011:1-24. 2. Oxman et al. N Engl J Med. 2005;352:2271-2284

% of HZ Cases With PHN 帶狀疱疹預防研究 : 減少發生帶狀疱疹後神經痛的效果帶狀疱疹後神經痛 : 假如將疼痛程度分為 10 個等級, 帶狀疱疹引起的疼痛程度不小於等級 3, 同時疼痛感自水泡紅疹出現後至少持續 90 天 30 25 20 15 10 5 12.5 8.6 0 Number of PHN Cases Number of HZ Cases Placebo (n=19,247) 80 642 ZOSTAVAX (n=19,254) 27 315 67% (95% CI: 48 79) Oxman, M.N. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults. N Engl J Med 2005 352:22, 2271-84.

效果及安全性測試 (ZEST) ZOSTAVAX 效果及安全性測試的結果顯示, ZOSTAVAX 能大幅降低 50-59 歲間男女性帶狀疱疹的發生率與施打安慰劑相比,ZOSTAVAX 有效降低帶狀疱疹發生率達 70%(30 個案例 vs. 99 個案例 ) 普遍來說, 病患對 ZOSTAVAX 的耐受度佳 1. Merck & Co. World Product Circular ZOSTAVAX. WPC-V211-ZST-R-I-072011. 2011:1-24

A Phase III Clinical Trial to Study the Safety, Tolerability, and Immunogenicity of Zoster Vaccine Live (Oka/Merck) in Subjects With a Prior History of Herpes Zoster Mills R et al. Vaccine 28 (2010) 4204-4209.

Statistical Analysis of VZV gpelisa Antibody Titer: 4 weeks post vaccination Endpoint ZOSTAVAX Placebo Estimated GMT Ratio p-value# n N = 100 Estimated GMT n N = 50 Estimated GMT (ZOSTAVAX vs. Placebo) (95% CI) GMT 100 811.5 50 392.7 2.07 (1.48, 2.88) <0.001 VZV = Varicella-zoster virus CI = Confidence Interval GMT = Geometric Mean Titer Mills R et al. Vaccine 28 (2010) 4204-4209

Clinical Adverse Experience Summary (Day 1 to 28) Following Any Vaccination ZOSTAVAX Placebo (N=100) (N=101) n (%) n (%) Subjects in population Subjects with follow-up 100 98 101 96 Number (%) of subjects: with no adverse experience 47 (48.0) 79 (82.3) with one or more adverse experience Injection-site adverse experience Systemic adverse experience 51 (52.0) 45 (45.9) 15 (15.3) 17 (17.7) 4 (4.2) 13 (13.5) with vaccine-related adverse experience Injection-site adverse experience Systemic adverse experience 45 (45.9) 45 (45.9) 2 (2.0) 4 (4.2) 4 (4.2) 0 (0.0) With serious adverse experiences 0 (0.0) 0 (0.0)

Post Marketing studies in USA Reference: Shingles (Herpes Zoster) Vaccine (Zostavax): A Review of Its Use in the Prevention of Herpes Zoster and Postherpetic Neuralgia in Adults Aged >50 Years. Gillian M. Keating. Drugs (2013) 73:1227 1244

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