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子宮頸癌 HPV 疫苗

子宮頸癌 HPV 疫苗. 陳子健醫師 . HPV (Human Papilloma Virus, 人類乳突病毒 ). 幾乎可以說 : 子宮頸癌 100% 是由 HPV 所引起的 沒有任何其他癌症的病因 , 有像子宮頸癌與 HPV 這樣強烈的關聯性. 感染 HPV  形成子宮頸上皮內之癌前病變  子宮頸癌. CIN 2/3 and AIS ― Established Surrogate Markers for Cervical Cancer. Definitive Efficacy. 0 to 1 Year. 0 to 5 Years.

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子宮頸癌 HPV 疫苗

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  1. 子宮頸癌HPV 疫苗 陳子健醫師

  2. HPV (Human Papilloma Virus, 人類乳突病毒) • 幾乎可以說: 子宮頸癌 100% 是由HPV所引起的 • 沒有任何其他癌症的病因, 有像子宮頸癌與HPV這樣強烈的關聯性

  3. 感染HPV  形成子宮頸上皮內之癌前病變  子宮頸癌

  4. CIN 2/3 and AIS ― Established Surrogate Markers for Cervical Cancer Definitive Efficacy 0 to 1 Year 0 to 5 Years Up to 20 Years InitialHPV Infection ContinuingInfection CIN 2/3 or AIS Cervical Cancer CIN 1 Cleared HPV Infection

  5. HPV和其他癌症也有相關性 *Includes cancer and intraepithelial neoplasia 1. Walboomers JM, Jacobs MV, Manos MM, et al. J Pathol. 1999;189:12–19. 2. World Health Organization. Geneva, Switzerland: World Health Organization; 1999:1–22. 3. Herrero R, Castellsagué X, Pawlita M, et al. J Natl Cancer Inst. 2003;95:1772–1783.

  6. 種類超過100 種 約有30–40種與外生殖器部位有關 高風險型 如HPV第16,18型 有致癌性 低風險型 如HPV第6,11型 低致癌性 外生殖器部位之疣 HPV (Human Papilloma Virus, 人類乳突病毒)

  7. HPV 之傳染途徑 • 性接觸 • 性交 • 外陰-外陰, 外陰-手, 外陰-口 • 與性接觸無關之途徑 • 產婦-新生兒 • 檢診手套, 子宮頸切片 • 其他接觸途徑

  8. 關於包皮 (N Engl J Med 2002 Apr 11;346(15):1105-12) • 沒割過包皮的男人，陰莖有高風險型HPV的比率為19.6% • 割過包皮的男人，陰莖有高風險型HPV的比率為5.5% • 割過包皮的男人，妻子較不會感染高風險型HPV

  9. 高風險型 HPV • HPV第16與18型, 是高風險型 HPV 當中最重要的兩種 • 六至七成的子宮頸癌, 由這兩種 HPV 引起

  10. HPV types in cervical cancer HPV genotype 16 Vaccine types 53.5 53.5% 18 17.2 70.7% 45 6.7 77.4% 31 2.9 80.3% 33 2.6 52 2.3 58 2.2 35 1.4 59 1.3 56 1.2 51 1.0 39 0.7 68 0.6 73 0.5 82 0.3 Other 1.2 X 4.4 0 10 20 30 40 50 60 70 80 90 100 Cancer cases attributed to the most frequent HPV genotypes (%) Munoz N et al. Int J Cancer 2004; 111: 278–85.

  11. HPV Type Distribution, Cervical Cancer (n=263) Source: Prevalence and Impacts of Cervical HPV Infections in Taiwan Tang-Yuan Chu, MD, PhD

  12. 低風險型 HPV • HPV第6與第11型, 是低風險型 HPV 當中最重要的兩種 • 九成以上的外生殖器部位的疣,由HPV第6與第11型所引起

  13. HPV往往可以被人體自動清除掉 • 在15–25歲的女性當中, 近八成的 HPV 感染是暫時性的1 • 七成的HPV感染在一年之內清除, 九成的HPV感染在兩年之內清除2 1. Meijer CJLM, Helmerhorst TJM, Rozendaal L, van der Linden JC, Voorhorst FJ, Walboomers JMM. Histopathology. 1998;33:83–86. 2. Ho GYF, Bierman R, Beardsley L, Chang CJ, Burk RD. N Engl J Med. 1998;338:423–428.

  14. 但若無法自行清除掉, 而感染持續存在 • 則有1/5 的機會, 形成 preinvasive cervical lesion

  15. HPV 所引發的抗體反應,既緩慢又微弱 • 不見得每個被感染的人, 都可以測到有抗體產生 • HPV 所引發的抗體反應, 因HPV型別的不同而有所差別

  16. HPV 不容易曝露給免疫系統發現 • HPV 的感染, 沒有”病毒血”階段1 • HPV 外殼蛋白質的表現延遲而有限1,2 • HPV 不會讓角質細胞破裂1, 3 • HPV的E6 and E7 抑制干擾素的訊息傳遞, 進而抑制細胞免疫反應1 • HPV 的感染, 沒有活化可呈現抗原的細胞1 1. Tindle RW. Nat Rev Cancer. 2002;2:1–7. 2. Scott M, Nakagawa M, Moscicki A-B. Clin Diagn Lab Immunol. 2001;8:209–220. 3. Frazer IH. Nature Rev Immunol. 2004;4:46–54.

  17. 以HPV疫苗, 大幅提高對於該型 HPV的抵抗力 為自然感染所引起抗體量之 • 11倍 (HPV 第6型) • 7倍 (HPV 第11型) • 105倍 (HPV 第16型) • 19倍 (HPV 第18型)

  18. 兩種HPV疫苗 • MSD: • HPV 第6, 11, 16, 18型 (台灣現行之疫苗) • GSK: • HPV 第16, 18型

  19. Rationale for a Quadrivalent HPV (Types 6, 11, 16, and 18) L1 VLP Vaccine

  20. 現行MSD之HPV疫苗 • Gardasil (嘉喜) • 保存於冰箱(2-80C), 效期36個月 • 3劑 (0個月, 2個月, 6個月) • 建議於9-17歲的兒童青少年, 以及18-26歲之女性 (將會延伸至45歲 …)

  21. Expected Indication GARDASIL®: Label at Launch 6 Single-dose 0.5 mL Syringes • Quadrivalent vaccine (HPV types 6, 11, 16, 18) • Yeast-derived, recombinant L1 VLP on aluminum adjuvant • Refrigerator stable (2-8 C), and 36 month expiry Char-acteristics 1x Vial Carton Indicated for the prevention of cancer, precancerous or dysplastic lesions, genital warts, and infection caused by human papillomavirus (HPV) types targeted by the vaccine For prevention of the following: • Cervical, vulvar, vaginal cancer (HPV 16, 18) • AIS and CIN 2 and 3 (HPV 16, 18) • CIN 1 (HPV 6,11,16,18) • Genital warts (condyloma acuminata) (HPV 6,11) • VIN 1,2,3 and VaIN 1,2, 3 (HPV 6,11,16,18) • HPV infection (HPV 6,11,16,18) Draft Indications GARDASIL® 10x Syringe Carton for Syringe without Safety Device • 3-dose regimen: 0, 2, 6 months • Recommended for children and adolescents 9 through 17 years of age and women 18 through 26 years of age • Safety and immunogenicity were determined in boys aged 9-15 years Dosage & Admin-istration

  22. 肌肉內注射 (deltoid, or thigh) • 不揉 • 不宜經臀部注射 • 對於yeast 過敏者, 不宜施打 • 施打之後, 在院內休息30分鐘, 觀察有無過敏反應

  23. 會不會因為施打疫苗, 而得到HPV的感染? 不會; 因為嘉喜四價HPV疫苗只是空包彈的彈殼, 並不含HPV病毒致病性的部位

  24. E7 E6 LCR** E1 L1 HPV 16(7,905 bp***) E4 E2 L2 E5 General Organization of a Papillomavirus Genome*,1 *Bars represent open reading frames. **LCR = long control region ***bp = base pair 1. Adapted from Münger K, Baldwin A, Edwards KM, et al. J Virol. 2004;78:11451–11460.

  25. Assembly of HPV Virus Like Particles L1 Protein (55–57 kD) L1 Capsomere (~280 kD) VLP (~20,000 kD) 72 Capsomeres 5 x L1 * VLP = Virus-like particle. 1. Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT. Proc Natl Acad Sci USA. 1992;89:12180–12184. 2. Syrjänen KJ, Syrjänen SM. Chichester, United Kingdom: John Wiley & Sons, Inc; 2000:11–51.

  26. 強大的預防效果 對於目前體內無HPV 6,11,16,18感染跡象的人 • 接種嘉喜疫苗 (Gardasil)之後  日後幾乎百分之百不會有HPV 6,11, 16,18所引起之各種病變

  27. CIN 2/3 and AIS ― Established Surrogate Markers for Cervical Cancer Definitive Efficacy 0 to 1 Year 0 to 5 Years Up to 20 Years InitialHPV Infection ContinuingInfection CIN 2/3 or AIS Cervical Cancer CIN 1 1 Efficacy Objective of Clinical Program for GARDASIL® – Demonstrate Prevention of HPV 16/18-CIN 2/3 and AIS Cleared HPV Infection

  28. Combined Phase II/Phase III Studies of Human HPV (Types 6, 11, 16, 18) L1 VLP Vaccine:Primary Efficacy Analysis Per-protocol population Median duration of follow-up = 4, 3, and 2 years depending on studies PP = received 3 vaccinations within 1 year; no major protocol violations; HPV 16/18 sero(-) at day 1 and HPV 16/18 DNA(-) day 1 to month 7; cases counted starting after month 7. CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ. Infectious Disease Society of America (IDSA) Meeting, October 5-9, 2005, in San Francisco, California

  29. 對於HPV 6/11/16/18-related genital wart, VIN 2/3 or VAIN 2/3之保障 • 對於體內目前無HPV6, 11,16,18感染跡象,總數17308人的研究統計 • Vaccine組 8641人, Placebo組 8667人 • HPV 6/11/16/18-related genital wart, VIN 2/3 or VAIN 2/3之發生 • Vaccine組 1 例 • Placebo組則有113例 • 99% Efficacy, 95% CI [95, 100]

  30. 預防性, 而非治療性 對於原本體內已有HPV 6或11或16或18感染跡象的人 • 接種嘉喜疫苗 (Gardasil)之後  日後發生原先所感染之HPV 型別所引起之病變之機會並沒有顯著地下降

  31. HPV vaccine在general population當中的efficacy, 隨著追蹤時間的增長而越加顯著 • 在general population當中 : • HPV vaccine 在開始施打之後的最初1-2年, efficacy並不顯著, 這是因為general population中, 已有部份的人有HPV infection或甚至已有病變發生。 • 然而, 隨著追蹤時間的增長, 效益越加顯著 • 施打之後, 30個月時的HPV 6/11/16/18-related external genital lesion cumulative incidence 大幅減少69% • 48個月時的HPV 16/18 CIN2/3 or AIS cumulative incidence則減少39% • 這是由於HPV vaccine最有效的對象為目前沒有HPV感染跡象者, 而一般大眾當中, 8成以上是如此

  32. 接種之後的有效年限 • The length of vaccine protection (immunity) is usually not known when a vaccine is first introduced. So far, studies have followed women for 6 years and found that they are protected. More research is being done to find out how long protection will last, and if a booster vaccine is needed years later.

  33. Placebo (N=9686) GARDASIL® (N=11,778) n (%) (%) n Result 9578 43 2 1 10 3 1 (0.4) (0.0) (0.0) (0.1) (0.0) (0.0) (0.5) (0.0) (0.0) (0.1) (0.0) (0.0) Subjects with follow-up Number of Subjects with serious AEs with serious VR AEs who died Discontinued due to AE Discon due to SAE Discon due to VR AE 11,641 59 5 3 15 4 0 Summary of SAEs, Deaths, Discontinuations Safety Population Days 1 to 15 Following Any Vaccination One subjects who received GARDASIL reported a serious VR AE beyond Day 15 after vaccination. Seven subjects who received GARDASIL and 6 subjects in the placebo group died beyond Day 15 after vaccination.

  34. 較常見的副作用 • 注射部位腫痛(85.4%) • 頭痛(39%) • 感冒症狀(9.6%) • 腹痛(9.4%) • 噁心感(7.5%) • 發燒(7.3%)等

  35. 施打之年齡 • 目前建議9-26歲 (將延伸至45歲) • 在開始有性經驗之前更好

  36. Age of first sexDurex report, 2005 (41 countries) Average: 17.3 yrs No. 5, 18.9 yrs

  37. 70 60 50 40 30 20 10 0 0 12 24 36 45 60 Risk of Acquiring HPV After First Intercourse Cumulative Risk of Cervical HPV Infection in Female Adolescents With Only 1 Sexual Partner1 Study of Female College Students2 70 N=242 N=603 60 40 Cumulative Risk of HPV Infection (%) Cumulative Risk of HPV Infection (%) 20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Months Since First Intercourse Months Since First Intercourse Adapted from Collins et al.1 Adapted from Winer et al.2 1. Collins S, Mazloomzadeh S, Winter H, et al. BJOG. 2002;109:96–98. 2. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226, by permission of Oxford University Press.

  38. Females 10–15 Years of Age Males 10–15 Years of Age Females 16–23 Years of Age Human HPV (Types 6, 11, 16, 18) L1 VLP VaccinePhase III Adolescent Immunogenicity Substudy: Anti-HPV GMTs* at Month 7 *GMT = geometric mean titers Presented at: European Society for Paediatric Infectious Diseases (ESPID). Valencia, Spain; May 18–20, 2005

  39. Antibody Titers by Age at Enrollment Anti-HPV 6 GMTs (Quadrivalent HPV vaccine) Efficacy Program Immunogenicity Bridge 1600 1500 1300 1100 900 Serum GMT with 95% CI, mMU/mL 700 500 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Age at Enrollment (Years) Merck, unpublished data, Presented at ACIP meeting, February 2006

  40. 所引發製造的抗體量 • 兒童青少年　>　 女青年 • 男　> 女

  41. US CDC’s ACIPRecommendation for Gardasil®June 29th, 2006 http://www.cdc.gov/od/oc/media/pressrel/r060629.htm

  42. 可否與其他疫苗一起注射 ? • 可與 Tdap, Td, MCV4, and hepatitis B vaccines 等疫苗同時施打

  43. 關於懷孕 GARDASIL® (N=10, 418) Placebo (N=9120) Result 1151 1272 264 1017 610 (60%) 407 (40%) 1115 1244 258 996 621 (62%) 375 (38%) Subjects with Pregnancies Number of Pregnancies Fetuses/Infants Ongoing Pregnancy/Unknown Known Outcome Live Births Fetal Loss

  44. GARDASIL® Placebo n n Infant/Fetus Congenital Anomalies EOP Within 30 Days of a Vaccination Anomaly in Live-Born Infant Anomaly in Fetal Loss Intrauterine Observation EOP Beyond 30 Days of a Vaccination Anomaly in Live-Born Infant Anomaly in Fetal Loss Intrauterine Observation 15 5 5 0 0 10 9 0 1 16 0 0 0 0 16 13 2 1 關於新生兒畸形 Estimated Onset of Pregnancy (EOP) could not be precisely ascertained in 10 women. N = Number of live birth outcomes.

  45. Should pregnant women be vaccinated? • The vaccine is not recommended for pregnant women. There has been limited research looking at vaccine safety for pregnant women and their developing fetus. So far, studies suggest that the vaccine has not caused health problems during pregnancy, nor has it caused health problems for the infant-- but more research is still needed. For now, pregnant women should complete their pregnancy before getting the vaccine. If a woman finds out she is pregnant after she has started getting the vaccine series, she should complete her pregnancy before finishing the three-dose series.

  46. Breast feeding • 接種HPV vaccine者, 可以進行 breast feeding

  47. 施打之前需要先篩檢嗎? • No. Girls/women should not get an HPV test or Pap test to determine if they should get the vaccine. An HPV test or a Pap test can tell that a woman may have HPV, but these tests cannot tell the specific HPV type(s) that a woman has. Even girls/women with one vaccine HPV type could get protection against the other vaccine HPV types they have not yet acquired.

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