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何謂子宮頸癌?
子宮頸分外子宮頸、內子宮頸，連接
陰道的是外子宮頸，是子宮頸癌的原
發位置
子宮頸癌是透過性接觸持續感染人類乳頭瘤病毒(HPV)
持續感染後，由子宮頸細胞病變逐漸惡化而成為癌症
癌細胞可繼而侵蝕並破壞子宮周圍組
織及有機會擴散到其餘器官
不是遺傳病
子宮頸 2
資料來源： 1. Baseman JG and Koutsky LA. The epidemiology of human papillomavirus infections. Journal of Clinical Virology. 2005; 32S:S16–S24.2. Stanley M. Immune responses to human papillomavirus. Vaccine. 2006; 24S1:S16-22..
正常的子宮頸
上皮鱗狀細胞癌變
Photos: PD Dr.Monika Hampl, Unifrauenklinik Düsseldorf
HPV病毒
普遍性
感染HPV病毒是十分普遍，高達80%女性在
一生會感染此病毒
透過性行為可不斷接觸HPV，持續感染致癌性
HPV便有可能發展成子宮頸癌
5
資料來源: 1.Brown DR, et al. A Longitudinal Study of Genital Human Papillomavirus Infection in a Cohort of Closely Followed Adolescent Women. The Journal of Infectious Diseases. 2005; 191:182–192.2. Koutsky L. Epidemiology of Genital Human Papillomavirus Infection. American Journal of Medicine. 1997; 102(5A):3-8.
3. Crum CP, Abbott DW, Quade BJ. Cervical cancer screening: from the Papanicolaou smear to the vaccine era. J Clin Oncol 2003; 21(10S); 224s-230s.4. Stanley M. Immune responses to human papillomavirus. Vaccine. 2006; 24S1:S16-22.
資料來源： 1. Chen SY et al. Journal of Virology. 1995; 69(5):3074-3083. 2. Munoz N et al. International Journal of Cancer. 2004; 111: 278-285.
HPV病毒>100種
高危型 (致癌) HPV病毒• 約16種• 可引致子宮頸癌
低危型HPV病毒
• 可引致性病疣
• 可引致皮膚疣
HPV病毒有超過100種類型
•高危型(致癌)HPV病毒：約有16種，會引致子宮頸癌的HPV病毒，包括
• HPV 16和18可導致70.7%的子宮頸癌
• HPV 45、31、33可導致12.2%的子宮頸癌
• 低危型HPV病毒，包括
• HPV6 、 11
• 只會引致性器官疣 (如椰菜花)或低度病變，但不會引致子宮頸癌
高危型 (致癌) HPV 與低危型HPV
82.9%
資料來源：1. Munoz N et al. International Journal of Cancer. 2004; 111: 278-85.
2. CDC. The Pink book. http://www.cdc.gov/vaccines/pubs/pinkbookldownloads/hpv.pdf. Accessed on 12 December 2011.
子宮頸細胞正常
細胞同時也可能回復正常
(通常在早期)
子宮頸癌的演化進程
細胞感染HPV婦女可能會傳染
病毒 受感染的細胞可能受到破壞並會形成病變
在多年後可能會出現侵入性
癌症
1 2 3 4 5 6
低度癌前病變(CIN*1)
CIN*3CIN*2
* CIN – 子宮頸上皮內瘤
高度癌前病變
資料來源：1. Burd EM. Human papillomavirus and Cervical Cancer. Clinical Microbiology Reviews. 2003; 16:1-17.2. Solomon D et al. The Journal of the American Medical Association. 2002; 287:2114–2119.
HIDE
8
9
預防子宮頸癌的重要性
卡波齊氏肉瘤
每十萬女性粗發病率
所
有
女
性
之
粗
發
病
率
10資料來源： Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10 [Internet]. Lyon, France:
International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr. Accessed on 12 December 2011.
子宮頸癌的發病及死亡數字
平均每3日便有1名香港女性因子宮頸癌死亡
11
年份 發病人數 死亡人數
2009 453 128
2008 358 120
2007 399 129
2006 459 133
2005 376 126
資料來源 : Hospital Authority. Hong Kong Cancer Registry website. http://www3.ha.org.hk/cancereg/e_stat.asp. Accessed on 6 March 2012.
HPV病毒感染在香港女性中有多普遍？
每12名香港女性中，
約有 1名現為HPV帶菌者
12資料來源：1. Chan PKS, Chang AR, et al. Prevalence and genotype distribution of cervical human papillomavirus infection: comparison between pregnant women and non-pregnant controls. Journal of Medical Virology 2002; 67: 583-588. 2. Chan PKS, Chang AR, et al. Determinants of cervical human papillomavirus infection: differences between high and low oncogenic risk types. Journal of Infectious Diseases 2002; 185: 28-35.
哪一個年齡段較容易受感染？
•在香港，女性感染HPV的年齡有兩個高峰期。
•第一高峰期：26-30歲
•第二高峰期：51-55歲
資料來源：Chan PKS, Chang AR, et al. Determinants of cervical human papillomavirus infection: differences between high and low oncogenic risk types. Journal of Infectious Diseases 2002; 185: 28-35..
HPV 感染率
20%
10%
中文大學一項針對2,080名香港女士的研究
13
哪些女性有更高的感染風險？
HPV感染率 HPV感染率上升的倍數
終生性伴侶數目 1 (2,199)2-3 (341)4 (64)
5.8%10.3%18.8%
1.0 (參考數值)1.6 (1.1-2.5)3.2 (1.6-6.2)
吸煙No (2,505)Yes (99)
6.2%19.2%
1.0 (參考數值)3.0 (1.7-5.3)
中文大學一項針對香港2,604名女士的研究：
•吸煙或性伴侶多人士
•但HPV感染在沒有這些危險因素的人群中也會出現，
如女性即使終生只有一名性伴侶也會感染
資料來源：Chan PKS, Ho WCS et al. Epidemiologic risk profile of infection with different groups of human papillomavirus. Journal of Medical Viology. 2009; 81:1635-1644.14
• 幾乎所有子宮頸癌都由感染高危型HPV 引起
• HPV 16, 18, 31, 33,45和51為全球與子宮頸癌相關的最常見HPV型別
小結 現時已清楚知道HPV感染為子宮頸癌的必要成因
如何預防子宮頸癌
1. 子宮頸細胞檢驗
• 可檢驗子宮頸是否已出現病變的細胞，但不能預防HPV感染
2. 接種疫苗
• 目前唯一預防高危型 (致癌) HPV感染的方法
資料來源：1. CDC. The Pink book. http://www.cdc.gov/vaccines/pubs/pinkbookldownloads/hpv.pdf. Accessed on 12 December 2011.
2. Australian Government Department of Health and Ageing Immunise Australia Program.
http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/hpv. Accessed on 12 December 2011.
有效預防子宮頸癌的方法
資料來源：1. CDC. The Pink book. http://www.cdc.gov/vaccines/pubs/pinkbookldownloads/hpv.pdf. Accessed on 12 December 2011. 2. Australian Government Department of Health and Ageing Immunise Australia Program. http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/hpv. Accessed on 12 December 2011.3. UK Department of Health. The Green book. http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_087787.pdf. Accessed on 12 December 2011.
18
香港女性：疫苗接種率不足7%
19
• 因爲各種不同的誤解遲遲不肯爲自己接種
本港接種率偏低的原因 不少女性認同需要接種子宮頸癌疫苗，然而因爲
各種不同的誤解遲遲不肯接種！
20資料來源：防癌教育學生問卷調查報告，香港中文大學醫學院公共衛生及基層醫療學院健康教育及促進健康中心，2009年
21
誤解與真相一
子宮頸癌是遺傳病「無得避」
22
• 不是遺傳病
• 是透過性接觸感染HPV引致，而感染後大多不會出現任何病徵
資料來源：Baseman JG and Koutsky LA. The epidemiology of human papillomavirus infections. Journal of Clinical Virology. 2005; 32S:S16–S24. 22
誤解與真相二
女兒只有十多歲，
待其長大才需要接種子宮頸癌預防疫苗
23
• 女童愈早接種，產生的抗體水平比其他年齡組別高
• 在未有性生活前接種，疫苗的保護亦會最大
• 很多歐美國家已將子宮頸癌預防疫苗納入國民免疫計劃中，例如美國現已為11-12歲的少女注射疫苗
資料來源：1. Pedersen C et al. Immunization of Early Adolescent Females with Human Papillomavirus Type 16 and 18 L1 Virus-like Particle Vaccine Containing AS04 Adjuvant. Journal of Adolescent Health. 2007; 40:564-571.2. Paavonen J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. The Lancet 2009; 374:301-314. 3. World Health Organization. WHO vaccine-preventable diseases: monitoring system 2011 global summary. http://apps.who.int/immunization_monitoring/en/globalsummary/ScheduleResult.cfm. Accessed on 6 March 2012.
誤解與真相三
疫苗只適合26歲或以下女性，
我已超過26歲，
加上已開始性行為，
即使接種疫苗亦無效？
24
• 疫苗在香港之註冊接種年齡已延至9歲或以上，無年齡上限
• 雖然疫苗未能治療已感染的病毒，但已開始有性生活的女性，接種疫苗可預防將來可能出現的 HPV感染
資料來源： 1. Bivalent HPV Vaccine - Hong Kong Full Prescribing Information 2010. 2. CDC. The Pink book. www.cdc.gov/vaccines/pubs/pinkbook/downloads/hpv.pdf. Accessed on 12 Dec 2011.3.Quadrivalent HPV Vaccine – Hong Kong Full Prescribing Information 2010.
誤解與真相四
我有固定性伴侶，從不濫交，
而且每次性行為均使用安全套，
那就不會感染HPV
25
• 女性即使在同一時間只有一名伴侶，妳一生中的任何一名性伴侶可能曾受感染，也能將病毒傳染給妳
• 安全套亦不足以完全保護免受HPV感染
資料來源: 1. Australian Government Department of Health and Ageing. National Cervical Screening Program. http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/hpv. Accessed on 5 August 2011. 2. Burd EM. Human papillomavirus and Cervical Cancer.Clinical Microbiology Reviews. 2003; 16:1-17.
誤解與真相五
我有定期做柏氏抹片檢查，
已可預防子宮頸癌
26
• 柏氏抹片檢查的目的是檢驗子宮頸有否出現病變的細胞，不能預防HPV感染
• 接種疫苗才是有效預防HPV感染的方法
資料來源： 1.HKSAR Department of Health. Cervical Screening Programme. http://www.cervicalscreening.gov.hk/tc_chi/cs/cs_what.php. Accessed on 5 August 2011.2.UK Department of Health. The Green book. http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@ah/@en/documents/digitalasset/dh_087787.pdf. Accessed on 8 August 2011.
27
子宮頸癌疫苗
28
• 約16種可引致子宮頸癌的高危型 (致癌)HPV病毒
資料來源： Munoz N et al. International Journal of Cancer. 2004; 111: 278-85.
引致子宮頸癌的HPV類型比率(%)
HPV 類型
2.32.21.41.31.21.00.70.60.50.31.2
4.4
53.5
2.6
17.2
6.72.9
0 10 20 30 40 50 60 70 80 90 100
X其他
827368395156593558523331451816
What should an ideal vaccine protect?理想的疫苗應保護甚麼？
~70%
HPV16、18、45 、31 、33型感染而引致佔總數約八成三的子宮頸癌
~83%
AS04-adjuvanted HPV vaccine composition疫苗成份
Optimized and stable VLP morphology1
Strong, sustained immune response
引發強而持久的免疫反應
Highly purified antigensassembled in VLPs
提供保護效能的抗原
提昇免疫反應及穩定抗原
AS04 Adjuvant 佐劑
+Aluminium
salt(Al(OH)3)
MPLImmunostimulant
HPV 16 L1 VLPs HPV 18 L1 VLPs
Antigen 抗原
1. Deschuyteneer et al. Human Vaccines 2010; 6:5, 407-419
兩種子宮頸癌疫苗
二合一疫苗
四合一疫苗
31
AS04佐劑疫苗
傳統疫苗
1. Vaccine Efficacy
疫苗保護效能
Vaccine Efficacy子宮頸癌預防疫苗的保護效能
Overall Efficacy整體保護效能
= +
Efficacy against vaccine types, HPV16/18
致癌HPV 16,18的保護效能
Efficacy against non-vaccine type HPV
HPV 16,18以外的致癌病毒保護效能
Vaccine Efficacy子宮頸癌預防疫苗的保護效能
Overall Efficacy整體保護效能
= +
Efficacy against vaccine types, HPV16/18
致癌HPV 16,18的保護效能
Efficacy against non-vaccine type HPV
HPV 16,18以外的致癌病毒保護效能
Phase III efficacy trial* conducted in 14 countries1 from: Europe, Asia-Pacific, North America, Latin America 第三期臨床研究在歐洲、亞太區、北美洲及拉丁美洲的14個國家進行。
隨機分派年齡 15–25 歲女性參與者
人數 = 18,644 (最大規模的子宮頸癌預防疫苗臨床研究)
時期 = 48 個月
1 Paavonen J et al. Lancet 2009; 374: 301-3142 Paavonen J et al. Lancet 2007; 369: 2161–70
PATRICIA (HPV-008)
Efficacy against HPV-16/18 CIN3+ (TVC-naïve) 疫苗對HPV16/18 所引致的CIN3+ 的保護效能
Endpoint Group N n
Vaccine Efficacy (95% CI)
% LL UL P-value
CIN3+ HPV-
16/18
Vaccine 5466 0
100.0 85.5 100.0 <0.0001Control 5452 27
CIN3+ HPV-16Vaccine 5466 0
100.0 83.5 100.0 <0.0001Control 5452 24
CIN3+ HPV-18Vaccine 5466 0
100.0 -50.7 100.0 0.0621Control 5452 4
TVC-naïve cohort: Population naïve to 14 oncogenic HPV types at baseline; N = number of evaluable women in each group; n = number of evaluable women reporting at least one event in each group;
TVC-naïve Cohort
Lehtinen M et al., Lancet Oncol 2012; 13: 89–99
PATRICIA (HPV-008)
TVC-naïve cohort (未感染HPV 病毒群組): Population naïve to 14 oncogenic HPV types at baseline
Overall Efficacy整體保護效能
= +
Efficacy against vaccine types, HPV16/18
致癌HPV 16,18的保護效能
Efficacy against non-vaccine type HPV
HPV 16,18以外的致癌病毒保護效能
Vaccine Efficacy
子宮頸癌預防疫苗的保護效能
Vaccine efficacy against non-vaccine oncogenic HPV type
疫苗對HPV16/18以外的致癌高危病毒的保護效能
(31, 33,45…)
Wheeler C et al., Lancet Oncol 2012; 13: 100–10Romanowski B. Human Vaccines 2011; 7:2, 161-169. Bosch FX, et al. Vaccine 2008; 26S:K1–K16.
(TVC-naive analysis; 48-month, end-of-study results)*Vaccine efficacy is different for each of the HPV types 16, 18, 31, 33, 45 and varies in different cohorts and endpoints.
HPV 病毒型號CIN2+的保護效能*
保護效能, % (95% CI)
HPV 31 89.4% (65.5-97.9)
HPV 33 82.3% (53.4-94.7)
HPV 45 100% (41.7-100)
Vaccine efficacy against individual HPV31, 33, 45
associated CIN2+ (TVC-naïve)
疫苗對個別HPV31, 33 及 45 所引致CIN2+的保護效能
HPV -16, 18, 31, 33 及 45 是全球 5 種最常見的 高危致癌 HPV 病毒類型
PATRICIA (HPV-008)
Vaccine efficacy against 12 non-vaccine type oncogenic HPV associated CIN2+ and CIN3+ (TVC-naïve) 疫苗對12種HPV16/18以外的致癌高危病毒類型所引致的CIN2+ 及CIN3+的保護效能
Wheeler C et al., Lancet Oncol 2012; 13: 100–10
* 12 non-vaccine HPV types: 31, 33, 35, 39, 45, 51, 52, 58, 59, 61, 66, 68.
排除同時感染HPV16/18未排除同時感染HPV16/18
PATRICIA (HPV-008)
HPV phylogenetic treeHPV病毒型號
與HPV 16 及18 相近的致癌病毒型號
HPV 16 與 HPV 31 及 33 相近
HPV 18與 HPV 45 相近
Adapted from de Villiers E, et al. Virology 2004; 324:17–27.
40
7 3242
3959
5544PCV113
116
7334
61
272a57
328
1029
5126 30
5356
66
RhPV1
70
18
45
583352
1635
31
Importance of AS04 adjuvant to enhance vaccine immune responseAS04 佐劑提昇免疫反應
在相同配方的疫苗中，AS04佐劑比較傳統Al(OH)3 鋁鹽，可引發更高及更持久的免疫反應
Time (months)
Statistically significant differences during the 4
yr. FU period
– Induction of a higher level of neutralizing antibody– 能產生更高的中和抗體水平
Giannini S, et al. Vaccine 2006
0 8 16 24 32 40 48
0
100
200
300
400
1000
0 8 16 24 32 40 48
0
100
200
300
400
1000
*
*
*
*
*
*
*
*** * *
Anti-V5 HPV16 Anti-J4 HPV18
Al(OH)3
AS04Al(OH)3
AS04
Overall Efficacy整體保護效能
= +
Efficacy against vaccine types, HPV16/18
致癌HPV 16,18的保護效能
Efficacy against non-vaccine type HPV
HPV 16,18以外的致癌病毒保護效能
Vaccine Efficacy
子宮頸癌預防疫苗的保護效能
Endpoint group N n
Vaccine Efficacy (95% CI)
% LL* UL P-value
CIN2+ irrespective of
HPV type in the lesion
in naïve women
vaccine 5466 61
64.9 52.7 74.2 <0.0001
control 5452 172
CIN3+ irrespective of
HPV type in the lesion
in naïve women
vaccine 5466 3
93.2 78.9 98.7 <0.0001
control 5452 44
TVC-naïve cohort: Population naïve to 14 oncogenic HPV types at baseline; N = number of evaluable women in each group;
n = number of evaluable women reporting at least one event in each group;
TVC-naïve Cohort
Vaccine efficacy against CIN2+ and CIN3+
irrespective to HPV types (TVC-naïve)
疫苗的整體保護效能
Lehtinen M et al., Lancet Oncol 2012; 13: 89–99
PATRICIA (HPV-008)
臨床研究顯示，對由任何高危HPV病毒(16,18, 31, 33, 45…)所引起的CIN3+
有高達93.2%的整體保護效能
歐盟及香港衛生署認可
CervarixTM— Macau Prescribing Information 2011CervarixTM– EU SPC 2012
PATRICIA (HPV-008)
2. Long-term immunogenicity
持久免疫反應
比自然感染抗體水平至少高8倍100 %擁有HPV16 抗體
比自然感染抗體水平至少高4倍100%擁有HPV18 抗體
HPV 16GMT, ED50
HPV 18GMT, ED50
Months after 1st vaccination
HPV-023HPV-007HPV-001
Naud et al. IPvC 2011. Presentation O18.04; CervarixTM. Hong Kong prescribing information 2011.
= Natural infection antibody levels
High and sustained anti-HPV 16/18 neutralizing antibodies up to 9.4 years (PBNA)提供高濃度及持久HPV16/18中和抗體達9.4年 (PBNA)
現時最新疫苗研究數據達9.4年
AS04-adjuvanted HPV vaccine: 9.4 years long term immunogenicity dataAS04佐劑子宮頸癌疫苗: 擁有9.4 年持久免疫反應數據
The longest follow-up study for a licensed cervical cancer vaccine. 是迄今子宮頸癌疫苗中的最長期跟進研究
9.4 years
follow up data
available
Naud et al. IPvC 2011. Presentation O18.04; CervarixTM Hong Kong prescribing information 2011
Roteli-Martins CM et al. Human Vaccines & Therapeutics 2012; 8(3): 1-8
Modeling of sustained antibody responses for least 20 years
推算疫苗抗體水平能維持至少20 年
1. David MP et al. Gynecol Oncol. 2009. 2. Fraser C, et al. Vaccine 2007; 25: 4324-4333. 3. Roteli-Martins CM, et al. Abstract presented in ESPID, France, May 2010. 4. Romanowski B. Human Vaccines 2011; 7:2, 161-169
HPV 16 HPV 18
三種數學模型推算，疫苗的HPV16/18 抗體水平能維持於自然感染水平之上至少20 年。
3. High Anti-body
比較市面兩種疫苗的免疫反應Head to Head Study
10
100
1000
10000
100000
4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
• GMTs were also consistently higher with AS04-Adjuvanted Bivalent HPV Vaccine in the older age groups (27−35 and 36−45 years)
• GMRs increased consistently over time for both HPV 16 and 18
• There was a strong correlation between PBNA and ELISA antibody responses
10
100
1000
10000
100000
4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Month
PBNA = pseudovirion-based neutralization assay; GMR = geometric mean ratio.* ATP cohort for immunogenicity, subjects HPV DNA-negative and seronegative at baseline.† Natural infection defined as GMTs in women from the HPV-010 study (NCT00423046) who had cleared a natural infection before enrolment (i.e. those who were seropositive and DNA-negative at Month 0; Einstein MH, et al. Hum Vaccine 2009; 5:1–15).
HPV 16 HPV 18
MonthG
MTs
, ED
50
GM
Ts, E
D5
0
4.4 5.1 5.8 9.0 9.4 12.57.53.7
Quadrivalent HPV vaccine
AS04-Adjuvanted Bivalent HPV Vaccine
Natural infection level from HPV-010 study†
5.9 7.3
Einstein MH, et al. EUROGIN 2011; abstract; Einstein MH, et al. Hum Vaccin 2009; 5:705–719.
GMR GMR
Serum neutralizing antibody responses through 36 months (PBNA) (women 18-26 years*)接種疫苗後36個月的血清中和抗體濃度變化
HPV-010 Head-to-Head Study
子宮癌頸疫苗有副作用嗎? 一般來說, 此疫苗的耐受性良好, 意即沒嚴重之副作用
輕微和短暫的紅腫
頭暈
頭痛
較嚴重者可能會發燒
