子宫颈癌疫苗
- 常见问题 与 新资讯 -
World Statistics of Cervical Cancer
(子宫颈癌 全球数据)
Worldwide, an estimated 470,000 new cases occur each year and of these cases, half of them die annually from cervical cancer (IARC 2002)
(每年 47 万新症, 其中一半会引致死亡)
80% of these deaths occur where resources are most limited (Parkin et al. 1993)
( 80% 死亡来自发展中国家)
每两分钟有一位妇女死於子宫颈癌1
Anita Mui died of lung failure arising from complications from cervical cancer at the age of 40
梅艳芳於40岁死於子宫颈癌的
并发症—肺衰竭
1. Ferlay J, et al. GLOBOCAN 2002 Cancer incidence, mortality and prevalence worldwide, 2004
有性行为的男女:
一生人至少 50% 的人曾感染 HPV
CDC Fact Sheet, Aug-2007
Prevention is Better than Cure !
预防胜於治疗 !
已有性经验的女性可否接种
接种是否无效
Gardasil 的研究基本上是招募有性经验的女性
- 94% 已经有性行为
- 平均有两个性伴侣
17%
25%
18%
11%
20%
Anti-HPV 6, 11, 16, or 18 Sero(+)
14%
14%
16%
7%
15%
HPV 6, 11, 16, or 18 PCR (+)
7%
7%
6%
5%
6%
LSIL or HSIL
3%
7%
3%
3%
4%
Chlamydia (+)
55%
46%
68%
50%
58%
Using Hormonal Contraception
16%
51%
7%
25%
23%
Past Pregnancy
2
2
2
2
2
Med. Lifetime # of Sex Partners
17
17
17
18
17
Mean Age at Sexual Debut (yrs)
93%
99%
92%
96%
94%
Non-virgin
20
21
20
21
20
Mean Age
25%
27%
44%
4%
100%
Percent of total
North America
N=5292)
Latin America
(N = 5666)
Europe
(N=9181)
Asia Pacific
(N=748)
Total
(N=20887)
Day 1 Parameter
Phase III Efficacy Program Day 1 Patient Parameter
Determined by PAP screen, LSIL, Low-grade squamous intraepithelial lesion, HSIL High-grade squamous intraepithelial lesion
(Information from MSD)
平均年龄
并非处女
一生中性伴侣
首次性行为年龄
参与 Gardasil 研究女性的背景 (20,887 位女仕)
73% 没有感染四种 HPV ( HPV 6, 11, 16, 18)
27%感染一种 HPV 或以上
~20% 感染任何一种
~6% 感染任何两种
~1.2% 感染任何三种
26 岁是否无效
较大年纪女性也有机会感染HPV
Chan et al. Determinants of cervical human papillomavirus infection: differences between high and low oncogenic risk types.
J Infect Dis 2002; 185: 28-35.
ALL HPV
HR HPV
LR HPV
Other HPV
效用可维持多久
研究指出Gardasil有 至少 5 年 的效用
- 有报导误以为最多只有 5 年的效用
10 000
1 000
100
10
GMT (mMU/mL)
GARDASIL
Natural infection
0
7
12
18
24
30
36
54
60
months
GARDASIL
100%
1st
2nd
3rd
Dose
Clinical efficacy*
Neutralising antibodies
(HPV type 16)
18
5 years
___PPTMAC11
* against infection, CIN (Cervical intraepithelial neoplasia) and genital warts due to
HPV types 6,11,18; 5 yrs follow up (after dose 1) of a subset (241 women, vaccine
& placebo) from a phase II efficacy study
___PPTMAC11
Villa L High Sust Eff Proph Quad HPV Vacc 5 Year Followup Br J Can 2006 95 1459
根据数学上的推算,HPV 抗体水平可以维持30年以上,但是真正的答案只有时间可以验证,在临床上得到证实.
Modified power law model (— )
Years After Vaccination
30 years
1
10
100
1000
0
5
10
15
20
25
30
GMT
(mMU/ml)
1. Adapted from Fraser C, Tomassini JE, Xi L, et al. Modeling the long-term antibody response of a human papillomavirus (HPV) virus-like particle (VLP) type 16 prophylactic vaccine. Vaccine
10
从乙型肝炎疫苗的经验得知:
- 有 10 – 50%的人, 抗体水平会在 5 年间跌至仪器 探测不到的水平,由於有免疫记忆,身体一样有保护作用
- 至今依然没有建议要注射加强剂 (Booster)
1. Wainwright RB, McMahon BJ, Bulkow LR, et al. JAMA. 1989;261:2362–2366. 2. Bauer T and Jilg W. Vaccine. 2006;24:572-577. 3. Mast E, Mahoney F, Kane M, Margolis H. Hepatitis B vaccine. In: Vaccine, 4th Ed. Plotkin SA, Orenstein WA editors. Elsevier Inc. USA publisher; 2004.
6
24
36
48
60
12
Months After First Vaccine Dose
虽然抗体水平跌至探测不到的水平,一旦接触到病毒或拟似病毒的刺激 (immune challenge) ,由於免疫系统已经有了记忆 (Immune memory),身体立即会制造大量抗体,防止病毒感染.
In vivo anti-HBs response
1. Bauer T, Jilg W. Vaccine. 2006;24:572–577.
Immune Challenge
Days
Anti-HBs [IU/I]
100
101
28
10
102
103
104
105
0
加卫苗GARDASIL 免疫记忆 (Immune memory)的研究 1*
*In subjects na ve to the relevant HPV type from Day 1 through Month 60.
Sven-Eric Olsson Induction of immune memory of quadrivalent vaccine Vaccine 25 (2007) 4931–4939
Ph II–P007 Dose-Ranging 16- to 23-year-old women
Challenge
by vaccine
HPV 6
HPV 16
HPV 11
HPV 18
显示注射完三针疫苗是俱有长期的保护性,
或有可能终生保护.
HPV infection is the most common sexually-transmitted infection worldwide. The lifetime risk of HPV infection exceeds 50%.
About 1/3 of genital HPV infections in women results in low grade cervical dysplasia, or cervical intraepithelial neoplasia grade 1. Thus, the lifetime risk for development of these lesions is 1 in 6.
In a smaller proportion of women, infection is manifested as CIN 2/3 or moderate- and high-grade cervical dysplasia. This lesion represents the immediate/obligate precursor to cervical cancer.
In the absence of screening, 1 in 30 women will develop cervical cancer. The goal of cervical cancer screening using the Pap test is to detect CIN 2/3 lesions and excise them before they transform into invasive cancer. In the U.S., Pap testing has reduced the risk of cervical cancer by 75%. Thus, on a population basis, Pap testing reduces the lifetime risk of cancer from 1 in 30 to about 1 in 120.
HPV infection also causes genital warts. The lifetime risk of these lesions in both men and women is 1 in 8.
Other important things to note:
The ACIP recommendations include vaccination of women regardless of existing Pap test abnormalities, HPV infection or genital warts, stating that these females still derive benefit from vaccination (protection against types not already acquired)
It is important to note that GARDASIL received a "category B" pregnancy rating, which is not common for vaccines and provides support for use in lactating women
ACIP also supports use in immunocompromsied females recognizing that the immune response to vaccination and vaccination effectiveness might be less in this category
Key Point
The vaccine was generally well tolerated, with no significant differences between GARDASIL and placebo regarding AEs.
Background
The subjects who were monitored using VRC-aided surveillance (detailed safety population) included 6,160 subjects who received GARDASIL and 4,064 subjects who received placebo.1
The number and percentage of subjects in the detailed safety population who reported injection-site adverse experiences (incidence ≥1% in one or more vaccination groups) Days 1 to 5 following any vaccination visit are shown. The most common injection-site adverse experiences reported were pain, swelling, and erythema. For most subjects, the maximum intensity rating of injection-site adverse experiences was mild or moderate. The percentages of subjects with moderate or severe injection-site adverse experiences were small but higher in the group that received GARDASIL than in the placebo group.1
Overall, 11.4% of subjects who received GARDASIL and 9.6% of placebo recipients reported a temperature of ≥ 100°F (≥ 37.8°C), oral equivalent. A total of 1.5% of subjects who received GARDASIL and 1.1% of placebo recipients reported a temperature of ≥ 102°F (≥ 38.9°C), oral equivalent (data not shown).1
Reference
1. Data on file, MSD.
1/Data on file/ V501_cervixcancer_2.7.4.1 summary clinical safety/ p 90-91/ Adapted from Table 2.7.4:13.
1/Data on file/ VRBPAC briefing document/p76/ 1
1/Data on file/ V501_cervixcancer_2.7.4.1 summary clinical safety/ p 99/ Table 2.7.4:15.
1/Data on file/ V501_cervixcancer_2.7.4.1 summary clinical safety/p. 88/ 3; p. 89/ 1.
1/Data on file/ VRBPAC briefing document/p 76/ 1.
1/Data on file/ V501_cervixcancer_2.7.4.1 summary clinical safety/ p 90-91/ Table 2.7.4:13.
Key Point
The vaccine was generally well tolerated, with no significant differences between GARDASIL and placebo regarding AEs.
Background
This slide presents the summary of clinical AEs reported from Day 1 to Day 15, following any study vaccination for the detailed safety population. Overall, the proportions of subjects reporting AEs were comparable between the 2 vaccination groups. In the group that received GARDASIL, 83% of subjects reported injection-site AEs, compared with 73.4% of placebo recipients.1
Few subjects reported a serious AE. The proportions of subjects who reported serious AEs were comparable between the 2 vaccination groups. Few subjects discontinued due to an AE.1
Ten patients in the GARDASIL group (overall safety population) died at any time during the clinical trials. None of the deaths were considered by the investigators to be vaccine or procedure related.1 The most common cause of death was motor vehicle accident (4 subjects who received GARDASIL and 3 placebo subjects), followed by overdose/suicide (1 subject who received GARDASIL and 2 subjects who received placebo), and pulmonary embolus/deep-vein thrombosis (1 subject who received GARDASIL and 1 placebo subject). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, and 1 case of arrhythmia in the group that received GARDASIL, and 1 case of asphyxia in the placebo group. The events reported were consistent with events expected in healthy adolescent and adult populations.2
The most frequently reported serious AEs for GARDASIL, compared to placebo and regardless of causality, were2:
Headache (0.03% GARDASIL vs 0.02% placebo)
Gastroenteritis (0.03% GARDASIL vs 0.01% placebo)
Appendicitis (0.02% GARDASIL vs 0.01% placebo)
Pelvic inflammatory disease (0.02% GARDASIL vs 0.01% placebo)
One case of bronchospasm and 2 cases of asthma were reported as serious AEs that occurred during Day 1–15 of any vaccination visit.2
References
GARDASIL Prescribing Information. Merck & Co., Inc., Whitehouse Station, NJ, USA.
Data on file, MSD.
1/Data on file/ VRBPAC briefing document/p 75/ Table 24.
1/Data on file/ VRBPAC briefing document/p75/ Table 24; p. 72/ 2.
1/Data on file/ VRBPAC briefing document/p74/ 2; p.75/ 1.
1/Data on file/ VRBPAC briefing document/p77/ 2.
2/Package Insert/p. 12/Lines 386-391.
2/Package Insert/p. 12/Lines 374-380.
1/Data on file/ VRBPAC briefing document/p.75/ 1.
2/Package Insert/p. 12/Lines 382-383.
Messages
100% efficacy lasting for 5 years with antibody titres (neutralising, HPV type specific) plateauing at high level will not drop off tomorrow
We therefore expect that Gardasil will protect a long time, 20, may be 30, may be 40 years, may be life-long
Comments/Additional information
Prevention of Human Papillomavirus infection is essentially through antibodies (neutralising, specific) and not through cell mediated immunity
The formulation with 225 μg of Merck's aluminium phosphate adjuvant has proven to stimulate high antibody response for Gardasil
It is very unusual that vaccines show a higher immune response than natural infection. Gardasil shows ~50 times higher immune response (note that the scale on the left is a log scale!) which is extremely high and exceptional already. Given the 100% efficacy this again shows that there is no sense in trying to induce even higher immune response.
Key Point
Over 30 years postvaccination, the modified power law mathematical model predicted a long-term plateau of antibody duration with a near life-long persistence.
Background
The duration over which antibody responses persist following HPV vaccination is unknown. To estimate the longevity of responses induced by an HPV-16 vaccine, two models were fitted to serum anti-HPV 16 levels, measured over a 48-month study period. The first was a power-law model of antibody decline, based on the biological dynamics of B-cell turnover, and the second was a modification of this model, which additionally allows for the long-term persistence of a memory B-cell subpopulation.1
An ideal HPV prophylactic vaccine would provide protection for at least 10 to 15 years during the greatest risk period for HPV infection. In this study, mathematical modeling of the long-term anti-HPV 16 responses, following vaccination with an efficacious HPV 16 L1 VLP vaccine, provided estimates of the duration of detection of vaccine-induced anti-HPV 16. Using the conventional power law model, it was estimated that, following administration of a three-dose regimen of HPV 16 vaccine, anti-HPV 16 levels will remain above those induced naturally by HPV 16 infection for a median of 12 years in 50% of the vaccinees, and above detectable levels for a median of 32 years. With the modified model, which fitted the data better (P 100 IU/l within 28 days after immune challenge. The T cells are able to trigger anti-HBs production of B cells, activated by the immune challenge. In case of HBV exposure, the immune memory rapidly leads to a vigorous anamnestic response, which often prevents acute infection, and most often acute disease, prolonged viremia, and chronic infection.1
Reference
1. Bauer T, Jilg W. Hepatitis B surface antigen-specific T and B cell memory in individuals who had lost protective antibodies after hepatitis B vaccination. Vaccine. 2006;24:572–577.
Key Point
There is evidence of an anamnestic response with GARDASIL .
Background
Subjects from the GARDASIL and placebo arms of the dose-ranging study were eligible to participate in an extension of the trial, which included scheduled visits for the collection of efficacy samples at Months 54 and 60. In addition, subjects in the extension received an injection of GARDASIL at Month 60 and provided serum samples for summarizing booster immunogenicity at Month 60, 1 week following Month 60, and at Month 61.1
The purpose of the extension was to provide efficacy and immunogenicity follow-up through 5 years Postdose 1 and to assess the impact of a booster dose of GARDASIL given 5 years following the first dose. Two hundred forty one subjects entered the extension phase, 222 of who received an injection of GARDASIL at Month 60. For subjects who received a primary series of GARDASIL in the base study, the Month 60 vaccination was a booster dose (102 subjects); for subjects who received placebo in the base study, the Month 60 vaccination was their first dose of GARDASIL (119 subjects), to be followed by second and third doses at Months 62 and 66, respectively.1
GMTs and the corresponding 95% confidence intervals for all time points through Month 61 were calculated for subjects in the extension phase of Protocol 007. In order to be eligible to be included in these summaries, subjects must have (1) received all 3 injections of their respective primary series of vaccine/placebo and a vaccination with GARDASIL at Month 60, (2) had serology data within acceptable day ranges of 4 weeks following Month 60, and (3) received no other HPV vaccine.1
As shown in the slide, there is evidence of a strong booster effect. Represented here are immunogenicity results in subjects who were seronegative to the relevant HPV type at Day 1 and PCR-negative to the relevant HPV type through Month 60.1
Reference
Data on file, MSD.
1/Data on file/V501-007 Results Memo - ACM/p.1/ 2.
1/Data on file/V501-007 Results Memo - ACM/p.1/ 3.
1/Data on file/V501-007 Results Memo - ACM/p.2/ 6.
1/Data on file/V501-007 Results Memo - ACM/p.2/ 6; p. 3/ 2.
1/Data on file/V501-007 Results Memo - ACM/p.14/Table 11.
1/Data on file/V501-007 Results Memo - ACM/p.16/Table 13.
1/Data on file/V501-007 Results Memo - ACM/p.15/Table 12.
1/Data on file/V501-007 Results Memo - ACM/p.17/Table 14.