中华流行病学杂志  2023, Vol. 44 Issue (5): 851-854   PDF    
http://dx.doi.org/10.3760/cma.j.cn112338-20221025-00905
中华医学会主办。
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文章信息

贾鑫华, 匡雪凤, 陈亚涵, 李煜霏, 毕兆峰, 吴婷, 乔友林.
Jia Xinhua, Kuang Xuefeng, Chen Yahan, Li Yufei, Bi Zhaofeng, Wu Ting, Qiao Youlin
人乳头瘤病毒疫苗长期保护效力研究进展
Progress in research of long-term protective efficacy of human papillomavirus vaccine
中华流行病学杂志, 2023, 44(5): 851-854
Chinese Journal of Epidemiology, 2023, 44(5): 851-854
http://dx.doi.org/10.3760/cma.j.cn112338-20221025-00905

文章历史

收稿日期: 2022-10-25
人乳头瘤病毒疫苗长期保护效力研究进展
贾鑫华1,2 , 匡雪凤1,2 , 陈亚涵3 , 李煜霏1,2 , 毕兆峰1 , 吴婷1 , 乔友林1,4     
1. 厦门大学公共卫生学院国家传染病诊断试剂与疫苗工程技术研究中心, 厦门 361102;
2. 国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院流行病学研究室, 北京 100021;
3. 首都医科大学燕京医学院, 北京 101300;
4. 中国医学科学院北京协和医学院群医学及公共卫生学院全球健康中心, 北京 100730
摘要: HPV疫苗对宫颈癌的预防作用已经在众多临床试验和真实世界中得到验证。其中试验人群的随访年限一般为5~6年。临床试验结束后,为了验证疫苗的长期有效性,部分地区开展了系列长期随访研究,本文检索了目前国内外对HPV疫苗长期保护效力相关研究。目前公开的数据显示对疫苗保护型别相关的宫颈上皮内瘤病变2级及以上保护效力均高于90%。
关键词: 宫颈癌    人乳头瘤病毒疫苗    效力    长期随访    
Progress in research of long-term protective efficacy of human papillomavirus vaccine
Jia Xinhua1,2 , Kuang Xuefeng1,2 , Chen Yahan3 , Li Yufei1,2 , Bi Zhaofeng1 , Wu Ting1 , Qiao Youlin1,4     
1. The State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen 361102, China;
2. Department of Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China;
3. Yanjing Medical College, Capital Medical University, Beijing 101300, China;
4. Center for Global Health, School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
Abstract: The efficacy of HPV vaccine in preventing cervical cancer has been demonstrated in numerous clinical trials and clinical uses. The follow-up after clinical trials usually last for 5-6 years to evaluate the long-term efficacy, and a series of long-term follow-up studies have been conducted in some regions. The literature retrieval of HPV vaccine long term efficiency research both at home and abroad indicated that the protective efficacy of the vaccine against vaccine-type-related cervical intraepithelial neoplasia grade 2 and above is higher than 90%.
Key words: Cervical cancer    Human papillomavirus vaccine    Efficacy    Long-term follow-up    

宫颈癌是常见的妇科恶性肿瘤之一。2020年全球宫颈癌新发604 327例,死亡341 831例[1],2015年我国宫颈癌新发约180 000例,超过5万例死于宫颈癌[2]。研究发现近95%的宫颈癌发生与HPV感染有关[3]。目前已发现超过200种HPV[4],根据致癌性将其分为高危型(HR-HPV)和低危型(LR-HPV)[5]。低危型HPV-6、HPV-11多与生殖器疣相关[6],HR-HPV与多种恶性肿瘤相关,包括女性的宫颈癌、外阴癌、阴道癌、肛门癌、口咽癌和男性的阴茎癌、肛门癌、口咽癌[7-9]。高危型HPV-16、HPV-18、HPV-31、HPV-33、HPV-35、HPV-39、HPV-45、HPV-51、HPV-52、HPV-56、HPV-58、HPV-59与宫颈癌的发生、发展相关[10]。HPV疫苗对宫颈癌有较好的预防作用,许多临床试验报告显示,对HPV-16、HPV-18感染和宫颈癌前病变的预防效果接近100%[7-16]。对疫苗长期效力的研究主要来自于疫苗人群的长期随访,和对疫苗接种人群在医疗系统中的监测。疫苗的长期保护效力数据将有助于增强公众信心,为HPV疫苗扩大免疫规划提供循证依据。本文旨在综述国内已上市疫苗的长期保护效力,目前已上市的有二价、四价、九价共3类5种,其中二价有3种,分别是以昆虫杆状细胞、大肠埃希菌和毕赤酵母为抗原表达体系。二价HPV疫苗可预防高危型HPV-16、HPV-18感染;四价HPV疫苗在二价的基础上,增加了低危型HPV-6、HPV-11,九价HPV疫苗在四价的基础上又增加了5种高危型(HPV-31、HPV-33、HPV-45、HPV-52、HPV-58)。在接种程序上,3种二价HPV疫苗9~14岁接种2剂次,超过15周岁接种3剂次;四价和九价HPV疫苗均接种3剂次。九价HPV疫苗在国内的疫苗保护效力验证还没有结束。基于毕赤酵母表达体系的二价疫苗数据暂时没有公开,其余二价疫苗对HPV-16、HPV-18相关的宫颈上皮内瘤病变(CIN)1级及以上(CIN1+)、2级及以上(CIN2+)和6个月持续性感染的效力均在80%以上[11-15]

1. 二价疫苗: 二价疫苗的长期随访研究主要集中在以昆虫杆状细胞表达体系的Cervarix[16-24],在哥斯达黎加、芬兰、巴西等地均有开展。其中在HPV 023项目中对受试者随访了8.4年[25],在HPV 023扩展项目中为9.4年[19]。迄今为止,二价疫苗最长的随访期为11.1年[16]

较为经典的二价疫苗的HPV 023扩展项目是一项双盲、随机、安慰剂对照研究,对象是15~25岁的女性,接种前细胞学正常。在接种疫苗9.4年后,疫苗组没有发生HPV-16、HPV-18相关的感染或细胞组织病理学异常。对HPV-16、HPV-18持续性感染的保护效力为100.0%,对低度鳞状上皮内病变的保护效力为95.0%,对CIN1+的保护效力为100.0%,对HPV-16、HPV-18相关CIN2+的保护效力为100.0%[19]。Porras等[16]的研究显示其二价疫苗女性针对HPV-16、HPV-18相关的CIN2+和CIN3级及以上(CIN3+)的累积保护效力分别为97.4%(95%CI:88.0%~99.6%)和94.9%(95%CI:73.7%~99.4%)。综合各项研究,在 < 25岁的女性中,对HPV-16、HPV-18相关CIN2+保护效力均为95.0%以上,对HPV-16、HPV-18相关的6个月持续性感染的保护效率为91.4%~100.0%,对HPV-16、HPV-18相关的12个月持续性感染保护效力为100.0%。

Wheeler等[22]的研究显示,二价疫苗对HPV-16、HPV-18持续感染、细胞学异常和CIN1+表现出较好的保护效力。Kurosawa等[20]对25~26岁的429名女性进行了9年的随访,结果显示,疫苗组HPV-16、HPV-18感染率为0(0/150),未接种组为5.4%(15/279),差异有统计学意义(P=0.001 8),疫苗保护效力为100.0%。疫苗组的交叉保护型HPV-31、HPV-45、HPV-52感染率明显低于未接种组(3.3% vs. 10.0%,P=0.013)。二价疫苗在长期随访中,HPV-16、HPV-18相关的CIN2+发病率为0~30/10 000人年,HPV-16、HPV-18相关6个月持续性感染的发病率为0~6/10 000人年。

2. 四价疫苗: 共检索到9项对四价疫苗的长期效力评价研究[26-34],集中在丹麦、冰岛、挪威、瑞典和美国等地。与二价疫苗的长期随访相比,部分四价疫苗长期随访评估了对男性接种HPV疫苗的长期效果。

Villa等[35]对四价疫苗的效力和免疫原性进行了5年的评估,研究对象为241名16~23岁的女性,结果显示,在疫苗组中没有出现HPV-6、HPV-11、HPV-16、HPV-18相关的CIN或生殖器疣的病例,安慰剂接受者中有6例出现HPV-6、HPV-11、HPV-16、HPV-18相关的CIN或生殖器疣。对来自丹麦、冰岛、挪威和瑞典的受试者,在基础研究结束后开展了10年的长期随访(V501-015-21)。通过登记数据来评估疫苗效力和安全性,在第5年和第10年通过血清学测试来评估免疫原性。此后再次增加了一个8年的延长期(V501-015-22),以继续评估长期效力和免疫原性。保护效力和安全性将通过基于登记数据的随访进行评估,而免疫原性在延长后的第4年和第8年左右通过血清学检测进行评估。此外,北欧地区P015项目随访8年[36],V501-018-11项目随访10年[31],FUTURE Ⅱ随访14年[26]。FUTURE Ⅱ研究在北欧地区进行,纳入16~23岁的女性接受了3剂次四价疫苗,并被跟踪调查了≥10年。在整个研究期间,方案验证人群(n=2 121)中没有观察到与HPV-16、HPV-18相关的CIN2+,保护效力为100.0%(95%CI:94.7%~100.0%),在接种疫苗后14年内有持续保护的趋势。对 > 23岁的女性最长随访期是P019-21试验中的10年,共3 919名24~45岁女性被纳入[34, 37],该研究证明了四价疫苗在预防HPV-6、HPV-11、HPV-16、HPV-18感染及其相关的CIN方面具有10年的保护效力。

对9~15岁人群的V501-018-11试验中,在10年的随访期间没有观察到CIN/阴茎上皮内瘤变及相关疾病(PIN)[31]。对于男性,一项在16个国家的46个中心进行长期随访纳入了异性恋和同性恋人群[33]。在之前的研究中接受过至少1剂次四价HPV疫苗的参与者被定义为早期疫苗接种组(EVG)。前试验中的安慰剂接受者在试验结束时被提供3剂次四价HPV疫苗。对EVG随访时间MQ1Q3)为9.5(0.1,11.5)年,而四价HPV疫苗在接受第三剂疫苗后随访时间MQ1Q3)为4.7(0.0,6.6)年。在这两组的长期随访中,均没有新报告的HPV-6、HPV-11、HPV-16、HPV-18相关的PIN或生殖器疣病例。V501-P020试验在18个国家入组了4 065名16~26岁的健康男性(包括异性恋男性或MSM)并随访了3年,证实了四价疫苗对男性HPV感染和生殖器疾病方面的保护效力[38-39]。在接种了四价疫苗的人群中,没有出现HPV-16、HPV-18相关的CIN2+。HPV-6、HPV-11、HPV-16、HPV-18相关的6个月持续性感染的发病率为30/10 000人年~60/10 000人年。

3. 九价疫苗: 九价HPV疫苗的长期随访共2项[40-41]。其中在丹麦、挪威和瑞典的长期随访为8年(斯堪的纳维亚项目)[40],研究对象是16~26岁女性,结果表明九价疫苗可以预防持续的HPV感染、细胞学异常、高级别病变以及与疫苗所覆盖的HPV类型相关的宫颈手术。在非洲、亚太、欧洲、拉丁美洲和北美洲地区进行的长期随访同样为8年(V503-002)[41]。疫苗接种后约8年,女性中没有出现与九价疫苗类型有关病变。

V503-002项目纳入了男性,在疫苗接种后的8年,没有出现与九价疫苗类型有关的PIN或生殖器疣的病例[41]

在九价的长期随访研究中,HPV-6、HPV-11、HPV-16、HPV-18、HPV-31、HPV-33、HPV-45、HPV-52、HPV-58相关的CIN、6个月持续性感染、12个月持续性感染发生率分别为18.6/10 000人年、49.2/10 000人年、24.5/10 000人年,男性的持续性感染发生率更低,6个月和12个月持续性感染发生率分别为37.2/10 000人年和12.4/10 000人年[40-41]

综上所述,二价、四价和九价疫苗对与疫苗相关的HPV型别引起的CIN1+的保护效力维持在80%以上。这些疫苗对与疫苗相关的HPV型别引起的CIN2+保护效力维持在90%以上,对6个月持续性感染和12个月持续性感染的保护效力同样维持在90%以上。这些结果表明,二价、四价和九价疫苗在预防与HPV相关的宫颈病变方面具有高度的持久保护效力。HPV疫苗是预防HPV感染、减少宫颈癌及癌前病变发生的有效措施,HPV疫苗效力是疫苗的核心。不同抗原表达体系保护效力有所差异,目前长期随访研究集中在进口的三种疫苗在国外人群的验证。与其他国家相比,我国HPV感染高发型别有所差异,国内上市的HPV疫苗的长期保护效力是接下来的研究方向之一。目前有多家国内厂商进行HPV疫苗的临床注册,对三期试验人群进行长期随访可以获得长期有效性、免疫原性和安全性的结果。

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