亚洲人群HPV疫苗免疫原性及安全性的Meta分析

Immunogenicity and safety of HPV vaccine in Asia population: a meta-analysis

摘要

目的 评估人乳头状瘤病毒(HPV)疫苗在亚洲人群中接种后的免疫原性和安全性。方法 本研究分别检索英文数据库(PubMed、Embase、Web of Science、Clinical Trails、Cochrane library)和中文数据库(中国知网、万方、维普),自建库至2022年4月,关于亚洲人群进行的HPV疫苗安全性和免疫原性临床试验文献.采用主题词与自由词灵活搭配检索并结合纳排标准筛选文献,对最终纳入文献进行质量评价并提取资料,应用Meta分析合并评估。结果 最终纳入16篇随机对照试验(RCT)研究,累计研究对象25485人.Meta分析表明对于HPV疫苗免疫原性,HPV16型特异性血清转化率合并效应值RR为43.74(16.51~115.85),HPV18型特异性血清转化率合并效应值RR为45.72(8.78~238.13).对于HPV疫苗安全性,二价与四价HPV疫苗接种局部不良事件风险试验组高于对照组,RR为1.52(1.34~1.73)和1.38(1.20~1.59).二价HPV疫苗与四价HPV疫苗试验组发生全身性不良事件的风险也高于对照组,RR分别为1.21(1.11~1.32)和1.13(0.99~1.30)。结论 接种亚洲人群HPV疫苗后血清抗体阳转率高于未接种者,提示接种HPV疫苗可以提高个体特异性抗体水平,接种HPV疫苗发生局部和全身性安全事件的风险均高于对照组,提示仍要高度重视HPV疫苗的安全性问题.

Abstract

Objective To evaluate immunogenicity and safety of human papillomavirus (HPV) vaccine in Asia population. Methods English databases such as PubMed, Embase, Web of Science, Clinical trails and Cochrane Library, and Chinese databases such as CNKI and Wan Fang Data were searched from their inception to April 2022 for randomized controlled trials (RCTs) about immunogenicity and safety of HPV vaccine. Using flexible collocation of subject words and free words, the literature were searched and screened according to inclusion and exclusion criteria. Then quality of the literature finally included was assessed and the data were extracted. A meta-analysis was conducted to merge the assessments through Review Manager 5.4 and Stata 14.0 software. Results 16 RCTs were included, and 25485 subjects were involved in these studies. Meta-analysis showed that HPV vaccine had good immunogenicity: the RR (relative risk) of HPV16 specific serum conversion rate merged effect value was 43.74 (16.51-115.85) and that of HPV18 specific serum conversion rate merged effect value was 45.72 (8.78-238.13). In safety of HPV vaccine, the risks of local adverse events caused by bivalent HPV vaccine (RR=1.52, 95%CI: 1.34-1.73) and quadrivalent HPV vaccine (RR=1.38, 95%CI: 1.20-1.59) in the experimental group were higher than those in the control group. Also, the risks of systemic adverse events caused by bivalent HPV vaccine (RR=1.21, 95%CI: 1.11-1.32) and quadrivalent HPV vaccine (RR=1.13, 95%CI: 0.99-1.30) in the experimental group were higher than those in the control group. Conclusion In these women population who had been inoculated HPV vaccine, the positive serum antibody conversion rate after inoculation of HPV vaccine for Asian population is higher than that in those women who hadn't been inoculated the HPV vaccine, suggesting that inoculation of HPV vaccine can improve individual's specific antibody level. However, the risks of local and systemic safety events caused by HPV vaccines in the experimental group are higher than those in the control group, suggesting that the safety problem of HPV vaccine should be emphasized.

关键词

人乳头瘤病毒 / HPV疫苗 / Meta分析 / 免疫原性 / 安全性

Key words

human papillomavirus / HPV vaccine / meta-analysis / immunogenicity / safety

参考文献

[1] Bhatla N, Aoki D, Sharma DN, et al. Cancer of the cervix uteri: 2021 update[J]. Int J Gynaecol Obstet. 2021, 155 Suppl 1(Suppl 1): 28-44.

[2] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.

[3] Ahmad A. Breast Cancer Statistics: Recent Trends[J]. Adv Exp Med Biol, 2019, 1152: 1-7.

[4] Zhao S, Huang L, Basu P, et al. Cervical cancer burden, status of implementation and challenges of cervical cancer screening in Association of Southeast Asian Nations (ASEAN) countries[J]. Cancer Lett, 2022, 525: 22-32.

[5] zur Hausen H. Papillomavirus infections-a major cause of human cancers[J]. Biochim Biophys Acta, 1996, 1288(2): F55-F78.

[6] Bergman H, Buckley BS, Villanueva G, et al. Comparison of different human papillomavirus (HPV) vaccine types and dose schedules for prevention of HPV-related disease in females and males[J]. Cochrane Database Syst Rev, 2019, 2019(11): CD013479.

[7] Gultekin M, Ramirez PT, Broutet N, et al. World Health Organization call for action to eliminate cervical cancer globally[J]. Int J Gynecol Cancer, 2020, 30(4): 426-427.

[8] Huang LM, Puthanakit T, Cheng-Hsun C, et al. Sustained Immunogenicity of 2-dose Human Papillomavirus 16/18 AS04-adjuvanted Vaccine Schedules in Girls Aged 9-14 Years: A Randomized Trial[J]. J Infect Dis, 2017, 215(11): 1711-1719.

[9] Garland SM, Cheung TH, McNeill S, et al. Safety and immunogenicity of a 9-valent HPV vaccine in females 12-26 years of age who previously received the quadrivalent HPV vaccine[J]. Vaccine, 2015, 33(48): 6855-6864.

[10] Einstein MH, Levin MJ, Chatterjee A, et al. Comparative humoral and cellular immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine in healthy women aged 18-45 years: follow-up through Month 48 in a Phase III randomized study[J]. Hum Vaccin Immunother, 2014, 10(12): 3455-3465.

[11] Basu P, Malvi SG, Joshi S, et al. Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study[J]. Lancet Oncol, 2021, 22(11): 1518-1529.

[12] Joura EA, Ulied A, Vandermeulen C, et al. Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27-45 years of age compared to women 16-26 years of age: An open-label phase 3 study[J]. Vaccine, 2021, 39(20): 2800-2809.

[13] Shing JZ, Hu S, Herrero R, et al. Precancerous cervical lesions caused by non-vaccine-preventable HPV types after vaccination with the bivalent AS04-adjuvanted HPV vaccine: an analysis of the long-term follow-up study from the randomised Costa Rica HPV Vaccine Trial[J]. Lancet Oncol, 2022, 23(7): 940-949.

[14] Huh WK, Joura EA, Giuliano AR, et al. Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial[J]. Lancet, 2017, 390(10108): 2143-2159.

[15] Puthanakit T, Huang LM, Chiu CH, et al. Randomized Open Trial Comparing 2-Dose Regimens of the Human Papillomavirus 16/18 AS04-Adjuvanted Vaccine in Girls Aged 9-14 Years Versus a 3-Dose Regimen in Women Aged 15-25 Years[J]. J Infect Dis, 2016, 214(4): 525-536.

[16] Qiao YL, Wu T, Li RC, et al. Efficacy, Safety, and Immunogenicity of an Escherichia coli-Produced Bivalent Human Papillomavirus Vaccine: An Interim Analysis of a Randomized Clinical Trial[J]. J Natl Cancer Inst, 2020, 112(2): 145-153.

[17] Lim BK, Ng KY, Omar J, et al. Immunogenicity and Safety of the AS04-adjuvanted Human Papillomavirus-16/18 Cervical Cancer Vaccine in Malaysian Women Aged 18-35 years: A Randomized Controlled Trial[J]. Med J Malaysia, 2014, 69(1): 2-8.

[18] Konno R, Yoshikawa H, Okutani M, et al. Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical intraepithelial neoplasia and cervical infection in young Japanese women[J]. Hum Vaccin Immunother, 2014, 10(7): 1781-1794.

[19] Kim YJ, Kim KT, Kim JH, et al. Vaccination with a human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in Korean girls aged 10-14 years[J]. J Korean Med Sci, 2010, 25(8): 1197-1204.

[20] Kim SC, Song YS, Kim YT, et al. Human papillomavirus 16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in 15-25 years old healthy Korean women[J]. J Gynecol Oncol, 2011, 22(2): 67-75.

[21] Khatun S, Akram Hussain SM, Chowdhury S, et al. Safety and immunogenicity profile of human papillomavirus-16/18 AS04 adjuvant cervical cancer vaccine: a randomized controlled trial in healthy adolescent girls of Bangladesh[J]. Jpn J Clin Oncol, 2012, 42(1): 36-41.

[22] Bhatla N, Suri V, Basu P, et al. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women[J]. J Obstet Gynaecol Res, 2010, 36(1): 123-132.

[23] Wu T, Hu YM, Li J, et al. Immunogenicity and safety of an E. coli-produced bivalent human papillomavirus (type 16 and 18) vaccine: A randomized controlled phase 2 clinical trial[J]. Vaccine, 2015, 33(32): 3940-3946.

[24] Ngan HY, Cheung AN, Tam KF, et al. Human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in healthy Chinese women from Hong Kong[J]. Hong Kong Med J, 2010, 16(3): 171-179.

[25] Zhu F, Li J, Hu Y, et al. Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years[J]. Hum Vaccin Immunother, 2014, 10(7): 1795-1806.

[26] Zhu FC, Hu SY, Hong Y, et al. Efficacy, immunogenicity and safety of the AS04-HPV-16/18 vaccine in Chinese women aged 18-25 years: End-of-study results from a phase II/III, randomised, controlled trial[J]. Cancer Med, 2019, 8(14): 6195-6211.

[27] Yoshikawa H, Ebihara K, Tanaka Y, Noda K. Efficacy of quadrivalent human papillomavirus (types 6, 11, 16 and 18) vaccine (GARDASIL) in Japanese women aged 18-26 years[J]. Cancer Sci, 2013, 104(4): 465-472.

[28] Chen W, Zhao Y, Xie X, et al. Safety of a quadrivalent human papillomavirus vaccine in a Phase 3, randomized, double-blind, placebo-controlled clinical trial among Chinese women during 90 months of follow-up[J]. Vaccine, 2019, 37(6): 889-897.

[29] Mikamo H, Yamagishi Y, Murata S, et al. Efficacy, safety, and immunogenicity of a quadrivalent HPV vaccine in Japanese men: A randomized, Phase 3, placebo-controlled study[J]. Vaccine, 2019, 37(12): 1651-1658.

[30] Li R, Li Y, Radley D, et al. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, double-blind, placebo-controlled trial in Chinese males and females[J]. Vaccine, 2012, 30(28): 4284-4291.

[31] Kang S, Kim KH, Kim YT, et al. Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, placebo-controlled trial in 176 Korean subjects[J]. Int J Gynecol Cancer, 2008, 18(5): 1013-1019.

[32] Villa A, Patton LL, Giuliano AR, et al. Summary of the evidence on the safety, efficacy, and effectiveness of human papillomavirus vaccines: Umbrella review of systematic reviews[J]. J Am Dent Assoc, 2020, 151(4): 245-254.

[33] Drolet M, Bénard É, Pérez N, et al. HPV Vaccination Impact Study Group. Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis[J]. Lancet, 2019, 394(10197): 497-509.

[34] Bruni L, Diaz M, Barrionuevo-Rosas L, et al. Global estimates of human papillomavirus vaccination coverage by region and income level: a pooled analysis[J]. Lancet Glob Health, 2016, 4(7): e453-e463.

[35] De Oliveira LH, Janusz CB, Da Costa MT, et al. HPV vaccine introduction in America: a decade of progress and lessons learned[J]. Expert Rev Vaccines, 2022, 21(11): 1569-1580.

[36] Zhu K, Tian Y, Dong X, et al. The cost-effectiveness of bivalent, quadrivalent, and nine-valent HPV vaccination in Asia: a systematic review[J]. Arch Gynecol Obstet, 2022, 306(1): 173-187.

[37] Muñoz N, Manalastas R Jr, Pitisuttithum P, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial[J]. Lancet, 2009, 373(9679): 1949-1957.

[38] Sow PS, Watson-Jones D, Kiviat N, et al. Safety and immunogenicity of human papillomavirus-16/18 AS04-adjuvanted vaccine: a randomized trial in 10-25-year-old HIV-Seronegative African girls and young women[J]. J Infect Dis, 2013, 207(11): 1753-1763.

[39] Skinner SR, Szarewski A, Romanowski B, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study[J]. Lancet, 2014, 384(9961): 2213-2227.

[40] Aldakak L, Huber VM, Rühli F, et al. Sex difference in the immunogenicity of the quadrivalent Human Papilloma Virus vaccine: Systematic review and meta-analysis[J]. Vaccine, 2021, 39(12): 1680-1686.

[41] Li Y, Zhu P, Wu M, et al. Immunogenicity and safety of human papillomavirus vaccine coadministered with other vaccines in individuals aged 9-25 years: A systematic review and meta-analysis[J]. Vaccine, 2020, 38(2): 119-134.

[42] GlaxoSmithKline Vaccine HPV-007 Study Group, Romanowski B, de Borba PC, et al. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years[J]. Lancet, 2009, 374(9706): 1975-1985.

[43] Garland SM, Pitisuttithum P, Ngan HYS, et al. Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries[J]. J Infect Dis, 2018, 218(1): 95-108.

[44] Ogawa Y, Takei H, Ogawa R, et al. Safety of human papillomavirus vaccines in healthy young women: a meta-analysis of 24 controlled studies[J]. J Pharm Health Care Sci, 2017, 3: 18.

[45] Lv H, Wang S, Liang Z, et al. Immunogenicity and safety of the 9-valent human papillomavirus vaccine in Chinese females 9-45 years of age: A phase 3 open-label study[J]. Vaccine, 2022, 40(23): 3263-3271.