九价人乳头瘤病毒疫苗接种后保护效果、免疫原性及安全性meta分析

Efficacy,immunogenicity and safety of vaccination of 9-valent human papillomavirus vaccine: a meta-analysis

目的评价九价人乳头瘤病毒(HPV)疫苗接种后保护效果、免疫原性及安全性,为中国HPV免疫策略制定提供循证依据。方法检索中国知网数据库(CNKI)、万方数据知识服务平台、维普期刊资源整合服务平台(VIP)、Medline/PubMed数据库、EMBASE数据库、Cochrane Library数据库和clinicaltrials.gov数据库,收集2018年8月31日之前公开发表的关于HPV疫苗接种后保护效果、免疫原性及安全性的相关文献,应用Stata 12.0软件对纳入的文献进行meta分析。结果最终纳入5篇英文文献共4个随机对照试验,累计研究对象16 239人。在符合方案(PP)人群中,九价HPV疫苗组较四价HPV疫苗组人群在预防HPV31、33、45、52、58基因型相关疾病方面表现出较强的保护效果,而HPV6、11、16、18基因型相关疾病2组人群预防效果差异无统计学意义(P> 0.05);在意向性分析(ITT)人群中,实验组接种前未发生HPV感染的接种者HPV31、33、45、52、58基因型相关疾病发生率低于对照组,保护率为100%(70.7%～100%),而接种前已发生HPV感染的接种者2组人群发病率差异无统计学意义(P> 0.05)。HPV31、33、45、52、58基因型疫苗株的抗体阳性率合并效应值为RR=8.43(95%CI=4.88～14.57),而HPV6、11、16、18基因型九价HPV疫苗组与四价HPV疫苗组的免疫学效果差异无统计学意义(P> 0.05)。九价HPV疫苗组注射部位局部反应发生率大于四价HPV疫苗组,合并效应值为RR=1.07(95%CI=1.05～1.08);全身不良反应的发生率2组差异无统计学意义(P> 0.05);九价HPV疫苗组严重不良反应发生率大于四价HPV疫苗组,合并效应值为RR=1.27(95%CI=1.05～1.54),但其中经证实的与疫苗相关的严重不良反应发生情况较少(<0.1%)且差异无统计学意义(P> 0.05);在PP人群中,九价HPV疫苗组较四价HPV疫苗组在预防HPV31、33、45、52、58基因型相关高级别宫颈、外阴、阴道疾病方面表现出较强的保护效果,而在预防HPV6、11、16、18基因型相关疾病中2组预防效果差异无统计学意义(P> 0.05)。结论九价HPV疫苗对预防相关类型HPV所致宫颈及外生殖器病变安全有效,免疫效果良好。

Objective To assess the efficacy,immunogenicity and safety of vaccination of 9-valent human papillomavirus (9vHPV) vaccine and to provide evidences for developing vaccination strategies for HPV vaccine in China. Methods We retrieved studies on the efficacy,immunogenicity and safety of the mass vaccination of 9vHPV vaccine and quadrivalent HPV (qHPV) vaccine published till August 31,2018 through China National Knowledge Infrastructure (CNKI),Wanfang Database,Chinese Sci-Tech Journals Database (VIP),Medline/PubMed,the Excerpta Medicadatabase (EMBASE),Cochrane Library,and the database of clinicaltrials.gov and conducted a meta-analysis using Stata 12.0. Results Totally four randomized controlled trials (RCTs) involving 16 239 participants and one other survey were included in the meta-analysis. The protective effect of 9vHPV vaccine was stronger than that of qHPV vaccine on diseases related to HPV31,33,45,52, and 58 infection but the protective effects of the two vaccines were not significantly different on diseases related to HPV 6, 11,16,and 18 (P > 0.05 for all) among protocol populations (PPs). The results of intention to treat (ITT) analysis demonstrated that the incidence rates of diseases related to HPV31,33,45,52,and 58 infection were lower among the participants without HPV infection before HPV vaccine inoculation than those among the controls,with the protection rates of 70.7%-100%;while the incident rates were not significantly different between the two groups for the participants with HPV infection before HPV vaccine inoculation (P > 0.05). The positive rates of serum HPV31,33,45,52,58 antibody were significantly higher among the participants having 9vHPV vaccine inoculation than those among the participants having qHPV vaccine inoculation,with a pooled rate ratio (RR) of 8.43 (95% confidence interval [95% CI]: 4.88-14.57);whereas there were no significant differences between the immunization effect of 9vHPV and qHPV vaccine inoculation on HPV 6, 11,16,and 18 (P > 0.05 for all). A higher incidence rate of reaction at injection site was reported among the participants with 9vHPV vaccine than that among those with qHPV vaccine,with a pooled RR of 1.07 (95% CI: 1.05-1.08),while the incidence rates of systemic adverse events were not significantly different between the participants with the two vaccines. Even though the incidence rate of serious adverse events was higher among the participants with 9vHPV vaccine than that among those with qHPV vaccine,with a pooled RR of 1.27 (95% CI: 1.05-1.54),the confirmed vaccination-related serious adverse events were rare (< 0.1%) and of insignificant difference between the two groups of participants. Among the PPs,the protective effects of 9vHPV vaccine inoculation against major cervical,vulvar,and vaginal diseases related to HPV31,33,45,52,and 58 infection were stronger than those of qHPV vaccine;but the protective effects of 9vHPV and qHPV vaccine inoculation against diseases related to HPV6,11,16,18 infection were not significantly different (P > 0.05). Conclusion The vaccination of 9vHPV vaccine is effective in prevention of cervical and genital disease associated with HPV infections of some genotypes.