HPV16/18二价疫苗预防宫颈癌前病变的Meta分析

目的评价人乳头状瘤病毒(human papillomaviruses,HPV)16/18二价疫苗在预防宫颈HPV16/18相关感染和癌前病变的作用,对预防接种人群提出合理化建议。方法通过Web of science搜索引擎搜索MEDLINE、Web of Science核心合集、BIOSIS Previews等数据库,通过Endnote X9 Online Search搜索EBSCO数据库,通过Cochrane Library搜索Cochran Central Register of Controlled Trials(CENTRAL)数据库。另外,通过www.clinicaltrials.gov临床试验平台获取相关文献和数据。搜索的英文主题词或关键词包括HPV16/18、bivalent vaccine、cervical neoplasm和clinical trial。采用Review manager 5.3评估HPV16/18二价疫苗接种的近期和远期疗效、可靠性、危险度和统计偏倚,并根据结果做预防接种管控分析。结果总计纳入了2004-2017年19篇英文文献报告的10个临床随机研究结果,40066例受试者进入Meta分析。在HPV阴性的健康女性受试者中,接种HPV16/18二价疫苗者与对照组相比HPV16/18相关宫颈偶发性感染(incident infection)、6个月和12个月的持续性感染(persistent infection,PI)相对风险(relative risk,RR)分别降低68%~78%、82%~94%和84%~97%;HPV16/18相关宫颈不典型鳞状细胞-意义未明及以上(ASC-US+)、宫颈上皮内瘤变1级及以上(CIN1+)和2级及以上(CIN2+)的患病RR分别降低89%~94%、87%~91%和87%~92%;任何HPV相关ASC-US+、CIN1+、CIN2+、CIN3+和原位癌(AIS)的患病RR,分别降低28%~29%、50%、64%~72%、86%~93%和93%。在健康女性受试者中,不管入组时HPV DNA状态如何,与对照组相比,接种二价疫苗至少降低1次HPV16/18相关ASC-US+、CIN1+、CIN2+、CIN3+和AIS患病RR,分别为57%、50%、45%、34%和70%;任何HPV表型相关CIN1+、CIN2+、CIN3+和AIS的患病RR降低,分别为26%~28%、28%~33%、34%~45%和77%。结论二价疫苗对于基线时没有感染HPV的年轻女性宫颈偶发性和持续性感染以及宫颈癌前病变具有良好的保护作用。即使对于HPV暴露的不同风险人群,二价疫苗对于降低宫颈癌前病变和原位癌的患病风险也有一定的作用。

HPV18 Utilizes Two Alternative Branch Sites for E6*I Splicing to Produce E7 Protein

Human papillomavirus 18(HPV18) E6 and E7 oncogenes are transcribed as a single bicistronic E6 E7 pre-mRNA. The E6 ORF region in the bicistronic E6 E7 pre-mRNA contains an intron. Splicing of this intron disrupts the E6 ORF integrity and produces a spliced E6*I RNA for efficient E7 translation. Here we report that the E6 intron has two overlapped branch point sequences(BPS) upstream of its 30 splice site, with an identical heptamer AACUAAC, for E6*I splicing. One heptamer has a branch site adenosine(underlined) at nt 384 and the other at nt 388. E6*I splicing efficiency correlates to the expression level of E6 and E7 proteins and depends on the selection of which branch site. In general, E6*I splicing prefers the 30 ss-proximal branch site at nt 388 over the distal branch site at nt 384. Inactivation of the nt 388 branch site was found to activate a cryptic acceptor site at nt 636 for aberrant RNA splicing. Together, these data suggest that HPV18 modulates its production ratio of E6 and E7 proteins by alternative selection of the two mapped branch sites for the E6*I splicing, which could be beneficial in its productive or oncogenic infection according to the host cell environment.