BIOMEDICAL COMPUTING SUPPORT FOR THE DIVISION OF CANCER EPIDEMIOLOGY AND GENETIC

全世界几乎所有的宫颈癌病例都是由致癌型HPV感染引起的。针对两种最重要的HPV类型HPV 16和18的预防性疫苗接种可以预防全球绝大多数宫颈癌病例。基于HPV L1结构蛋白的疫苗可自组装成构象正确的病毒粒子样颗粒（病毒样颗粒或VLPs），已被证明在预防与HPV-16/18相关的宫颈癌前病变方面通常是安全的、免疫原性的和有效的。哥斯达黎加正在进行基于社区的HPV16/18 VLP疫苗3期随机对照试验。选择哥斯达黎加进行3期试验，是因为我们在那里进行了广泛成功的科学合作，宫颈癌的持续高风险，全民医疗系统提供了全国性的联系，并且在许多年的密切临床随访中有很高的参与率的可能性。哥斯达黎加参加HPV-16/18疫苗试验的7,466名妇女的随机化和三剂疫苗接种已成功完成。自登记以来，每年或每半年对妇女进行积极跟踪。目前，妇女正在完成试验的头四年随访，并被要求参加延长（长达10年）的研究随访阶段。当妇女完成四年的积极随访时，将按照试验数据和安全监测委员会（DSMB）的建议，并经监督试验的机构审查委员会（irb）批准，向试验参与者提供交叉疫苗接种。迄今为止，审判仍是蒙在鼓里的。计划进行探索性分析，预计在第一个4年随访结束时或当发生足够数量的事件需要进行评估时，将对该疫苗的预防效果进行初步分析。对该疫苗治疗效益的评估已经完成。分析结果表明，对已经感染的妇女接种疫苗对清除HPV感染没有任何作用。因此，该疫苗不应用于治疗已建立的HPV感染或其相关病变。为了支持疫苗试验，正在进行或计划开展各种方法学和辅助项目，以最大限度地提高主要努力的成果。这包括免疫相关保护的评估，包括病毒中和、总类型特异性抗体和抗体贪婪度的测量。目前正在检查自然感染妇女的保护的免疫学相关性，并正在进行研究，以更好地了解为什么接种疫苗的妇女可能受到保护，免受疫苗配方中未包括的HPV类型的侵害。正在进行或计划进行几项分析，以评估接种疫苗和未接种疫苗的妇女宫颈和其他部位HPV感染以及宫颈瘤变的自然史。

Infections with oncogenic types of HPV cause virtually all cases of cervical cancer worldwide. Prophylactic vaccination against HPV 16 and 18, two of the most important HPV types, could protect against a large majority of the cases of cervical cancer globally. Vaccines based on the L1 structural protein of HPV that self-assemble into conformationally-correct virion-like particles (virus-like particles or VLPs) have been shown to be generally safe, immunogenic and effective at preventing precancerous lesions of the cervix associated with HPV-16/18. A community-based Phase 3 randomized controlled trial of an HPV16/18 VLP vaccine is underway in Costa Rica. Costa Rica was chosen for the Phase 3 trial because of our extensive successful scientific collaborations there, the continued high risk of cervical cancer, the universal medical system providing national linkage, and the likelihood of very high participation over the many needed years of close clinical follow-up. Randomization and 3-dose vaccination of 7,466 women enrolled into the HPV-16/18 Vaccine Trial in Costa Rica has been successfully completed. Women have been followed actively on an annual or semi-annual basis since enrollment. Women are now completing their first four years of follow-up in the trial and are being asked to enroll in the extended (up to 10 years) follow-up phase of the study. As women complete four years of active follow-up, cross-over vaccination will be offered to trial participants, as recommended by the trial Data and Safety Monitoring Board (DSMB) and once approved by the Institutional Review Boards (IRBs) overseeing the trial. To date, the trial remains masked. Exploratory analyses are planned and the primary analysis of the prophylactic effect of this vaccine is expected at the end of the first 4-years of follow-up or when sufficient numbers of events occur to warrant evaluation. Evaluation of the therapeutic benefit of this vaccine has been completed. Results from the analysis indicate that the vaccine does not have any effect on clearance of HPV infections, when administered to women who already have an established infection. Thus, the vaccine should not be used to treat established HPV infections or their associated lesions. In support of the vaccine trials, a variety of methodologic and ancillary projects are underway or planned, that will maximize the yield of the main effort. This includes evaluation of immunological correlates of protection, including viral neutralization, total type-specific antibodies, and measures of antibody avidity. Immunological correlates of protection among naturally infected women are being examined and studies are underway to better understand why vaccinated women might be protected against HPV types not included in the vaccine formulation. Several analyses are underway or planned to evaluate the natural history of HPV infection at cervical and other sites and of cervical neoplasia in vaccinated and unvaccinated women.