HPV Vaccine Trial

在世界范围内，几乎所有的宫颈癌病例以及其他各种肛门生殖器和头颈部癌症的亚群都是由致癌型HPV感染引起的。针对HPV-16和HPV-18这两种最重要的HPV类型的预防性疫苗接种可以预防全球绝大多数宫颈癌病例和相当大比例的其他HPV相关癌症。基于HPV L1结构蛋白的疫苗可自组装成构象正确的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。在哥斯达黎加进行了一项基于社区的HPV16/18 VLP疫苗3期随机对照试验。哥斯达黎加被选为试验地点，是因为我们在那里开展了广泛成功的科学合作，宫颈癌的高风险，全民医疗系统提供了全国性的联系，以及在需要的多年密切临床随访期间，参与率很高的可能性。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。在头四年的随访中，每年或每半年对妇女进行一次积极随访，此后每两年进行一次。在盲法试验阶段，女性已经完成了前四年的随访，并已被纳入延长（长达10年）的随访研究阶段。在4年盲法试验阶段结束时，向试验参与者提供交叉疫苗接种。从这个研究结果表明,1)疫苗是非常有效的防止新的感染人乳头状瘤病毒类型16或18岁,2)对人乳头状瘤病毒疫苗可提供部分保护类型系统有关HPV 16或18,3)现有疫苗不帮助治疗感染,4)少于3个剂量的疫苗保护以及全系列3-dose至少4年,5)疫苗预防HPV感染在肛门,6)疫苗的影响随着接种年龄的增加而下降；7)疫苗接种在接种个体的血清中诱导交叉中和电位；8)自然HPV感染产生的适度抗体水平提供部分防止再次感染的保护；9)来自HIV感染率高的地区的疫苗产生的抗体水平与我们在哥斯达黎加的试验中观察到的抗体水平相当。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，不受疫苗配方中未包括的HPV类型的影响，以及为什么单剂疫苗（只接种初级疫苗）似乎可以保护数年。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。这项工作由校内NCI基金和美国国立卫生研究院妇女健康研究办公室（ORWH）资助。它以前与Z01 CP010177项目有关。

Infections with oncogenic types of HPV cause virtually all cases of cervical cancer worldwide and subsets of various other anogenital and head and neck cancers. Prophylactic vaccination against HPV-16 and HPV-18, two of the most important HPV types, could protect against a large majority of the cases of cervical cancer globally and a considerable proportion of other HPV-associated cancers. Vaccines based on the L1 structural protein of HPV that self-assemble into conformationally-correct 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 was conducted in Costa Rica. Costa Rica was chosen for the trial because of our extensive successful scientific collaborations there, the 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 in the first four years of follow-up and every two years thereafter. Women have completed their first four years of follow-up in the blinded phase of the trial and have been enrolled in the extended (up to 10 years) follow-up phase of the study. Cross-over vaccination was offered to trial participants at the end of the four-year blinded phase of the trial. Results from this study have shown that 1) the vaccine is highly effective at preventing new infections with HPV types 16 or 18, 2) the vaccine confers partial protection against HPV types phylogenetically related to HPV 16 or 18, 3) the vaccine does not help treat existing infections, 4) fewer than 3 doses of the vaccine protects as well as the full 3-dose series for at least 4 years, 5) the vaccine protects against HPV infection at the anus, 6) Vaccine impact declines with increasing age at vaccination, 7) vaccination induces cross-neutralizing potential in sera of vaccinated individuals, 8) modest levels of antibodies generated by natural HPV infection provide partial protection against re-infection, and 9) antibody levels generated in vaccines from regions with high HIV infection rates are comparable to those observed among participants in our trial in Costa Rica. 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 and why a single vaccine dose (prime-only) appears to protect for several years. 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. This effort is sponsored by Intramural NCI funds and by the NIH Office of Research on Women's Health (ORWH). It was formerly associated with Project Z01 CP010177.