HPV Vaccine Trial

致癌类型的HPV感染几乎导致全世界所有宫颈癌病例以及各种其他肛门生殖器和头颈部癌症的子集。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的L1结构蛋白的疫苗，其自组装成构象正确的VLP，已被证明通常是安全的，免疫原性的，并有效地预防与HPV-16/18相关的宫颈癌前病变。 在哥斯达黎加进行了一项基于社区的HPV 16/18 VLP疫苗的3期随机对照试验。 选择哥斯达黎加进行试验是因为我们在那里进行了广泛成功的科学合作，宫颈癌的高风险，提供国家联系的普遍医疗系统，以及在需要多年密切临床随访的情况下参与率很高的可能性。 哥斯达黎加HPV-16/18疫苗试验的7 466名妇女的随机化和3剂疫苗接种已成功完成。 在跟踪的头四年，每年或每半年对妇女进行一次积极跟踪，此后每两年跟踪一次。女性已在试验的设盲期完成了前4年的随访，并已入组研究的延长（长达10年）随访期。在试验的4年设盲期结束时，为试验参与者提供交叉接种。 这项研究的结果表明：1）该疫苗在预防HPV 16或18型新感染方面非常有效，2）该疫苗对与HPV 16或18型遗传相关的HPV类型提供部分保护，3）该疫苗无助于治疗现有感染，4）少于3剂的疫苗保护以及完整的3剂系列至少4年，5）疫苗保护肛门免受HPV感染，6）疫苗影响随着接种时年龄的增加而下降，7）疫苗接种诱导接种个体血清中的交叉中和潜力，8）由自然HPV感染产生的适度水平的抗体提供部分保护以防止再感染，以及9）来自HIV感染率高的地区的疫苗中产生的抗体水平与我们在哥斯达黎加的试验中的参与者中观察到的抗体水平相当。 为了支持疫苗试验，正在进行或计划进行各种方法学和辅助项目，以最大限度地提高主要工作的产量。这包括评价保护的免疫学相关性，包括病毒中和、总类型特异性抗体和抗体亲合力的测量。 自然感染妇女的免疫保护相关性正在研究中，研究正在进行中，以更好地了解为什么接种疫苗的妇女可能会对疫苗配方中不包括的HPV类型提供保护，以及为什么单剂量疫苗（仅初免）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感染的自然史以及宫颈肿瘤的自然史。这项工作由NCI校内基金和NIH妇女健康研究办公室（ORWH）赞助。它以前与项目Z 01 CP 010177相关。

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.