Pagliusi Sonia R, Teresa Aguado M
Initiative for Vaccine Research, Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland.
Vaccine. 2004 Dec 16;23(5):569-78. doi: 10.1016/j.vaccine.2004.07.046.
Last year, the World Health Organization (WHO) convened a gathering of experts, including scientists, national regulatory authorities, industry representatives, epidemiologists and government officials from both developed and developing countries to discuss appropriate endpoint measurements for HPV vaccine efficacy and effectiveness trials. The consultation also considered the regulatory requirements and public health issues that vaccine candidates should address before deployment, particularly in developing countries. This report summarizes the discussions and the conclusions reached over the course of the consultation. The general consensus of the consultation was that it would be desirable to have a globally-agreed, measurable efficacy endpoint for considering deployment of HPV vaccines in public health settings. After hearing from experts about virological and clinical endpoints to be considered, requirements of regulatory authorities of various countries and endpoints used to measure efficacy and effectiveness for another known cancer vaccine (hepatitis B), the experts agreed that ethical and time considerations make it necessary to use a surrogate endpoint, and not invasive cervical cancer, to define efficacy of HPV vaccines. While regulatory authorities of each country ultimately will determine the endpoints required for licensure, the consultation recommended that the endpoint for efficacy in population-based studies be, based on current knowledge, histologically-classified cervical intraepithelial neoplasias (CIN) of moderate or high-grade, as well as cancer. Since persistent infection with the same high-risk type is considered a predictor for moderate or high-grade cervical dysplasias and cancer, they might represent a useful endpoint in future vaccine efficacy studies. Indeed, if vaccines prove to be effective against transient or persistent HPV infections, it is likely that they will protect women against cervical cancer. The consultation recognized that in the context of many developing countries, efficacy alone might not provide enough information for countries to decide whether or not to adopt HPV vaccines as a public health prevention tool against cervical cancer. The consultation unanimously agreed that additional clinical bridging studies as well as studies to clarify local epidemiology should be conducted in certain developing countries to determine the potential impact of vaccination. Such countries should also undertake targeted interventions to ensure acceptability and programmatic feasibility of the vaccination. Recognizing that upon vaccine introduction it will be some years before a reduction in cervical cancer is detectable at the population level, the consultation stressed the importance of maintaining existing cervical screening programmes while such long-term studies are conducted. The following paper explains the background and rationale behind these conclusions and elaborates on specific considerations for vaccine study and introduction in developing countries.
去年，世界卫生组织（WHO）召集了一次专家会议，参会人员包括科学家、各国监管机构人员、行业代表、流行病学家以及来自发达国家和发展中国家的政府官员，目的是讨论人乳头瘤病毒（HPV）疫苗效力和效果试验合适的终点指标测量方法。此次磋商还考虑了候选疫苗在推广应用前，尤其是在发展中国家推广前应满足的监管要求和公共卫生问题。本报告总结了磋商过程中的讨论情况及达成的结论。磋商的普遍共识是，最好能有一个全球公认的、可测量的效力终点指标，以便考虑在公共卫生环境中推广HPV疫苗。在听取了专家关于需考虑的病毒学和临床终点指标、各国监管机构的要求以及用于衡量另一种已知癌症疫苗（乙肝疫苗）效力和效果的终点指标后，专家们一致认为，出于伦理和时间方面的考虑，有必要使用替代终点指标而非浸润性宫颈癌来定义HPV疫苗的效力。虽然各国监管机构最终将确定疫苗获批所需的终点指标，但此次磋商建议，基于目前的认知，在基于人群的研究中，效力终点指标应为组织学分类的中度或高度宫颈上皮内瘤变（CIN）以及癌症。由于持续感染同一高危型别被认为是中度或高度宫颈发育异常及癌症的预测指标，它们可能是未来疫苗效力研究中一个有用的终点指标。事实上，如果疫苗被证明对短暂或持续的HPV感染有效，那么很可能它们将保护女性预防宫颈癌。磋商认识到，在许多发展中国家的背景下，仅效力可能无法为各国决定是否采用HPV疫苗作为预防宫颈癌的公共卫生工具提供足够信息。磋商一致同意，应在某些发展中国家开展额外的临床桥接研究以及澄清当地流行病学情况的研究，以确定疫苗接种的潜在影响。这些国家还应采取有针对性的干预措施，以确保疫苗接种的可接受性和项目可行性。认识到在引入疫苗后，要过数年才能在人群层面检测到宫颈癌发病率的下降，磋商强调在开展此类长期研究时维持现有宫颈筛查项目的重要性。下文解释了这些结论背后的背景和基本原理，并详细阐述了在发展中国家进行疫苗研究和引入疫苗的具体考虑因素。
