Bill & Melinda Gates Foundation, Seattle, WA, USA.
Bill & Melinda Gates Foundation, Seattle, WA, USA.
Vaccine. 2024 Nov 14;42(25):126100. doi: 10.1016/j.vaccine.2024.07.001. Epub 2024 Jul 14.
Cervical cancer is a major cause of morbidity and mortality globally with a disproportionate impact on women in low- and middle-income countries. In 2021, the World Health Organization (WHO) called for increased vaccination, screening, and treatment to eliminate cervical cancer. However, even with widespread rollout of human papillomavirus (HPV) prophylactic vaccines, millions of women who previously acquired HPV infections will remain at risk for progression to cancer for decades to come. The development and licensing of an affordable, accessible therapeutic HPV vaccine, designed to clear or control carcinogenic HPV and/or to induce regression precancer could significantly contribute to the elimination efforts, particularly benefiting those who missed out on the prophylactic vaccine. One barrier to development of such vaccines is clarity around the regulatory pathway for licensure. In Washington, D.C. on September 12-13, 2023, a meeting was convened to provide input and guidance on trial design with associated ethical and regulatory considerations. This report summarizes the discussion and conclusions from the meeting. Expert presentation topics included the current state of research, potential regulatory challenges, WHO preferred product characteristics, modeling results of impact of vaccine implementation, epidemiology and natural history of HPV infection, immune responses related to viral clearance and/or precancer regression including potential biomarkers, and ethical considerations. Panel discussions were held to explore specific trial design recommendations to support the licensure process for two vaccine indications: (1) treatment of prevalent HPV infection or (2) treatment of cervical precancers. Discussion covered inclusion/exclusion criteria, study endpoints, sample size and power, safety, study length, and additional data needed, which are reported here. Further research of HPV natural history is needed to address identified gaps in regulatory guidance, especially for therapeutic vaccines intended to treat existing HPV infections.
宫颈癌是全球发病率和死亡率的主要原因，对中低收入国家的妇女影响不成比例。2021 年，世界卫生组织（WHO）呼吁增加疫苗接种、筛查和治疗，以消除宫颈癌。然而，即使广泛推出人乳头瘤病毒（HPV）预防性疫苗，数以百万计的先前感染 HPV 的妇女在未来几十年仍将面临癌症进展的风险。开发和许可一种负担得起、可获得的治疗性 HPV 疫苗，旨在清除或控制致癌 HPV 和/或诱导癌前病变消退，将为消除努力做出重大贡献，特别是受益于那些错过预防性疫苗的人。开发此类疫苗的一个障碍是明确许可的监管途径。2023 年 9 月 12 日至 13 日，在华盛顿特区举行了一次会议，就试验设计以及相关的伦理和监管考虑因素提供意见和指导。本报告总结了会议的讨论和结论。专家演讲主题包括研究现状、潜在监管挑战、世卫组织首选产品特征、疫苗实施影响的建模结果、HPV 感染的流行病学和自然史、与病毒清除和/或癌前病变消退相关的免疫反应，包括潜在的生物标志物，以及伦理考虑。举行小组讨论，以探索支持两种疫苗适应症许可过程的具体试验设计建议：（1）治疗现有的 HPV 感染；或（2）治疗宫颈前病变。讨论涵盖了纳入/排除标准、研究终点、样本量和功效、安全性、研究长度和额外需要的数据，这些都在这里报告。需要进一步研究 HPV 的自然史，以解决监管指南中确定的差距，特别是对于旨在治疗现有 HPV 感染的治疗性疫苗。
