A randomised, observer-blind, non-inferiority trial to evaluate alternative human papillomavirus vaccination schedules in young females in West Africa

宫颈癌一直与人类乳头状瘤病毒(HPV)感染有关。这种癌症在撒哈拉以南非洲地区比世界上任何其他地方都更频繁发生，是这种情况下女性癌症相关死亡的最常见原因。此外，随着人口老龄化，非洲大陆的宫颈癌负担预计将在未来15年翻一番。对于那些被诊断患有宫颈癌的人来说，在这种环境下生存的机会也比世界上许多其他地区低得多。在缺乏宫颈筛查计划的情况下，诊断往往很晚，可用治疗也可能有限。两种不同的HPV类型--16型和18型--与全球近四分之三的宫颈癌有关，包括在撒哈拉以南非洲。目前已经有针对HPV类型的疫苗和抗体，这些抗体被认为是起保护作用的，可以在接种疫苗后通过血液测试来衡量抗体，作为疫苗产生的免疫力的指标。当给成年女性接种3剂HPV疫苗时，已被证明非常有效-产生高水平的抗体，并在迄今的研究中持续保护人们免受HPV感染，从而预防宫颈癌长达10年以上。进一步的研究表明，HPV疫苗在青少年中产生的抗体水平甚至高于成年人。事实上，在世界其他地区进行的研究表明，仅接种2剂疫苗的青少年产生的抗体水平高于成年女性，即使在接种3剂疫苗后也是如此。早期数据现在开始表明，即使是单剂HPV疫苗也可以提供足够水平的抗体来预防感染，从而预防宫颈癌，尽管这需要进一步研究。鉴于疫苗在预防HPV感染和宫颈癌方面的有效性已被证明在其他环境中是有效的，如果要在撒哈拉以南非洲地区预防宫颈癌的大部分负担，需要克服的主要障碍是方案实施--即各国是否有能力持续向目标女性人口的高比例提供所需数量的疫苗剂量。世界卫生组织目前建议给9至13岁的女孩接种两剂疫苗，并在两次接种之间留出至少6个月的间隔。然而，在撒哈拉以南非洲的大部分地区，没有建立起提供这种方案的既定制度，也没有可靠地接触到少女的简单方法。虽然以学校为基础的方案取得了一些成功，但许多女性没有完成小学教育，或者只是在这个年龄段才不稳定地上学。因此，确保两剂疫苗的可靠接种是一个重大挑战。这项试验将提出两个主要问题，这两个问题都旨在使撒哈拉以南非洲和其他地区的国家更容易提供可靠的HPV疫苗计划：1.需要2或3剂HPV疫苗才能提供保护，还是1剂就足够了？确保所有女性接种一剂HPV疫苗比确保她们都接种间隔至少6个月的2剂要容易得多，成本也低得多。HPV疫苗可以接种给9岁以下的女孩吗？校本课程的设计可以更灵活地针对出勤率最高的年龄。此外，通过已建立的儿童健康方案提供HPV疫苗，这些方案继续监测儿童的发育情况，并向儿童提供维生素和铁补充剂，直到5岁或6岁成为可能，从而影响成本和疫苗覆盖范围。还将审查提供疫苗的各种时间表和方式的成本，并将调查西非农村地区的疫苗接受度，以确保试验对公共卫生政策产生最大的未来影响

Cervical cancer is consistently associated with infection with the human papilloma virus (HPV). The cancer occurs more frequently in sub-Saharan Africa than anywhere else in the world and is the most common cause of cancer-related death in females in this setting. In addition, the burden of cervical cancer on the continent is expected to double over the next 15 years as the population gets older. For those diagnosed with cervical cancer, the chances of survival are also much lower in this setting than in many other parts of the world. In the absence of cervical screening programmes, the diagnosis is often made late and the treatment available may also be limited.Two different HPV types, type 16 and type 18, are associated with nearly three quarters of all cervical cancer worldwide, including in sub-Saharan Africa. Vaccines are already available against both HPV types and antibodies, which are thought to be responsible for protection, can be measured with a blood test after vaccination as an indicator of the immunity the vaccine generated.When given to adult women, 3 doses of an HPV vaccine have been shown to be extremely effective - generating high levels of antibody and providing sustained protection from HPV infection and hence cervical cancer for upwards of 10 years in studies so far. Further research has gone onto show that the level of antibody generated by the HPV vaccines in young adolescents is even higher than in adults. Indeed, in studies conducted in other parts of the world, young adolescents given just 2 doses of the vaccine have been shown to generate higher levels of antibody than those generated in adult women, even following 3 doses. Early data are now beginning to suggest that even a single dose of an HPV vaccine may provide sufficient levels of antibody to prevent infection, and hence cervical cancer, although this needs to be further studied.Given how effective at preventing HPV infection and cervical cancer the vaccines have been shown to be in other settings, the main hurdle to overcome if much of the burden of cervical cancer across sub-Saharan Africa is to be prevented is one of programme implementation - i.e. the capacity of countries to consistently deliver the required number of vaccine doses to a high proportion of the target female population. The WHO currently recommends that 2 doses of the vaccines are given to 9 to 13 year old girls and that a gap of at least 6 months is left between doses. However, there is no established system in place across much of sub-Saharan Africa to deliver such a programme and no easy way to reliably access adolescent females. While school-based programmes have shown some success, many females do not complete primary education or attend school only inconsistently at this age. Consequently ensuring the reliable delivery of 2 vaccine doses is a major challenge.This trial will ask 2 main questions, both of which aim to make it easier for countries across sub-Saharan Africa and elsewhere to reliably deliver HPV vaccine programmes:1. Are 2 or 3 HPV vaccine doses needed to provide protection or would 1 dose be enough?It would be much easier and cheaper to ensure all females get a single dose of an HPV vaccine than to ensure they all get 2 doses separated by at least 6 months.2. Could the HPV vaccines be given to girls younger than 9 years of age? School-based programmes could be designed more flexibly to target the age of peak school attendance. Also, the delivery of HPV vaccines through established child health programmes which continue to monitor growth and to provide vitamin and iron supplements to children until 5 or 6 years becomes possible thus impacting on cost as well as vaccine coverage.The costs of the various schedules and ways to deliver the vaccines will also be examined and vaccine acceptability in rural West Africa will also be explored to ensure the maximum future impact of the trial on public health policy