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

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