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

The trial will investigate the potential future utility of alternative HPV vaccination schedules in West Africa. The schedules aim to reduce the financial and logistical burden of HPV vaccine rollout and to provide new opportunities to optimise coverage. The following questions will be addressed:

1. Does the administration of 1 or 2 doses of a quadrivalent HPV vaccine (qHPV) result in lower type-specific seroconversion rates in 9 to 12 year old females in West Africa compared to a 3 dose schedule?
2. Does the administration of 2 doses of qHPV result in lower type-specific seroconversion rates in 4 to 8 year old females in West Africa compared to 3 doses in 9 to 12 year old females?
3. What are the long term health and economic implication of a reduced dose schedule and/or a younger age of routine vaccination in a low income West African setting?

A randomised, observer-blind, non-inferiority trial will be undertaken. 9 to 12 year old females will be randomised to receive 1, 2 or 3 doses of a qHPV over up to six months. An additional group of 4 to 8 eight year old females will be recruited and will receive two doses of qHPV.

The following outcome measures will be examined:
Primary:
- HPV types 16 and 18 neutralising antibody seroconversion rates at 7 months
Secondary:
- HPV types 16 and 18 neutralising antibody seropositivity rates at 12, 24 and 48 months
- HPV types 16 and 18 neutralizing antibody GMT at 7, 12, 24 and 48 months
- HPV types 16 and 18 antibody avidity at 7, 12, and 48 months
Exploratory:
HPV specific B-cell and T-cell responses will also be examined in a sub-set of subjects

A sample size of 256 participants per group is based on a reference 3 dose seroconversion rate of 99% and a non-inferiority margin of 5%. The figure provides over 90% power to determine the non-inferiority of the primary outcome measure using a 1-sided alpha of 1.25% allowing for multiplicity two HPV types and an attrition rate of up to 10%.

In April 2014, the WHO Strategic Advisory Group of Experts on Immunisation highlighted the need for 'head-to-head comparisons of various alternative schedules...especially in low and middle income countries' and also for cost-effectiveness analysis and modelling data to be to generated from the same setting. Similarly, 'Is 1 dose as good as 2 or 3 doses?' was emphasised as a global research priority during the closing plenary session of the 29th Annual International Papillomavirus Conference in August 2014. Hence, there is a clear mandate, both from the WHO and also from leaders in the field of HPV research to explore alternative schedules which serve predominately to facilitate vaccine implementation across low and middle income countries. Consequently, the results of the trial are expected to impact on HPV vaccination policy at the highest level.
Nationally, not only in The Gambia, but also across sub-Saharan Africa and elsewhere, the alternative schedules will not only reduce the logistical and financial burden of HPV vaccine roll-out but will also increase the opportunities for countries to achieve the high vaccine coverage required in the absence of established programmes to reach young adolescents. Campaign-based vaccine delivery is regularly undertaken, highly effectively, across sub-Saharan Africa and, with appropriate communication, could be used to deliver HPV vaccines. The Gambia vaccinated well over 90% of children and young adults with a Men A vaccine in under a week in 2013 and regularly achieves comparable coverage during measles and polio campaigns. Single dose schedules are particularly amenable to such delivery strategies while also reducing the burden of school or community based approaches.
Extending the age window for vaccination will also provide new opportunities to reach the target population. The Integrated Child Health Programme in The Gambia monitors the growth of children until they are 6 years of age. Over the same period, vitamin A and mebendazole are administered 6 monthly alongside iron supplements, as recommended by the WHO. These interventions are delivered by the same public health teams who administer the routine EPI vaccines providing a real future opportunity for HPV delivery within a routine programme. The coverage achievable through school-based campaigns will similarly be enhanced through both extending the age window and reducing the dose number. In the Gambia, 97% of children enrol in lower basic education at 6 or 7 years of age with gender parity at this point. While overall 74% of children complete lower basic education at 11 or 12 this figure is only between 55 and 60% in females with a more pronounced discrepancy in rural areas. Thus, school-based programmes targeting 7 and 8 year olds will routinely attain higher coverage while also providing a greater opportunity for catch-up in subsequent years.
Finally at an individual and family level cervical cancer is responsible for more than 50 000 deaths of women across sub-Saharan Africa annually. Many of these occur in women at an age when they are caring for many children and are an important breadwinner for a household or compound. Thus, the knock-on effects beyond the individual loss are significant. At least 70% of these deaths are now preventable through vaccination and it is ultimately at the level of the individual and family where the benefits of timely roll-out will be felt.
It is unlikely that a single approach will be applicable to all low and middle income countries, even in sub-Saharan Africa. The alternative schedules aim to significantly broaden the opportunities to achieve coverage and reduce programme burden but will also need to be tailored to local circumstances. The health economic analysis and component of the proposal exploring vaccine acceptability, aim to address these further key elements of successful programme implementation thus ensuring the maximum impact of the proposal overall.