A Dose Reduction Immunobridging Study of two HPV vaccines in Tanzanian girls

Cervical cancer is the commonest cancer among women aged between 15 and 44 years in Tanzania. Mortality from the disease is extremely high because screening programmes are frequently absent or limited in scale and women usually present late, leaving palliative care as the only option. HPV vaccines are most effective if provided to girls who have not yet acquired HPV infection. In Tanzania we have shown that HPV vaccine is safe, is very acceptable and can be delivered with high coverage (around 80%) but setting up and sustaining an HPV vaccination programme for young girls requires considerable investment in human and financial resources.

Despite high acceptability of the vaccine in East Africa, a number of studies have estimated that the cost of delivering HPV vaccine is considerably higher than costs for delivering traditional infant/child vaccinations, even if vaccine is subsidized by the GAVI Alliance. This is primarily because of start-up costs to establish outreach programmes and associated personnel costs with involvement of teachers and nurses who must spend significant time away from their health posts to deliver vaccine, especially if multiple doses are needed.

There is global interest in simplifying delivery by reducing the number of doses of HPV vaccine. The cost savings of offering fewer doses of HPV vaccine would be substantial and would also result in less time that health personnel are away from their stations and simplification of vaccine delivery. If a single dose could be given, this could halve the costs of vaccine delivery, making HPV vaccine more accessible to the populations that need it most. Recently, the WHO recommended that 2 doses of HPV vaccine could be given to girls aged less than15 years, based on studies in high and upper middle income countries. However in Africa there are high rates of infections like malaria and worms that can affect immune responses to vaccines. We need be sure that a reduction in the number of vaccine doses does not reduce the protective immune response of these vaccines.

We are planning a randomised trial in healthy Tanzanian females aged 9-14 years to establish whether a single dose of HPV vaccine produces immune responses that are likely to be effective in preventing cervical cancer in Africa. We will compare two different HPV vaccines, the bivalent (2-v) vaccine that protects against HPV 16/18 (the cause of 70% of cancers) and a new 9-valent (9-v) vaccine that protects against 9 HPV types.

Our trial will enrol and randomise 900 girls aged 9-14 years into 6 groups. They will receive either the 2-v or the 9-v HPV vaccine, as 1, 2 or 3 doses. Girls will be followed up for 36 months after the first dose so we can measure the quality and sustainability of immune responses. We will compare the girls receiving 1 or 2 doses with those receiving 3 doses of the same vaccine, to ensure that the reduced dose regimen produces an immune response that is not inferior to the standard 3 doses. We will also compare the immune responses in our study with results from other countries without a high prevalence of malaria and worm infections, and where the vaccine has been shown to be protective. This will give us information about whether a reduction in the number of doses is likely to be protective in Africa.

This trial will address fundamental questions about HPV vaccine dose reduction in a setting where the potential impact is greatest, and will be extremely important in informing future HPV vaccination policy.

Sub-Saharan Africa (SSA) has the highest cervical cancer incidence and mortality rates in the world; however, few countries have HPV vaccination programmes to prevent cervical cancer because of the costs involved. It is considerably more expensive to deliver HPV vaccine than the traditional infant EPI vaccines. If a single dose of HPV vaccine can be shown to elicit an immune response that is likely to be effective in preventing cervical cancer, it would simplify and greatly reduce the cost of vaccine delivery. Although a 2 dose regimen in girls under 15 years was recently approved based on antibody levels from studies in high and upper middle income countries, there is increasing recognition that vaccine efficacy depends on both quantity and quality of the antibodies induced. The quality of the immune response with reduced dose regimens may be affected by intercurrent infections such as malaria or helminths. Furthermore, HPV vaccines use different adjuvants which may affect their immunogenicity, theoretically meaning that some vaccines may be more suitable for dose reduction.

We will enrol 900 healthy Tanzanian girls aged 9-14 years into an unblinded, randomised, immunobridging trial with 6 arms. Girls will be randomised to receive 1, 2 or 3 doses of the bivalent (2-v) HPV vaccine or the new 9-valent (9-v) vaccine. We will examine the quality and sustainability of the vaccine immune response up to 36 months, by measuring antibody titre, neutralising antibody, antibody avidity and memory B cell responses, and comparing immune responses between arms. We will bridge our immunogenicity results to those in adult women in whom efficacy has been demonstrated, in order to infer efficacy for single and 2 dose regimens in girls under 15 years in SSA. The WHO has highlighted the need for head-to-head comparisons of reduced dose schedules of different HPV vaccines as a research priority. This trial will provide rigorous evidence for the feasibility of dose reduction in Africa.

The highest cervical cancer incidence and mortality rates are found in sub-Saharan Africa with incidence rates of around 54 per 100,000 in Tanzania. Prophylactic HPV vaccines have the potential to substantially improve the health of women in the continent. However, introduction of these vaccines has been slower in developing countries with a major barrier being cost of the vaccine and vaccine delivery. Generally the costs to initiate and sustain an HPV vaccination programme are substantially higher than for traditional EPI vaccines. The study seeks to address this by determining whether simplified reduced dose schedules can be delivered in sub-Saharan Africa without impacting the vaccine immune response to the vaccine. Findings from the single dose vaccine arms will also be applicable for GAVI non-eligible low and middle income countries.

The potential beneficiaries of this study include:
1. Policy makers: this trial will be the first to investigate the impact on quality of immune responses with 1 and 2 doses of HPV vaccine, and the first trial of the 9-valent vaccine, in sub-Saharan Africa and will provide policy makers with data to inform future HPV vaccination programmes. They will learn about these research findings through 2, 3 and 5 below and through dissemination via relevant global web-based networks such as Cervical Cancer Action (www.cervicalcanceraction.org) which disseminate important research findings and promote policy discussions.
2. Ministry of Health and Social Welfare (MOHSW): Tanzania is planning a national HPV vaccination programme and is conducting a GAVI-supported demonstration project in 2014-15, so the country is committed to preventing cervical cancer through vaccination. This trial will help the MOHSW develop the most cost-effective strategy for HPV vaccine delivery and will inform the Tanzanian National Cervical Cancer Prevention and Control Strategy. We are well-linked into the MOHSW; Watson-Jones is a member of the Technical Advisory Committee for the National Cervical Cancer Prevention and Control Strategy and NIMR Mwanza Centre is part of the MOHSW. We comment and input on policy related to cervical cancer control through our previous and current research experience. This allows us to rapidly disseminate our research findings and lessons learnt in MOHSW meetings, workshops and through policy documents and reports.
3. International organizations and the wider research community: trial results will be provided to WHO and to the GAVI Alliance who provide funds towards HPV vaccines in GAVI eligible countries. Watson-Jones is a member of the GAVI Independent Review Committee. Both Watson-Jones and Changalucha participate in regular WHO workshops and meetings related to HPV vaccination and its delivery. Lessons learnt from this study will inform future HPV vaccination projects and programmes globally.
4. Economists: this study will provide economists with data to model the costs and effects of delivering reduced dose schedules of different HPV vaccines. Dissemination of the costing results will follow the strategies described above. In addition we will specifically work with WHO, as we did for our last trial, to ensure that our data can be used for the WHP costing tool for cervical cancer prevention
(http://www.who.int/immunization/diseases/hpv/cervical_cancer_costing_tool/)
5. GAVI-eligible countries applying for HPV vaccine support: the results of this trial will be used to inform other GAVI-eligible countries about potential alternative HPV vaccine delivery strategies.
6. Adolescent females: Girls participating in the trial will receive education about HPV and will benefit from HPV vaccination which will provide long term health benefits. If the results lead to more rapid and extensive roll-out of HPV vaccination then a potential impact is a major reduction in morbidity and mortality due to cervical cancer.
7. Parents and communities: this study will raise awareness about cervical cancer.