Adding Male Single Dose HPV Vaccination to Female HPV Vaccination in Tanzania (Add-Vacc)

The WHO has recently announced its commitment to end cervical cancer as a public health problem globally. Cervical cancer is the commonest cancer among women aged between 15 and 44 years in East Africa and is the leading cause of cancer-related mortality. It is caused by infection with human papillomavirus (HPV), a sexually transmitted virus. Infection with HPV can also cause other diseases such as genital warts, which affect both men and women.

In high income countries, cervical cancer is prevented by vaccinating girls against HPV infection before they start having sex and screening sexually active women for HPV infection and/or cervical abnormalities. However, in many countries in Africa and other parts of the world, many women still die of the disease because screening programmes are absent or limited, and vaccination is only just starting to be rolled out. In Tanzania, which has one of the highest rates of cervical cancer in the world, HPV vaccines were introduced to 14-year-old girls in 2018.

Evidence suggests that setting up and sustaining an HPV vaccination programme for young girls requires considerable investment in human and financial resources. These new programmes are finding it challenging to deliver the vaccines to most girls who should be receiving them. This will make it difficult to eliminate cervical cancer as HPV will still be able to spread in young people. Scientists therefore need to explore novel ways to deliver the vaccine to prevent infection to those who are not vaccinated.

If enough people receive the HPV vaccine, then their unvaccinated sexual partners can also be protected. This has been shown in countries like Australia and Scotland, where vaccination of girls resulted in a decline in rates of HPV-related diseases in boys as well as girls. Given the challenges in getting enough girls vaccinated in many countries, one approach to controlling cervical cancer by preventing infection in unvaccinated girls is to offer the vaccine to their potential male sexual partners (known as gender-neutral vaccination).

We propose to conduct a trial to test this strategy in Tanzania. We will see if we can reduce the amount of HPV infection present in communities by vaccinating of boys alongside vaccination of girls. We will do this using a single dose of HPV vaccine in boys, which may be sufficiently protective to prevent infection in boys and also prevent spread of HPV to unvaccinated girls.

We will conduct a study called a cluster-randomised trial among communities in Tanzania (where each community is a cluster). In 2020, we will start by doing a baseline survey in 26 communities to determine how many boys and girls aged 16-22 years have HPV infection. We will then randomly select 13 communities where boys aged 14-18 years will be given HPV vaccine alongside the routine female HPV vaccination that is being given by the Tanzanian government. Three years after offering boys the vaccination, we will go back into the communities and do another survey to determine how many boys and girls aged 16-22 years-old have HPV infection. We will then be able to show whether the proportion of people infected with HPV differs between the communities that did and did not have male vaccination. At the same time, we will also be able to measure the impact of the girls-only vaccination on HPV infection by comparing the proportion of 16-22-year-old girls infected with HPV in the female-only vaccination communities at baseline and 3 years later.

In our study, we will also follow up 200 vaccinated boys in order to check their immune responses to the vaccine, and we will do interviews in the communities to explore people's views about offering boys vaccination. We will also look at the cost of adding in vaccination of boys to the programme.

This work will be extremely important in informing future HPV vaccination strategies and will be the first randomised trial of gender-neutral vaccination in Africa.

The Director-General of the World Health Organization (WHO) has announced a target to eliminate cervical cancer as a public health problem. Sub-Saharan Africa has the highest cervical cancer incidence and mortality rates in the world. However, few African countries have HPV vaccination programmes to prevent cervical cancer because of the costs involved. Prophylactic HPV vaccination has been routinely offered to girls prior to sexual debut in 85 countries globally and vaccines have become available to the poorest countries through Gavi support. However, recent data on vaccine coverage in target age groups in some countries has been lower than expected. The recently announced WHO call to eliminate cervical cancer will require novel approaches to reduce HPV acquisition and its sequelae. As well as screening for cervical cancer lesions in older females, other strategies being considered include gender-neutral vaccination that can potentially provide individual protection for boys and can also maximise protection of unvaccinated girls and boys against HPV acquisition.

Tanzania introduced two-dose HPV vaccination with the 4-valent vaccine, Gardasil, into its national immunisation programme in 2018. Our trial, Add-Vacc, is a cluster-randomised trial of single dose HPV vaccination given to a multi-year cohort of 14-18-year-old boys alongside routine female HPV vaccination, with a nested observational cohort of vaccinated boys for immunogenicity and safety. Impact evaluation of male vaccination, alongside routine female vaccination, on population HPV prevalence will be measured in a cross-sectional survey of males and females aged 16-22 years three years after the intervention. We will also explore the acceptability of gender-neutral vaccination and the cost effectiveness of adding in male vaccination to a female HPV vaccination programme.

The highest cervical cancer incidence and mortality rates are found in sub-Saharan Africa. Prophylactic HPV vaccines have the potential to substantially reduce the rates of the disease. However, following the relatively slow introduction of these vaccines in many countries, there have been challenges with achieving good coverage in girls. Meeting the recently announced WHO goal to eliminate cervical cancer as a public health problem will require novel strategies to improve the ability of vaccines to prevent HPV infection in young people. The study seeks to address this by determining whether gender-neutral vaccination can reduce the community prevalence of HPV infection compared to female-only vaccination.

Potential beneficiaries include:

1. Policy makers: this trial will be the first to investigate the impact of gender-neutral vaccination on HPV prevalence in sub-Saharan Africa by offering one dose to boys aged 14-18 years and will provide policy makers with data to inform future HPV vaccination programmes. Policy makers will learn about the research findings through 2, 3 and 5 below and through dissemination via relevant global web-based networks such as HPV World and Cervical Cancer Action, which disseminate important research findings and promote policy discussions.

2. Tanzanian Ministry of Health, Community Development, Gender, Elderly and Children (MOH): Tanzania has started a national HPV vaccination programme, vaccinating 14-year-old girls with two doses of the 4-valent vaccine. The country is committed to preventing cervical cancer through vaccination. This trial will help the MOH 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 MOH; Watson-Jones and Changalucha have been members of the Technical Advisory Committee for the National Cervical Cancer Prevention and Control Strategy and NIMR Mwanza Centre is part of the MOH. Our close links with the Expanded Programme on Immunization and the Directorate of Preventative Services in the MOH allows us to rapidly disseminate our research findings and lessons learnt in 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 GAVI 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 and Watson-Jones sits on the research working group of the WHO/IARC-convened Elimination of Cervical Cancer consortium and is a member of the PATH-convened Single-Dose HPV Vaccine Evaluation Consortium. Study results will inform future HPV vaccination research and programmes globally.

4. Economists: this study will provide economists with data to model the costs and effects of delivering reduced dose schedules and gender-neutral vaccination. Dissemination of the costing results will follow the strategies described above. We will specifically work with WHO to ensure that our data can be used for the WHP costing tool for cervical cancer prevention.

5. GAVI-eligible countries applying for HPV vaccine support: the trial results may be used to inform other GAVI eligible countries about potential alternative HPV vaccine strategies.

6. Adolescents: Girls and boys participating in the trial vaccination phase and the surveys will receive education about HPV. Participating boys will benefit from HPV vaccination. If the results lead to a significant reduction in community HPV prevalence with gender-neutral vaccination compare to female vaccination, then a potential impact is an ongoing reduction of transmission of HPV at community level.

7. Parents, health workers and communities: this study will raise awareness about cervical cancer.