Title: Complex Cochrane systematic reviews to evaluate and compare the evidence for Human Papillomavirus (HPV) vaccination for the primary prevention of cervical cancer and other HPV-related diseases
Funder: Department of Health and Social Care

Abstract: Background_x000D_ Cervical cancer is the fourth most common cancer in women worldwide, affecting over half a million per year. Cervical cancer is caused by high-risk types of human papillomavirus (HPV), which are responsible for many cancers of the vulva, vagina, anus and head and neck cancers, affecting both women & men. HPV is acquired via sexual contact - most people are exposed to HPV. Although most clear HPV within a few months, some will not and are at risk of developing cancers. _x000D_ _x000D_ Vaccines are available to prevent infection with HPV. However, despite effective screening tests and a vaccine for HPV, women are still dying from cervical cancer, or are exposed to the risk of screening- and treatment-related harm. A variety of reasons contribute to avoidable cervical cancer, including lack of access to or reluctance to have HPV vaccination and reluctance/barriers to accessing cervical screening._x000D_ _x000D_ A number of HPV vaccines have been developed and a variety of vaccination strategies are used in different countries._x000D_ _x000D_ Aims of research_x000D_ We intend to look at the benefits and harms of HPV vaccination to provide robust and unbiased evidence for patients, clinicians and policymakers to enable fully informed decision-making. _x000D_ _x000D_ Design and methodology_x000D_ We will compare different vaccines and dosing strategies used in different studies, so we determine the most effective vaccination strategy for girls and boys before they are exposed to HPV. This type of study is known as a network meta-analysis (NMA), since it pulls together information from a range of different studies of treatment A versus treatment B or treatment B versus treatment C etc. Using NMA methods we can see how treatment A compares with treatment C, even if they have not been directly compared in a study._x000D_ _x000D_ We know from existing large studies that HPV vaccines have few serious side effects. Cervical cancer was rare in the clinical trials, in part because women were closely followed up with screening and pre-cancer treated. However, RCTs have relatively short times scales (7 months to 8 years) compared to the one to several decades needed to develop HPV-related cancers or pregnancy-related complications from treatment of cervical pre-cancer. We will look at different types of studies, assessing HPV vaccination at a population level. This level of data will give us a much clearer idea about uncommon benefits and harms of vaccination, looking at outcomes meaningful to people. These studies will inform governments about vaccination programmes, but will also inform young people and their parents/carers when making decisions about vaccination._x000D_ _x000D_ Patient and public involvement_x000D_ The reviews examine the most important questions raised through a public priority setting partnership on early diagnosis of cancer. As there is a lot of public interest and controversy surrounding HPV vaccination, we will form an independent advisory group (IAG) to oversee review production, ensuring that they are performed openly and are responsive to community concerns, including relevant outcomes and considerations. _x000D_ _x000D_ Dissemination_x000D_ This is a very topical subject, there is much misinformation surrounding HPV vaccination. We will publicise results with help from the Cochrane Consumer Network and Cochrane Knowledge Translation, engaging with conventional and social media, as well as working with Gynaecological Cancer Charities. We hope this work will provide trusted information so people can make decisions based on fact and not fear

Lay abstract: Research question_x000D_ What are the benefits and harms of HPV vaccination and the best vaccine strategy?_x000D_ _x000D_ Background_x000D_ Preventative healthcare is the main focus of the Department of Health and Social Care’s Strategy for Healthcare. Cervical cancer is the 4th most common cancer amongst women worldwide, 99% caused by high-risk types of human papillomavirus (HPV). HPV is also responsible for many cancers of the vulva, vagina, anus and head and neck cancers, affecting women and men. The large geographical variation in cervical cancer incidence and survival correlates with availability of primary and secondary prevention strategies and prevalence of HPV infection. _x000D_ _x000D_ Preventing and detecting cancer early is a priority within healthcare, especially within the UK. The recent Detecting Cancer Early Priority Setting Partnership priorities were finding simple, painless and cost-effective screening tests and improving access to cancer prevention strategies. We have worked with the NCRI Gynae Cancer Subgroups to identify reviews that encompass these priorities. _x000D_ _x000D_ Uptake of HPV vaccination varies widely between countries, ranging from 8% to 98% (83.9% in UK). Reasons include organisation of immunisation programmes, resistance from healthcare providers, adverse media coverage and concerns about safety. Even large RCTs are unable to fully evaluate rare harms and longer-term benefits of HPV vaccination, which may take decades to be realised, e.g. cancer rates. Analysis of recent non-randomised, population-level data is important to more fully inform the ‘debate’ about vaccination._x000D_ _x000D_ Results of single-dose vaccination studies are due shortly and comparative analyses are needed to inform future HPV vaccine strategies. These will have implications for screening intervals and change cost-effectiveness of immunisation and screening programmes. HPV vaccination, especially in countries where screening programmes are currently unaffordable, has the potential to be transformative._x000D_ _x000D_ Aims and objectives_x000D_ We will evaluate the harms and benefits of HPV vaccination to prevent cervical cancer and other HPV-related diseases and compare different vaccines and dosing strategies. _x000D_ _x000D_ Methods_x000D_ 1. Network meta-analysis (NMA) of HPV vaccination for the prevention of HPV-related disease _x000D_ 2. Population-level effects of HPV vaccination programmes on HPV-related disease and harms from vaccination_x000D_ _x000D_ Timelines for delivery_x000D_ Provisional search strategies have informed grant costings. Protocols will be submitted by October 2021 and reviews submitted for peer review by November 2022 for publication by March 2023. This is an ambitious time-frame for complex reviews, hence the importance of dedicated systematic reviewer support & involvement of Cochrane Crowd. _x000D_ _x000D_ Anticipated impact and dissemination_x000D_ A previous Cochrane HPV vaccination review (Altmetric score of 1496) is within the top 1% of all research in terms of impact. It is the 6th most impactful Cochrane review. 90% of Altmetric outputs are from the public, with a worldwide interest; it is an extremely high priority topic area. We will disseminate using conventional and social media, working with cancer charities. These data will inform WHO and national government immunisation strategy at a global level. We are aware that this will subject the reviews to significant scrutiny from communities with concerns about HPV vaccination. This heightens the need for an active Independent Advisory Group (IAG) to help develop robust reviews and play a central role in being responsive to community concerns.

Research activity codes: 3.4 VACCINES
Health categories: CANCER AND NEOPLASMS;INFECTION