Title: NOVEL: Nonavalent HPV vaccine after local conservative treatment for cervical pre-invasive disease: a randomised controlled trial
Funder: Medical Research Council

Abstract: Background: Although the benefit of HPV vaccine is limited in women with ongoing infections, evidence from previously conducted trial hint that the vaccination may be of value in women that have undergone conisation (treatment that removed a cone-shaped part of the cervix). This is probably because these women represent a subset of the female population particularly sensitive to the infection and the development of precancer/cancer. Repeat conisations may further increase the risk of preterm birth in women of reproductive age. If this study demonstrates benefits from prophylactic vaccination, this will add a new clinical indication for the vaccine for all women planned for conisation._x000D_ _x000D_ Aims: To this end, we propose a multicentric controlled trial that will randomly allocate women planned for conisation for presumed high-grade cervical precancer to receive or not the HPV vaccine (Gardasil 9™). Our objective is to demonstrate that the vaccine when initiated at the time of conisation will reduce subsequent persistent HPV infection in women with high-grade precancer._x000D_ _x000D_ Design & Methods: Women aged 18-55 will be approached when a clinical decision has been made to proceed with conisation. Women will be randomly allocated to the vaccine (n=500) or no vaccine arm (n=500). Our primary outcomes include the rate of HPV infections that persist for 6 months and secondary and tertiary outcomes include rates of precancerous lesions and safety. _x000D_ _x000D_ Patient and public involvement: Patients and the wider public have been involved from the design of this proposal. Their involvement will continue throughout the study and will guide the priority questions to be addressed, the development of research reports in lay language and the dissemination of the results._x000D_ _x000D_ Dissemination: The results will be published in open access journals with a wide medical readership and will be presented in national and international meetings, web documents, leaflets, public presentations and media interviews. We will work closely with Jo’s Trust cervical cancer charity that plays an important role in educating patient communities.

Lay abstract: Background_x000D_ The HPV vaccine is highly efficacious in HPV-naïve populations but has limited benefits in women with ongoing infections at the time of vaccination. Two secondary analyses of the phase III trials provided indirect evidence of a possible benefit from vaccination in women receiving local treatment for cervical intra-epithelial neoplasia (CIN) by conisation with up to a 65% reduction in the risk of recurrent CIN2 or worse disease (Joura BMJ 2012; Hidesheim Am J Obstet Gynecol 2016). Women who develop CIN in the first place constitute a subgroup of the infected women who are particularly sensitive to the infection and as a result rapidly acquire re-infections post-conisation. New and persistent infections place these women after conisation at higher risk of pre-invasive or invasive recurrent disease that can be more difficult to detect and prevent. Furthermore, repeat conisations substantially increase reproductive morbidity and preterm birth in subsequent pregnancies. The value of vaccination in this setting is one of the most frequent queries by patients and clinicians._x000D_ _x000D_ Aims_x000D_ We aim to conduct a controlled randomized (1:1) multicentre trial (UK, Finland, Sweden) trial to evaluate the efficacy of Gardasil 9™ HPV vaccine as compared to the control un-vaccinated population against incident, prevalent and recurrent infections (present for >6 months interval) with oncogenic HPV types 6/11/16/18/31/33/45/52/58 post-conisation._x000D_ _x000D_ Methods_x000D_ We will recruit 1000 females aged 18 to 55 years, attending for conisation for presumed CIN2/3. The experimental arm (N=500) will receive 3 doses of Gardasil 9™ HPV vaccine (0, 2, 6 month schedule) and the control group will not be vaccinated (N=500). The composite primary endpoints include incident, prevalent and recurrent infections (>6 months interval) with vaccine HPV types 6/11/16/18/31/33/45/52/58. The secondary and tertiary endpoints include rates of recurrent CIN and safety. Enrolling 500 subjects per arm and using a two-sided alpha level of 0.05 will give 90% power to detect a significant effect of vaccination on composite measure of persistent HPV infections post conisation and allows for 22% losses to follow-up (Soderlund-Strand J Med Virol 2014; Elfgren Am J Obs Gynecol 2000). _x000D_ _x000D_ Anticipated Impact & Timeframe _x000D_ If this study demonstrates benefits in this high-risk population, the national vaccination programme, currently targeting pre-pubertal girls, will be expanded to include women post-conisation when the results of this trial will be published in 2024. The impact will be substantial for decades after the publication despite national prophylactic vaccination programmes. In the next decade after publication and assuming 100% coverage from prophylactic vaccine, the results will be applicable to 280,000 women in England alone. If we take into account that vaccination coverage of vaccination is likely to be lower, the numbers are expected to be even higher. The impact will continue for several decades after although the numbers will progressively reduce until we see the full impact of prophylactic vaccination 52 years later, in 2060. If we further rake into account the population exchange from less affluent societies were coverage is very low, the impact of this study will remain relevant for several decades after publication This is in line with current efforts to find alternative paths to accelerate the impact of the vaccine.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION