The KEN SHE Study on HPV-vaccine Efficacy

Study Overview
=================
Brief Summary
-----------------
The KEN SHE Study aims to identify effective cervical cancer prevention strategies. Cervical cancer is caused by an infection with Human Papillomavirus, also called HPV. In Kenya, about 2,500 women die from this condition each year. The study is conducted by Kenya Medical Research Institute (KEMRI) sites, based in Kisumu, Thika and Nairobi and the University of Washington, Seattle, USA. The purpose of this study is to learn whether a single dose of the HPV vaccine prevents HPV infection among adolescents and young women. Using a single dose will lower the cost of providing HPV vaccination (compared to two doses) and will make it possible for more women to receive the vaccination and be protected from cervical cancer. The study will involve approximately 21 clinic visits over a period of 55 months. All visits will involve blood draws and many will involve pelvic swabs. Participants will receive an FDA-approved HPV vaccine and a meningococcal vaccine.

Detailed Description
-----------------
Cervical cancer is the leading cause of new cancer cases among women in Africa. Preliminary evidence suggested a single-dose of the HPV vaccine would be over 95% effective in preventing vaccine type-specific HIV infection, supporting HPV vaccination as a scaleable intervention for cervical cancer prevention. The overall aim of the study is to provide timely results of both single-dose HPV vaccine efficacy and estimates of the cost, cost-effectiveness, and budget impact for dissemination and translation to policy. Several HPV vaccines are available. The KEN SHE Study will determine the efficacy of two HPV vaccines: bivalent and nonavalent vaccines. At the start of the study, young women were randomly sorted into three arms. In arm 1, the women received the bivalent HPV vaccine. In arm 2, the women received the nonavalent HPV vaccine. And in arm 3, the women received a meningococcal vaccine. The three-arm study structure makes it possible to compare the women who received an HPV vaccine to those who did not receive an HPV vaccine during the study. A formal primary analysis was planned to be conducted after 18 months of follow-up to provide early evidence on single-dose HPV vaccine efficacy. The principal results of the primary analysis conducted 18 months after enrollment were to demonstrate whether the single-dose HPV vaccine strategy prevents incident persistent HPV vaccine type specific infection among young women, by comparing the rate of new HPV infections among women who receive the vaccine immediately to those receiving delayed vaccination. Single dose HPV vaccination was highly effective at the month 18 primary analysis timepoint. Thus, as recommended by the Data Saftey Monitoring Board, participants should receive a blinded crossover vaccination. Participants who received the HPV vaccine at enrollment will receive the meningococcal vaccine and participants who received the meningococcal vaccine at enrollment, will receive the HPV vaccine (i.e. crossover vaccination). Questions remain regarding the durability of single-dose HPV vaccine efficacy which may limit the uptake of single-dose HPV vaccination. To ensure that vaccine efficacy is durable, crossover vaccination and follow-up will be conducted using a blinded crossover study design. This design will allow comparison of the early and late vaccine efficacy to ensure that single-dose HPV vaccine clinical efficacy does not wane over time. Thus, the study will contribute data on both single-dose HPV vaccine efficacy and durability of the effect. A final analysis will be conducted with the conclusion of up to 55 months of follow-up; if waning protection is detected, participants will receive the World Health Organization recommended course of HPV vaccination. With the introduction of the crossover vaccination, the primary study endpoint is now persistent vaccine type specific HPV infection at months 18 and 18 months after blinded crossover vaccination. The quantitative antibody response will be documented at months 1 and 24 to support immunobridging analyses to girls and adolescents for the single-dose bivalent and nonavalent vaccines. Using the data on persistent infections and health economic models, we will assess the impact on cervical cancer incidence. Specifically, investigators will compare the incidence of high-risk vaccine HPV types overall and the distribution of HPV types by study arm. Investigators will assess the immunologic response to single-dose HPV vaccination, specifically regarding long lasting B cell responses to support the durability of the single-dose vaccination approach. Data on the magnitude of the antibody response at months 1 and 24 will support immunobridging analyses to young girls and adolescents. The 24 month antibody result will be used to assess durability of the response and will be directly comparable to other studies of the single-dose HPV vaccine which are uniformly using the month 24 antibody result as the primary outcome. Further, among the women who received immediate HPV vaccine, investigators will estimated the durability of the bivalent and nonavalent HPV vaccines by measuring the antibody response and cumulative incidence of persistent cervical HPV over the duration of follow-up. Costing analyses will assess the resources required for scale-up of single-dose HPV vaccination. Enrollment took 12 months and there are 55 months of follow-up for each participant. The endpoint-driven trial design among women at risk of HPV acquisition will provide primary results after 18 months of follow-up, and, with the extended follow-up, evidence on durability over three years. The study duration is 78 months.

Official Title
-----------------
KENya Single-dose HPV-vaccine Efficacy - The KEN-SHE Study

Conditions
-----------------
Papillomavirus Infections

Intervention / Treatment
-----------------
* Biological: immediate Gardasil 9, delayed MenVeo vaccine
* Biological: immediate MenVeo vaccine, delayed Gardasil 9
* Biological: immediate Cervarix, delayed MenVeo vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Born female Age 15 to 20 years HIV-negative No history of HPV vaccination Sexually active: history of 1-5 lifetime partners Resident within study area without plans to move away in the next 37 months Exclusion Criteria: Allergies to vaccine components or latex, Pregnancy Hysterectomy Autoimmune, degenerative, and genetic diseases Investigator discretion

Ages Eligible for Study
-----------------
Minimum Age: 15 Years
Maximum Age: 20 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: At the start of our study, young women will be randomly sorted into three arms. In arm 1, the women will receive the bivalent HPV vaccine. In arm 2, the women will receive the nonavalent HPV vaccine. And in arm 3, the women will receive a meningococcal vaccine. At the crossover vaccine timepoint, those in arms 1 and 2 will receive the meningococcal vaccine, while those in arm 3 will receive either the bivalent or nonavalent HPV vaccine. The three arm study structure makes it possible to compare the women who received an HPV vaccine to those who did not receive an HPV vaccine during the study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>immediate Cervarix, delayed MenVeo vaccine | Biological: immediate Cervarix, delayed MenVeo vaccine<br>* Intervention is immediate administration of bivalent HPV vaccine and delayed MenVeo vaccine<br>|
| Experimental: Arm 2<br>immediate Gardasil 9, delayed MenVeo vaccine | Biological: immediate Gardasil 9, delayed MenVeo vaccine<br>* Intervention is immediate administration of 9-valent HPV vaccine and delayed MenVeo vaccine<br>|
| Active Comparator: Arm 3<br>immediate MenVeo, delayed Gardasil 9 vaccine | Biological: immediate MenVeo vaccine, delayed Gardasil 9<br>* Intervention is immediate administration of MenVeo vaccine and delayed administration of Gardasil 9<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Persistent HPV 16/18 infection across arms | Incident persistent HPV 16/18 infection across arms to measure HPV16/18 and HPV 16/18/31/33/45/52/58/6/11 vaccine efficacy | Primary analysis at month 18 | 
| Persistent HPV 16/18/21/33/45/52/58 infection across arms | Incident persistent HPV 16/18/21/33/45/52/58 infection across the HPV 16/18/31/33/45/52/58/6/11 and immediate meningococcal (delayed HPV) vaccine arms to measure HPV 16/18/31/33/45/52/58/6/11 vaccine efficacy | Primary analysis at month 18 | 
| Durability of HPV vaccine efficacy using blinded crossover vaccination design | Incident persistent HPV 16/18/21/33/45/52/58 infection will be compared between the early and late vaccine efficacy periods | Primary analysis 18 months after crossover vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-inferiority of vaccine response in girls aged 15-20 compared to girls age 9-14 | Antibody response after single-dose bivalent or nonavalent vaccination in 15-20 year old adolescents compared to 9-14 year old girls in the DoRIS study | Secondary analysis at 24 months after enrollment and 18 months post crossover vaccination | 
| Cost of single-dose HPV vaccination | Cost of single-dose HPV vaccination to support implementation strategies for single-dose HPV vaccination following World Health Organization recommendation in high cervical cancer burden settings. | Secondary analysis at 18 months post crossover vaccination | 
| Cost-effectiveness of single-dose HPV vaccination | Cost-effectiveness of single-dose HPV vaccination to support implementation strategies for single-dose HPV vaccination following World Health Organization recommendation in high cervical cancer burden settings. | Secondary analysis at 18 months post crossover vaccination | 
| Budget impact of single-dose HPV vaccination | Budget impact of single-dose HPV vaccination to support implementation strategies for single-dose HPV vaccination following World Health Organization recommendation in high cervical cancer burden settings. | Secondary analysis at 18 months post crossover vaccination | 
| Immune memory following single-dose HPV vaccination | B-cell marker levels following single-dose bivalent and nonavalent vaccination. | Secondary analysis at 19 months post crossover vaccination |