Prime-boost Vaccine Study in Women With Low-grade Cervical HPV Lesions

Study Overview
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Brief Summary
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A Phase 1b/2 multi-centre study evaluating the safety, efficacy and immunogenicity of prime-boost vaccines ChAdOx1-HPV and MVA-HPV in women with HPV related low grade cervical lesions.

Detailed Description
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The study consists of an open label, non-randomised, dose escalation Lead in phase. 9 participants with high-risk HPV, in cohorts of 3 in 3 dose ascending groups, will be vaccinated after SMC safety data reviews. This is followed by a blinded, randomised Main phase with 96 participants with high-risk HPV, in parallel running dose cohorts (three different doses of ChAdOx1-HPV plus two different doses of MVA-HPV versus placebo plus placebo boost). At least 60 of these participants will take part in the immunogenicity sub-study. A blinded, randomised expansion phase investigating the effects of up to two different main phase doses against placebo will be further defined prior to commencing this phase of the study.

Official Title
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A Phase 1b/2, Randomised, Placebo-controlled, Dose-ranging Study to Evaluate Safety, Tolerability and Immunogenicity of a Chimpanzee Adenovirus (ChAdOx1)-Vectored Multigenotype High Risk Human Papillomavirus (hrHPV) Vaccine and Modified Vaccinia Ankara (MVA)-Vectored Multigenotype hrHPV Vaccine in Women With Low-grade HPV-related Cervical Lesions

Conditions
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HPV Infection, CIN1

Intervention / Treatment
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* Biological: ChAdOx1-HPV
* Biological: MVA-HPV
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females aged ≥25 and ≤55 years of age at screening. Persistent hrHPV infection defined as a documented cervical infection with hrHPV type(s) in the 6 to 18 months prior to screening and confirmed at screening (participants in the main and expansion phases only). Participants in the lead-in phase are only required to have the screening result. Low- grade cervical lesion (CIN1 or HPV-related change only) confirmed by histology and/or cytology report within the 1 year prior to screening. Not pregnant or breast feeding and one of the following: Of non-childbearing potential (i.e. women who have had a hysterectomy or tubal ligation or are postmenopausal, as defined by no menses for at least 12 months and without an alternative medical cause) Of childbearing potential but agrees to practice highly effective contraception for 4 weeks prior to administration of the first dose of study vaccine and throughout the study until 8 weeks after administration of the second dose. Highly effective methods of contraception include one or more of the following: Male partner who is sterile (medically effective vasectomy) prior to the female participant's entry into the study and is the sole sexual partner for the female participant Hormonal (oral, intravaginal, transdermal, implantable or injectable). Progestogen-only hormonal contraceptives without inhibition of ovulation are not considered to be highly effective. An intrauterine hormone releasing system An intrauterine device Bilateral tubal occlusion Sexual abstinence, only if the participant refrains from heterosexual intercourse during the entire study period and it is the usual lifestyle of the participant Willing to abstain from sexual activity for 48 hours prior to all swabbing procedures Exclusion Criteria: Presence of any significant acute or chronic, uncontrolled medical (or psychiatric) illness, including blood dyscrasias. Immunosuppression as a result of underlying illness or treatment including: Use of high dose corticosteroids ( >10 mg/day prednisone or equivalent) for ≥7 days (inhaled, otic and ophthalmic corticosteroids are permitted) Primary immune deficiency disease Use of synthetic or biologic disease-modifying antirheumatic drugs History of bone marrow or solid organ transplant History of any other clinically significant autoimmune or immunosuppressive disease Positive diagnostic tests (for human immunodeficiency virus, hepatitis B or hepatitis C) indicating chronic infection. Evidence of high grade cervical lesions by colposcopy or by Papanicolaou (Pap) smear test in the 1 year prior to screening. Any history of anaphylaxis in reaction to vaccination or history of allergic reactions likely to be exacerbated by any component of the vaccine, e.g. severe allergy to eggs. Receipt of any investigational drug or investigational vaccine within 3 months prior to administration of ChAdOx1-HPV on Day 0, or prior participation in a clinical study of any HPV vaccine. Receipt of any adenoviral based vaccine within 3 months prior to administration of ChAdOx1 HPV on Day 0, or plan to receive an adenoviral-based vaccine within 3 months after Day 0. Receipt of any live vaccines within the 30 days or inactivated vaccine within the 14 days prior to administration of ChAdOx1-HPV on Day 0 or planned to occur in the 2 months after the Day 0 vaccination. Current or history of illicit drug use within the 6 months prior to screening. Current or history of severe alcohol abuse within the 6 months prior to screening. Any laboratory test which is abnormal and deemed by the Investigator to be clinically significant which will potentially affect the participation in the study. Current known infection with severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) Any other finding that, in the opinion of the Investigator, deems the participant unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lead-in Group A ChAdOx1-HPV low dose and MVA-HPV low dose<br>Prime-boost vaccine doses: ChAdOx1-HPV (2 x 10^8 vp) and MVA-HPV (1 x 10^7 pfu) | Biological: ChAdOx1-HPV<br>* Trial vaccine<br>Biological: MVA-HPV<br>* Trial vaccine<br>|
| Experimental: Lead-in Group B ChAdOx1-HPV mid dose and MVA-HPV low dose<br>Prime-boost vaccine doses: ChAdOx1-HPV (2 x 10^9 vp) and MVA-HPV (1 x 10^7 pfu) | Biological: ChAdOx1-HPV<br>* Trial vaccine<br>Biological: MVA-HPV<br>* Trial vaccine<br>|
| Experimental: Lead-in Group C ChAdOx1-HPV high dose and MVA-HPV high dose<br>Prime-boost vaccine doses: ChAdOx1-HPV (2 x 10^10) vp and MVA-HPV (1 x 10^8 pfu) | Biological: ChAdOx1-HPV<br>* Trial vaccine<br>Biological: MVA-HPV<br>* Trial vaccine<br>|
| Experimental: Group 1 ChAdOx1-HPV mid dose and MVA-HPV low dose<br>Prime-boost vaccine doses: ChAdOx1-HPV (2 x 10^9 vp) and MVA-HPV (1 x 10^7 pfu) | Biological: ChAdOx1-HPV<br>* Trial vaccine<br>Biological: MVA-HPV<br>* Trial vaccine<br>|
| Experimental: Group 2 ChAdOx1-HPV high dose and MVA-HPV low dose<br>Prime-boost vaccine doses: ChAdOx1-HPV (2 x 10^10 vp) and MVA-HPV (1 x 10^7 pfu) | Biological: ChAdOx1-HPV<br>* Trial vaccine<br>Biological: MVA-HPV<br>* Trial vaccine<br>|
| Experimental: Group 3 ChAdOx1-HPV low dose and MVA-HPV high dose<br>Prime-boost vaccine doses: ChAdOx1-HPV (2 x 10^8 vp) and MVA-HPV (1 x 10^8 pfu) | Biological: ChAdOx1-HPV<br>* Trial vaccine<br>Biological: MVA-HPV<br>* Trial vaccine<br>|
| Experimental: Group 4 ChAdOx1-HPV mid dose and MVA-HPV high dose<br>Prime-boost vaccine doses: ChAdOx1-HPV (2 x 10^9 vp) and MVA-HPV (1 x 10^8 pfu) | Biological: ChAdOx1-HPV<br>* Trial vaccine<br>Biological: MVA-HPV<br>* Trial vaccine<br>|
| Experimental: Group 5 ChAdOx1-HPV high dose and MVA-HPV high dose<br>Prime-boost vaccine doses: ChAdOx1-HPV (2 x 10^10 vp) and MVA-HPV (1 x 10^8 pfu) | Biological: ChAdOx1-HPV<br>* Trial vaccine<br>Biological: MVA-HPV<br>* Trial vaccine<br>|
| Placebo Comparator: Group 6 Placebo Saline<br>Sodium Chloride (0.9%) | Biological: Placebo<br>* Saline placebo vaccine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events to measure safety and reactogenicity | Measure of adverse events, serious adverse events (SAEs), ≥Grade 3 study vaccine-related adverse events reported. | 3 months for the lead-in and 12 months for the main phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the dose of ChAdOx1-HPV plus MVA-HPV vaccines for further development | Measurement of the highest multi-parameter index made of CD4+ magnitude, CD4+ avidity and CD8+ magnitude at peak timepoint | 3 months for lead in phase and 12 months for main phase | 
| Determine the effect of ChAdOx1-HPV plus MVA-HPV vaccines on the clearance of high risk HPV infection | The percentage of hrHPV infection clearance | 12 months for main phase only | 
| Determine the effect of ChAdOx1-HPV plus MVA-HPV vaccines on cervical intraepithelial neoplasia (CIN) | The percentage of cervical lesions cleared as determined by colposcopy | 12 months for main phase only |