First-In-Human Study of ChAdOx1-HBV & MVA-HBV Vaccines (VTP-300) for Chronic HBV

This is an open-label study to determine the safety, tolerability and immunogenicity of ChAdOx1-HBV and MVA-HBV vaccines, with or without nivolumab, in patients with chronic HBV who are virally suppressed with oral anti-viral therapies.

This is a multi-centre study conducted in 52 participants, who will each be administered 2 vaccine injections (IM) on Day 0 and Day 28 as follows:

Group 1: MVA-HBV + MVA-HBV (now closed) Group 2: ChAdOx1-HBV + MVA-HBV Group 3: ChAdOx1-HBV + MVA-HBV + nivolumab (IV infusion) Group 4: ChAdOx1-HBV + nivolumab + MVA-HBV + nivolumab (now closed)

Participants are randomised to treatment as the groups are initiated with a 1:1:1:1 allocation. Version 6.0 of the study protocol has closed Groups 1 and 4 to further randomisation; recruitment will now be in a 1:1 ratio between Groups 2 and 3 only. A sentinel participant is dosed in Group 1, with further participants in Group 1 only being dosed at least 48h later. Group 2 is initiated following a Day 7 safety assessment of the first 6 participants in Group 1. Groups 3 and 4 are initiated following a Day 7 safety assessment of the first 6 participants in Group 2.

The primary objective of the study is to determine the safety and reactogenicity of the treatment regimens; this will be assessed by analysis of the incidence and severity of (serious) adverse events and any changes in laboratory values and vital signs.

The secondary objectives of the study are the determination of the immunogenicity of the ChAdOx1-HBV and MVA-HBV vaccines and the impact of PD-blockade, as well as the effect on HBV markers; these are assessed by measurements of the magnitude and avidity of HBV-specific CD4+ and CD8+ T cells and the magnitude of HBV markers.

Following first vaccination, participants remain in the study for 9 months and attend clinic visits for vaccination and assessments on Days 0, 7, 28, 35 and Months, 3, 6 and 9.

Eligibility Criteria:
Inclusion Criteria:

1. Adult males or females aged ≥18 to ≤65 years at screening (according to country/local regulations)
2. BMI ≤32kg/m2
3. Able to provide informed consent indicating they understand the purpose of, and procedures required, for the study and are willing to participate
4. If female, willing not to become pregnant up to 8 weeks after last dose of study vaccine and up to 5 months after the last dose of nivolumab
5. If female: 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 post menopausal, as defined by no menses in ≥1 year and without an alternative medical cause)
   * Of childbearing potential but agrees to practice highly effective contraception for 4 weeks prior to study vaccine and 8 weeks after study vaccine and 5 months after the last dose of nivolumab. Highly effective methods of contraception include one or more of the following:

     (i) 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

   (ii) Combined (oestrogen and progestogen-containing) hormonal contraception associated with inhibition of ovulation:
   * oral
   * intravaginal
   * transdermal

   (iii) Progestogen-only hormonal contraception associated with inhibition of ovulation:
   * oral
   * injectable
   * implantable

   (iv) An intrauterine device

   (v) Bilateral tubal occlusion
6. Documented evidence of chronic HBV infection (e.g. HBsAg positive ≥6 months with detectable HBsAg levels at screening)
7. Receipt of only either entecavir, tenofovir (tenofovir alafenamide fumarate or tenofovir disoproxil fumarate), or besifovir for at least 12 months before screening
8. Virally suppressed (HBV-DNA viral load \< 40 IU/mL for ≥ 1 year)
9. HBsAg levels \<4000 IU/mL

Exclusion Criteria:

1. Presence of any significant acute or chronic, uncontrolled medical/psychiatric illness
2. Hepatitis C virus (HCV) antibody positive.
3. HIV antibody positive
4. Co-infection with hepatitis D virus
5. Documented cirrhosis or advanced fibrosis indicated by a liver biopsy within 6 months prior to screening (Metavir activity grade A3 and stages F3 and F4; Ishak stages 4-6).

   In the absence of a documented liver biopsy, either 1 of the following (not both):
   * Screening Fibroscan with a result \> 9 kilopascals (kPa) (or the equivalent) within ≤ 6 months of screening, OR
   * Screening FibroTest \>0.48 and aspartate aminotransferase (AST) to platelet ratio index (APRI) of \>1.
6. ALT \>3 x upper limit of normal (ULN), international normalized ratio (INR) \>1.5 unless the participant was stable on an anticoagulant regimen affecting INR, albumin \<3.5 g/dL, direct bilirubin \>1.5 x ULN, platelet count \< 100,000/microlitre.
7. A history of liver decompensation (e.g. ascites, encephalopathy or variceal haemorrhage)
8. Prior hepatocellular carcinoma
9. Chronic liver disease of a non-HBV aetiology
10. History or evidence of autoimmune disease or known immunodeficiency of any cause
11. Presence of active infection
12. Evidence of interstitial lung disease, active pneumonitis, myocarditis, or a history of myocarditis
13. Past history of thyroid disorder or abnormal thyroid function at screening that is still active and uncontrolled
14. Prolonged therapy with immunomodulators (e.g. corticosteroids such as prednisone \> 10 mg/day) or biologics (e.g. monoclonal antibodies, IFN) within 3 months of screening
15. Receipt of immunoglobulin or other blood products within 3 months prior to enrolment
16. Receipt of any investigational drug or vaccine within 3 months prior to screening
17. Receipt of any adenoviral-based vaccine within 3 months prior to administration of ChAdOx1-HBV on Day 0, or plan to receive an adenoviral-based vaccine within 3 months after Day 0
18. Receipt of any live vaccines within 30 days prior to screening
19. Receipt of any inactivated vaccines within 14 days prior to screening,
20. History of severe hypersensitivity or anaphylactic reactions likely to be exacerbated by any component of the vaccine or nivolumab
21. Malignancy within 5 years prior to screening with the exception of specific cancers that are cured by surgical resection (e.g. except basal cell skin carcinoma of the skin and cervical carcinoma). Participants under evaluation for possible malignancy are not eligible
22. Current alcohol or substance abuse judged by the Investigator to potentially interfere with participant safety and compliance
23. Significant cardiac disease or unstable uncontrolled cardiac disease
24. Any laboratory test which is abnormal, and which is deemed by the Investigator to be clinically significant
25. Cytotoxic agents, other anti HBV or traditional herbal medicines which, in the opinion of the Investigator, may have activity against HBV within the previous 6 months prior to randomization
26. Any other finding that, in the opinion of the Investigator, deems the participant unsuitable for the study