First in Human Study of ChAdOx1-HBV in Healthy Participants and Participants With Chronic hepB Infection

Phase 1

Completed

Conditions: Hepatitis B
Healthy

Interventions: Biological: ChAdOx1-HBV

Registration Number: NCT04297917

Lead Sponsor: Barinthus Biotherapeutics

Brief Summary: This is a Phase 1, first in human study of ChAdOx1-HBV. The study will be conducted in 40 healthy participants and 12 participants with CHB and virally suppressed with oral antiviral medication. This will be an open-label, non randomised dose escalation study comparing the safety, tolerability and immunogenicity of 2 different doses of ChAdOx1 HBV vaccine. T cell responses in healthy participants who have received a prior two-dose series of AZD1222 will be compared with those who have received either the Pfizer COVID 19 vaccine or the Moderna mRNA COVID 19 vaccine.

Detailed Description: This is a first in man human study of a therapeutic vaccine for chronic hepatitis B infection(ChAdOx1-1HBV). The vaccine was given to participants in a dose escalation strategy (two doses). Five healthy participants was administered the low dose first (cohort 1). Dose escalation was only initiated in the next 5 healthy participants (cohort 2) following Safety Monitoring Committee (SMC) review.

Six CHB participants was administered the low dose (cohort 3) before the dose escalation was initiated in the remaining 5 CHB participants (cohort 4).

Twenty-six healthy participants (15 who have received two doses of AZD1222 \[cohort 5\] and 11 who have received at least two prior doses of Pfizer/Moderna mRNA COVID 19 vaccine \[cohort 6\]) were dosed in parallel with the high dose used in cohorts 2 and 4.

Each participant received 1 dose of the vaccine (intramuscular injection). Participants (Volunteers \& patients) in cohorts 1 to 4 attended up to 9 study visits and cohorts 5 \& 6 attended up to 4 visits in total. The last visit was 24 weeks after vaccination for cohorts 1 to 4 and 12 weeks for cohorts 5 \& 6.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 47

Inclusion Criteria

Adult males or females aged ≥18 to ≤65 years at screening
Body Mass Index ≤30 kg/m2
Able to provide informed consent indicating they understand the purpose of, and procedures required, for the study and are willing to participate
If female, willing not to become pregnant up to 8 weeks after last dose of study vaccine, not breast feeding
If female: Not pregnant, 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)
- Sexual abstinence, only if the participant refrains from heterosexual intercourse during the entire study period and it is the usual lifestyle of the participant
- Of childbearing potential but agrees to practice highly effective contraception for 4 weeks prior to study vaccine and 8 weeks after study vaccine. 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), An intrauterine hormone releasing system, An intrauterine device and Bilateral tubal occlusion

Healthy participants (cohorts 1 and 2):
Considered to be healthy with no current conditions that may significantly impair participant safety or influence study results, in the opinion of the Investigator

Participants with well controlled CHB (cohorts 3 and 4):
Documented evidence of chronic HBV infection (e.g. HBsAg positive ≥6 months with detectable HBsAg levels at screening)
Receipt of only either entecavir or tenofovir for at least 12 months before screening
Virally suppressed (HBV DNA <40 IU/mL for ≥6 months)
HBsAg <4000IU/mL

Participants with well controlled CHB (cohorts 3 and 4):

Documented evidence of chronic HBV infection (e.g. HBsAg positive ≥6 months with detectable HBsAg levels at screening) 8. Receipt of only either entecavir or tenofovir for at least 12 months before screening 9. Virally suppressed (HBV DNA <40 IU/mL for ≥6 months) 10. HBsAg <10000 IU/mL

Healthy participants (cohort 5):

Considered to be healthy with no current conditions that may significantly impair participant safety or influence study results, in the opinion of the Investigator 12. Adult males or females aged ≥40 to ≤60 years at screening 13. Completed second dose of COVID-19 AZD1222 vaccine 10 to 18 weeks before enrolment

Healthy participants (cohort 6):

Considered to be healthy with no current conditions that may significantly impair participant safety or influence study results, in the opinion of the Investigator
Adult males or females aged ≥40 to ≤60 years at screening
Received the latest dose of Completed of either Pfizer (Comirnaty®) or Moderna (Spikevax) mRNA COVID 19 vaccine 6 to 30 weeks before enrolment

Exclusion Criteria

Presence of any significant acute or chronic, uncontrolled medical/ psychiatric illness
Hepatitis C virus antibody positive.
Human immunodeficiency virus antibody positive
History or evidence of autoimmune disease or known immunodeficiency of any cause
Prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics (e.g. monoclonal antibodies, interferon) within 3 months of screening
Receipt of immunoglobulin or other blood products within 3 months prior to screening
Receipt of any investigational drug or vaccine within 3 months prior to screening
Cohorts 1-4: Receipt of any adenoviral 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

Cohorts 5 and 6: Receipt of any adenoviral vaccine (other than AZD1222 per inclusion criterion 13) 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
Receipt of any live vaccines within 30 days prior to screening
Receipt of any inactivated vaccines within 14 days prior to screening
History of allergic disease or reactions likely to be exacerbated by any component of the vaccine
Any history of anaphylaxis in reaction to vaccination
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
Current alcohol or substance abuse judged by the Investigator to potentially interfere with participant safety and compliance
Significant cardiac disease or unstable uncontrolled cardiac disease
Any laboratory test at screening which is abnormal and which is deemed by the Investigator to be clinically significant
Any other finding that, in the opinion of the Investigator, deems the participant unsuitable for the study Additionally, for healthy participants (cohorts 1, 2, 5 and 6)
HBsAg positive Additionally, for participants with well controlled CHB (cohorts 3 and 4)
Co infection with hepatitis delta
Documented cirrhosis or advanced fibrosis indicated by a liver biopsy within 6 months prior to screening.

In the absence of an appropriate liver biopsy, either 1 of the following:
- Screening Fibroscan with a result >9 kPa within ≤6 months of screening or
- Screening FibroTest >0.48 and aspartate aminotransferase (AST) to platelet ratio index of >1 In the event of discordant results between non-invasive methods, the Fibroscan result will take precedence.
Alanine transaminase (ALT) >3 × upper limit of normal, international normalised ratio (INR) >1.5 unless the participant was stable on an anticoagulant regimen affecting INR, albumin <35 g/L, total bilirubin >2 mg/dL, platelet count <100,000/mL
A history of liver decompensation (e.g. ascites, encephalopathy or variceal haemorrhage)
Prior or current hepatocellular carcinoma
Chronic liver disease of a non HBV aetiology
Any herbal supplements and or other medicines with potential liver toxicity within the previous 3 months prior to enrolment into this study

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Healthy Volunteers with low dose vaccination	ChAdOx1-HBV	5 Healthy Volunteers receiving low dose vaccination
Healthy Volunteers with high dose vaccination	ChAdOx1-HBV	5 Healthy Volunteers receiving high dose vaccination
Chronic Hepatitis B participants with low dose vaccination	ChAdOx1-HBV	6 participants with Chronic Hepatitis B infection receiving low dose vaccination
Chronic Hepatitis B participants with high dose vaccination	ChAdOx1-HBV	5 participants with Chronic Hepatitis B infection receiving high dose vaccination
Healthy Volunteers who have had COVID-19 AZD1222 vaccine	ChAdOx1-HBV	15 participants who have had 2 doses of COVID-19 AZD1222 vaccine receiving high dose vaccination.
Healthy Volunteers who have had Pfizer/Moderna mRNA COVID 19 vaccine	ChAdOx1-HBV	11 participants who have had 2 doses of either Pfizer/Moderna mRNA COVID 19 vaccine receiving high dose vaccination

Primary Outcome Measures

Name	Time	Method
Incidence of Safety and Reactogenicity Events: Adverse Events	Recorded in the eCRF from the date the informed consent is signed, at all clinic visits (D0, D1, D7, D14, D28, D56, D84) to cover the period since the previous visit and during the visit and up to 168 days post-vaccination (6 months)	Adverse events and/or adverse events leading to study discontinuation. Percentages are based on the number of participants in the Safety Analysis Set.
Incidence of Safety and Reactogenicity Events: Serious Adverse Events	From day 0 to up to 6 months	Serious adverse events related to the study vaccine. Percentages are based on the number of participants in the Safety Analysis Set.
Incidence of Safety and Reactogenicity Events: Grade ≥3 Local Reactions	From day 0 to day 3	Local reactions were collected by the investigator pre and post vaccination on Day 0. In addition, local reactions were captured in the participant diary card on Days 1, 2 and 3. The number and percentage of participants who experienced any symptom are summarised.
Incidence of Safety and Reactogenicity Events: Grade ≥3 Systemic Reactions	From day 0 to day 3	Systemic reactions were collected by the investigator pre and post vaccination on Day 0 and captured in the participant diary card on Days 1, 2 and 3. The number and percentage of participants who experienced any symptom are summarised.
Effect of Prior AZD1222 on the CD8+ T Cell Magnitude and Phenotype as Measured by Multiparameter Flow Cytometry	Baseline, Day 14, 28, 56, 84	Intracellular cytokine staining analysis to measure IFNγ, produced by HBV antigen or hexon-specific CD8+ T cells in PBMC across study timepoints

Secondary Outcome Measures

Name	Time	Method
Reduction in HBsAg Titre Post-vaccination in CHB Participants	Baseline, Day 28, 56, 84 and 168	For the CHB participants only. HBsAg levels were measured at each scheduled follow-up timepoint (Day 28, Day 56, Day 84 and Day 168). A summary of the change is obtained by summarising the difference in the log-transformed results \[log(HbsAg at baseline + 1) - log(HbsAg at follow-up + 1)\] and back-transforming to absolute values (IU/mL). The mean change is then the Geometric Mean (GM) ratio, where a GM ratio \> 1 is equivalent to a reduction in HbsAg.
Loss of Both HBeAg and HBsAg	Baseline and Day 168	For the CHB participants only, loss of HBeAg and HBsAg at the End of Study assessment (Day 168) include all CHB participants in the denominator. Numerators include participants with a) detectable HBeAg and HBsAg at the Day 0 pre-dose assessment and b) undetectable HBeAg and HBsAg at the End of Study assessment.
Proportion of CHB Participants With HBeAg and HBsAg Seroconversion	Baseline, Day 28, 56, 84 and 168	The seroconversion of HBeAg and HBsAg is defined as loss of response to the antigen (defined as a value below the limit of detection (i.e. Not detected) and development of antibody to either HBeAg or surface antigen (HBsAg) (defined as a measurable value above the limit of detection (i.e. Detected). The number and percentage of CHB participants meeting the criteria for seroconversion will be summarised.
Reduction of Hepatitis B DNA Levels in CHB Participants	Baseline, Day 28, 56, 84 and 168	Change in hepatitis B DNA levels is defined by subtracting the DNA levels at each follow-up visit (Day 28, Day 56, Day 84 and Day 168) from the DNA levels pre-vaccination (Day 0). A positive change is equivalent to a reduction in DNA levels. Any results recorded as Not Detected were replaced with zero prior to summarising while any recorded as Detected or 1 (the limit of detection) were replaced with 0.5, prior to summarising. The denominator is the number of participants in the analysis set.
Percentage of CD4+ and CD8+ Expressing IFNγ at Baseline and Days 14, 28, 56, and 84 After Vaccination	Baseline, 14, 28, 56, and 84	CD4+ and CD8+ cells were analyzed at selected baseline and follow up study visits (Day 0, Day 14, Day 28, Day 56, and/or Day 84) using intracellular cytokine staining (ICS) data from a flow cytometer. Outcome 'A Multiparameter Index Made of CD4+Magnitude, CD4+ Avidity and CD8+ Magnitude' was not calculated.
Total T Cell Response to the Core Antigen Encoded by ChAdOx1-HBV as Measured in a Peptide-stimulated ELISpot Assay	Baseline, Day 14, 28, 56, 84 and 168	This was determined by using PMBCs in IFN-γ ELISpot assays to investigate the breadth of HBV specific T cell responses. Assessment of immune response was based on the number of IFN-γ spot-forming units (SFU) per 10\^6 PBMC in response to stimulation with each antigenic peptide pool. For CHB-LD, CHB-HD, HP-LD, HP-HD the background correction is derived by subtracting the relevant DMSO control result and replacing any negative values or values \< 25 with zero prior to summarising.
Total T Cell Response to the Pol1-Pol4 Antigen Encoded by ChAdOx1-HBV as Measured in a Peptide-stimulated ELISpot Assay	Baseline, Day 14, 28, 56, 84 and 168	This was determined by using PMBCs in IFN-γ ELISpot assays to investigate the breadth of HBV specific T cell responses. Assessment of immune response was based on the number of IFN-γ spot-forming units (SFU) per 10\^6 PBMC in response to stimulation with each antigenic peptide pool. For CHB-LD, CHB-HD, HP-LD, HP-HD the background correction is derived by subtracting the relevant DMSO control result and replacing any negative values or values \< 25 with zero prior to summarising.
Total T Cell Response to the Pre S1/S2 Surface Antigen Encoded by ChAdOx1-HBV as Measured in a Peptide-stimulated ELISpot Assay	Baseline, Day 14, 28, 56, 84 and 168	This was determined by using PMBCs in IFN-γ ELISpot assays to investigate the breadth of HBV specific T cell responses. Assessment of immune response was based on the number of IFN-γ spot-forming units (SFU) per 10\^6 PBMC in response to stimulation with each antigenic peptide pool. For CHB-LD, CHB-HD, HP-LD, HP-HD the background correction is derived by subtracting the relevant DMSO control result and replacing any negative values or values \< 25 with zero prior to summarising.
Total T Cell Response to the Sii Surface Antigen Encoded by ChAdOx1-HBV as Measured in a Peptide-stimulated ELISpot Assay	Baseline, Day 14, 28, 56, 84 and 168	This was determined by using PMBCs in IFN-γ ELISpot assays to investigate the breadth of HBV specific T cell responses. Assessment of immune response was based on the number of IFN-γ spot-forming units (SFU) per 10\^6 PBMC in response to stimulation with each antigenic peptide pool. For CHB-LD, CHB-HD, HP-LD, HP-HD the background correction is derived by subtracting the relevant DMSO control result and replacing any negative values or values \< 25 with zero prior to summarising.
Effect of Prior AZD1222 on the CD4+ T Cell Magnitude and Phenotype as Measured by Multiparameter Flow Cytometry	Baseline, Day 14, 28, 84	Intracellular cytokine staining analysis to measure IFNγ, produced by hexon-specific CD4+ T cells in PBMC across study timepoints
Effect of Prior AZD1222 on the CD8+ T Cell Magnitude and Phenotype as Measured by Multiparameter Flow Cytometry	Baseline, Day 14, 28, 84	Intracellular cytokine staining analysis to measure IFNγ, produced by hexon-specific CD8+ T cells in PBMC across study timepoints

Trial Locations

Locations (4): University Hospital Southampton NHS Foundation Trust
🇬🇧
Southampton, Hampshire, United Kingdom
Oxford University Hospitals Nhs Foundation Trust
🇬🇧
Oxford, Oxfordshire, United Kingdom
Centre for Clinical Vaccinology and Tropical Medicine (CCVTM)
🇬🇧
Headington, Oxford, United Kingdom
Medicines Evaluations Unit
🇬🇧
Manchester, United Kingdom
University Hospital Southampton NHS Foundation Trust
🇬🇧Southampton, Hampshire, United Kingdom