Immunogenicity and Safety of a 3-Antigen Hepatitis B Vaccine vs a Single-Antigen Hepatitis B Vaccine: A Phase 3 Randomized Clinical Trial.

Importance: There is a need for improved immunogenicity of hepatitis B virus (HBV) vaccines among young adults with risk of infection. Objectives: To demonstrate manufacturing equivalence of a 3-antigen (3A) HBV vaccine, evaluate noninferiority of seroprotection rate (SPR) of 3A-HBV vs single-antigen (1A) HBV after 2 and 3 vaccine doses, and compare safety and reactogenicity between 3A-HBV and 1A-HBV vaccines. Design, Setting, and Participants: This phase 3, double-blinded, randomized clinical trial included healthy adults aged 18 to 45 years randomized to 1 of three 3A-HBV groups or 1 control group receiving 1A-HBV. The trial was conducted at 37 community clinics and academic hospitals in Canada, Europe, the United Kingdom, and the United States between December 2017 and October 2019. Participants were followed up for 48 weeks after the first vaccination. Interventions: Intramuscular administration of 3A-HBV (10 µg) or 1A-HBV (20 µg) on days 0, 28, and 168. Main Outcomes and Measures: Geometric mean concentration (GMC) of serum hepatitis B surface antibodies (anti-HBs) and proportion of participants achieving seroprotection. Results: Of 2838 participants, 1638 (57.8%) were women, 2595 (91.5%) were White, and 161 (5.7%) were Black or African American. A total of 712 participants (25.1%) were randomized to the 1A-HBV group and 2126 (74.9%) to 3A-HBV. The mean (SD) age at informed consent was 33.5 (8.0) years. The study demonstrated 3A-HBV lot-to-lot consistency, as the 2-sided 95% CIs for each pairwise comparison for the anti-HBs GMC ratios were within 0.67 and 1.50 (eg, adjusted GMC ratio, lot A vs lot B: 0.82; 95% CI, 0.67-1.00; lot A vs lot C: 0.95; 95% CI, 0.78-1.15; lot B vs lot C: 1.16; 95% CI, 0.95-1.41). The SPR of the pooled 3A-HBV was noninferior to 1A-HBV and higher than 1A-HBV after 2 vaccinations at day 168 (90.4% [95% CI, 89.0%-91.8%] vs 51.6% [95% CI, 47.5%-55.6%]) and 3 vaccinations at day 196 (99.3% [95% CI, 98.7%-99.6%] vs 94.8% [95% CI, 92.7%-96.4%]). The mean GMC of anti-HBs with 3A-HBV was 7.9 times higher after 2 vaccinations at day 168 and 3.5 times higher after 3 vaccinations at day 196 compared with 1A-HBV (after 2 vaccinations, 3A-HBV: GMC, 118.7 mIU/mL; 95% CI, 108.0-129.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: GMC, 15.0 mIU/mL; 95% CI, 12.9-17.5 mIU/mL; SE, 1.0 mIU/mL; after 3 vaccinations, 3A-HBV: GMC, 5442.4 mIU/mL; 95% CI, 4967.0-5963.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: 1567.2 mIU/mL; 95% CI, 1338.0-1834.0 mIU/mL; SE, 1.0 mIU/mL). Rates of local and systemic reactogenicities were higher with 3A-HBV compared with 1A-HBV (local: 1805 of 2124 [85.0%] vs 469 of 712 [65.9%]; systemic: 1445 [68.0%] vs 428 [60.1%]). Vaccine discontinuation due to adverse events (AE) was uncommon, and serious AEs were infrequent, reported in 42 participants (2.0%) and 3 participants (0.4%) in the 3A-HBV and 1A-HBV groups, respectively. Conclusions and Relevance: In this study, consistently higher antibody concentrations and SPRs were found with 3A-HBV after 2 and 3 doses vs 1A-HBV in adults aged 18 to 45 years old. The safety and efficacy of 3A-HBV shows its usefulness for the prevention of hepatitis B in young healthy adults. Trial Registration: Clinicaltrials.gov Identifier: NCT03408730; EU Clinical Trials Number: 2017-001820-22.

Immunogenicity and safety of a tri-antigenic versus a mono-antigenic hepatitis B vaccine in adults (PROTECT): a randomised, double-blind, phase 3 trial.

BACKGROUND: The seroprotection rate (SPR) of hepatitis B vaccination in adults is suboptimal. The aim of this study was to compare the SPR of a tri-antigenic hepatitis B vaccine (TAV), with a mono-antigenic vaccine (MAV) in adults of all ages. METHODS: This was a multicentre, double-blind, phase 3, randomised controlled trial (PROTECT) comparing the immunogenicity and safety of TAV with MAV in 28 community and hospital sites in the USA, Finland, Canada, and Belgium. Adults (aged ≥18 years) seronegative for hepatitis B virus (HBV), including those with well-controlled common chronic conditions, were randomly assigned (1:1) and stratified by study centre and age according to a web-based permuted blocked randomisation. Participants received either TAV or MAV which were administered as an intramuscular dose (1 mL) of TAV (10 µg; Sci-B-Vac, VBI Vaccines [SciVac, Rehovot, Israel]) or MAV (20 µg; Engerix-B [GlaxoSmithKline Biologicals, Rixensart, Belgium]) on days 0, 28, and 168 with six study visits and 24 weeks of follow-up after the third vaccination. Participants, investigators, and those assessing outcomes were masked to group assignment. The co-primary outcomes were to show non-inferiority of the SPRs 4 weeks after the third vaccination with TAV versus MAV in adults aged 18 years and older, as well as superiority in adults aged 45 years and older. SPR was defined as the percentage of participants attaining anti-HBs titres of 10 mIU/mL or higher. Non-inferiority of TAV to MAV was concluded if the lower limit of the 95% CI for the between-group difference was greater than -5%. Non-inferiority was assessed in the per-protocol set of participants (aged ≥18 years) and superiority was assessed in all participants (aged ≥45 years) who received at least one vaccination and had at least one evaluable immunogenicity sample after baseline (full analysis set). Safety analyses were a secondary outcome and included all participants who received at least one injection. This trial is registered at Clinicaltrials.gov (NCT03393754) and EudraCT (2017-001819-36) and is closed to new participants. FINDINGS: Between Dec 13, 2017, and April 8, 2019, 1607 participants (796 allocated to TAV and 811 allocated to MAV) were randomly assigned and distributed across age cohorts of 18-44 years (299 of 1607; 18·6%), 45-64 years (716 of 1607; 44·6%), and 65 years and older (592 of 1607; 36·8%). In participants aged 18 years and older, SPR was 91·4% (656 of 718) in the TAV group versus 76·5% (553 of 723) in the MAV group (difference 14·9%, 95% CI 11·2-18·6), showing non-inferiority in the per-protocol set. In participants aged 45 years and older, SPR was 89·4% (559 of 625) in the TAV group versus 73·1% (458 of 627) in the MAV group (difference 16·4%, 95% CI 12·2-20·7), showing superiority in the full analysis set. TAV was associated with higher rates of mild or moderate injection site pain (63·2% [503 of 796] in TAV vs 36·3% [294 of 811] in MAV), tenderness (60·8% [484 of 796] in TAV vs 34·8% [282 of 811] in MAV), and myalgia (34·7% [276 of 796] vs 24·3% [197 of 811] in MAV). Otherwise, the safety profile of TAV was similar to that of MAV. INTERPRETATION: The safety and efficacy of TAV shows its usefulness for the prevention of HBV infection in adults, including those with stable and controlled chronic conditions. FUNDING: VBI Vaccines.

Rapid and high seroprotection rates achieved with a tri-antigenic Hepatitis B vaccine in healthy young adults: Results from a Phase IV study.

BACKGROUND: Sci-B-Vac® is a tri-antigenic recombinant Hepatitis B vaccine (TAV) containing the small (s), medium (pre-S2) and large (pre-S1) hepatitis B surface (HBs) antigens. To comply with vaccine licensure, a new reference standard batch was qualified by characterizing the seroprotection rate (SPR) for anti-HBs titers ≥10 mIU/mL, following vaccination. METHODS: Ninety-one healthy adults aged 20-40 years were enrolled in an open label, single-arm phase IV study receiving three IM doses of 10 µg TAV at 0, 1 and 6 months. Immunogenicity was evaluated monthly and at 7, 9 and 12 months. The primary endpoint to qualify the reference standard was an SPR ≥95% by month 7. Secondary endpoints were proportion of high responders (anti-HBs titers ≥100 mIU/mL) and geometric mean concentrations (GMC) of HBs antibodies each month. Participants were followed for safety to month 12. RESULTS: The primary endpoint was met 2 months after the second dose at month 3 [SPR 98.8%; 95% CI: 93.7%, 99.7%]. Proportion of high responders at months 3 and 7 were 81.4% and 97.6%, respectively. GMC at months 3 and 7 were 413.6 mIU/mL and 6799.9 mIU/mL, respectively. TAV was safe and well-tolerated. CONCLUSIONS: The new reference standard batch of TAV was qualified successfully, demonstrating efficacy, a favorable safety profile and a rapid onset of seroprotection, including after two vaccine doses. Clinical trial registry: NCT04179786.

Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study.

BACKGROUND: Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. METHODS: In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. RESULTS: A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. DISCUSSIONS: A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. CLINICAL TRIALS REGISTRATION: NCT01857869.