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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Vesikari reported being the majority shareholder of Nordic Research Network Oy. Dr Finn reported receiving grants from VBI Vaccines during the conduct of the study; receiving grants from Pfizer, Sanofi, GlaxoSmithKline, AstraZeneca, and Valneva outside the submitted work; being a member of the UK NITAG (Joint Committee for Vaccination and Immunisation); and serving as chair of the World Health Organization Euro Technical Advisory Group of Experts on Immunisation. Dr van Damme reported that the University of Antwerp received grants from GlaxoSmithKline, Sanofi, Janssen Vaccines, Curevac, Merck, and Merck Sharp & Dohme for the conduct of vaccine trials and grants from PATH, the Bill & Melinda Gates Foundation, the Belgian Centre for Expertise, and the Flemish Research Fund for the conduct of research and vaccine trials. Dr Aronson reported receiving grants from VBI Vaccines during the conduct of the study; receiving personal fees from Sanofi, Eli Lilly and Co, Novo Nordisk, Boehringer Ingelheim, HTL Strefa, Gilead, BD Technologies, Takeda, and Merck and receiving grants from Xeris, Medpace, Kowa, and Zealand outside the submitted work. Dr Manns reported receiving consulting fees from Roche, Bristol Myers Squibb, Gilead, Enyo Pharma, and Curevac and receiving lecture honoraria and travel support from Roche, Bristol Myers Squibb, and Gilead outside the submitted work. Dr Faust reported receiving grants from VBI Vaccines during the conduct of the study; serving on the advisory boards of Medimmune, Sanofi, Pfizer, Seqrius, Sandoz, and Merck; and receiving grants Pfizer, Sanofi, GlaxoSmithKline, Johnson & Johnson, Merck, AstraZeneca, and Valneva outside the submitted work. Dr Ramasamy reported receiving grants from VBI Vaccines during the conduct of the study. Dr Machluf reported being an employee of VBI Vaccines during the conduct and outside the submitted work. Ms Spaans reported being employee of VBI Vaccines during the conduct of the study. Dr Anderson reported receiving personal fees from VBI Vaccines during the conduct of the study and outside the submitted work. Dr Popovic reported receiving personal fees from VBI Vaccines during the conduct of the study and outside the submitted work. Dr Diaz-Mitoma reported receiving personal fees from VBI Vaccines during the conduct of the study; owning shares in VBI Vaccines outside the submitted work; and being the cited inventor of patents owned by VBI Vaccines. No other disclosures were reported.

Figures

Figure 1.. Study Flowchart

Per-protocol set 1 included those who received all 3 vaccinations, had evaluable serum immunogenicity samples at baseline and at the point of interest, were seronegative at baseline, and had no major protocol deviations leading to exclusion. Per-protocol set 2 included those in per-protocol set 1, except those who attended study visits 3 and 4 outside of the defined windows. 1A-HBV indicates single-antigen hepatitis B virus vaccine; 3A-HBV, 3-antigen HBV; AE, adverse event; and SAE, serious AE. aIndividuals may have multiple reasons for exclusion.

Figure 2.. Seroprotection Rates and Serum Hepatitis B Surface Antibody (Anti-HB) Concentrations in Pooled 3-Antigen Hepatitis B Virus Vaccine (3A-HBV) and Single-Antigen (1A-HBV) Groups

A, Comparison of seroprotection rate in the pooled 3A-HBV group to 1A-HBV group in the per-protocol set 2, at study days 168, 196, and 336. B, The antibody response, as measured by geometric mean concentration of anti-HBs, at study day 168 (ie, 20 weeks following the second vaccination and prior to the third vaccination), study day 196 (4 weeks after the third vaccination), and study day 336 as well as adjusted estimates of geometric mean concentrations by vaccine group and visit in per-protocol set 2. There were no meaningful differences in GMCs at study days 168, 196, and 336 across the three lots of 3A-HBV.