Immunogenicity and Safety of an Investigational Hepatitis B Vaccine

Background: Hepatitis B vaccines have been an important prevention tool of infection control for over 25 years, but are known to be less effective in hypo-responsive populations. More effective vaccines using second-generation adjuvants such as Toll-Like Receptor (TLR) agonists have been shown to improve vaccine response resulting in 97% seroprotection after 2 doses in healthy adults 40-70 years of age in previous studies.

Objective: : HEPLISAV is an investigational vaccine that contains hepatitis B surface antigen (HBsAg) and a TLR-9 agonist, 1018 immunostimulatory sequence (ISS). This Phase 3 study compared the seroprotection rate (SPR defined as antibody to HBsAg [anti-HBsAg] ≥ 10 mIU/mL), geometric mean concentration of anti-HBsAg (GMC) and safety of HEPLISAV, with that of a licensed vaccine in healthy subjects 18 - 55 years of age.

Methods: A randomized, observer-blinded study comparing 2 doses of HEPLISAV given at 0, 1 months with 3 doses of licensed vaccine (Engerix-B, 20 mcg) given at 0, 1 and 6 months. Subjects were randomized 3:1 (HEPLISAV: Engerix-B). All subjects received vaccinations at months 0, 1 and 6.  Subjects in the HEPLISAV group received saline placebo at month 6. The primary immunogenicity endpoint was the comparison of SPR, measured at month 3 for HEPLISAV versus month 7 for Engerix-B. The primary hypothesis was that the HEPLISAV was non-inferior to Engerix-B.   Secondary immunogenicity endpoints included SPR and GMC at months 1, 2, 3, 6 and 7.

Results: 2428 subjects enrolled in this study; 1820 to HEPLISAV and 608 to Engerix-B. Demographic characteristics were similar between the two arms. The primary endpoint SPR was 95.1% after 2 doses of HEPLISAV and 81.1% after 3 doses of Engerix-B; non-inferiority of HEPLISAV was established because the difference in SPR between the two groups was 13.8% (95% CI, 10.5% and 17.5%).   The GMC of the HEPLISAV group was consistently higher at all time points.  At study month 7, GMC was similar between the groups.  A review of safety indicates that HEPLISAV is safe, well-tolerated and comparable to Engerix-B with regard to local and systemic adverse events and serious adverse events.  Two cases of ANCA-associated vasculitis were seen; one in a HEPLISAV subject and one in an Engerix-B subject.  A subsequent review of adverse events potentially associated with autoimmune conditions revealed no difference between groups. Conclusions: The availability and use of HEPLISAV as a short-regimen 2 dose vaccine could make significant contributions to improving the effectiveness of hepatitis B vaccination and reducing the burden of vaccination to infection control practices for indicated adults.