Timo Vesikari [1], Aino Forstén [1], Vlad Popovic [2], Lutz Maubach [3], Ole-Christian Skare [3] and Francisco Diaz-Mitoma [2]

Affiliates

Nordic Research Network Oy, Tampere, Finland [1], VBI Vaccines Inc., Cambridge, Massachusetts, United States [2], Syneos Health, Oslo / Munich, Europe [3]

Abstract

Background and Aim: Hepatitis B virus (HBV) infection is a serious public health problem that can be effectively prevented with hepatitis B vaccination. The magnitude of the immune response to HBV vaccination can be measured by serum levels of anti-HBs and their persistence, which is believed to be dependent upon the induced peak levels. Single-antigen HBV vaccines (1A-HBV) contain the small (S), yeast-derived, HBV surface antigen (HBsAG). 3-antigen HBV vaccine (3A-HBV) is characterized by production in mammalian cells and contains two additional hepatitis B surface antigens, pre-S1 and pre-S2. The pre-S1 antigen codes for the NTCP binding site inducing key neutralizing antibodies that potentially block virus hepatocyte binding. PROTECT and CONSTANT were the 2 pivotal trials that showed non-inferiority (age ≥ 18) of 10 µg 3A-HBV vs. 20 µg 1A-HBV and protocol defined clinical superiority in age ≥ 45. PROTECT was a double-blind, randomized, Phase 3 study to evaluate immunogenicity and safety of 3A-HBV (*PreHevbriTM) and 1A-HBV (Engerix-B®). Three doses of vaccine were administered IM at days 1, 28, and 168. Seroprotection rate (SPR – % of subjects achieving anti-HBs ≥ 10 mIU/mL) and geometric mean concentration (GMC) of anti-HBs were evaluated for 12 months. Following the completion of PROTECT, this investigator-initiated study aimed to assess the long-term persistence of anti-HBs titers 2-3 years after the 3rd dose in the Finland cohort.

Method: Subjects were eligible for the follow-up study if they had been enrolled in PROTECT study and had achieved seroprotection (anti-HBs ≥ 10 mIU/mL). Between February 2021 and June 2021, subjects were contacted to participate in the follow-up study. Serum samples were tested for Anti-HBs titers at the central laboratory (LabConnect, USA) using the same validated anti-HBs quantitative assay [VITROS, Ortho 3600 NJ, USA] used in the PROTECT study.

Results: Of the 528 subjects contacted, 465 participated in the follow-up study. 244 [52.5%] were vaccinated with 3A-HBV and 221 [47.5%] with 1A-HBV. Baseline characteristics were balanced, mean age was 59 years. Data from the PROTECT study demonstrated a peak GMC of anti-HBs of 8021.9 mIU/mL for 3A-HBV and 3787.3 mIU/mL for 1A-HBV 4 weeks after the third dose (Day 196). Data from this study showed that approximately 2.5 years following Day 196 in the PROTECT study, the mean concentration of anti-HBs was 1382.9 mIU/mL for 3A-HBV participants and 251.4 mIU/mL for 1A-HBV participants. Additionally, more than 2x the number of subjects vaccinated with 3A-HBV retained anti-HBs ≥ 100 mIU/mL compared to 1A-HBV (72.9% vs. 32.6%). After approximately 2.5 years, 27.6% in the 1A-HBV group and 11.9% in the 3A-HBV group no longer had seroprotective levels of anti-HBs (titers < 10 mIU/mL).

Conclusion: 2.5 years after achieving peak seroprotection in the PROTECT study, almost 30% of 1A-HBV participants lost measurable HBs antibodies, the percentage no longer having seroprotective levels of anti-HBs (< 10 mIU/mL) was more than double in the 1A-HBV group compared to the 3A-HBV group. Mean anti-HBs titers were five times higher in the 3A-HBV group. Longevity of titers may contribute to protection.

*PreHevbriTM received market authorization in the EU and UK in 2022 and is the same product as Sci-B-Vac®, licensed in Israel in 2000 and used in clinical trials. It received marketing authorization in the US as PreHevbrioTM in 2021.