HEPLISAV B Solution for injection in pre-filled syringe Ref.[28057] Active ingredients: Hepatitis B, purified antigen

Pharmacotherapeutic group: Vaccines, Viral Vaccines, Hepatitis Vaccine
ATC code: J07BC01

Mechanism of action

HEPLISAV B is comprised of recombinant hepatitis B surface antigen and the CpG 1018 adjuvant, which is a 22-mer immunostimulatory sequence oligonucleotide.

HEPLISAV B induces specific antibodies against HBsAg (anti-HBs).

The biological actions of CpG 1018 are exerted locally at the injection site and draining lymph nodes. The adjuvant CpG 1018 component of HEPLISAV B has the following effects: (1) activates plasmacytoid dendritic cells (pDCs) through the pattern recognition receptor Toll-like receptor 9; (2) converts pDCs into highly efficient antigen-presenting cells that present the processed HBsAg to CD4+ T cells; and, (3) promotes Th1 T-cell differentiation through the production of IFN-alpha and IL-12. This activation results in a high and sustained antibody response, likely due to the rapid generation of large numbers of anti-HBs-secreting plasmacytes and HBsAg-specific memory B and T cells.

Immune responses to HEPLISAV B

No efficacy trials were conducted due to the application of the well-established immune correlate of protection to the immune response (anti-HBs concentration ≥10 mIU/ml correlates with protection against HBV infection). The immunogenicity of HEPLISAV B was evaluated in 3 randomized, active controlled, observer-blinded, multicentre phase 3 clinical trials (HBV-10 with 3:1 randomisation, HBV-16 with 4:1 randomisation, and HBV-23 with 2:1 randomisation) including 9365 adults aged 18 to 70 years given HEPLISAV B, and 3867 adults given the comparator hepatitis B vaccine (Engerix-B 20 mcg HBsAg). HEPLISAV B was given as a 2-dose schedule at 0 and 1 month and Engerix-B was given using a 3-dose schedule at 0, 1, and 6 months.

Baseline characteristics were balanced between the treatment arms for age, sex, race, ethnicity, and body mass index (BMI). In the pooled analysis including all 3 trials, the mean age was 49.3 and 49.4 in the HEPLISAV B arm and Engerix-B arms, respectively and there were 50.8% and 51.5% female participants who received HEPLISAV B and Engerix-B, respectively.

The trials evaluated the seroprotection rates (SPR: percentage of vaccinated persons whose anti-HBs antibody levels were ≥10 mIU/ml after vaccination) after the second dose of HEPLISAV B compared to after the third dose of Engerix-B. The SPR and peak geometric mean concentration (GMC) after a 2-dose schedule of HEPLISAV B were statistically significantly higher than after a 3-dose schedule of Engerix-B (lower bound of the 95% confidence interval of the difference in SPRs between HEPLISAV B and Engerix-B was greater than 0%; lower bound of the 95% confidence interval of the ratio of GMCs between HEPLISAV B and Engerix-B was greater than 1.0) in all 3 trials (Table 1, Table 2).

Table 1. Comparison of Seroprotection Rates Between HEPLISAV B and Engerix-B at Peak Weeks in Pooled Trials HBV-23, HBV-16 and HBV-10 (mITT Population):

N = number of evaluable subjects; n = number of seroprotected subjects; SPR = Seroprotection Rate, CI = confidence interval.
Seroprotection is defined as anti-HBs ≥10 mIU/mL.
Peak week comparison is for HEPLISAV B at Week 24 and Engerix-B at Week 28.
The confidence intervals on seroprotection rates are calculated using the two-sided Clopper-Pearson method.
The confidence interval on the difference between treatment groups is calculated using the Miettinen and Nurminen method without stratification.

Table 2. Comparison of Anti-HBs Geometric Mean Concentrations at Peak Weeks Between HEPLISAV B and Engerix-B in Pooled Trials HBV-23, HBV-16 and HBV-10 (mITT Population):

Peak week for HEPLISAV B is Week 24. Peak week for Engerix-B is Week 28

SPR results were collected at each study visit in two of the pivotal trials, HBV-10 (week 4 to 28) and HBV-16 (week 4 to 52). HEPLISAV B induced significantly higher SPRs than Engerix-B across all study visits in both studies (Figure 1).

Figure 1. Seroprotection Rates by Visit in Trials HBV-16 and HBV-10 (Per Protocol Population):

In all three trials, SPRs induced by HEPLISAV B were statistically significantly higher than those induced by Engerix-B in older adults, men, obese individuals, smokers and subjects with type II diabetes mellitus (Table 3).

Table 3. Comparison of Seroprotection Rates Between HEPLISAV B and Engerix-B at Peak Weeks by Category in Pooled Trials HBV-23, HBV-16 and HBV-10 (mITT Population):

BMI = body mass index; CI = confidence interval; N = number of evaluable subjects; n = number of seroprotected subjects;
SPR = Seroprotection Rate; T2D = type 2 diabetes.
Seroprotection is defined as anti-HBs = 10 mIU/mL.
Peak week comparison is for HEPLISAV B at Week 24 and Engerix-B at Week 28.
The confidence intervals on seroprotection rates are calculated using the two-sided Clopper-Pearson method.
The confidence interval on the difference between treatment groups is calculated using the Miettinen and Nurminen method without stratification.

Haemodialysis

In a phase 3, randomized, open-label, multicentre study of 116 adult subjects with haemodialysis-dependent chronic kidney disease (CKD) who were non-responders to previous hepatitis B vaccination, participants received a 1-dose booster regimen of HEPLISAV B or Fendrix, or a double booster dose of Engerix-B.

Week 4 SPR in the HEPLISAV B group (42.1% n=16/38) was higher than the SPR in the Engerix-B group (18.9%, n=7/37) and the Fendrix group (29.3%, n=12/41). At Week 12, the SPR was 24.3% (n=9/37) in the HEPLISAV B group, 13.9% (n=11/41) in the Engerix-B group, and 26.8% (n=11/41) in the Fendrix group.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with HEPLISAV B in one or more subsets of the paediatric population for the prevention of hepatitis B virus infection (see section 4.2 for information on paediatric use).