Immunogenicity and safety of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B vaccine in patients with chronic kidney disease

Highlights

• Phase 3 trial of investigational hepatitis B vaccine in chronic kidney disease.

• HBsAg-1018 induced superior seroprotection to HBsAg-Eng.

• HBsAg-1018 induced more durable seroprotection than HBsAg-Eng.

• The safety profile of HBsAg-1018 was similar to that of HBsAg-Eng.

Abstract

Background

Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and patients with chronic kidney disease (CKD) are commonly hyporesponsive to HBV vaccines. Current recommendations for CKD patients are to utilize 4 double-doses (2 × 20 mcg HBsAg) of a licensed hepatitis B vaccine (HBsAg-Eng).

Methods

An observer-blind, randomized, active-controlled, parallel group, multicenter trial was conducted among 521 patients 18–75 years of age with CKD, comparing 3 single doses of an investigational hepatitis B vaccine (20 mcg rHBsAg + 3000 mcg 1018, a toll-like receptor 9 agonist) given at 0, 4, and 24 weeks to 4 double-doses of HBsAg-Eng (2 × 20 mcg rHBsAg + 500 mcg alum) given at 0, 4, 8, and 24 weeks (total of 8 injections). Participants were followed for 1 year.

Results

Among 467 participants in the modified intent-to-treat population, at the primary endpoint at week 28, the seroprotection rate (SPR: % with anti-HBs ≥ 10 mIU/mL) in the HBsAg-1018 group (89.9%) met criteria for noninferiority and superiority to the SPR in the HBsAg-Eng group (81.8%). At week 28, the percentage of participants with anti-HBs ≥ 100 mIU/mL in theHBsAg-1018 group (73.6%) was significantly higher than in the HBsAg-Eng group (63.2%). In addition, the geometric mean concentration of anti-HBs in the HBsAg-1018 group (587.1 mIU/mL) was significantly higher than in the HBsAg-Eng group (156.5 mIU/mL). At weeks 8 and 12 after the first study injection, SPRs in the HBsAg-1018 group were significantly higher than in the HBsAg-Eng group. At 52 weeks, the immune response toHBsAg-1018 remained higher than to HBsAg-Eng. HBsAg-1018 was generally well tolerated and had a similar safety profile to HBsAg-Eng.

Conclusion

In CKD patients, 3 doses of HBsAg-1018 induced significantly higher seroprotection, earlier seroprotection, and more durable seroprotection than 4 double doses of HBsAg-Eng.

Introduction

Hepatitis B virus (HBV) infection remains a major global public health problem especially for chronic kidney disease (CKD) patients receiving hemodialysis. CKD patients are at increased risk of exposure to HBV in the hemodialysis setting because of the high prevalence of HBV, a treatment procedure with high-volume blood access, and transmission risk from the reuse of equipment and supplies for multiple patients. When infected, patients with CKD have a high risk of developing chronic hepatitis B infection and the sequelae of chronic active hepatitis including cirrhosis and hepatocellular carcinoma [1].

Vaccination is an important tool in preventing the transmission of HBV [2], [3]. Currently licensed HBV vaccines containing recombinant hepatitis B surface antigen (rHBsAg) adjuvanted with aluminum hydroxide (alum) achieve seroprotection (antibody to hepatitis B surface antigen [anti-HBs] ≥ 10 mIU/mL) in greater than 90% of the healthy adult population after 3 doses over a 6-month period. While vaccination has proven effective in healthy adults, seroprotection rates (SPRs: proportion of participants with anti-HBs ≥ 10 mIU/mL) are reduced in several subgroups including persons with CKD, diabetes mellitus, or human immunodeficiency virus (HIV) infection [4], [5], [6], [7], [8].

Patients with chronic renal failure have defects in both humoral and cellular immunity, which lead to reduced responses to vaccination [7], [9]. The vaccine regimens for CKD currently recommended in the United States and Europe result in SPRs of 33–92% with most below 70% [9], [10]. Some studies have demonstrated higher response rates in CKD patients prior to becoming dialysis dependent [1], [11] and, therefore, CKD patients are often vaccinated in advance of initiating hemodialysis [1].

Patients with CKD depend on the persistence of antibodies against HBsAg for long-term protection against HBV infection because of their impaired anamnestic responses to the antigen [12]. An anti-HBs level ≥ 10 mIU/mL has been shown to correlate with protection against HBV infection [13] and, in patients with CKD, long-term maintenance of such a level is necessary since breakthrough infections may occur in persons with levels < 10 mIU/mL [14], [15], [16]. The duration of protection against HBV infection depends on the peak post-vaccination antibody level [17], [18]. Some authors have proposed that a level ≥ 100 mIU/mL is desirable in CKD patients because the duration of seroprotection is longer for them than for patients with a level of 10–99 mIU/mL [19], [20], [21]. In fact, the Standing Committee on Vaccination in Germany has recently recommended that all patients on hemodialysis receive a booster injection of hepatitis B vaccine when their anti-HBs concentration decreases below 100 mIU/mL [22].

An investigational hepatitis B vaccine, HBsAg-1018, (HEPLISAV™, Dynavax Technologies, Berkeley, California) contains 20 mcg of rHBsAg and a 22-mer synthetic phosphorothioate oligodeoxyribonucleotide, 1018 adjuvant, a class B oligonucleotide. 1018, like bacterial and viral DNA, is thought to have the following effects: (1) activation of plasmacytoid dendritic cells (pDCs) through the pattern recognition receptor Toll-like receptor 9 (TLR9); (2) conversion of pDCs into activated dendritic cells that present the processed HBsAg component of the vaccine to CD4+ T-cells; and (3) promotion of Th1 T-cell differentiation through the production of interferon alpha and interleukin-12. This activation results in a high and sustained antibody response.

Results of a phase 3 trial in generally healthy adults demonstrated two doses of HBsAg-1018 met the primary endpoint of noninferiority and superiority to three doses HBsAg-Eng (Engerix-B^®, GlaxoSmithKline Biologicals, Rixensart, Belgium) and induced a superior peak SPR than HBsAg-Eng with a similar safety profile [23]. Here we present data on a phase 3 trial comparing the immunogenicity and safety of three doses of HBsAg-1018 with four double doses of HBsAg-Eng in patients with CKD.