Investigational 2-Dose Dynavax Heplisav Hepatitis B Vaccine May Work Better than Standard 3-Dose Energix-B Vaccine

An investigational hepatitis B virus (HBV) vaccine may offer the same degree of protection with 2 doses as the standard Engerix-B vaccine does with 3 doses, according to a study presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen.

M.L. Pecoraro from Dynavax Technologies and colleagues conducted a Phase 3 study called PHAST (Phase 3 Heplisav Short-regimen Trial) to assess the safety and efficacy of HBsAg-ISS (brand name Heplisav), a vaccine containing hepatitis B surface antigen (HBsAg) combined with a new class of adjuvant (1018 Immunostimulatory Sequence, or ISS), a toll-like receptor 9 (TLR-9) agonist.

A previous study demonstrated that 2 doses of the HBsAg-ISS vaccine provided 100% seroprotection after 2 doses in adults aged 18-39 years. The current approved HBV vaccines contain HBsAg with an aluminum hydroxide adjuvant, administered in 3 doses over a 6 month period. (In addition to Engerix-B, there is also a combined hepatitis A and B vaccine known as Twinrix.)

The present study evaluated the proportion of participants who exhibited a seroprotective immune response after 2 doses of Heplisav administered at baseline and 1 month later. This was compared to the proportion who exhibited a protective response after 3 doses of the licensed Engerix-B vaccine administered at baseline and 1 and 6 months later. (Participants in the Heplisav arm received a placebo shot in lieu of the third Engerix-B dose.)

This Phase 3 randomized, observer-blind study included 2428 participants aged 11 to 55 years recruited at some 20 sites in Canada and Germany. Participants were randomly assigned in a 3:1 ratio to receive Heplisav or Engerix-B. Demographic characteristics were similar in the 2 arms.

The primary immunogenicity endpoint was seroprotective immune response, , defined as anti-HBsAg antibodies ? 10 mIU/mL, measured 2 months after the last dose of Heplisav (month 3) and 1 month after the last dose of Engerix-B (month 7).

Results

A similar proportion of participants were excluded from analysis in both groups (14% in the Heplisav arm, 12% in the Engerix-B arm).

Among the 2101 participants included in the per protocol analysis 1566 Heplisav, 535 Engerix-B), those who received Heplisav had higher anti-HBsAg antibodies titers than those who received Engerix-B, despite fewer doses.

Heplisav conferred protection more rapidly than Engerix-B, with 24% vs 4% of participants, respectively achieving seroprotection by month 1, and 89% vs 26%, respectively, doing so by month 2.

The percentage of study participants reaching the primary endpoint was 95.1% (at month 3) in the Heplisav arm compared with 81.1% (at month 7) in the Engerix-B arm.

The difference between the 2 arms was 13.8 %, meeting the pre-defined threshold for non-inferiority.

Heplisav was also more effective than Engerix-B in the subgroup of participants aged 40-55 -- older individuals tend to have weaker immune response -- with seroprotection rates of 92% and 75%, respectively.

Safety profiles were similar for both vaccines.

Adverse events were uncommon in both study arms, with 1 case of vasculitis (blood vessel inflammation) in each group.

Based on these findings, the investigators concluded, "This study successfully demonstrated that a short, 2 dose regimen of HBsAg-ISS is non-inferior to the current 3 dose regimen of Engerix-B."

The researchers noted that the easier dosing regimen may lead to higher adherence, given that many people fail to complete all 3 shots in the Engerix-B schedule, and missing the final dose can comprise development of full immunity.

However, according to a Dynavax press release, the U.S. Food and Drug Administration (FDA) placed a clinical hold on Heplisav after receiving the report of a severe adverse event, Wegener's granulomatosis -- an uncommon form of vasculitis -- in the Heplisav arm. (A different type of vasculitis, microscopic polyangiitis, occurred in the Energix-B arm.)

Dynavax Technologies, Berkeley, CA; Dalhousie University, Halifax, Nova Scotia, Canada; Herridge Clinic, Ottawa, Ontario, Canada.

5/12/09

Reference

ML Pecoraro, JT Martin, S Halperin, and others. A phase 3 safety and efficacy study comparing immunogenicity of two doses of HBsAg combined with immunostimulatory sequence with three doses of licensed hepatitis vaccine. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009. Abstract 1040.

Other Source

Dynavax Technologies Corp. Dynavax Presents Additional Phase 3 Data for HEPLISAV Hepatitis B Vaccine at EASL Medical Conference. Press release. April 27, 2009.