HEPLISAV-B is a hepatitis B vaccine composed of rHBsAg mixed with a synthetic oligonucleotide containing CpG motifs that stimulate innate immunity through TLR9. This vaccine was recently approved by the FDA in view of its superior efficacy.Areas covered: Published literature on HEPLISAV-B was critically reviewed. Four randomized controlled trials among 7,056 subjects receiving 2 doses of HEPLISAV-B and 3,214 subjects receiving 3 doses of Engerix-B showed superior seroprotection rate (SPR) (anti-HBs ≥10 mIU/mL) of 90 – 100%, compared with 71 – 90% in those receiving Engerix-B. Furthermore, the seroprotection rate was also significantly higher in HEPLISAV-B compared with Engerix-B recipients in persons with traditionally poor vaccine response such as older adults, diabetics and those with chronic kidney disease. The safety profiles among 9,871 subjects were similar between HEPLISAV-B and Engerix-B .Expert opinion: HEPLISAV-B, a CpG adjuvant mixed with HBsAg, is more efficacious and produced earlier seroprotection compared to existing vaccines, with a favourable safety profile. The shorter, two-dose regimen, earlier seroprotection, higher adherence and a higher seroprotection rate, especially in populations with traditionally poor vaccine response, makes this an important therapeutic option in hepatitis B vaccination.