Adjuvanted Recombinant Hepatitis B Vaccine (Heplisav-B)
By Uerica Wang, PharmD, BCPS
Pharmacist, Stanford Health Care, Stanford, CA
Dr. Wang reports no financial relationships relevant to this field of study.
Heplisav-B is a new hepatitis B vaccine approved by the FDA in November 2017. The indication for Heplisav-B is the prevention of infection caused by all known subtypes of hepatitis B virus (HBV) in adults 18 years of age or older. Heplisav-B contains an antigen similar to other HBV vaccines currently on the market. However, it uses a synthetic oligonucleotide 1018 instead of alum as an adjuvant. This new adjuvant stimulates rapid activation of the innate immune system via toll-like receptor 9 (TLR9) and supports the induction of B and T lymphocytes in the adaptive immune system.1-5
Heplisav-B is administered in two doses over one month. This compares favorably to older HBV vaccines, which are given in three doses over a six-month period. Nelson et al conducted a population-based study using the Vaccine Safety Datalink from 1997-2004. The researchers showed low compliance rates with the three-dose hepatitis B vaccine series. Less than 60% of the HBV vaccine initiators completed the three-dose series. Compliance rates were low at 45% among adolescents and 41% in 18-29 year olds at one year. Table 1 lists costs and formulations currently available in the United States.1-5
GUIDELINES
Heplisav-B was discussed in a meeting of the Advisory Committee on Immunization Practices (ACIP) on Feb. 12, 2018. Per Dynavax’s press release on Feb. 21, 2018, “Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) voted unanimously in favor of including Heplisav-B on its list of ACIP recommended products for use to vaccinate adults against hepatitis B.” CDC will review and approve the ACIP recommendations before publishing in the Morbidity and Mortality Weekly Report (MMWR).6
CLINICAL TRIALS
The immunogenicity of Heplisav-B was studied in three pivotal trials. These trials were multi-center, observer-blinded, randomized, and active controlled. Patients were excluded if they had any history of HBV infection or vaccine, were pregnant or breastfeeding, had HIV infection, immunosuppression, or any history of autoimmune disease. The primary endpoint for Heplisav-B trials was to demonstrate non-inferiority of seroprotection rates (SPR) compared with Engerix-B. SPR is defined as the percentage of patients with anti-HBV surface antibody level ≥ 10 mIU/mL. Heplisav-B was given at 0 and 4 weeks plus a placebo dose at 24 weeks. The active control group received Engerix-B at 0, 4, and 24 weeks. Patients were followed for 52 weeks after the first injection.
The first study by Halperin et al was conducted in healthy adults ages 18-55 years.7 SPR in the Heplisav-B group at week 12 (95.1%) was non-inferior and superior to that of the Engerix-B at week 28 (81.2%). Peak SPR occurred in the Heplisav-B group at week 24 compared to week 28 in the Engerix-B group. SPR rate also was achieved earlier in the Heplisav-B group at week 8 (88.5%) than Engerix-B at week 28 (81.1%).7
Heyward et al conducted a second study in adults 40-70 years of age.8 SPR at week 12 for Heplisav-B was significantly higher (90.1%) than SPR of Engerix-B at week 32 (70.5%). Peak SPR of Heplisav-B was 95.1% at 24 weeks compared to 72.8% at 28 weeks for Engerix-B. More Heplisav-B patients achieved SPR at week 8 (76.6%) than the Engerix-B group at week 28 (72.8%).8
The third study conducted by Jackson et al looked at adults 18-70 years of age.9 The researchers evaluated SPR in patients with type 2 diabetes mellitus and stratified patients by age group.
In patients with type 2 diabetes, SPR at 28 weeks was 90% in Heplisav-B compared to 65.1% in Engerix-B group. SPR rates decreased with increasing age. However, SPR rates were all significantly higher in the Heplisav-B (95.4% at 24 weeks) than the Engerix-B (81.3% at 28 weeks) group.9
Table 1: Hepatitis B Vaccine Cost Comparison1 |
||||
Vaccine |
How Supplied |
Average Wholesale Price for 1 mL Vials |
Usual Dose in Adults |
Cost per Treatment (Average Wholesale Price) |
|
Heplisav-B (Dynavax) |
0.5 mL solution in single-dose vials |
$115 |
0.5 mL IM given as two doses administered at 0 and 1 month |
$230 |
|
Recombivax-HB (Merck) |
0.5, 1 mL suspension in single-dose vials and prefilled syringes |
$74.60 (10 mcg/mL) $199.10 |
Immunocompetent adults: 1 mL (10 mcg/mL) IM for 3 doses administered at 0,1, and 6 months Immunocompromised adults: 1 mL (40 mcg/mL) dose administered at 0,1, and 6 months |
$224.40 $597.30 |
|
Engerix-B (GSK) |
0.5, 1 mL suspension in single-dose vials and prefilled syringes |
$62.85 (20 mcg/mL) |
Immunocompetent adults: 1 mL IM for three doses administered at 0,1, and 6 months Immunocompromised adults: 2 mL per dose at 0,1,2, and 6 months |
$188.55 $502.80 |
|
Twinrix (GSK) Hepatitis A and B |
1 mL suspension (hepatitis A virus antigen 720 ELISA units and hepatitis B surface antigen 20 mcg/mL) in prefilled syringe |
$120.90 |
1 mL IM given on 0-, 1-, and 6-month schedule for a total of three doses |
$362.70 |
ADVERSE EFFECTS
The most common reported adverse effects were at the injection site.1,2 They include pain (22.8-38.5%), erythema (0.7-4.1%), and swelling (0.6-2.3%). The most common general adverse reactions reported are fatigue (10.8-17.4%), headache (8.1-16.9%), malaise (7-9.2%), myalgia (6.4-8.5%), and fever (≤ 2%). Injection site adverse reactions were reported more frequently compared to the Engerix-B group. Serious adverse events and deaths were similar between the two groups.1,2
SIGNIFICANT DRUG INTERACTIONS
It is important to note that immunosuppressive therapies may reduce the effectiveness of Heplisav-B.1,2
CONCLUSION
Heplisav-B is a recently approved hepatitis B virus vaccine with a synthetic oligonucleotide immunostimulatory adjuvant. It is FDA-indicated for prevention of hepatitis B in adults ≥ 18 years of age. In clinical trials, Heplisav-B induced significantly more immunogenicity and higher SPR at earlier time points than Engerix-B. Heplisav-B also produced a safety profile similar to Engerix-B. Because Heplisav-B has a one month dosing regimen, it may improve challenges of HBV vaccine completion by improving adherence.
REFERENCES
- Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc. March 2, 2018.
- Heplisav-B- highlights of prescribing information. Dynavax Technologies 2017. March 2, 2018.
- Halperin SA, McNeil S, Langley JM, et al. Safety and immunogenicity of different two-dose regimens of an investigational hepatitis B vaccine (hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide) in healthy young adults. Vaccine 2012;30:5445-5448.
- Scheiermann J, Klinman DM. Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer. Vaccine 2014;32:6377-6389.
- Nelson JC, Bittner RC, Bounds L, et al. Compliance with multiple-dose vaccine schedules among older children, adolescents, and adults: Results from a vaccine safety datalink study. Am J Public Health 2009;99 Supple 2):S389-S397.
- Dynavax. Press Release. Dynavax’s Heplisav-B [hepatitis B vaccine (recombinant), adjuvanted] recommended by CDC Advisory Committee on Immunization Practices for the prevention of hepatitis B in adults. Feb. 21, 2018. Available at: http://investors.dynavax.com/news-releases/news-release-details/dynavaxs-heplisav-btm-hepatitis-b-vaccine-recombinant-adjuvanted. Accessed March 11, 2018.
- Halperin SA, Ward B, Cooper C, et al. Comparison of safety and immunogenicity of two doses of investigational hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide and three doses of a licensed hepatitis B vaccine in healthy adults 18-55 years of age. Vaccine 2012;30:2556.
- Heyward WL, Kyle M, Blumenau J, et al. Immunogenicity and safety of an investigational hepatitis B vaccine with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40-70 years of age. Vaccine 2013;31:5300.
- Jackson S, Lentino J, Kopp J, et al. Immunogenicity of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed hepatitis B vaccine in adults. Vaccine 2018;36:668-674.
Heplisav-B is a new hepatitis B vaccine approved by the FDA in November 2017.
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