HEPLISAV-B: Uses, Dosage & Side Effects

What Is HEPLISAV-B and What Is It Used For?

HEPLISAV-B is a sterile suspension for intramuscular injection that contains 20 micrograms of recombinant hepatitis B surface antigen (HBsAg) produced in yeast cells (Hansenula polymorpha) combined with 3,000 micrograms of CpG 1018 adjuvant. The hepatitis B surface antigen is the primary protein found on the outer envelope of the hepatitis B virus. When introduced into the body through vaccination, it triggers the immune system to produce antibodies (anti-HBs) that provide protection against future hepatitis B infection. The recombinant production method ensures that no live virus is used in the manufacturing process, making it impossible for the vaccine to cause hepatitis B infection.

What sets HEPLISAV-B apart from other hepatitis B vaccines is its unique adjuvant, CpG 1018. Traditional hepatitis B vaccines, such as Engerix-B and Recombivax HB, use aluminum hydroxide (alum) as an adjuvant to enhance the immune response. While effective, aluminum-based adjuvants primarily stimulate a Th2-biased humoral immune response. CpG 1018, in contrast, is a synthetic 22-mer phosphorothioate oligodeoxynucleotide (a short segment of synthetic DNA) that mimics bacterial DNA motifs. It acts as an agonist of toll-like receptor 9 (TLR9), which is expressed on plasmacytoid dendritic cells and B cells within the innate immune system. Activation of TLR9 by CpG 1018 triggers a cascade of immunological events, including the activation of plasmacytoid dendritic cells, production of type I interferons, promotion of a Th1-biased immune response, enhanced B-cell activation and differentiation into antibody-secreting plasma cells, and generation of robust immunological memory.

This dual stimulation of both innate and adaptive immune pathways results in a more rapid and potent antibody response compared to conventional aluminum-adjuvanted vaccines. The clinical significance of this enhanced immunogenicity is twofold: first, it allows for a simplified two-dose vaccination schedule (at 0 and 1 month) rather than the traditional three-dose regimen (at 0, 1, and 6 months); and second, it achieves higher seroprotection rates, particularly in populations that historically respond poorly to hepatitis B vaccination.

Hepatitis B virus (HBV) infection remains a major global health challenge. According to the World Health Organization, approximately 296 million people worldwide are living with chronic hepatitis B infection, and an estimated 820,000 deaths occur annually from HBV-related complications, including cirrhosis and hepatocellular carcinoma (liver cancer). Hepatitis B is transmitted through contact with infected blood or body fluids, including sexual transmission, mother-to-child transmission during birth, sharing of needles or syringes, and occupational exposure in healthcare settings. While hepatitis B is preventable through vaccination, global vaccination coverage in adults remains suboptimal, partly due to the inconvenience of the three-dose schedule and the lower efficacy of conventional vaccines in certain high-risk populations.

HEPLISAV-B was evaluated in three pivotal phase III clinical trials involving more than 10,000 adult participants:

• HBV-23 Trial: This randomized, observer-blinded, active-controlled trial enrolled 8,374 adults aged 18–70 years, comparing HEPLISAV-B (two doses at 0 and 1 month) with Engerix-B (three doses at 0, 1, and 6 months). HEPLISAV-B demonstrated non-inferior seroprotection rates (anti-HBs ≥10 mIU/mL) at 4 weeks after the final dose (95.4% vs. 81.3% for Engerix-B) and superior seroprotection at 8 weeks after the first dose (55.2% vs. 9.3%). Notably, seroprotection was achieved approximately 4 months earlier with the two-dose HEPLISAV-B regimen.
• HBV-16 Trial: This trial specifically evaluated HEPLISAV-B in adults with type 2 diabetes mellitus, a population with well-documented reduced vaccine responsiveness. HEPLISAV-B achieved seroprotection rates of approximately 90% compared to 65–70% for Engerix-B in this population.
• HBV-17 Trial: This trial assessed the immunogenicity and safety of HEPLISAV-B in adults aged 40–70 years. Again, HEPLISAV-B demonstrated significantly higher seroprotection rates compared to the conventional vaccine.

HEPLISAV-B was first approved by the U.S. Food and Drug Administration (FDA) in November 2017 for use in adults aged 18 years and older. It represents a significant advancement in hepatitis B vaccination, offering a more convenient schedule with superior immunogenicity. The CDC Advisory Committee on Immunization Practices (ACIP) has included HEPLISAV-B among the recommended hepatitis B vaccines for adults, and in 2022, ACIP expanded the universal hepatitis B vaccination recommendation to include all adults aged 19–59 years and adults 60 years and older with risk factors.

What Should You Know Before Receiving HEPLISAV-B?

Contraindications

HEPLISAV-B is contraindicated in individuals who have experienced a severe allergic reaction (e.g., anaphylaxis) after a previous dose of any hepatitis B–containing vaccine or to any component of HEPLISAV-B. The vaccine contains recombinant hepatitis B surface antigen (HBsAg), CpG 1018 adjuvant (a synthetic oligodeoxynucleotide), sodium phosphate dibasic dodecahydrate, sodium chloride, polysorbate 80, and water for injection. Individuals with known hypersensitivity to any of these components should not receive the vaccine.

It is important to distinguish between a true contraindication (severe allergic reaction) and a precaution. A mild injection site reaction, low-grade fever, or malaise following a previous hepatitis B vaccination is not a contraindication to receiving HEPLISAV-B and does not preclude future vaccination. However, if there is uncertainty about the nature or severity of a previous reaction, consultation with an allergist or immunologist is recommended before proceeding with vaccination.

Warnings and Precautions

Before receiving HEPLISAV-B, discuss the following with your healthcare provider:

• Immunosuppression: Individuals receiving immunosuppressive therapy (including high-dose corticosteroids, chemotherapy, radiation therapy, or biologic immunomodulators) or those with immune-compromising conditions (such as HIV infection with low CD4 counts, organ transplant recipients on immunosuppressive drugs, or primary immunodeficiency disorders) may have a diminished immune response to HEPLISAV-B. While vaccination is still generally recommended in these populations (as some protection is better than none), the seroprotection rate may be lower than in immunocompetent individuals. Post-vaccination serologic testing (anti-HBs levels) may be warranted to confirm adequate seroprotection in immunosuppressed patients.
• Bleeding disorders: As with any intramuscular injection, HEPLISAV-B should be administered with caution to individuals with thrombocytopenia (low platelet count), bleeding disorders (such as hemophilia), or those receiving anticoagulant therapy. In these cases, the injection should be administered with a fine needle followed by firm pressure applied to the injection site without rubbing for at least 2 minutes. Subcutaneous administration may be considered as an alternative, although this is an off-label route and may result in a reduced immune response.
• Acute illness: Vaccination should be deferred in individuals with moderate or severe acute illness with or without fever. Minor illness, such as a mild upper respiratory infection, is not a reason to delay vaccination.
• Latex sensitivity: The pre-filled syringe tip cap may contain natural rubber latex. Individuals with a history of severe latex allergy (anaphylaxis) should inform their healthcare provider, though the amount of latex in the tip cap is extremely small. For individuals with a history of contact-type latex allergy (e.g., rash from latex gloves), vaccination can generally proceed without concern.

Pregnancy and Breastfeeding

There are limited data on the use of HEPLISAV-B in pregnant women. Animal developmental and reproductive toxicity studies conducted with HEPLISAV-B did not reveal any evidence of harm to the fetus, impaired fertility, or adverse effects on postnatal development. However, as a precautionary measure, vaccination with HEPLISAV-B should generally be deferred until after pregnancy unless the woman is at significant risk for hepatitis B infection. Pregnant women who require hepatitis B vaccination should discuss the relative risks and benefits with their healthcare provider, and in many cases, a conventional hepatitis B vaccine with a longer safety track record may be preferred.

It is not known whether HEPLISAV-B is excreted in human breast milk. However, because many vaccines are considered compatible with breastfeeding, and there is no known mechanism by which a recombinant protein vaccine or CpG oligonucleotide adjuvant could harm a breastfed infant, HEPLISAV-B can generally be administered to breastfeeding women if indicated. The decision to vaccinate during breastfeeding should be made in consultation with the healthcare provider, weighing the woman’s risk of hepatitis B exposure against the theoretical risks.

How Does HEPLISAV-B Interact with Other Drugs?

As a vaccine containing a recombinant protein antigen and a synthetic oligodeoxynucleotide adjuvant, HEPLISAV-B is not metabolized by cytochrome P450 (CYP) enzymes and is not expected to participate in traditional pharmacokinetic drug interactions. However, certain medications and conditions can affect the immune response to vaccination, which is the primary consideration when evaluating interactions with HEPLISAV-B.

The most important category of medications that can affect the response to HEPLISAV-B is immunosuppressive therapies. These include systemic corticosteroids (at immunosuppressive doses, generally defined as prednisone equivalent ≥20 mg/day for ≥14 days), conventional immunosuppressants (such as azathioprine, mycophenolate mofetil, methotrexate, and cyclosporine), biologic immunomodulators (such as anti-TNF agents, anti-CD20 antibodies like rituximab, and other monoclonal antibodies that affect immune function), and cancer chemotherapy and radiation therapy. In patients receiving these treatments, the immune response to HEPLISAV-B may be blunted, potentially resulting in lower seroprotection rates. When possible, vaccination should ideally be completed before initiating immunosuppressive therapy. If this is not feasible, vaccination should still be offered, as a partial immune response may provide some degree of protection.

Regarding co-administration with other vaccines, the FDA-approved prescribing information notes that HEPLISAV-B was not evaluated in clinical trials for concomitant administration with other vaccines. However, based on general vaccinology principles established by the CDC and WHO, inactivated vaccines (such as HEPLISAV-B) can generally be administered simultaneously with other inactivated or live vaccines at different anatomical sites using separate injection equipment. There is no immunological basis for expecting interference between HEPLISAV-B and other routinely recommended adult vaccines, such as influenza, pneumococcal, tetanus-diphtheria-pertussis (Tdap), or COVID-19 vaccines.

What Is the Correct Dosage of HEPLISAV-B?

The recommended dosage schedule for HEPLISAV-B consists of two doses of 0.5 mL each, administered by intramuscular injection into the deltoid muscle of the upper arm. The first dose is given at the elected date (month 0), and the second dose is administered approximately one month later (month 1). This two-dose schedule is a significant advantage over conventional hepatitis B vaccines, which require three doses administered at 0, 1, and 6 months. The simplified schedule not only reduces the number of clinic visits required but also compresses the time to full seroprotection from approximately 7 months to approximately 2 months.

Adults

For all adults aged 18 years and older, the standard dosage is two intramuscular injections of 0.5 mL each, administered at 0 and 1 month. The vaccine should be injected into the deltoid muscle of the upper arm using a needle of appropriate length (typically a 1-inch to 1.5-inch needle for adults, depending on body habitus). The injection should not be administered in the gluteal region, as injection into the buttock has been associated with reduced immunogenicity for hepatitis B vaccines due to the thickness of subcutaneous fat tissue.

Before administration, the pre-filled syringe should be visually inspected for particulate matter and discoloration. The suspension should appear as a clear to slightly opalescent, colorless to slightly yellow liquid. If the vaccine appears cloudy, contains particulate matter, or has an abnormal color, it should not be used. The syringe should be gently shaken before use, but vigorous shaking should be avoided.

Children

HEPLISAV-B is not approved for use in individuals under 18 years of age. Pediatric and adolescent patients should receive conventional hepatitis B vaccines (Engerix-B or Recombivax HB) according to established childhood immunization schedules. The FDA approval and clinical trial data for HEPLISAV-B are limited to the adult population, and the immunological effects of CpG 1018 adjuvant in children have not been fully characterized.

Elderly

The standard two-dose regimen of HEPLISAV-B (0.5 mL at 0 and 1 month) applies to elderly adults. One of the notable advantages of HEPLISAV-B is its superior immunogenicity in older adults compared to conventional vaccines. In clinical trials, adults over 40 years of age showed significantly higher seroprotection rates with HEPLISAV-B compared to Engerix-B. This is particularly important because immune senescence (the age-related decline in immune function) is a well-documented factor that reduces the effectiveness of conventional hepatitis B vaccines in older populations.

Missed Dose

If the second dose of HEPLISAV-B is missed or delayed beyond the recommended one-month interval, it should be administered as soon as possible without restarting the vaccination series. There is no need to restart the series regardless of the interval between doses. General vaccinology principles support that extending the interval between doses does not diminish the final immune response; however, the individual remains unprotected until the series is completed. If the second dose is significantly delayed (e.g., more than 4 months), post-vaccination serologic testing may be considered to confirm adequate seroprotection.

Overdose

No cases of overdose with HEPLISAV-B have been reported in clinical trials or post-marketing surveillance. Because each dose is provided in a single pre-filled syringe containing a fixed volume of 0.5 mL, the risk of accidental overdose is minimal. In the unlikely event that a larger-than-recommended dose is inadvertently administered, the patient should be monitored for any adverse effects, and the event should be reported to the vaccine manufacturer and the appropriate pharmacovigilance authority (e.g., the Vaccine Adverse Event Reporting System, or VAERS, in the United States). No specific antidote exists, but given the mechanism of action of the vaccine, no serious harm from an overdose would be expected.

What Are the Side Effects of HEPLISAV-B?

The safety profile of HEPLISAV-B has been extensively evaluated in clinical trials involving more than 10,000 adult participants, with additional data from ongoing post-marketing surveillance. Overall, HEPLISAV-B has a safety profile comparable to conventional hepatitis B vaccines. The majority of adverse reactions are local (injection site) reactions that are mild to moderate in severity and self-limiting.

In the pivotal HBV-23 trial, adverse reactions were systematically collected using electronic diary cards for 7 days after each vaccination. The following side effects were reported based on their frequency of occurrence:

It is important to contextualize these side effects within the broader framework of vaccine safety. Injection site reactions and systemic symptoms such as fatigue, headache, and myalgia are expected consequences of immune system activation and are observed with virtually all vaccines. They reflect the body’s innate immune response being triggered, which is a necessary prerequisite for the development of protective adaptive immunity. The vast majority of these reactions resolve spontaneously within 1–3 days and do not require medical intervention.

In the large-scale HBV-23 trial, the incidence of serious adverse events (SAEs) was similar between the HEPLISAV-B and Engerix-B groups, and no new safety signals were identified. Post-marketing surveillance through the Vaccine Adverse Event Reporting System (VAERS) and active surveillance studies (such as the Vaccine Safety Datalink) have continued to monitor the safety profile of HEPLISAV-B since its approval, and no unexpected safety concerns have emerged.

One area of initial regulatory scrutiny was the potential for cardiac safety events. During earlier clinical development, a numerical imbalance in acute myocardial infarction (AMI) cases was observed in the HEPLISAV-B group compared to the control group, although this was not statistically significant and was not replicated in subsequent trials. The FDA required a post-marketing observational study to further evaluate cardiac safety. Results from this study, which included over 30,000 HEPLISAV-B recipients, did not identify an increased risk of AMI or other major adverse cardiovascular events, providing additional reassurance regarding the cardiac safety profile.

How Should You Store HEPLISAV-B?

Proper storage of HEPLISAV-B is essential to maintaining vaccine potency and effectiveness. The vaccine must be stored under refrigerated conditions at a temperature of 2–8°C (36–46°F). It should be kept in its original packaging to protect it from light, as exposure to light can degrade the antigen and adjuvant components over time. The pre-filled syringes should be stored horizontally to prevent the syringe contents from settling unevenly.

Freezing must be strictly avoided, as freezing can cause irreversible damage to the recombinant protein antigen and the CpG 1018 adjuvant. A frozen vaccine may undergo structural changes that reduce its immunogenicity and could potentially cause increased local reactogenicity at the injection site. If there is any suspicion that the vaccine has been exposed to freezing temperatures (e.g., during storage or transport), it should not be used. The “shake test” is not a reliable method for detecting freeze-damaged hepatitis B vaccines, so if there is doubt about proper cold chain maintenance, the vaccine should be discarded.

Once removed from refrigeration, HEPLISAV-B should ideally be administered as soon as possible. Like most inactivated vaccines, brief excursions to room temperature during preparation and transport to the patient are acceptable, but the vaccine should not be stored at room temperature for extended periods. Healthcare facilities should maintain cold chain documentation and use temperature monitoring devices to ensure proper storage conditions are maintained at all times.

The expiration date is printed on the outer carton and the pre-filled syringe label. HEPLISAV-B should not be used after the expiration date. Any unused vaccine or waste material should be disposed of in accordance with local regulations for pharmaceutical waste and sharps disposal.

What Does HEPLISAV-B Contain?

HEPLISAV-B is a sterile, preservative-free suspension for intramuscular injection. Each 0.5 mL dose contains the following components:

The recombinant hepatitis B surface antigen (HBsAg) is produced using a genetically engineered strain of the methylotrophic yeast Hansenula polymorpha (also known as Pichia angusta). The yeast cells are transformed with a plasmid containing the gene for the major surface antigen of hepatitis B virus (adw2 subtype). The HBsAg is harvested from the yeast cells, purified through a series of chromatographic and ultrafiltration steps, and then combined with the CpG 1018 adjuvant to form the final vaccine product.

Notably, HEPLISAV-B does not contain any aluminum salts (unlike Engerix-B and Recombivax HB), no mercury-based preservatives (such as thimerosal), no antibiotics, and no egg proteins or gelatin. The absence of aluminum as an adjuvant is a distinguishing feature, as the CpG 1018 adjuvant replaces the need for aluminum-based immune potentiation. This may be relevant for individuals who prefer to minimize their exposure to aluminum, although it should be noted that the amounts of aluminum in conventional vaccines are well below the safety thresholds established by regulatory authorities.

The vaccine appears as a clear to slightly opalescent, colorless to slightly yellow liquid. The pre-filled syringe is made of glass and is fitted with a plunger stopper that does not contain natural rubber latex (in the current formulation; earlier formulations had a latex-containing tip cap, which has since been updated). The vaccine is supplied as a single-dose pre-filled syringe containing 0.5 mL of suspension.