Ask the Experts: Hepatitis B

Results (114)

About 30%–50% people who are 5 years of age or older with acute (recently acquired) hepatitis B have initial signs or symptoms when infected with hepatitis B virus (HBV). Children younger than age 5 years and newly infected immunosuppressed adults rarely show any symptoms. When present, signs and symptoms of hepatitis B might include nausea, lack of appetite, tiredness, muscle, joint, or abdominal pain, fever, diarrhea or vomiting, headache, dark urine, clay-colored stools, and yellowing of the skin and whites of the eyes (jaundice). People who have such signs or symptoms generally feel quite ill and might need to be hospitalized. People with chronic (life-long) HBV infection might have no symptoms, have no evidence of liver disease, or have a range of disease from chronic hepatitis to cirrhosis or hepatocellular carcinoma, a type of liver cancer.

Last reviewed: July 21, 2023

If signs or symptoms of illness occur, they begin an average of 90 days (range: 60–150 days) after exposure to HBV.

Last reviewed: July 21, 2023

Persons with chronic HBV infection (those with persistent hepatitis B surface antigen [HBsAg] in the serum for at least 6 months) serve as the main reservoir for HBV transmission.

HBV is transmitted through percutaneous (through the skin), mucosal, or non-intact skin exposure to infectious blood or body fluids. HBV is concentrated most highly in blood, and percutaneous exposure is an efficient mode of transmission. Semen and vaginal secretions are infectious, and HBV also can be detected in saliva, tears, and bile. Cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid are also considered potentially infectious. Urine, feces, vomitus, nasopharyngeal washings, sputum, and sweat are not efficient vehicles of transmission unless they contain blood because they contain low quantities of infectious HBV. Hepatitis B surface antigen (HBsAg) found in breast milk is also unlikely to lead to transmission so HBV infection is not a contraindication to breastfeeding.

Among adults in the U.S., HBV is transmitted primarily by percutaneous exposure to blood (for example, injection drug use) and sexual contact. HBV is transmitted efficiently by sexual contact both among heterosexuals and among men who have sex with men (MSM). Transmission can occur from interpersonal contact (e.g., sharing a toothbrush or razor, contact with exudates from dermatologic lesions, or contact with HBsAg-contaminated surfaces) and in settings such as schools, child care centers, and facilities for developmentally disabled persons. Transmission of HBV from transfusion of blood or blood products is rare because of donor screening and viral inactivation procedures. Other possible sources of infection include contaminated medical or dental instruments, unsafe injections, needle-stick injuries, organ transplantation, and dialysis.

In 2019, a total of 3,192 cases of acute hepatitis B were reported to CDC, corresponding to 20,700 estimated acute infections (based on the estimated ratio of acute cases reported to actual acute cases). The most commonly reported risk behaviors and exposures were injection drug use (35%), multiple sex partners (23%), and surgery (10%), followed by other sexual and bloodborne risk behaviors; risk behavior and exposure information were missing for 37.1% of cases.

Last reviewed: July 21, 2023

Yes. Even though tattooing and body piercing are not thought to be a significant mode of transmission for HBV, tattooing and body piercing have the potential to transmit bloodborne infections, including HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV), if the person doing the tattoos or body piercing does not use good infection control practices. The Centers for Disease Control and Prevention (CDC) recommends that instruments or materials (including ink), intended to penetrate the skin be used once, then disposed of or thoroughly cleaned and sterilized between clients. Personal service workers who do tattooing or body piercing should be educated about the transmission of bloodborne pathogens and what precautions are needed to prevent transmission.

People considering getting a tattoo or having a body part pierced should ask staff at the establishment what procedures they use to prevent the spread of bloodborne infections. They also might call the local health department to find out what sterilization procedures are required by law or ordinance for tattooing and body piercing establishments.

Last reviewed: July 21, 2023

There are no specific data on transmission of bloodborne viruses through oral-genital sex. Saliva has not been associated with HBV transmission unless biting has taken place. HBV is not spread by kissing, hugging, sneezing, coughing, food or water, sharing eating utensils or drinking glasses, or casual contact.

Last reviewed: July 21, 2023

Generally speaking, no. A person with laboratory evidence of resolved hepatitis B infection is considered immune. Vaccination of such individuals is not harmful but is not necessary.

Last reviewed: July 21, 2023

HBV is stable in the environment and remains viable for 7 or more days on environmental surfaces at room temperature. HBV can be transmitted despite the absence of visible blood. Any high level disinfectant that is tuberculocidal will inactivate HBV. The Environmental Protection Agency also registers disinfectants specifically approved for use against HIV and HBV; a current list is available at this website: www.epa.gov/pesticide-registration/list-d-epas-registered-antimicrobial-products-effective-against-human-hiv-1.

Last reviewed: July 21, 2023
Table 1: Hepatitis B laboratory nomenclature
HBsAg: Hepatitis B surface antigen is a marker of infectivity. Its presence indicates either acute or chronic HBV infection.
anti-HBs: Antibody to hepatitis B surface antigen is a marker of immunity. Its presence indicates an immune response to HBV infection, an immune response to vaccination, or the presence of passively acquired antibody. (It is also known as HBsAb, but this abbreviation is best avoided since it is often confused with abbreviations such as HBsAg.)
anti-HBc (total): Antibody to hepatitis B core antigen is a nonspecific marker of acute, chronic, or resolved HBV infection. It is not a marker of vaccine-induced immunity. It may be used in prevaccination testing to determine previous exposure to HBV infection. (It is also known as HBcAb, but this abbreviation is best avoided since it is often confused with other abbreviations.)
IgM anti-HBc: IgM antibody subclass of anti-HBc. Positivity indicates recent infection with HBV (<6 mos). Its presence indicates acute infection.
HBeAg: Hepatitis B “e” antigen is a marker of a high degree of HBV infectivity, and it correlates with a high level of HBV replication. It is primarily used to help determine the clinical management of patients with chronic HBV infection.
Anti-HBe: Antibody to hepatitis B “e” antigen may be present in an infected or immune person. In persons with chronic HBV infection, its presence suggests a low viral titer and a low degree of infectivity.
HBV-DNA: HBV Deoxyribonucleic acid is a measure of viral load and reflects viral replication. It correlates well with infectivity. It is used to assess and monitor the treatment of patients with chronic HBV infection.
Last reviewed: July 21, 2023
Table 2
Tests Results Interpretation Vaccinate?
HBsAg
anti-HBc
anti-HBs
negative
negative
negative
susceptible vaccinate if indicated
HBsAg
anti-HBc
anti-HBs
negative
negative
positive with >10mIU/mL*
immune due to vaccination (or may represent passive transfer of antibodies from receipt of HBIG) no vaccination necessary
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
negative
positive
negative
positive
immune due to natural infection no vaccination necessary
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
negative
positive
positive
positive
acute resolving infection no vaccination necessary
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
positive
positive
positive
negative
acutely infected no vaccination necessary
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
positive
positive
negative
negative
chronically infected no vaccination necessary (may need treatment)
HBsAg
anti-HBc
anti-HBs
negative
positive
negative
four interpretations possible† use clinical judgment

* Postvaccination testing, when it is recommended, should be performed 1-2 months after the last dose of vaccine. Infants born to HBsAg-positive mothers should be tested for HBsAg and anti-HBs after completion of at least 3 doses of a licensed hepatitis B vaccination series, at age 9-18 months (generally at the next well child visit).

†1. May be distantly immune, but the test may not be sensitive enough to detect a very low level of anti-HBs in serum

2. May be susceptible with a false positive anti-HBc

3. May be chronically infected and have an undetectable level of HBsAg present in the serum

4. Passive transfer of antibody following HBIG administration or from an HBsAg-positive mother to her newborn

Last reviewed: July 21, 2023

Serologic testing for immunity is not necessary or recommended after routine vaccination of infants, children, or adults. Testing for anti-HBs after vaccination is recommended for the following groups whose subsequent clinical management depends on knowledge of their immune status:

  • Infants born to HBsAg-positive women and infants born to women whose HBsAg status remains unknown (for example, infants surrendered shortly after birth); postvaccination serologic testing should consist of testing for anti-HBs and HBsAg and should not occur before age 9 months
  • Healthcare professionals and public safety workers at risk for blood or body fluid exposure
  • Hemodialysis patients (and other persons who might require outpatient hemodialysis), people living with HIV, and other immunocompromised people (such as hematopoietic stem-cell transplant [HSCT] recipients or people receiving chemotherapy), to determine the need for revaccination and the type of follow-up testing, and
  • Sex partners of HBsAg-positive people, to determine if they have not achieved immunity and will need revaccination and to continue to use other methods of protection against HBV infection.

Testing of individuals other than infants should be performed 1–2 months after administration of the final dose of the vaccine series using a method that allows determination of a protective concentration of anti-HBs (10 mIU/mL or higher). Testing of infants should take place after administration of the final dose of the vaccine series when the infant is age 9 through 12 months. Testing should not be done earlier than 9 months to avoid inadvertent detection of HBIG administered at birth and to maximize the likelihood of detecting HBV infection, if present.

Last reviewed: July 21, 2023

Some isolated positive anti-HBc results are false positives (it is the most common false positive HBV marker). If that can be established, the individual can and likely should be vaccinated, assuming there is an indication or desire to be protected. If the positive anti-HBc is believed to be a true positive, the individual would not require vaccination since they have already (presumably) had HBV infection. Isolated positive anti-HBc could indicate low-level chronic infection. In an infant isolated anti-HBc could indicate passive transfer of antibody from a mother who is HBsAg positive, which is why anti-HBc testing of infants is not recommended.

Additional resources for the evaluation of isolated anti-HBc antibody results are available from the University of Washington: www.hepatitisb.uw.edu/go/screening-diagnosis/diagnosis-hbv/core-concept/all and from CDC: www.cdc.gov/hepatitis-b/hcp/diagnosis-testing/#cdc_hcp_diagnosis_interpreting-how-to-interpret-test-results.

Last reviewed: July 21, 2023

Reporting of adequate and inadequate is acceptable only if your lab is using mIUs as the measurement for anti-HBs and the cutoff is below 10 mIU for reporting inadequate anti-HBs and 10 mIU or higher for reporting adequate anti-HBs. You should check with your lab to be certain this is being done.

Last reviewed: July 21, 2023

Most likely this person has a resolved HBV infection and is immune. However, it would be preferable to test her again for all these serologic markers, and also quantify the anti-HBs result. If the results are still positive for anti-HBc, and anti-HBs is less than the immune level of 10 mIU/mL, you can give her one dose of HepB vaccine and test again in 1–2 months. If the anti-HBs is positive (10 mIU/mL or higher), she is immune. No further action is needed other than to document the results. If the anti-HBs is still negative, complete the vaccine series and test again 1–2 months after the last dose of vaccine.

Last reviewed: July 21, 2023

For the general public, only one HepB series is routinely recommended in a lifetime, with specific exceptions described below.

As of April 2022, CDC recommends HepB vaccination of the following:

  • Routine HepB vaccination of all infants, beginning with a birth dose.
  • Routine HepB vaccination of all children and adults through age 59 years.
  • Vaccination of all adults age 60 years and older with risk factors for hepatitis B:
    • People at risk for infection by sexual exposure
      • Sex partners of people testing positive for HBsAg
      • Sexually active people who are not in a long-term, mutually monogamous relationship (e.g., those with more than one sex partner during the previous 6 months)
      • People seeking evaluation or treatment for a sexually transmitted infection
      • Men who have sex with men
    • People at risk for infection by percutaneous or mucosal exposure to blood
      • People with current or recent injection drug use
      • Household contacts of people testing positive for HBsAg
      • Residents and staff members of facilities for people with developmental disabilities
      • Health care and public safety personnel with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids
      • People on maintenance dialysis, including in-center or home hemodialysis and peritoneal dialysis, and people who are predialysis
      • People with diabetes, at the discretion of the treating clinician
    • Others
      • International travelers to countries with high or intermediate levels of endemic HBV infection (HBsAg prevalence of 2% or higher)
      • People with hepatitis C virus infection
      • People with chronic liver disease (including, but not limited to, people with cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an alanine aminotransferase or aspartate aminotransferase level greater than twice the upper limit of normal)
      • People with HIV infection
      • People who are incarcerated
  • Adults age 60 or older years without known risk factors for hepatitis B infection may receive HepB.

People with documentation of complete vaccination or documentation of previous HBV infection generally do not need to be vaccinated; however, there is no evidence that administration of additional doses of HepB to someone who is already immune or infected is harmful. Serologic testing is not required before vaccination and should not pose a barrier to access to vaccination. If testing is done, it may be done at the same visit when the first dose of vaccine is administered.

Revaccination is recommended only for individuals for whom post-vaccination serologic testing (PVST) is recommended and evidence of nonresponse is found. Annual serologic testing of people undergoing dialysis is recommended, with booster doses administered when detectable antibodies drop below 10 mIU/mL. Annual testing and revaccination may be indicated for other immunocompromised people. See CDC 2018 ACIP recommendations for a detailed discussion of these issues: www.cdc.gov/mmwr/volumes/67/rr/pdfs/rr6701-H.pdf (pages 21-24).

Last reviewed: July 21, 2023

All current and recent past ACIP recommendations concerning hepatitis B vaccination are available at: www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/hepb.html.

The most recent recommendations for adult HepB vaccination were published in MMWR on April 1, 2022. This publication details the routine catch-up recommendation for HepB vaccination of all adults age 19 through 59 years. The document is available at www.cdc.gov/mmwr/volumes/71/wr/pdfs/mm7113a1-H.pdf.

The 2018 comprehensive ACIP HepB recommendations publication contains detailed guidance on pediatric vaccination, post-vaccination serologic testing of healthcare professionals and other select high risk individuals, as well as the prevention of mother-to-child transmission of hepatitis B. It is available at www.cdc.gov/mmwr/volumes/67/rr/pdfs/rr6701-H.pdf.

In addition to the published recommendations, CDC has produced a frequently asked questions page for HBV infection and HepB vaccination: www.cdc.gov/hepatitis/hbv/hbvfaq.htm.

Last reviewed: August 19, 2023

Four hepatitis B (HepB) vaccines are currently licensed in the United States. Three of them contain recombinant hepatitis B surface antigen (HBsAg) produced in yeast cells. PreHevbrio (VBI), is a 3-antigen recombinant hepatitis B vaccine that is derived from mammalian (Chinese hamster ovary) cells.

HepB vaccines are available as HepB-only formulations; two of them are also available in combination with other vaccines. Heplisav-B (Dynavax) and PreHevbrio are both approved only for people 18 years of age and older. Engerix-B (GSK) and Recombivax HB (Merck) are approved for vaccination starting at birth and are available in both pediatric and adult formulations. For the 3-dose series of Engerix-B or Recombivax HB, people 0 through 19 years of age receive a 0.5 mL dose regardless of their height or weight; people 20 years of age and older receive a 1.0 mL dose.

Three combination vaccines that contain HepB are available in the United States. Pediarix (GSK) is approved for children 6 weeks through 6 years of age and contains HepB, DTaP, and inactivated poliovirus (IPV). Twinrix (GSK) is approved for adults 18 years of age and older and contains HepB and inactivated hepatitis A virus (HepA). Vaxelis (MCM Company) is approved for use in children 6 weeks through 4 years of age and contains HepB, DTaP, Hib, and IPV.

Last reviewed: July 21, 2023

No. It is the volume of the dose, not the antigen content, that is important. People 20 years and older should always receive a 1.0 mL dose of either Engerix-B or Recombivax HB when using those products. Likewise, people younger than 20 years should always receive a 0.5 mL dose of the pediatric formulation of either Engerix-B or Recombivax HB.

Last reviewed: July 21, 2023

Heplisav-B (Dynavax) was approved by the Food and Drug Administration (FDA) in November 2017 for people 18 years of age and older. Heplisav-B contains a novel adjuvant (CpG 1018) that binds to Toll-like receptor 9 to stimulate the immune response to HBsAg. It is provided in a single dose 0.5 mL vial and given as a 2-dose series with doses separated by 1 month (4 weeks).

Heplisav-B was approved based on clinical trials that compared seroprotection rates (SPR, defined as anti-HBs of 10 mIU or higher, and indicative of protection against hepatitis B infection) following 2 doses of Heplisav-B to rates following 3 doses of Engerix-B (GSK). Among people 18 through 70 years of age, SPRs were 90%–95% following 2 doses of Heplisav-B and 65%–81% following 3 doses of Engerix-B. Local reactions were most commonly reported (injection site pain, redness, and swelling) and were similar in frequency to those following Engerix-B.

The package insert for Heplisav-B is available here: www.fda.gov/media/108745/download.

Last reviewed: July 21, 2023

PreHevbrio (VBI) was approved by the FDA in November 2021 for people age 18 years and older. It is a triple-antigen (containing S, Pre-S1, and Pre-S2 HBV surface proteins) recombinant vaccine produced in mammalian cells (Chinese hamster ovary cells), and containing an alum adjuvant. It is given intramuscularly in a 3-dose series of 1.0 mL (10 mcg) doses administered on a 0-, 1-, and 6-month schedule. The most common side effects of vaccination are injection site pain and tenderness, as well as fatigue, muscle aches, and headache.

PreHevbrio was approved based on clinical trials conducted in adults age 18 years and older that compared seroprotection rates (SPR, defined as anti-HBs of 10 mIU or higher, and indicative of protection against HBV infection) following 3 doses of PreHevbrio to rates following 3 doses of Engerix-B (GSK). The SPR for PreHevbrio among adults age 18 years or older ranged from 83.6% to 99.2% (overall, 91.2% for all adults) compared to Engerix-B, which ranged from 64.7% to 91.1% (overall, 76.5% for all adults).

PreHevbrio was included as an option for HepB vaccination of adults age 18 years or older in the current ACIP recommendations published on April 1, 2022: www.cdc.gov/mmwr/volumes/71/wr/pdfs/mm7113a1-H.pdf.

The package insert for PreHevbrio is available here: www.fda.gov/media/154561/download.

Last reviewed: July 21, 2023

The schedule for HepB vaccination depends on the brand in use. Heplisav-B is administered intramuscularly on a 2-dose schedule with doses separated by 1 month (4 weeks). Routine primary vaccination with PreHevbrio, Engerix-B, Recombivax HB, or Twinrix consists of three intramuscular doses administered on a 0-, 1-, and 6-month schedule.

Alternative vaccination schedules for Engerix-B and Recombivax HB (for example, 0, 1, and 4 months or 0, 2, and 4 months) have been demonstrated to elicit dose-specific and final rates of seroprotection similar to those obtained on a 0-, 1-, and 6-month schedule. Increasing the interval between the first 2 doses has little effect on immunogenicity or the final antibody concentration. The third dose confers the maximum level of seroprotection and provides long-term protection.

Recombivax HB may be administered in a 2-dose schedule at 0 and 4–6 months for adolescents age 11 through 15 years using the adult formulation (1.0 mL). Pediarix (GSK) and Vaxelis (MCM) combination vaccines are administered at age 2, 4, and 6 months; they are not used for the birth dose. Twinrix may be administered on an accelerated 4-dose schedule at 0, 7, and 21–30 days, followed by a dose at 12 months.

HepB vaccination of adult (age 20 years and older) hemodialysis patients consists of high-dose (40 µg) Recombivax HB administered on a 0-, 1-, and 6-month schedule or high-dose (2 mL) Engerix-B administered on a 0-, 1-, 2-, and 6-month schedule. Heplisav-B and PreHevbrio have not been studied in patients on hemodialysis.

Last reviewed: July 21, 2023

For all ages, when the HepB schedule is interrupted, the vaccine series does not need to be restarted. If the Heplisav-B series is interrupted, the second (final) dose should be given as soon as possible. For Engerix-B, Recombivax HB, and PreHevbrio, if the series is interrupted after the first dose, the second dose should be administered as soon as possible, and the second and third doses should be separated by at least 8 weeks. If only the third dose has been delayed, it should be administered as soon as possible.

Last reviewed: July 21, 2023

The minimum interval between the two doses of Heplisav-B is 4 weeks. For the 3-dose series vaccines, Engerix-B, PreHevbrio, and Recombivax HB, the minimum interval between the first and second doses is 4 weeks. The final dose of vaccine must be administered at least 8 weeks after the second dose and should follow the first dose by at least 16 weeks. Vaccine doses administered 4 or fewer days before the minimum interval or age are considered valid. Doses received 5 or more days before the minimum interval or age should be repeated using the correct schedule. Because of the unique accelerated schedule for Twinrix, the 4-day “grace period” does not apply to the first three doses of this vaccine when administered on a 0-, 7-, 21–30-day, and 12-month schedule.

Last reviewed: July 21, 2023

What you do depends on when the error is identified. If the error is discovered while the person is still in the office, you can administer the other “half” of the Engerix-B dose. If the error is discovered later, the dose should not be counted. The person should be recalled to the office and given a full age-appropriate 1.0 mL repeat dose. The same recommendation would apply if the error was with Recombivax HB.

Last reviewed: July 21, 2023

Studies indicate that immunologic memory remains intact for at least 30 years and confers protection against clinical illness and chronic HBV infection, even though anti-HBs levels that once measured adequate might become low or decline below detectable levels. If exposed to HBV, people whose immune systems are competent will mount an anamnestic response and develop protective anti-HBs. Studies are on-going to assess whether booster doses of HepB will be needed in the future.

Last reviewed: July 21, 2023

You should use condoms until a postvaccination blood test (hepatitis B surface antibody, or anti-HBs) shows that your partner is protected from HBV infection. The efficacy of latex condoms in preventing infection with HBV is unknown, but their proper use might reduce the risk of transmission. Your sexual partner should have the 2- or 3-dose series of HepB vaccine (depending on brand) and postvaccination blood testing 1 to 2 months after the last dose of vaccine. If your partner’s test shows adequate anti-HBs (at least 10 mIU/mL), then they should be protected against HBV infection.

Last reviewed: July 21, 2023

In its 2006 ACIP recommendation for the prevention of hepatitis B, an accelerated 4-dose series of hepatitis B vaccine (which was not FDA-approved) was described as acceptable. CDC experts no longer recommend that approach when travel is imminent because other FDA-approved options exist.

The simplest option is Heplisav-B: its 2-dose series may be completed in 4 weeks. If Heplisav-B is unavailable, another option is to give the first 3 doses of the 4-dose accelerated schedule for Twinrix (HepA-HepB) at 0 days, 7 days, and 21-30 days and to have her return for a fourth dose 12 months after dose 1. Although this patient does not need the hepatitis A component, a combination vaccine such as Twinrix may be used if a single antigen option is not feasible; the additional doses of hepatitis A vaccine are not harmful.

Last reviewed: July 21, 2023

It is not necessary to restart or add doses to the HepB series (or any other routine vaccine series) because of a prolonged interval between doses. Just continue the series from the point where it was interrupted. Note that the 2-dose Recombivax HB series using the adult formulation is approved only for adolescents 11 through 15 years of age. At age 16 years, the schedule reverts to the standard pediatric formulation 3-dose schedule rather than 2 adult doses.

Last reviewed: July 21, 2023

Yes. You should draw the blood first and then administer the first dose of vaccine, as transient HBsAg-positivity has been detected after a dose of HepB (see related question).

Last reviewed: July 21, 2023

It is advisable to wait at least 4 weeks. Published studies have found that transient HBsAg-positivity can be detected for up to 18 days after HepB vaccination (up to 52 days among hemodialysis patients). This does not mean the person is infected with HBV. However, donating too close to receipt of HepB could cause a person to be permanently deferred from blood donation if that person tests transiently HBsAg positive after the vaccine dose.

Last reviewed: July 21, 2023

The January 2018 recommendations are available at www.cdc.gov/mmwr/volumes/67/rr/pdfs/rr6701-H.PDF.

Last reviewed: July 21, 2023

Yes; people who are identified as being at risk for HBV infection during pregnancy should be vaccinated. They also should be counseled concerning other methods to prevent HBV infection. Providers should administer an age-appropriate 3-dose series of Twinrix, Engerix-B or Recombivax HB.

Until safety data are available for Heplisav-B or PreHevbrio administration during pregnancy, ACIP does not recommend the use of either of these products to vaccinate during pregnancy. Pregnancy testing prior to administration of these products is not recommended.

Last reviewed: July 21, 2023

There are insufficient data available to inform assessment of Heplisav-B or PreHevbrio vaccine-associated risks during pregnancy.

Dynavax has established a Heplisav-B Vaccination in Pregnancy Registry in order to understand the effect (if any) of Heplisav-B vaccination during pregnancy. Individuals who receive Heplisav-B within 28 days before pregnancy or at any time during pregnancy are encouraged to participate in the registry by calling 1-844-443-7734 (toll-free).

VBI has established a registry that monitors pregnancy outcomes in mothers exposed to PreHevbrio during pregnancy. Individuals who receive PreHevbrio during pregnancy are encouraged to contact 1-888-421-8808 (toll-free).

Last reviewed: July 21, 2023

Decreased seroconversion rates might occur among preterm infants with birth weights less than 2,000 grams after administration of HepB at birth. However, by the chronological age of 1 month, all preterm infants, regardless of initial birth weight, are likely to respond as adequately as larger infants. Infants who weigh less than 2,000 grams born to HBsAg-positive mothers and mothers with unknown HBsAg status (if the mother’s HBsAg status cannot be determined within 12 hours of birth) must receive immunoprophylaxis with HepB and hepatitis B immune globulin (HBIG) within 12 hours of birth. The initial vaccine dose should not be counted toward completion of the hepatitis B series, and 3 additional doses of HepB should be administered, beginning when the infant is age 1 month. Infants weighing less than 2,000 grams born to HBsAg-negative mothers should receive the first dose of the HepB series at hospital discharge or at chronological age 1 month (even if weight is still less than 2,000 grams), whichever comes first.

Last reviewed: July 21, 2023

Screening should be done with the hepatitis B surface antigen (HBsAg) test only. This blood test will tell whether a mother has current HBV infection that can be transmitted to the infant. Ordering a total antibody to hepatitis B core antigen (total anti-HBc) and/or anti-HBs are not useful when screening to prevent perinatal HBV infections and should not be included in screening during pregnancy for risk of perinatal HBV infection. Total anti-HBc will be positive in all HBsAg-positive people and anti-HBs is rarely positive in an HBsAg-positive person. Pregnant people who are found to be positive should be tested for HBV DNA to guide the use of maternal antiviral therapy during pregnancy for the prevention of perinatal HPV transmission (see MMWR 2018;67 [RR-1]:13).

An infant born to a mother for whom HBsAg screening test results during pregnancy are not available but other evidence suggesting maternal HBV infection exists (e.g., presence of HBV DNA, HBeAg-positive, or mother known to be chronically infected with HBV) should be managed as if born to an HBsAg-positive mother. The infant should receive both HepB and HBIG within 12 hours of birth. The mother should also be referred to their jurisdiction’s Perinatal Hepatitis B Prevention Program for case management to ensure that the infant receives timely prophylaxis and follow-up.

Last reviewed: July 21, 2023

Twinrix is licensed as a 3-dose series for people age 18 years and older (minimum interval between dose 1 and dose 2 is 4 weeks; minimum interval between dose 2 and dose 3 is 5 months). It is also approved for use in an accelerated 4-dose schedule in adults, with doses given at 0, 7, and 21-30 days, followed by a booster dose at 12 months. There is no accelerated schedule for single antigen HepA or HepB vaccines, so the recommendations below presume the use of the Twinrix 3-dose routine schedule, with a minimum interval between dose 1 and dose 2 of 4 weeks.

If Twinrix is not available or if you choose not to use Twinrix to complete the hepatitis A (HepA) and hepatitis B (HepB) series, you should do the following:

  • If 1 dose of Twinrix was given, complete the series with 2 adult doses of HepA and 2 adult doses of HepB.
  • If 2 doses of Twinrix were given, complete the schedule with 1 adult dose of HepA and 1 adult dose of HepB.

Another way to consider this is as follows:

  • A dose of Twinrix contains a standard adult dose of HepB and a pediatric dose of HepA. So, a dose of Twinrix can be substituted for any dose of the HepB series but not for any dose of the HepA series.
  • Any combination of 3 doses of adult HepB or 3 doses of Twinrix is a complete series of HepB vaccine
  • One dose of Twinrix and 2 doses of adult HepA is a complete series of HepA
  • Two doses of Twinrix and 1 dose of adult HepA is a complete series of HepA
Last reviewed: June 3, 2024

Yes. Mothers who have received HepB should still be screened for HBsAg early in each pregnancy. Just because a pregnant person has been vaccinated does not mean they are HBsAg negative. Since postvaccination testing is not performed for most vaccinated people, the mother could have been vaccinated when already actively infected.

Last reviewed: July 21, 2023

The earlier the evaluation is done, the better. Consultation with or referral to a liver disease specialist (such as a hepatologist, gastroenterologist, or infectious disease specialist) should be done. The consulting/referral physician should be aware of the patient’s obstetrical status. In addition, the patient’s sex partner and children or other household contacts should be tested for HBV infection (total anti-HBc and HBsAg) as soon as possible. If any are susceptible to HBV infection (total anti-HBc and HBsAg negative), they should be vaccinated. If any are HBsAg positive, they should be referred to or have consultation with a liver disease specialist.

Last reviewed: July 21, 2023
  • Infants born to mothers for whom HBsAg testing results during pregnancy are not available but other evidence suggestive of maternal HBV infection exists (for example presence of HBV DNA, HBeAg-positive, or mother known to be chronically infected with HBV) should be managed as if born to an HBsAg-positive mother.
  • Mothers admitted for delivery without documentation of HBsAg test results should have blood drawn and tested as soon as possible after admission.
  • While test results are pending, all infants with birth weights of 2,000 grams or more born to mothers without documentation of HBsAg test results should receive the first dose of single-antigen HepB (without HBIG) within 12 hours of birth. Only single antigen HepB vaccine should be used for the birth dose.
  • If the mother is determined to be HBsAg positive, the infant should receive HBIG as soon as possible but no later than age 7 days, and the vaccine series should be completed according to a recommended schedule for infants born to HBsAg-positive mothers.
  • If the mother is determined to be HBsAg negative, the vaccine series should be completed according to a recommended schedule for infants born to HBsAg-negative mothers.
Last reviewed: July 21, 2023

Preterm infants weighing less than 2,000 grams (4.4 pounds) at birth have a decreased response to HepB administered before age 1 month. By age 1 month, medically stable preterm infants, regardless of initial birth weight or gestational age, have an immunologic response to HepB vaccination that is comparable to that of full-term infants. For preterm infants weighing less than 2,000 grams at birth:

  • If maternal HBsAg status is positive:
    • Give hepatitis B immune globulin (HBIG) plus HepB vaccine within 12 hours of birth. The birth dose (the initial HepB dose) should not be counted as part of the vaccine series.
    • Give 3 additional HepB doses (for a total of 4 doses) at ages 1, 2 to 3, and 6 months, or HepB-containing combination vaccine (Pediarix or Vaxelis) at ages 2, 4, and 6 months. The final dose should not be administered before 24 weeks of age.
    • Test for HBsAg and anti-HBs at age 9–12 months, or 1–2 months after the final dose of the vaccine series if completion of the series is delayed. Testing should not be performed before age 9 months (anti-HBs resulting from use of HBIG might still be positive and therefore misleading) or within 1 month of the most recent HepB dose (testing for HBsAg sooner than 1 month of a vaccine dose might produce a transient HBsAg-positivity).
  • If maternal HBsAg status is unknown:
    • If the mother’s HBsAg status cannot be determined within 12 hours of birth give HBIG plus HepB vaccine. The birth dose of vaccine should not be counted as part of the 3 doses required to complete the HepB series.
    • Three additional doses of vaccine (for a total of 4 doses) should be administered according to the recommended schedule on the basis of the mother’s HBsAg test result. The final dose in the series should not be administered before 24 weeks of age.
  • If it is not possible to determine the mother’s HBsAg status:
    • The vaccine series should be completed according to a recommended schedule for infants born to HBsAg positive mothers.
  • If the maternal HBsAg status is negative:
    • If you are certain that appropriate maternal testing was done and a copy of the mother’s original laboratory report indicating that she was HBsAg negative during this pregnancy is placed on the infant’s chart, delay the first dose of HepB vaccine until age 1 month or hospital discharge (even if weight is still less than 2,000 grams), whichever comes first. Complete the vaccine series per the recommended schedule.

For preterm infants weighing 2,000 grams or more at birth, follow the recommendations for full-term infants including a HepB dose within 24 hours of birth.

Last reviewed: July 21, 2023

In 2015, CDC revised the recommendation for the timing of hepatitis B serologic testing for infants born to an HBsAg-positive woman. Postvaccination testing (HBsAg and hepatitis B surface antibody [anti-HBs]) is now recommended 1 to 2 months after completion of at least three doses of the HepB vaccine series, but not before 9 months of age. For a child vaccinated on schedule, testing should be done at age 9 to 12 months. Testing should not be performed before age 9 months because hepatitis B immune globulin (HBIG) might still be present at age 6 to 8 months, nor should testing be performed within 1 month of the most recent HepB dose because a transient false positive HBsAg might occur. Antibody to hepatitis B core (anti-HBc) testing of infants or children is not recommended because passively acquired maternal anti-HBc might be detected up to age 24 months in children of HBV-infected mothers. Children who are HBsAg positive should receive medical evaluation and ongoing follow-up. For additional information, see www.cdc.gov/mmwr/pdf/wk/mm6439.pdf, pages 1118–20.

Last reviewed: July 21, 2023

HBsAg-negative infants with anti-HBs levels 10 mIU/mL or higher are protected and need no further medical management. HBsAg-negative infants with anti-HBs less than 10 mIU/mL should be revaccinated with a single dose of hepatitis B vaccine and receive postvaccination serologic testing 1–2 months later. Infants whose anti-HBs remains less than 10 mIU/mL following single dose revaccination should receive 2 additional doses of HepB to complete the second series, followed by postvaccination serologic testing 1–2 months after the final dose.

Based on clinical circumstances or family preference, HBsAg-negative infants with anti-HBs less than 10 mIU/mL may instead be revaccinated with a second, complete 3-dose series, followed by postvaccination serologic testing performed 1–2 months after the final dose of vaccine.

Last reviewed: July 21, 2023

Available data do not suggest a benefit from administering additional HepB vaccine doses to infants who have not attained anti-HBs of mIU/mL or higher following receipt of two complete HepB series. HBsAg-positive infants should be referred for appropriate follow-up with a physician who specializes in evaluating infants with liver disease.

Last reviewed: July 21, 2023

Yes. An HBsAg-positive mother who wishes to breastfeed should be encouraged to do so, including immediately following delivery. However, the infant should receive HBIG and HepB vaccine within 12 hours of birth. Although HBsAg can be detected in breast milk, studies done before HepB was available showed that breastfed infants born to HBsAg-positive mothers did not demonstrate an increased rate of perinatal or early childhood HBV infection. More recent studies have shown that, among infants receiving post-exposure prophylaxis to prevent perinatal HBV infection, there is no increased risk of infection among breastfed infants.

Last reviewed: July 21, 2023

Yes. The use of a 4-dose HepB schedule is acceptable when giving the monovalent HepB vaccine birth dose followed by the use of Pediarix (DTaP-HepB-IPV) or Vaxelis (DTaP-IPV-Hib-HepB). The use of a 4-dose HepB schedule, including schedules with a birth dose, has not increased vaccine reactogenicity and results in higher final antibody titers that should correlate with longer duration of detectable antibody. The federal Vaccines for Children (VFC) program provides up to four doses of HepB for VFC-eligible children. You may still use monovalent HepB in a 3-dose series.

Last reviewed: July 21, 2023

According to subject matter experts at CDC, your electronic health record is correct. The CDC website states that HepB dose #4, if given, must be at 24 weeks of age or later, at least 16 weeks from dose #1, and at least 8 weeks from dose #2. There is no minimum interval requirement between dose #4 and the previous dose. This information is not published in any current ACIP statement but it can be found under “Hepatitis B” at www.cdc.gov/vaccines/programs/cocasa/reports/algorithm-ref.html.

Last reviewed: July 21, 2023

Yes. Poorer immune response rates are seen in infants who complete the vaccination series prior to age 6 months. Do not count dose #3, which you gave at age 4 months. Repeat dose #3 when the infant is at least 6 months of age (no earlier than age 24 weeks).

Last reviewed: July 21, 2023

If an infant received an adult dose of HepB (contains twice the antigen in a dose of the pediatric formulation), the dose can be counted as valid and does not need to be repeated. Hepatitis B vaccines are very safe vaccine and no unusual adverse events would be expected because of this administration error. The next (age appropriate) dose should be given on the usual schedule.

Last reviewed: July 21, 2023

The minimum age for the last dose of HepB is age 24 weeks (the minimum age is the youngest age that is acceptable for giving a vaccine and having it “count” as a valid dose.) This allows healthcare providers more flexibility in administering HepB should a parent bring an infant in for a well-baby check before the infant reaches a full 6 months of age. If the third dose is given prior to age 24 weeks the dose should not be counted. Poorer response rates are seen in infants who complete the vaccination series prior to age 24 weeks. The third dose should be repeated when the infant is at least age 24 weeks.

Last reviewed: July 21, 2023

Yes. CDC recommends that all children age 0 through 18 years be fully vaccinated against hepatitis B. This recommendation is also endorsed by AAP and AAFP and is published as part of the annual Recommended Childhood and Adolescent Immunization Schedule (www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html). Vaccination should be initiated for children and teenagers not previously vaccinated and vaccination completed for all those whose vaccine series is incomplete.

All children and adolescents younger than age 19 years (including internationally adopted children) who were born in Asia, the Pacific Islands, Africa, or other intermediate or high-endemic countries or who have at least one parent who was born in a high-endemic area should be tested for HBsAg and should complete the vaccine series if they were not previously vaccinated or were incompletely vaccinated.

Last reviewed: July 21, 2023

Yes. There are data that show adequate seroprotection using this schedule in young adults. If this schedule is used, you should be aware that the studies were in young adults and might not translate to older adults (age 40 years or older). There are other schedules that offer flexibility in vaccination as well. View www.immunize.org/catg.d/p2081.pdf for a review of different schedules.

Last reviewed: July 21, 2023

There is no need to restart the series. Give the second dose of HepB now and be sure there are at least 8 weeks between that dose and the third dose. Increasing the interval between the first two doses has little effect on immunogenicity or final antibody concentration. The third dose confers the maximum level of seroprotection but acts primarily as a booster and appears to provide optimal long-term protection. Longer intervals between the last two doses result in higher final antibody levels but might increase the risk for acquisition of HBV infection among people who have a delayed response to vaccination. No differences in immunogenicity have been observed when one or two doses of hepatitis B vaccine produced by one manufacturer are followed by doses from a different manufacturer.

Last reviewed: July 21, 2023

For the 2-dose adolescent schedule, the adult dose of Recombivax HB (1.0 mL dose) is administered to adolescents age 11 through 15 years, with the second dose given 4 to 6 months after the first dose. In immunogenicity studies, antibody concentrations and end seroprotection rates (at least 10 mIU/mL of anti-HBs) were similar with the 2-dose schedule and the 3-dose schedule (0.5 mL dose). As with other HepB vaccination schedules, if administration of the 2-dose schedule is interrupted, it is not necessary to restart the series. Children and adolescents who have begun vaccination with a pediatric (0.5 mL) dose of Recombivax HB should complete the 3-dose series with this dose. If it is not clear which dose an adolescent was administered at the start of a series, the series should be completed with the 3-dose schedule. Heplisav-B, the 2-dose HepB vaccine given with a 4-week interval between doses, is licensed only for adolescents and adults beginning at age 18 years.

Last reviewed: July 21, 2023

The 2-dose Recombivax HB schedule is only approved for use in children age 11 through 15 years. A 16-year-old child would need two additional doses of pediatric HepB to complete a 3-dose series.

Last reviewed: July 21, 2023

The dosage depends on the schedule and manufacturer of the vaccine that you are using. For children 11 through 15 years of age, the 2-dose Recombivax HB volume is 1.0 mL. Otherwise, the 3-dose schedule of Recombivax HB or Engerix B is 0.5 mL through age 19 years. Heplisav-B, the 2-dose HepB vaccine given with a 4-week interval between 0.5 mL doses, is licensed for adolescents and adults beginning at age 18 years. Immunize.org offers a handy resource with charts detailing the correct dosages and schedules for monovalent HepB and HepA vaccines and combination products that include HepA and HepB vaccines. Go to www.immunize.org/catg.d/p2081.pdf.

Last reviewed: July 21, 2023

All foreign-born people (including immigrants, refugees, asylum seekers, and internationally adopted children) born in Asia, the Pacific Islands, Africa, and other regions with high or intermediate endemicity of HBV infection should be tested for HBsAg, regardless of vaccination status. Initiating HepB vaccination of immigrant children should not be delayed while awaiting HBsAg test results: you may draw blood for testing then administer the first dose of vaccine at the same visit. All people found to be HBsAg-positive should have ongoing medical management by a physician knowledgeable about hepatitis B and its complications.

Last reviewed: July 21, 2023

In April 2022, CDC published updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for the use of hepatitis B vaccine (HepB) in adults. In addition to routine universal childhood HepB vaccination, CDC now recommends catch-up vaccination of all adults younger than age 60 years not previously vaccinated. CDC also recommends that healthcare providers offer HepB vaccination to all adults age 60 or older and routinely given to any adult in this age group known to be at risk. Access the ACIP recommendation: www.cdc.gov/mmwr/volumes/71/wr/pdfs/mm7113a1-H.pdf.

Last reviewed: July 21, 2023

In March 2023, CDC published updated hepatitis B screening and testing guidelines for all adults age 18 years or older. In brief, it is recommended that all adults should be serologically screened for hepatitis B at least one time using a triple panel test, regardless of vaccination history. The triple panel includes antibody
to hepatitis B surface antigen (anti-HBs), total core antibody (anti-HBc), and surface antigen (HBsAg). Pregnant people should be tested for HBsAg during each pregnancy, regardless of testing or vaccination history. After the one-time screening, unvaccinated, susceptible individuals at ongoing risk should be tested periodically for infection. In addition, anyone who requests testing should be tested. Access the CDC recommendations: www.cdc.gov/mmwr/volumes/72/rr/pdfs/rr7201a1-H.pdf.

Last reviewed: July 21, 2023

Anyone can be infected with hepatitis B. Everyone can benefit from knowing their status and being protected. The majority of adults reported to CDC in recent years with acute hepatitis B have no reported risk factor for infection. Risk factors for exposure are so numerous and diverse that most adults, even those who don’t think of themselves as at risk, may find themselves at risk at some point in their lives.

Infants and children have been routinely vaccinated since the 1990s. As a result, we see very little hepatitis B in the routinely vaccinated age groups; however, rates have been steady or rising in unvaccinated older adults. CDC recommends extending this vaccine protection to all adults in a catch-up vaccination program. This is a crucial step toward the goal of eliminating hepatitis B and the liver disease and cancer it causes.

Last reviewed: July 21, 2023

PreHevbrio (VBI, 3-dose series), Heplisav-B (Dynavax, 2-dose series), and Twinrix (GSK, combination HepA-HepB, 3-dose series) are approved for adults age 18 years and older. Engerix-B (GSK) and Recombivax HB (Merck), both administered as a 1.0 mL 3-dose series, are approved for adults age 20 years and older; young adults who are age 19 receive the 0.5 mL pediatric dose of Engerix-B and Recombivax HB.

Last reviewed: July 21, 2023

In general, one HepB series is needed in a lifetime, with rare exceptions described at the end of this answer.

As of April 2022, CDC recommends HepB vaccination of all adults age 60 or older who are in any of the following risk groups (vaccination also may be offered to age 60 and older, regardless of risk):

  • All adults age 60 years and older with risk factors for hepatitis B:
    • People at risk for infection by sexual exposure
      • Sex partners of people testing positive for HBsAg
      • Sexually active people who are not in a long-term, mutually monogamous relationship (e.g., those with more than one sex partner during the previous 6 months)
      • People seeking evaluation or treatment for a sexually transmitted infection
      • Men who have sex with men
    • People at risk for infection by percutaneous or mucosal exposure to blood
      • People with current or recent injection drug use
      • Household contacts of people testing positive for HBsAg
      • Residents and staff members of facilities for people with developmental disabilities
      • Healthcare and public safety personnel with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids
      • People on maintenance dialysis, including in-center or home hemodialysis and peritoneal dialysis, and people who are predialysis
      • People with diabetes, at the discretion of the treating clinician
    • Others
      • International travelers to countries with high or intermediate levels of endemic hepatitis B virus (HBV) infection (HBsAg prevalence of 2% or higher)
      • People with hepatitis C virus infection
      • People with chronic liver disease (including, but not limited to, people with cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an alanine aminotransferase or aspartate aminotransferase level greater than twice the upper limit of normal)
      • People with HIV infection
      • People who are incarcerated

The official CDC recommendations for HepB vaccination of adults are available at www.cdc.gov/mmwr/volumes/71/wr/pdfs/mm7113a1-H.pdf. Immunize.org has developed a standing order template for adult HepB vaccination: www.immunize.org/catg.d/p3076.pdf.

In general, people who have documented completion of a HepB series at any point or who have a history of previous HBV infection should not receive additional HepB vaccination, although there is no evidence that additional vaccination is harmful. In settings where the patient population has a high rate of previous HBV infection, prevaccination testing, which may be performed at the same visit when the first dose of vaccine is administered, might reduce costs by avoiding complete vaccination of people who are already immune. However, prevaccination testing is not required and should not create a barrier to vaccination.

Revaccination may be indicated for certain high-risk adults, including healthcare workers who are documented non-responders to an initial HepB series, and certain people who receive dialysis or who are immunocompromised. For specific revaccination guidance, see the 2018 ACIP recommendations for the prevention of hepatitis B at www.cdc.gov/mmwr/volumes/67/rr/pdfs/rr6701-H.pdf (pages 23–24).

People with risk factors who are 60 and older should be vaccinated and other people older than 60 may be vaccinated.

Last reviewed: July 21, 2023

Prior vaccine recommendations put the burden on the patient to ask for HepB vaccination if they wanted it. The recommendations published in 2022 make vaccinating adults much easier because CDC recommends that healthcare providers routinely offer HepB vaccine to ALL adult patients, including those over 60 without known risk factors. The idea of this change is to shift the burden of requesting vaccination off the patient and instead allow the provider to offer the vaccine routinely.

Last reviewed: July 21, 2023

The HepB series is now recommended for all people age 59 years and younger. Among older age groups the risk of acute hepatitis B is lower: HepB may be administered to unvaccinated adults with diabetes age 60 years and older at the discretion of the treating clinician.

In 2011, CDC first published ACIP recommendations that HepB vaccine be given to adults with diabetes because of studies showing that adults with diabetes and no other hepatitis B risk factors had twice the odds of developing acute hepatitis B compared to adults without diabetes or other risk factors. There also have been a number of outbreaks of HBV infection in settings that provide assisted blood glucose monitoring for people with diabetes.

No serologic testing or additional HepB vaccination is recommended for adults who have documentation of receiving a complete HepB series at any time in the past. For those who did not complete the vaccination series, no maximum interval between doses exists that would make the HepB vaccination series ineffective or that would require restarting the series.

Last reviewed: July 21, 2023

No, gestational diabetes is not classified as a risk factor for acute hepatitis B infection. The increased risk of acute hepatitis B infection has been associated with type 1 and type 2 diabetes; however, all people age 59 years or younger are now recommended to be vaccinated against hepatitis B.

Last reviewed: July 21, 2023

The deltoid muscle is recommended for routine intramuscular (IM) vaccination among adults. The anterolateral thigh also can be used. The gluteus muscle should not be used as a site for administering HepB. Please refer to the Immunize.org document Administering Vaccines to Adults: Dose, Route, Site, and Needle Size (available at www.immunize.org/catg.d/p3084.pdf) for complete information on this issue.

Last reviewed: July 21, 2023

Serologic testing for immunity after HepB vaccination is recommended only for people whose subsequent clinical management depends on knowledge of their immune status. Testing is not necessary after routine vaccination of adults.

Post-vaccination anti-HBs testing of certain adults is recommended for the following reasons:

  • To determine the need for revaccination and the type of follow-up testing:
    • HCP and public safety workers at risk for blood or body fluid exposure
    • Hemodialysis patients (and others who might require outpatient hemodialysis)
    • People with HIV, and other immunocompromised people (e.g., hematopoietic stem-cell transplant recipients or people receiving chemotherapy)
  • To determine the need for revaccination and for other methods of protection against HBV infection:
    • Sex partners or needle-sharing partners of HBsAg-positive people

Testing should be performed 1 to 2 months after the last dose of vaccine.

Last reviewed: July 21, 2023

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