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Issue 1365: May 22, 2018
Ask the Experts: CDC Experts Answer Your Questions
As a thank-you to our loyal IAC Express readers, we will periodically publish extra editions such as this one, with new "Ask the Experts" Q&As answered by CDC experts.
IAC extends thanks to our experts: Andrew T. Kroger, MD, MPH; Candice L. Robinson, MD, MPH; Raymond A. Strikas, MD, MPH, FACP, FIDSA; and JoEllen Wolicki, BSN, RN, all from the National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC).
Editor’s note: The Advisory Committee on Immunization Practices (ACIP) recently published two new statements on hepatitis B-containing vaccines—a comprehensive statement in January 2018 and a statement addressing the use of adjuvanted hepatitis B vaccine (Heplisav-B, Dynavax) in April 2018. The “Ask the Experts: Hepatitis B” topic on the IAC website (www.immunize.org/askexperts/experts_hepb.asp) has been revised to reflect information published in these two documents. This special edition of IAC Express contains some of the new or significantly revised Q&As available on our website.
Hepatitis B Vaccines
Q: How is hepatitis B virus (HBV) transmitted?
A: 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). Risk factors for sexual transmission among heterosexuals include having unprotected sex with an infected partner, having unprotected sex with more than one partner, and a history of another sexually transmitted infection (STI).
Risk factors associated with sexual transmission among MSM include having multiple sex partners, history of another STI, and anal intercourse. 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.
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Q: Please describe the currently available hepatitis B vaccines.
A: All hepatitis B (HepB) vaccines currently available in the United States contain recombinant hepatitis B surface antigen (HBsAg) produced in yeast cells. Hepatitis B vaccines are available as a single-antigen formulation and in combination with other vaccines. Of the three single antigen vaccines available in the United States, Engerix-B (GlaxoSmithKline) and Recombivax HB (Merck) are approved for vaccination starting at birth. Heplisav-B (Dynavax) is approved only for persons 18 years of age and older.
Engerix-B and Recombivax HB are available in both pediatric and adult formulations. For the 3-dose series of both vaccines, persons 0 through 19 years of age receive a 0.5 mL dose regardless of their height or weight. Persons 20 years of age and older receive a 1.0 mL dose.
Two combination vaccines that contain hepatitis B are available. Pediarix (GlaxoSmithKline) is approved for children 6 weeks through 6 years of age and contains HepB, DTaP, and inactivated poliovirus. Twinrix (GlaxoSmithKline) is approved for persons 18 years of age and older and contains HepB and inactivated hepatitis A virus. Comvax (Merck), a combination vaccine that contained HepB and Haemophilus influenzae type b is no longer available in the United States.
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Q: Please provide information about Heplisav-B.
A: HepB-CpG (Heplisav-B, Dynavax) was approved by the Food and Drug Administration in November 2017 for persons 18 years of age and older. Heplisav-B contains a novel immunostimulatory adjuvant (CpG 1018) that binds to Toll-like receptor 9 to stimulate a directed 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.
Heplisav-B was approved based on clinical trials that compared seroprotection rates (SPR, defined as anti-HBs of 10 mIU or higher) following 2 doses of Heplisav-B to rates following 3 doses of Engerix-B (GlaxoSmithKline). Among persons 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.
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Q: The adult formulation of Engerix-B contains twice as much antigen per dose as the adult formulations of Recombivax HB. If a patient received 10 mcg (1 mL) of Recombivax for the first dose, and I stock only Engerix, should I give a 10 mcg (0.5 mL) dose of Engerix for subsequent doses?
A: No. It is the volume of the dose, not the antigen content, that is important. Persons 20 years and older should always receive a 1.0 mL dose of either Engerix-B or Recombivax HB. Likewise, persons younger than 20 years should always receive a 0.5 mL dose of the pediatric formulation of either Engerix-B or Recombivax HB.
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Q: Where can I locate CDC's recommendations for hepatitis B vaccination?
A: The most recent comprehensive recommendations for hepatitis B vaccination were published in January 2018. The document is available at www.cdc.gov/mmwr/volumes/67/rr/pdfs/rr6701-H.PDF. Recommendations for the use of adjuvanted hepatitis B vaccine (Heplisav-B, Dynavax) were published in April 2018 and are available at www.cdc.gov/mmwr/volumes/67/wr/pdfs/mm6715a5-H.pdf.
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Q: What is the schedule for hepatitis B vaccine?
A: Primary vaccination with Engerix-B, Recombivax HB, or Twinrix consists of three intramuscular doses administered on a 0-, 1-, and 6-month schedule. Heplisav-B is administered intramuscularly on a 2-dose schedule with doses separated by 1 month.
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 11 through 15 years of age using the adult formulation (1.0 mL). Pediarix is administered at ages 2, 4, and 6 months; it is not used for the birth dose. Twinrix may be administered on an accelerated schedule at 0, 7, and 21–30 days, followed by a dose at 12 months.
Hepatitis B vaccination of adult (20 years old 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. The Heplisav-B schedule for hemodialysis patients is two 0.5 mL doses, separated by 1 month.
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Q: If the vaccination series is interrupted does the series need to be restarted?
A: For all ages, when the hepatitis B vaccine schedule is interrupted, the vaccine series does not need to be restarted. For Engerix-B and Recombivax HB, 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. If the Heplisav-B series is interrupted, the second (final) dose should be given as soon as possible.
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Q: What are the minimum intervals between doses in the hepatitis B vaccine series?
A: For Engerix-B 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. The minimum interval between doses of Heplisav-B is 4 weeks.
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Q: We inadvertently gave a 25-year-old a pediatric (0.5 mL) dose of Engerix-B. Can we just give her another pediatric dose or should she receive a repeat adult dose?
A: 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.
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Q: Can Heplisav-B (Heplisav-B) be used to complete a vaccination series started with Engerix-B or Recombivax HB?
A: Yes. However, data are limited on the safety and immunogenicity effects when Heplisav-B is interchanged with hepatitis B vaccines from other manufacturers. When feasible, the same manufacturer’s vaccines should be used to complete the series. However, vaccination should not be deferred when the manufacturer of the previously administered vaccine is unknown or when the vaccine from the same manufacturer is unavailable.
The 2-dose hepatitis B vaccine series for adults only applies when both doses in the series consist of Heplisav-B. Series consisting of a combination of 1 dose of Heplisav-B and a vaccine from a different manufacturer should consist of 3 total vaccine doses and should adhere to the 3-dose schedule minimum intervals of 4 weeks between dose 1 and 2, 8 weeks between dose 2 and 3, and 16 weeks between dose 1 and 3. Doses administered at less than the minimum interval should be repeated. However, a series containing 2 doses of Heplisav-B administered at least 4 weeks apart is valid, even if the patient received a single earlier dose from another manufacturer.
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Q: An adolescent received the first dose of hepatitis B vaccine at age 11 years but did not return for subsequent doses. If the patient comes back at age 16 years, is it necessary to repeat the first dose of the series?
A: It is not necessary to restart or add doses to the hepatitis B 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.
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Q: Who should be tested for anti-HBs after vaccination?
A: 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
- Healthcare professionals and public safety workers at risk for blood or body fluid exposure
- Hemodialysis patients (and other persons who might require outpatient hemodialysis), HIV-infected persons, and other immunocompromised persons (such as hematopoietic stem-cell transplant recipients or persons receiving chemotherapy), to determine the need for revaccination and the type of follow-up testing, and
- Sex partners of HBsAg-positive persons, 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 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).
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Q: How should I manage an infant of an HBsAg-positive mother who tests negative for anti-HBs after 3 properly spaced doses of vaccine?
A: 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 hepatitis B vaccine 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.
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Q: What should I do if an infant tests negative for anti-HBs after 2 complete vaccine series?
A: Available data do not suggest a benefit from administering additional hepatitis B vaccine doses to infants who have not attained anti-HBs of mIU/mL or higher following receipt of two complete hepatitis B vaccine series. HBsAg-positive infants should be referred for appropriate follow-up with a physician who specializes in evaluating infants with liver disease.
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Q: If an infant got a dose of the adult formulation of hepatitis B vaccine in error, should the dose be counted? When should the next dose be scheduled for this infant? Do we need to be concerned about a possible adverse event?
A: If an infant received an adult dose of hepatitis B vaccine (contains twice the antigen in a dose of the infant/child/adolescent formulation), the dose can be counted as valid and does not need to be repeated. Hepatitis B vaccine is a 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.
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Q: Describe the 2-dose regimen for hepatitis B vaccine for certain adolescents.
A: For the 2-dose 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 hepatitis B 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.
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Q: How should we complete the series if a 12-year-old starts the 2-dose Recombivax HB adult formulation series but fails to receive dose 2 before his or her 16th birthday?
A: 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 hepatitis B vaccine to complete a 3-dose series.
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Q: Which hepatitis B vaccines can be given to adult patients?
A: Twinrix (combination HepA-HepB, 3-dose series) and Heplisav-B (2-dose series) are approved for adults age 18 years and older. Engerix-B and Recombivax HB (as a 1.0 mL 3-dose series) are approved for adults age 20 years and older.
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Q: Can a dialysis or pre-dialysis patient receive Heplisav-B vaccine?
A: Yes.
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Q: Can Heplisav-B be used for vaccinating healthcare professionals?
A: Yes. Heplisav-B is approved as a 2-dose schedule for persons age 18 years and older, including healthcare professionals. The doses should be separated by at least 4 weeks.
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Q: Is it safe for a healthcare professional to be vaccinated during pregnancy?
A: Yes. Many years of experience with hepatitis B vaccines indicate no apparent risk for adverse events to a developing fetus. Current hepatitis B vaccines contain noninfectious hepatitis B surface antigen (HBsAg) and should pose no risk to the fetus. If not vaccinated, a pregnant woman may contract an HBV infection during pregnancy, which might result in severe disease for the newborn. Women who breastfeed their babies and are healthcare professionals can and should be vaccinated against hepatitis B if they haven’t been previously vaccinated. Receipt of the vaccine is not a reason to discontinue breastfeeding.
There are no clinical studies of Heplisav-B in pregnant women. Available human data on Heplisav-B administered to pregnant women are insufficient to assess vaccine-associated risks in pregnancy. Until safety data are available for Heplisav-B, providers should continue to vaccinate pregnant women needing hepatitis B vaccination with a vaccine from a different manufacturer.
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Q: What should be done if a healthcare professional's postvaccination anti-HBs test is negative (less than 10 mIU/mL) 1–2 months after the last dose of vaccine?
A: Repeat the 2- or 3-dose series (depending on vaccine brand) and test for anti-HBs 1–2 months after the final dose of the repeat series. Heplisav-B may be used for revaccination following an initial hepatitis B vaccine series that consisted of doses of Heplisav-B or doses from a different manufacturer. Heplisav-B may also be used to revaccinate new healthcare personnel (including the challenge dose) initially vaccinated with a vaccine from a different manufacturer in the distant past who have anti-HBs less than 10 mIU/mL upon hire or matriculation.
If the test is still negative after a second vaccine series, the person should be tested for HBsAg and total anti-HBc to determine their HBV infection status. People who test negative for HBsAg and total anti-HBc should be considered vaccine non-responders and susceptible to HBV infection. They should be counseled about precautions to prevent HBV infection and the need to obtain hepatitis B immune globulin (HBIG) prophylaxis for any known or likely exposure to HBsAg-positive blood. Those found to be HBsAg negative but total anti-HBc positive were infected in the past and require no vaccination or treatment. If the HBsAg and total anti-HBc tests are positive, the person should receive appropriate counseling for preventing transmission to others as well as referral for ongoing care to a specialist experienced in the medical management of chronic HBV infection. They should not be excluded from work.
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Q: We have a new employee with documentation of having received a series of hepatitis B vaccine as an adolescent. He now tests negative for hepatitis B surface antibody (anti-HBs). How should we manage him?
A: ACIP recommends that healthcare personnel with written documentation of having received a properly spaced series of hepatitis B vaccine in the past (such as in infancy or adolescence) but who now test negative for anti-HBs should receive a single "booster" dose of hepatitis B vaccine and be retested 1–2 months later. Those who test positive following the "booster" dose are immune and require no further vaccination or testing. Those who test negative should complete a second series of hepatitis B vaccine on the usual schedule and be tested again 1–2 months after the last dose. Heplisav-B may be used to revaccinate new healthcare personnel (including the challenge dose) initially vaccinated with a vaccine from a different manufacturer in the distant past who have anti-HBs less than 10 mIU/mL upon hire or matriculation. For more information see www.cdc.gov/mmwr/volumes/67/rr/pdfs/rr6701-H.PDF, pages 21–22.
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Q: How should hepatitis B vaccine be stored?
A: All hepatitis B-containing vaccine should be stored at refrigerator temperature at 2°C to 8°C (35°F to 46°F). The vaccines must not be frozen. Any vaccine exposed to freezing temperature should not be used. Do not use these or any other vaccines after the expiration date shown on the packaging. Any vaccine administered after its expiration date should be repeated.
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How to submit a question to Ask the Experts
IAC works with CDC to compile new Ask the Experts Q&As for our publications based on commonly asked questions. We also consider the need to provide information about new vaccines and recommendations. Most of the questions are thus a composite of several inquiries.
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