Hepatitis B Vaccine

Introduction

Hepatitis B virus (HBV) infection has been identified as a major public health problem worldwide and in India. A safe and effective vaccine to prevent Hepatitis B (HepB) diseases is available for nearly 3 decades. The vaccine was first introduced in the mid-1980 and became part of the recommended immunization schedule in the United States in the early 1990's. Since then, the incidence of acute HepB has dropped by more than 95 percent in children and adolescents, and by more than 75 percent overall. At the global level, the epidemiology of HBV is changing rapidly, as vaccination programs become the standard of health care. Of the 2.6 crores (26 million) infants born annually in India, approximately 10 lakh (one million) run a lifetime risk of developing chronic HBV infections. Nearly 170 World Health Organization (WHO) member countries have adopted a national policy of immunizing all infants at birth. Universal vaccination beginning at birth has been very effective in preventing perinatal transmission and reducing early viral exposures and the development of chronic HepB infection in children and adults.

The world’s first recombinant (r) HepB vaccine produced in single-antigen (HBsAg) formulation by recombinant DNA technology has been in use since 1986. The monovalent vaccines contain 10 to 40 µg of HBsAg protein/mL, and a completed 3-dose vaccination schedule at 0 - 1 and 6 months, results in a minimum protective level of anti-HBs of at least 10 mIU/mL in most recipients, which provides long-term protection. Outside the US, other levels of antibody may be used to determine immunity. Although the concentration of rHBsAg protein differs among vaccine products, rates of seroprotection are probably equivalent when given to immunocompetent infants, children, adolescents, or young adults in the doses recommended.

In the United States, two monovalent vaccines being used continually over 3 decades, to prevent HepB infection among infants, children, and adults; these vaccines are manufactured using recombinant technology and neither contains blood products. Recently CDC approved 3 other combinations (Combo’s) vaccines for use beyond neonatal age groups. (Table-1).

Table -1: CDC & ACIP approved HepB vaccines & doses of both monovalent and combo’s vaccines.

In India, the HepB vaccines are of public health importance and the government has initiated since the year 2002 with further expansion in a phased manner. The available and the marketed monovalent brands are many, over 20 commercial products, with affordable price ranges & may be equally immunogenic despite recombinant sAg component differences. Interchange of brands is permitted but not routinely recommended. The national policy in India recommends that children receive 3 doses including a birth dose for all new-borns (within 24 h of delivery), for all institutional deliveries. (Table-2)

Table 2: Three doses - childhood Immunization schedules (monovalent HepB vaccine); US-ACIP & India-ACVIP

Treatment

Hep B Vaccine Recommendation in general & specific:

Recommended specifically for all infants and children; also for adults in high-risk groups be vaccinated. Since every person is at some risk for infection, vaccination schedules & guidelines should be individualized for each situation. A regimen of 0-1-6 months schedule of immunization has been most widely used and proven to be ideal with protective anti-HBs antibody titers attained at the end of the 3-doses vaccination. This schedule prevents infections acquired during early childhood, adolescent and older, which accounts for most of the HBV- related disease burden at the global level. However, this schedule does not prevent perinatal transmission of HBV infections because it does not include a dose of HepB vaccine at birth. In high endemic countries, where a high proportion of HBV infections are acquired perinatally, the first dose of HepB vaccine should be given as soon as possible (<24 hours) after birth. India has been designated by WHO as intermediate to high endemic for HepB infection.

• Universal immunization of infants beginning at birth prevents perinatal transmission of maternal infection to newborn and early childhood, which accounts for most of the HBV-related disease burden and

• The monovalent HepB vaccine should be used for birth dose or any doses administered before age 6 weeks. The HepB containing combination vaccines (there are many varieties of combos are available in the Indian pharmaceutical markets- see table 3) can be administered for the 2nd and 3rd doses.

• A 4- dose to be administered if a birth dose is given and a combo is used (at 1-2, 4, and 6 months) to complete the series.

• HepB vaccine is considered one of the safest and most effective vaccines ever made. The immunogenicity and long-term efficacy of newborn and infant immunization have been proven extensively.

• No booster dose vaccination is recommended for immunocompetent children and adults based on the findings of many from other long-term cohort studies with many decades of follow-up [ J Infect Dis. (2016).First published online: January 21, 2016, http://jid.oxfordjournals.org/content/early/2016/01/21/infdis.jiv748.full ]

• HepB vaccine is a T-cell dependent vaccine and there is always a possibility of the anamnestic immune response to subsequent exposure to the virus again in the future.

• There is no evidence of serious adverse events that have been causally linked except soreness and redness at the injection site.

• Vaccine administrations: Intramuscular injection in the anterolateral thigh for infants or deltoid region for children and adults. Do not give in the gluteal region & this has been associated with decreased immunogenicity. Intradermal route is not approved universally.

IAP recommended HBV Vaccines (2014):

A variety of schedules may be used for HepB immunization in national programs. (http://www.iapcoi.com/hp/pdf/9-%20HEPATITIS%20B%20VACCINE.pdf). The IAP recommends vaccine given to all children in any of the following schedules: (i) Birth, 1 and 6 months (ii) Birth, 6 and 14 weeks (iii) 6, 10 and 14 weeks (iv) Birth, 6 weeks, 6 months (v) Birth, 6 weeks,10 weeks, 14 weeks. Three doses are generally required to complete the immunization series, although there is an alternate two-dose accelerated vaccination schedule for adolescents Aged 11--15 Years.

Combination Vaccine Schedule:

In table 3, IAP authorized Combo’s containing HepB formulary is summarized;

Table 3: IAP approved HepB containing Combo’s are

Over the past several years either DTaP or DTwP based HepB containing combos has been incorporated in childhood immunization programs at regional and national (NIP) levels. The list of WHO pre-qualified HepB containing combo formularies are numerous and available for developing countries through UNICEF support. The decision to incorporate combos containing the HepB component in the national EPI schedules may result in administering 4- doses, which is acceptable. Table 4 summarizes, an illustrative example of HepB based combo’s schedules that are incorporated in childhood immunization since 2009 in a nearby Middle-East country (Abu Dhabi Health Authority, UAE - Immunization schedule).

Table 4. Childhood (Combo’s) Immunization schedule – Health Authority, Abu Dhabi 2015 -2016

HepB Immunization Strategies:

A wide-ranging immunization strategy to eliminate HBV transmission has been employed progressively at a global level, focusing primarily on the following aspects;

1. Routine immunization (standard 3 doses regime) of children and adolescents

• Infants who did not receive a birth dose should receive 3 doses on a schedule of 0, 1 to 2 months, and 6 months starting as soon as feasible.

• Catch-up vaccination: Unvaccinated persons should complete a 3-dose series.

• A 2-dose series (doses separated by at least 4 months) of the adult formulation. Recombivax HB is licensed for use in children aged 11 through 15 years.

The duration of protection among children and adolescents who have received the recombinant HepB vaccination series is known to belong. Less is known about the duration of protection of the vaccination series after being administered during infancy.

2. Universal immunization of infants soon after birth (HepB birth dose);

This schedule prevents perinatal transmission of maternal infection to newborn and early childhood, which accounts for most of the HBV-related disease burden in countries with high endemicity. Also, administering the vaccine earlier in life makes it easier to achieve high immunization coverage.

• Birth dose, a monovalent HepB vaccine is given to all newborns before hospital discharge.

• The second dose should be administered at age 1 to 2 months; a minimum interval of 4 weeks, and

• The 3rd dose at 6 months of age, at least 8 weeks after the second dose & at least 16 weeks after the first dose.

The monovalent vaccine should be used for birth dose or any HepB doses administered before age 6 weeks. The HepB containing combination vaccines can be administered for the 2nd and 3rd doses. Administration of a total of 4 doses is permitted when a combination vaccine containing HepB is administered after the birth dose.

3. Prevention of perinatal HBV infection through routine screening of all pregnant women

• Infants at greatest risk of infection were those born to women who were younger, HB e-antigen positive, or who had a high viral load or those infants who received less than 3 HepB vaccine doses.

• Infants born to HBsAg-positive mothers, administer the vaccine and 0.5 mL of HBIG within 12 hours of birth. These infants should be tested for HBsAg and antibody to HBsAg (anti-HBs) 1 to 2 months after completion of the vaccine series at age 9 through 18 months (preferably at the next well-child visit).

• If the mother’s HBsAg status is unknown, within 12 hours of birth administer HepB vaccine regardless of birth weight. For infants weighing less than 2,000 grams, administer HBIG in addition to the HepB vaccine within 12 hours of birth. Determine mother’s HBsAg status as soon as possible and, if the mother is HBsAg-positive, also administer HBIG for infants weighing 2,000 grams or more as soon as possible, but no later than age 7 days.

4. Immunization of previously unimmunized adults at increased risk of infection.

Should vaccinate any person seeking protection from HBV infection and persons with any of the following indications:

• Persons with end-stage renal disease (including patients receiving hemodialysis), persons with HIV infection, and persons with chronic liver disease;

• Health care personnel who are potentially exposed to blood or other infectious body fluids;

• Household contacts and sex partners of HB sAg -positive persons and staff members of institutions for persons with developmental disabilities

• Diabetic patients: at the discretion of the treating clinician based on the likelihood of acquiring infection, including the risk posed by an increased need for assisted blood glucose monitoring

• Persons seeking evaluation or treatment for a sexually transmitted disease (STD); current or recent injection drug users; and men who have sex with men;

Dosing schedules in adults & at high risk:

• Administer missing doses to complete a 3-dose series to those persons not vaccinated or not completely vaccinated.

• If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, give 3 doses at 0, 1, and 6 months;

  alternatively

  , a 4-dose Twinrix schedule may be used, administered on days 0, 7, and 21-30, followed by a booster dose at 12 months.

• Adult patients receiving hemodialysis or with other immunocompromising conditions should receive 1 dose of 40 mcg/mL (Recombivax HB) administered on a 3-dose schedule at 0, 1, and 6 months or 2 doses of 20 mcg/mL (Engerix-B) administered simultaneously on a 4-dose schedule at 0, 1, 2, and 6 months.

Immunization during Pregnancy or Lactation

Pre and Post vaccination serologic testing aspects:

The individual clinician is in the best position to determine which tests are most appropriate for a particular patient.

Pre vaccination sero-susceptible testing is NOT INDICATED routinely for children or adolescents. Post-vaccination Serologic Testing (PVST) for anti-HBs is NOT NECESSARY after routine vaccination of healthy people but is recommended 1 to 2 months after the third or 4th vaccine dose for the following specific groups:

• Infants born to sAg-positive mothers should be tested for sAg and antibody (anti-HBs) titer, 1 to 2 months after completion of the vaccine series at age 9 through 18 months

Also, the PVST for anti-HBs is recommended for the following specific groups of individuals namely; a) hemodialysis patients - should test antibody level annually b) chemotherapy receiving immunocompromised patients including, hematopoietic stem-cell transplant recipients, c) people with HIV infection d) persons at occupational risk of exposure from percutaneous injuries or mucosal or non-intact skin exposures and, etc.

Management of vaccine non-responders;

Conclusion:

To conclude, newborn and infant HepB vaccination programs should become an integral part of national immunization schedules worldwide. A variety of schedules may be used for HepB immunization in national programs, depending on the local clinical burden, parental immunization attitude, and regional epidemiological situations. High coverage with the primary vaccine series among infants has the greatest overall impact on the prevalence of chronic HBV infection and its serious consequences including liver cirrhosis and hepatocellular cancer. It is very vital and crucial for health care professionals to work together closely at the national and regional Health Ministry levels to maximize the impact of hepatitis control activities.