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Hepatitis B Virus: A Comprehensive Strategy for Eliminating Transmission
in the United States Through Universal Childhood Vaccination:
Recommendations of the Immunization Practices Advisory Committee (ACIP)
Immunization Practices Advisory Committee
Membership List, September 1991
CHAIRMAN EX OFFICIO MEMBERS
Samuel L. Katz, M.D. John La Montagne, Ph.D. Duke University Medical
Center National Institutes of Health
EXECUTIVE SECRETARY Carolyn Hardegree, M.D.
Food and Drug Administration Claire V. Broome, M.D. Centers for Disease
Control LIAISON REPRESENTATIVES
MEMBERS American Academy of Family Physicians
Ronald C. Van Buren, M.D.
- Stanley E. Broadnax, M.D. Columbus, Ohio Cincinnati Health Department
American Academy of Pediatrics
- James D. Cherry, M.D. Georges Peter, M.D. University of California
School Providence, Rhode Island
of Medicine (Los Angeles)
Caroline B. Hall, M.D. Mary Lou Clements, M.D. Rochester, New York Johns
Hopkins University (Baltimore, Maryland) American College of Physicians
Pierce Gardner, M.D. David W. Fraser, M.D. Stonybrook, New York
Swarthmore College (Pennsylvania) American Hospital Association
William Schaffner, M.D.
- Caroline B. Hall, M.D. Nashville, Tennessee University of Rochester
School of Medicine and American Medical Association
Dentistry (New York) Edward A. Mortimer, Jr., M.D.
Cleveland, Ohio Carlos E. Hernandez, M.D. Kentucky Department for
Canadian National Advisory Committee
Health Services on Immunization
Susan E. Tamblyn, M.D., Dr. P.H. Gregory R. Istre, M.D. Stratford,
Ontario Medical City Hospital Canada (Dallas, Texas)
Department of Defense Carlos H. Ramirez-Ronda, M.D. Michael Peterson,
D.V.M. University of Puerto Rico M.P.H., Dr. P.H.
School of Medicine (San Juan) Washington, D.C.
Mary E. Wilson, M.D. National Vaccine Program Mount Auburn Hospital
Kenneth J. Bart, M.D. (Cambridge, Massachusetts) Rockville, Maryland
The following statement updates all previous recommendations on
protection against hepatitis B virus infection, including use of hepatitis B
vaccine and hepatitis B immune globulin for prophylaxis against hepatitis B
virus infection (MMWR 1985;34:313-24, 329-35, MMWR 1987;36:353-66, and MMWR
1990;39{No. RR-2}:8-19) and universal screening of pregnant women to prevent
perinatal hepatitis B virus transmission (MMWR 1988;37:341-46, 51, and MMWR
1990;39{No. RR-2}:8-19). Recommendations concerning the prevention of other
types of viral hepatitis are found in MMWR 1990;39(No. RR-2): 1-8, 22-26.
This document provides the rationale for a comprehensive strategy to
eliminate transmission of hepatitis B virus in the United States. This
prevention strategy includes making hepatitis B vaccine a part of routine
vaccination schedules for all infants.
INTRODUCTION
The acute and chronic consequences of hepatitis B virus (HBV) infection
are major health problems in the United States. The reported incidence of
acute hepatitis B increased by 37% from 1979 to 1989, and an estimated
200,000-300,000 new infections occurred annually during the period 1980-
1991. The estimated 1 million-1.25 million persons with chronic HBV
infection in the United States are potentially infectious to others. In
addition, many chronically infected persons are at risk of long-term
sequelae, such as chronic liver disease and primary hepatocellular
carcinoma; each year approximately 4,000-5,000 of these persons die from
chronic liver disease (1).
Immunization with hepatitis B vaccine is the most effective means of
preventing HBV infection and its consequences. In the United States, most
infections occur among adults and adolescents (2,3). The recommended
strategy for preventing these infections has been the selective vaccination
of persons with identified risk factors (1,2). However, this strategy has
not lowered the incidence of hepatitis B, primarily because vaccinating
persons engaged in high-risk behaviors, life-styles, or occupations before
they become infected generally has not been feasible. In addition, many
infected persons have no identifiable source for their infections and thus
cannot be targeted for vaccination (2).
Preventing HBV transmission during early childhood is important because
of the high likelihood of chronic HBV infection and chronic liver disease
that occurs when children less than 5 years of age become infected (3).
Testing to identify pregnant women who are hepatitis B surface antigen (HBsAg)-positive
and providing their infants with immunoprophylaxis effec- tively prevents
HBV transmission during the perinatal period (4,5). Integrating hepatitis B
vaccine into childhood vaccination schedules in populations with high rates
of childhood infection (e.g., Alaskan Natives and Pacific Islanders) has
been shown to interrupt HBV transmission (6).
This document provides the rationale for a comprehensive strategy to
eliminate transmission of HBV and ultimately reduce the incidence of
hepatitis B and hepatitis B-associated chronic liver disease in the United
States. The recommendations for implementing this strategy include making
hepatitis B vaccine a part of routine vaccination schedules for infants.
EPIDEMIOLOGY AND PREVENTION OF HEPATITIS B VIRUS INFECTION
Infections among Infants and Children
In the United States, children become infected with HBV through a variety
of means. The risk of perinatal HBV infection among infants born to
HBV-infected mothers ranges from 10% to 85%, depending on each mother's
hepatitis B e antigen (HBeAg) status (3,7,8). Infants who become infected by
perinatal transmission have a 90% risk of chronic infection, and up to 25%
will die of chronic liver disease as adults (9). Even when not infected
during the perinatal period, children of HBV-infected mothers remain at high
risk of acquiring chronic HBV infection by person-to-person (horizontal)
transmission during the first 5 years of life (10). More than 90% of these
infections can be prevented if HBsAg-positive mothers are identified so that
their infants can receive hepatitis B vaccine and hepatitis B immune
globulin (HBIG) soon after birth (4,5).
Because screening selected pregnant women for HBsAg has failed to
identify a high proportion of HBV-infected mothers (11,12), prenatal HBsAg
testing of all pregnant women is now recommended (1,13,14). Universal
prenatal testing would identify an estimated 22,000 HBsAg-positive women and
could prevent at least 6,000 chronic HBV infections annually (3). Screening
and vaccination programs for women and infants receiving care in the public
sector have already been initiated through state immunization projects.
Horizontal transmission of HBV during the first 5 years of life occurs
frequently in populations in which HBV infection is endemic. The risk of
chronic infection is age dependent, ranging from 30% to 60% for children 1-5
years of age (15). Worldwide, it has been recommended that, in popula- tions
in which HBV infection is acquired during childhood, hepatitis B vaccine
should be integrated into routine vaccination schedules for infants, usually
as a part of the World Health Organization's Expanded Programme on
Immunization (16). In the United
States, racial/ethnic groups shown to have high rates of childhood HBV
infection include Alaskan Natives (6,17), Pacific Islanders (18), and
infants of first-generation immigrant mothers from parts of the world where
HBV infection is endemic, especially Asia (19,20). Vaccination
programs to prevent perinatal, childhood, and adult HBV infections among
Alaskan Natives were begun in late 1982; as a result, the incidence of acute
hepatitis B in this population has declined by over 99% (6). Hepatitis B
vaccine was integrated into vaccination schedules for infants in American
Samoa beginning in 1986 and by 1990 was incorporated into the schedules of
the remaining Pacific Islands under U.S. jurisdiction.
Each year, approximately 150,000 infants are born to women who have
immigrated to the United States from areas of the world where HBV infection
is highly endemic (3). Children born to HBsAg-positive mothers can be
identified through prenatal screening programs. However, children born to
HBsAg-negative immigrant mothers are still at high risk of acquiring HBV
infection, usually from other HBV carriers in their families or communities
(3,19,20). Infections among these children can be prevented by making
hepatitis B vaccine part of their routine infant vaccinations (1).
Infections among Adolescents and Adults
In the United States most persons with hepatitis B acquire the infection
as adolescents or adults. Several specific modes of transmission have been
identified, including sexual contact, especially among homosexual men and
persons with multiple heterosexual partners; parenteral drug use;
occupational exposures; household contact with a person who has an acute
infection or with a chronic carrier; receipt of certain blood products; and
hemodialysis. However, over one-third of patients with acute hepatitis B do
not have readily identifiable risk factors (1,2).
The rates of HBV infection differ significantly among various racial and
ethnic groups (2,21). For example, the prevalence of infection among
adolescents and adults has been shown to be threefold to fourfold greater
for blacks than for whites and to be associated with serologic evidence of
previous infection with syphilis (21,22).
Efforts to vaccinate persons in the major risk groups have had limited
success. For example, programs directed at injecting drug users failed to
motivate them to receive three doses of vaccine (CDC, unpublished data).
Health-care providers are often not aware of groups at high risk of HBV
infection and frequently do not identify candidates for vaccination during
routine health-care visits (CDC, unpublished data). In addition, there has
been limited vaccination of susceptible household and sexual contacts of
HBsAg carriers identified in screening programs for blood donors (23).
Hepatitis B vaccination of health-care workers appears to have resulted in a
substantial decrease in the rate of disease in this group, but has had
little effect on overall rates of hepatitis B (2). Moreover, to achieve
widespread vaccination of persons at occupational risk, regulations have had
to be developed to ensure implementation of vaccination programs (24).
Educational programs to reduce parenteral drug use and unprotected sexual
activity are important components of the strategy to prevent infection with
the human immunodeficiency virus (HIV), which causes acquired
immunodeficiency syndrome. These programs appear to have reduced the risk of
HBV infections among homosexual men but have not had an impact on hepatitis
B attributable to parenteral drug use or heterosexual trans- mission (2).
Educational efforts alone are not likely to fully eliminate the high-risk
behaviors responsible for HBV transmission.
EPIDEMIOLOGY AND PREVENTION OF HEPATITIS DELTA VIRUS INFECTION
Hepatitis delta virus (HDV) is a defective virus that causes infection
only in the presence of active HBV infection (25). HDV infection occurs as
either coinfection with HBV or superinfection of an HBV carrier. Coinfec-
tion usually resolves; superinfection, however, frequently causes chronic
HDV infection and chronic active hepatitis. Both types of infection may
cause fulminant hepatitis.
Routes of transmission are similar to those of HBV. In the United States,
HDV infection most commonly affects persons at high risk of HBV infection,
particularly injecting drug users and persons receiving clotting factor
concentrates (26). Preventing acute and chronic HBV infection of susceptible
persons will also prevent HDV infection.
STRATEGY TO ELIMINATE HEPATITIS B VIRUS TRANSMISSION
A comprehensive strategy to prevent HBV infection, acute hepatitis B, and
the sequelae of HBV infection in the United States must eliminate
transmission that occurs during infancy and childhood, as well as during
adolescence and adulthood. In the United States it has become evident that
HBV transmission cannot be prevented through vaccinating only the groups at
high risk of infection. No current medical treatment will reliably eliminate
chronic HBV infection and thus eliminate the source of new infections in
susceptible persons (27). Therefore, new infections can be prevented only by
immunizing susceptible persons with hepatitis B vaccine. Routine visits for
prenatal and well-child care can be used to target hepatitis B prevention. A
comprehensive prevention strategy includes a) prenatal testing of pregnant
women for HBsAg to identify newborns who require immunoprophylaxis for the
prevention of perinatal infection and to identify household contacts who
should be vaccinated, b) routine vaccin- ation of children born to HBsAg-negative
mothers, c) vaccination of certain adolescents, and d) vaccination of adults
at high risk of infection.
Infants and children can receive hepatitis B vaccine during routine
health-care visits; no additional visits would be required. Costs include
that of the vaccine and the incremental expense associated with delivering
an additional vaccine during a scheduled health-care visit. Implementation
of this immunization strategy would be greatly facilitated by the develop-
ment and use of multiple-antigen vaccines (e.g., diphtheria-tetanus-
pertussis {DTP}/hepatitis B, Haemophilus influenzae type b conjugate/
hepatitis B). These vaccines would reduce the number of injections received
by the infant, reduce the cost of administration, and greatly facilitate
widespread vaccine delivery.
Since most HBV infections occur among adults, disease control could be
accelerated by vaccinating emerging at-risk populations, such as adoles-
cents and susceptible contacts of chronic HBV carriers. The recommendation
for universal infant vaccination neither precludes vaccinating adults
identified to be at high risk of infection nor alters previous recommen-
dations for postexposure prophylaxis for hepatitis B (1).
The reduction in acute hepatitis B and hepatitis B-associated chronic
liver disease resulting from universal infant vaccination may not become
apparent for a number of years. However, universal HBsAg screening of
pregnant women to prevent perinatal HBV infection has been shown to be cost
saving (28, CDC, unpublished data), and the estimated cost of universal
hepatitis B vaccination for infants is less than the direct medical and
work-loss costs associated with the estimated 5% lifetime risk of infection
(CDC, unpublished data). Currently, the cost of an infant's dose of
hepatitis B vaccine delivered in the public sector is about the same as each
of the other childhood vaccinations. Vaccinating adolescents and adults is
substantially more expensive because of the higher vaccine cost and the
higher implementation costs of delivering vaccine to target populations. In
the long term, universal infant vaccination would eliminate the need for
vaccinating adolescents and high-risk adults.
PROPHYLAXIS AGAINST HEPATITIS B VIRUS INFECTION
Two types of products are available for prophylaxis against HBV
infection. Hepatitis B vaccine, which provides long-term protection against
HBV infection, is recommended for both preexposure and postexposure
prophylaxis. HBIG provides temporary protection (i.e., 3-6 months) and is
indicated only in certain postexposure settings.
Hepatitis B Immune Globulin
HBIG is prepared from plasma known to contain a high titer of antibody
against HBsAg (anti-HBs). In the United States, HBIG has an anti-HBs titer
of >100,000 by radioimmunoassay. The human plasma from which HBIG is
prepared is screened for antibodies to HIV; in addition, the process used to
prepare HBIG inactivates and eliminates HIV from the final product. There is
no evidence that HIV can be transmitted by HBIG (29,30).
Hepatitis B Vaccine
Two types of hepatitis B vaccine have been licensed in the United States.
One, which was manufactured from the plasma of chronically infected persons,
is no longer produced in the United States. The currently available vaccines
are produced by recombinant DNA technology.
The recombinant vaccines are produced by using HBsAg synthesized by
Saccharomyces cerevisiae (common bakers' yeast), into which a plasmid
containing the gene for HBsAg has been inserted. Purified HBsAg is obtained
by lysing the yeast cells and separating HBsAg from the yeast components by
biochemical and biophysical techniques. Hepatitis B vaccines are packaged to
contain 10-40 ug of HBsAg protein/mL after adsorption to aluminum hydroxide
(0.5 mg/mL); thimerosal (1:20,000 concentration) is added as a preservative.
Routes and sites of administration.
The recommended series of three intramuscular doses of hepatitis B
vaccine induces a protective antibody response (anti-HBs >=10 milli-inter-
national units {mIU}/mL) in >90% of healthy adults and in >95% of infants,
children, and adolescents (31-33). Hepatitis B vaccine should be admin-
istered only in the deltoid muscle of adults and children or in the antero-
lateral thigh muscle of neonates and infants; the immunogenicity of the
vaccine for adults is substantially lower when injections are administered
in the buttock (34). When hepatitis B vaccine is administered to infants at
the same time as other vaccines, separate sites in the anterolateral thigh
may be used for the multiple injections. This method is preferable to
administering vaccine at sites such as the buttock or deltoid.
Compared with three standard doses admistered intramuscularly, three low
doses of plasma-derived or recombinant vaccine administered intra- dermally
to adults result in lower seroconversion rates (55%-81%) and lower final
titers of anti-HBs (35-38), although four doses of plasma-derived vaccine
administered intradermally have produced responses comparable with vaccine
administered intramuscularly (39). Plasma-derived vaccine admin- istered
intradermally to infants and children does not induce an adequate antibody
response (40). At this time, low-dose intradermal vaccination of adults
should be performed only under research protocol with written informed
consent. Persons who have been vaccinated intradermally should be tested for
anti-HBs. Those with an inadequate response (anti-HBs <10 mIU/ mL) should be
revaccinated with three full doses of vaccine administered intramuscularly.
Intradermal vaccination should not be used for infants or children.
Vaccination during pregnancy.
On the basis of limited experience, there is no apparent risk of adverse
effects to developing fetuses when hepatitis B vaccine is admin- istered to
pregnant women (CDC, unpublished data). The vaccine contains noninfectious
HBsAg particles and should cause no risk to the fetus. HBV infection
affecting a pregnant woman may result in severe disease for the mother and
chronic infection for the newborn. Therefore, neither pregnancy nor
lactation should be considered a contraindication to vaccination of women.
Vaccine Usage
Preexposure prophylaxis
Vaccination schedule and dose. The vaccination schedule most often used
for adults and children has been three intramuscular injections, the second
and third administered 1 and 6 months, respectively, after the first. An
alternate schedule of four doses has been approved for one vaccine that
would allow more rapid induction of immunity. However, for preexposure
prophylaxis, there is no clear evidence that this regimen provides greater
protection than that obtained with the standard three-dose schedule.
Each vaccine has been evaluated to determine the age-specific dose at
which an optimum antibody response is achieved. The recommended dose varies
by product and the recipient's age and, for infants, by the mother's HBsAg
serologic status (Table_1). In general, the
vaccine dose for children and adolescents is 50%-75% lower than that
required for adults (Table_1).
Incorporating hepatitis B vaccine into childhood vaccination schedules
may require modifications of previously recommended schedules. However, a
protective level of anti-HBs (>=10 mIU/mL) was achieved when hepatitis B
vaccine was administered in a variety of schedules, including those in which
vaccination was begun soon after birth (5,8,41).
In a three-dose schedule, increasing the interval between the first and
second doses of hepatitis B vaccine has little effect on immunogenicity or
final antibody titer. The third dose confers optimal protection, acting as a
booster dose. Longer intervals between the last two doses (4-12 months)
result in higher final titers of anti-HBs (42,43). Several studies have
shown that the currently licensed vaccines produce high rates of serocon-
version (>95%) and induce adequate levels of anti-HBs when administered to
infants at birth, 2 months, and 6 months of age or at 2 months, 4 months,
and 6 months of age (CDC, Merck Sharpe & Dohme, SmithKline Beecham, unpub-
lished data). When the vaccine is administered in four doses at 0, 1, 2, and
12 months, the last dose is necessary to ensure the highest final antibody
titer.
When hepatitis B vaccine has been administered at the same time as other
vaccines, no interference with the antibody response of the other vaccines
has been demonstrated (44).
If the vaccination series is interrupted after the first dose, the second
dose should be administered as soon as possible. The second and third doses
should be separated by an interval of at least 2 months. If only the third
dose is delayed, it should be administered when convenient.
The immune response when one or two doses of a vaccine produced by one
manufacturer are followed by subsequent doses from a different manufacturer
has been shown to be comparable with that resulting from a full course of
vaccination with a single vaccine.
Larger vaccine doses or an increased number of doses are required to
induce protective antibody in a high proportion of hemodialysis patients
(45,46) and may also be necessary for other immunocompromised persons (e.g.,
those who take immunosuppressive drugs or who are HIV positive), although
few data are available concerning response to higher doses of vaccine by
these patients (47).
Prevaccination testing for susceptibility. Susceptibility testing is not
indicated for immunization programs for children or for most adoles- cents
because of the low rate of HBV infection and the relatively low cost of
vaccine. For adults, the decision to do prevaccination testing should
include an analysis of cost effectiveness because of the higher cost of the
vaccine. Testing for prior infection should be considered for adults in risk
groups with high rates of HBV infection (e.g., injecting drug users,
homosexual men, and household contacts of HBV carriers). The decision for
testing should be based on whether the costs of testing balance the costs of
vaccine saved by not vaccinating already-infected persons. Estimates of the
cost effectiveness of testing depend on three variables: the cost of
vaccination, the cost of testing for susceptibility, and the expected
prevalence of immune persons. If susceptibility testing is being considered,
careful attention should also be given to the likelihood of patient
follow-up and vaccine delivery.
For routine testing, only one antibody test is necessary (antibody either
to the core antigen {anti-HBc} or anti-HBs). Anti-HBc testing identifies all
previously infected persons, including HBV carriers, but does not
differentiate carriers and non-carriers. The presence of anti-HBs identifies
previously infected persons, except for HBV carriers. Neither test has a
particular advantage for groups expected to have HBV carrier rates <2%, such
as health-care workers. Anti-HBc may be preferable so that unnecessary
vaccination of HBV carriers can be avoided in groups with high carrier
rates.
Postvaccination testing for serologic response. Such testing is not
necessary after routine vaccination of infants, children, or adolescents.
Testing for immunity is advised only for persons whose subsequent clinical
management depends on knowledge of their immune status (e.g., infants born
to HBsAg-positive mothers, dialysis patients and staff, and persons with HIV
infection). Postvaccination testing should also be considered for persons at
occupational risk who may have exposures from injuries with sharp
instruments, because knowledge of their antibody response will aid in
determining appropriate postexposure prophylaxis. When necessary, postvac-
cination testing should be performed from 1 to 6 months after completion of
the vaccine series. Testing after immunoprophylaxis of infants born to HBsAg-positive
mothers should be performed from 3 to 9 months after the completion of the
vaccination series (see section on Postexposure prophylaxis).
Revaccination of nonresponders. When persons who do not respond to the
primary vaccine series are revaccinated, 15%-25% produce an adequate
antibody response after one additional dose and 30%-50% after three
additional doses (48). Therefore, revaccination with one or more additional
doses should be considered for persons who do not respond to vaccination
initially.
Postexposure prophylaxis
After a person has been exposed to HBV, appropriate immunoprophylactic
treatment can effectively prevent infection. The mainstay of postexposure
immunoprophylaxis is hepatitis B vaccine, but in some settings the addition
of HBIG will provide some increase in protection.
Table_2 provides a guide to recommended treatment for various HBV
exposures.
Transmission of perinatal HBV infection can be effectively prevented if
the HBsAg-positive mother is identified and if her infant receives appro-
priate immunoprophylaxis. Hepatitis B vaccination and one dose of HBIG,
administered within 24 hours after birth, are 85%-95% effective in
preventing both HBV infection and the chronic carrier state (4,5,8).
Hepatitis B vaccine administered alone in either a three-dose or four-dose
schedule (Table_1), beginning within 24 hours
after birth, is 70%-95% effective in preventing perinatal HBV infections
(8,41). The infants of women admitted for delivery who have not had prenatal
HBsAg testing pose problems in clinical management. Initiating hepatitis B
vaccination at birth for infants born to these women will provide adequate
postexposure prophylaxis if the mothers are indeed HBsAg positive. The few
infections not prevented by either of these treatment regimens were most
likely acquired in utero or may be due to very high levels of maternal
HBV-DNA (49).
Serologic testing of infants who receive immunoprophylaxis to prevent
perinatal infection should be considered as an aid in the long-term medical
management of the few infants who become HBV carriers. Testing for anti-HBs
and HBsAg at 9-15 months of age will determine the success of the therapy
and, in the case of failure, will identify HBV carriers or infants who may
require revaccination.
Recommendations for postexposure prophylaxis in circumstances other than
the perinatal period (Table_2) have been
addressed in a previous statement and are reprinted as Appendix A to this
document.
Vaccine Efficacy and Booster Doses
Clinical trials of the hepatitis B vaccines licensed in the United States
have shown that they are 80%-95% effective in preventing HBV infection and
clinical hepatitis among susceptible children and adults (5,33,41,50). If a
protective antibody response develops after vaccination, vaccine recipients
are virtually 100% protected against clinical illness.
The duration of vaccine-induced immunity has been evaluated in long- term
follow-up studies of both adults and children (48,51). Only the
plasma-derived hepatitis B vaccine has been evaluated because it has had the
longest clinical use; however, on the basis of comparable immunogen- icity
and short-term efficacy, similar results would be expected with recombinant
vaccines. The magnitude of the antibody response induced by the primary
vaccination series is predictive of antibody persistence, and a logarithmic
decline of antibody levels occurs over time. Among young adults (homosexual
men and Alaskan Eskimos) who initially responded to a three- dose vaccine
series, loss of detectable antibody has ranged from 13% to 60% after 9 years
of follow-up. For children vaccinated after the first year of life, the rate
of antibody decline has been lower than for adults (51). The peak antibody
titers for infants are lower than those for children immunized after 12
months of age, but the rate of antibody decline is comparable with that
observed for adults in the same population.
Long-term studies of healthy adults and children indicate that immuno-
logic memory remains intact for at least 9 years and confers protection
against chronic HBV infection, even though anti-HBs levels may become low or
decline below detectable levels (48,51,52). In these studies, the HBV
infections were detected by the presence of anti-HBc. No episodes of
clinical hepatitis were reported and HBsAg was not detected, although brief
episodes of viremia may not have been detected because of infrequent
testing. The mild, inapparent infections among persons who have been
previously vaccinated should not produce the sequelae associated with
chronic HBV infection and should provide lasting immunity. In general,
follow-up studies of children vaccinated at birth to prevent perinatal HBV
infection have shown that a continued high level of protection from chronic
HBV infections persists at least 5 years (52,53).
For children and adults whose immune status is normal, booster doses of
vaccine are not recommended, nor is serologic testing to assess antibody
levels necessary. The possible need for booster doses will be assessed as
additional information becomes available. For hemodialysis patients,
vaccine-induced protection may be less complete and may persist only as long
as antibody levels are >=10 mIU/mL. For these patients, the need for booster
doses should be assessed by annual antibody testing, and a booster dose
should be administered when antibody levels decline to <10 mIU/mL.
Vaccine Side Effects and Adverse Reactions
Hepatitis B vaccines have been shown to be safe when administered to both
adults and children. Over 4 million adults have been vaccinated in the
United States, and at least that many children have received hepatitis B
vaccine worldwide.
Vaccine-associated side effects
Pain at the injection site (3%-29%) and a temperature greater than 37.7 C
(1%-6%) have been among the most frequently reported side effects among
adults and children receiving vaccine (5,31-33,50). In placebo-controlled
studies, these side effects were reported no more frequently among vaccinees
than among persons receiving a placebo (33,50). Among children receiving
both hepatitis B vaccine and DTP vaccine, these mild side effects have been
observed no more frequently than among children receiving DTP vaccine alone.
Serious adverse events
In the United States, surveillance of adverse reactions has shown a
possible association between Guillain-Barre syndrome (GBS) and receipt of
the first dose of plasma-derived hepatitis B vaccine (54, CDC unpublished
data). GBS was reported at a very low rate (0.5/100,000 vaccinees), no
deaths were reported, and all reported cases were among adults. An estimated
2.5 million adults received one or more doses of recombinant hepatitis B
vaccine during the period 1986-1990. Available data from reporting systems
for adverse events do not indicate an association between receipt of
recombinant vaccine and GBS (CDC, unpublished data).
Until recently, large-scale hepatitis B vaccination programs for infants
(e.g., Taiwan, Alaska, and New Zealand) have primarily used plasma- derived
hepatitis B vaccine. No association has been found between vaccin- ation and
the occurrence of severe adverse events, including seizures and GBS (55, B.
McMahon and A. Milne, unpublished data). However, systematic surveillance
for adverse reactions has been limited in these populations, and only a
small number of children have received recombinant vaccine. Any presumed
risk of adverse events possibly associated with hepatitis B vaccination must
be balanced against the expected risk of acute and chronic liver disease
associated with the current 5% lifetime risk of HBV infection in the United
States. It is estimated that, for each U.S. birth cohort, 2,000-5,000
persons will die from HBV-related liver disease.
As hepatitis B vaccine is introduced for routine vaccination of infants,
surveillance for vaccine-associated adverse events will continue to be an
important part of the program in spite of the current record of safety. Any
adverse event suspected to be associated with hepatitis B vaccination should
be reported to the Vaccine Adverse Event Reporting System (VAERS). VAERS
forms can be obtained by calling 1-800-822-7967.
RECOMMENDATIONS
Prevention of Perinatal Hepatitis B Virus Infection
- All pregnant women should be routinely tested for HBsAg during an
early prenatal visit in each pregnancy, preferably at the same time other
routine prenatal laboratory testing is done. HBsAg testing should be
repeated late in the pregnancy for women who are HBsAg negative but who
are at high risk of HBV infection (e.g., injecting drug users, those with
intercurrent sexually transmitted diseases) or who have had clinically
apparent hepatitis. Tests for other HBV markers are not necessary for the
purpose of maternal screening. However, HBsAg- positive women identified
during screening may have HBV-related liver disease and should be
evaluated (56).
- Infants born to mothers who are HBsAg positive should receive the
appropriate doses of hepatitis B vaccine (Table_1)
and HBIG (0.5 mL) within 12 hours of birth. Both should be administered by
intra- muscular injection. Hepatitis B vaccine should be administered
concur- rently with HBIG but at a different site. Subsequent doses of
vaccine should be administered according to the recommended schedule (Table_3).
- Women admitted for delivery who have not had prenatal HBsAg testing
should have blood drawn for testing. While test results are pending, the
infant should receive hepatitis B vaccine within 12 hours of birth, in a
dose appropriate for infants born to HBsAg-positive mothers (Table_1).
- If the mother is later found to be HBsAg positive, her infant should
receive the additional protection of HBIG as soon as possible and within
7 days of birth, although the efficacy of HBIG administered after 48
hours of age is not known (57). If HBIG has not been administered, it is
important that the infant receive the second dose of hepatitis B vaccine
at 1 month and not later than 2 months of age because of the high risk
of infection. The last dose should be administered at age 6 months (Table_3).
*
- If the mother is found to be HBsAg negative, her infant should
continue to receive hepatitis B vaccine as part of his or her routine
vaccinations (Table_3 and
Table_4), in the dose appropriate for
infants born to HBsAg-negative mothers (Table_1).
- In populations in which screening pregnant women for HBsAg is not
feasible, all infants should receive their first dose of hepatitis B
vaccine within 12 hours of birth, their second dose at 1-2 months of age,
and their third dose at 6 months of age as a part of their childhood
vaccinations and well-child care (Table_3).
- Household contacts and sex partners of HBsAg-positive women identified
through prenatal screening should be vaccinated. The decision to do
prevaccination testing of these contacts to determine susceptibility to
HBV infection should be made according to the guidelines in the section "Prevaccination
testing for susceptibility." Hepatitis B vaccine should be administered at
the age-appropriate dose (Table_1) to those
determined to be susceptible or judged likely to be susceptible to
infection.
Universal Vaccination of Infants Born to HBsAg-Negative Mothers
- Hepatitis B vaccination is recommended for all infants, regardless of
the HBsAg status of the mother. Hepatitis B vaccine should be incor-
porated into vaccination schedules for children. The first dose can be
administered during the newborn period, preferably before the infant is
discharged from the hospital, but no later than when the infant is 2
months of age (Table_4). Because the highest
titers of anti-HBs are achieved when the last two doses of vaccine are
spaced at least 4 months apart, schedules that achieve this spacing may be
preferable (Table_4). However, schedules with
2-month intervals between doses, which conform to schedules for other
childhood vaccines, have been shown to produce a good antibody response (Table_4)
and may be appropriate in populations in which it is difficult to ensure
that infants will be brought back for all their vaccinations. The develop-
ment of combination vaccines containing HBsAg may lead to other schedules
that will allow optimal use of combined antigens.
- Special efforts should be made to ensure that high levels of hepatitis
B vaccination are achieved in populations in which HBV infection occurs at
high rates among children (Alaskan Natives, Pacific Islanders, and infants
of immigrants from countries in which HBV is endemic).
Vaccination of Adolescents
All adolescents at high risk of infection because they are injecting drug
users or have multiple sex partners (more than one partner/6 months) should
receive hepatitis B vaccine. Widespread use of hepatitis B vaccine is
encouraged. Because risk factors are often not identified directly among
adolescents, universal hepatitis B vaccination of teenagers should be
implemented in communities where injecting drug use, pregnancy among
teenagers, and/or sexually transmitted diseases are common. Adolescents can
be vaccinated in school-based clinics, community health centers, family
planning clinics, clinics for the treatment of sexually transmitted
diseases, and special adolescent clinics.
The 0-, 1-, and 6-month schedule is preferred for vaccinating adoles-
cents with the age-appropriate dose of vaccine (Table_1).
However, the choice of vaccination schedule should take into account the
feasibility of delivering three doses of vaccine over a given period of
time. The use of alternate schedules (e.g., 0, 2, and 4 months) may be
advisable to achieve complete vaccination.
Vaccination of Selected High-Risk Groups
Efforts to vaccinate persons at high risk of HBV infection should follow
the vaccine doses shown in Table_1. High-risk
groups for whom vaccination is recommended include:
- Persons with occupational risk. HBV infection is an occupational
hazard for health-care workers and for public-safety workers who have
exposure to blood in the workplace (24,58). The risk of acquiring HBV
infections from occupational exposures depends on the frequency of
percutaneous and permucosal exposure to blood or blood-contaminated body
fluids. Any health-care or public-safety worker may be at risk for HBV
exposure, depending on the tasks he or she performs. Workers who perform
tasks involving contact with blood or blood-contaminated body fluid should
be vaccinated (24,58, 59). For public-safety workers whose exposure to
blood is infrequent, timely postexposure prophylaxis should be considered
rather than routine preexposure vaccination.
For persons in health-care fields, vaccination should be completed
during training in schools of medicine, dentistry, nursing, laboratory
technology, and other allied health professions, before trainees have
their first contact with blood.
- Clients and staff of institutions for the developmentally disabled.
Susceptible clients in institutions for the developmentally disabled, as
well as staff who work closely with clients, should be vaccinated.
Susceptible clients and staff who live or work in smaller residential
settings with known HBV carriers should also receive hepatitis B vaccine.
Clients discharged from residential institutions into community programs
should be screened for HBsAg so that appropriate measures can be taken to
prevent HBV trans- mission. These measures should include both
environmental controls and appropriate use of vaccine.
Staff of nonresidential day-care programs for the develop- mentally
disabled (e.g., schools, sheltered workshops) attended by known HBV
carriers have a risk of infection comparable with that of health-care
workers and therefore should be vaccinated (60). The risk of infection for
other clients appears to be lower than the risk for staff. Vaccination of
clients in day care programs may be considered. Vaccination of classroom
contacts is strongly encouraged if a classmate who is an HBV carrier
behaves aggres- sively or has special medical problems (e.g., exudative
dermatitis, open skin lesions) that increase the risk of exposure to his
or her blood or serous secretions.
- Hemodialysis patients. Hepatitis B vaccination is recommended for
susceptible hemodialysis patients. Vaccinating patients early in the
course of their renal disease is encouraged because patients with uremia
who are vaccinated before they require dialysis are more likely to respond
to the vaccine (61). Although their serocon- version rates and anti-HBs
titers are lower than those of healthy persons, patients who respond to
vaccination will be protected from infection, and the need for frequent
serologic testing will be reduced (62).
- Recipients of certain blood products. Patients who receive
clotting-factor concentrates have an increased risk of HBV infection and
should be vaccinated as soon as their specific clotting disorder is
identified. Prevaccination testing is recom- mended for patients who have
already received multiple infusions of these products.
- Household contacts and sex partners of HBV carriers. All household and
sexual contacts of persons identified as HBsAg positive should be
vaccinated. The decision to do prevaccination testing to determine
susceptibility to HBV infection should be made according to the guidelines
described earlier in the section "Prevaccination testing for
susceptibility." Hepatitis B vaccine should be admin- istered at the
age-appropriate dose (Table_1) to those deter-
mined to be susceptible or judged likely to be susceptible to infection.
- Adoptees from countries where HBV infection is endemic. Adopted or
fostered orphans or unaccompanied minors from countries where HBV
infection is endemic should be screened for HBsAg (3). If the children are
HBsAg positive, other family members should be vaccinated (63).
- International travelers. Vaccination should be considered for persons
who plan to spend more than 6 months in areas with high rates of HBV
infection and who will have close contact with the local population.
Short-term travelers who are likely to have contact with blood (e.g., in a
medical setting) or sexual contact with residents of areas with high or
intermediate levels of endemic disease should be vaccinated. Vaccination
should begin at least 6 months before travel to allow for completion of
the full vaccine series, although a partial series will offer some
protection. The alternate four-dose schedule (see
Table_1) should provide protection if the first three doses can be
delivered before departure.
- Injecting drug users. All injecting drug users who are susceptible to
HBV should be vaccinated as soon as their drug use begins. Because of the
high rate of HBV infection in this population, prevaccination screening
should be considered as outlined in the section "Prevaccination testing
for susceptibility." Injecting drug users known to have HIV infection
should be tested for anti-HBs response after completion of the vaccine
series. Those who do not respond to vaccination should be counseled
accordingly.
- Sexually active homosexual and bisexual men. Susceptible sexually
active homosexual and bisexual men should be vaccinated. Because of the
high rate of HBV infection in this population, prevaccination screening
should be considered as described in the section "Prevac- cination testing
for susceptibility." Men known to have HIV infection should be tested for
anti-HBs response after completion of the vaccine series. Those who do not
respond to vaccination should be counseled accordingly.
- Sexually active heterosexual men and women. Vaccination is recom-
mended for men and women who are diagnosed as having recently acquired
other sexually transmitted diseases, for prostitutes, and for persons who
have a history of sexual activity with more than one partner in the
previous 6 months (2). Most patients seen in clinics for sexually
transmitted diseases should be considered candidates for vaccination.
- Inmates of long-term correctional facilities. Prison officials should
consider undertaking screening and vaccination programs directed at
inmates with histories of high-risk behaviors.
EVOLVING ISSUES IN HEPATITIS B IMMUNIZATION PROGRAMS
Hepatitis B vaccine has now been used extensively throughout the world
and is currently being incorporated into the Expanded Programme on Immuni-
zation of the World Health Organization (16). New information, vaccines, and
technology will have implications for this effort, and adjustments and
changes are expected to occur over the years. Some of the issues that can be
expected to be addressed in clinical and operational studies include the
following:
- In most developing countries with hepatitis B immunization programs,
the first dose of vaccine is administered to all infants soon after birth
to prevent perinatal infections; pregnant women are not screened for HBsAg;
and HBIG is not used (8,16,45). The feasibility and effectiveness of
incorporating this approach into the hepatitis B prevention strategy for
the United States must be evaluated.
- Booster doses of hepatitis B vaccine have not been recommended because
of the persistence of protective efficacy 9 years after vaccination
(48,51). The duration of protective efficacy for adolescents who were
vaccinated during infancy or childhood must be evaluated; the results will
determine future recommendations concerning booster doses.
- Flexible dosage schedules are required to effectively integrate
hepatitis B vaccine into current and future immunization programs for
infants. Schedules may change as optimum dosage and timing are studied and
new information becomes available.
- Multiple-antigen vaccines that incorporate HBsAg as one component are
currently being evaluated. The routine use of these vaccines may alter
childhood vaccination schedules or may result in the administration of
additional doses of certain antigens. However, these vaccines should
greatly facilitate vaccine delivery and minimize the number of injections.
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If a four-dose schedule is used (Table_1 and
Table_3), the second and third doses should be
administered at 1 and 2 months of age, respec- tively, and the fourth dose
at 12-18 months of age.
Table_1
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settings to landscape and use a small font size.
TABLE 1. Recommended doses of currently licensed hepatitis B vaccines
================================================================================================
Recombivax HB * Engerix-B *
------------------ ------------------
Group Dose (ug) (mL) Dose (ug) (mL)
--------------------------------------------------------------------------
Infants of HBsAg + -negative
mothers and children
<11 years 2.5 (0.25) 10 (0.5)
Infants of HBsAg-positive
mothers; prevention of 5 (0.5) 10 (0.5)
perinatal infection
Children and adolescents
11-19 years 5 (0.5) 20 (1.0)
Adults >=20 years 10 (1.0) 20 (1.0)
Dialysis patients and
other immunocompromised
persons 40 (1.0) & 40 (2.0) @
--------------------------------------------------------------------------
* Both vaccines are routinely administered in a three-dose series. Engerix-B has also been
licensed for a four-dose series administered at 0, 1, 2, and 12 months.
+ HBsAg = Hepatitis B surface antigen.
& Special formulation.
@ Two 1.0-mL doses administered at one site, in a four-dose schedule at 0, 1, 2, and 6 months.
================================================================================================
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Table_2
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settings to landscape and use a small font size.
TABLE 2. Guide to postexposure immunoprophylaxis for exposure to hepatitis B virus
====================================================================================
Type of exposure Immunoprophylaxis Reference
-------------------------------------------------------------------------------
Perinatal Vaccination + HBIG * p. 11-12
Sexual -- acute infection HBIG +/- Vaccination Appendix
Sexual -- chronic carrier Vaccination p. 12, 15
Household contact --
chronic carrier Vaccination p. 12, 15
Household contact -- None unless
acute case known exposure Appendix
Household contact -- acute
case, known exposure HBIG +/- vaccination Appendix
Infant (<12 months) --
acute case in primary HBIG + vaccination
care-giver Appendix
Inadvertent -- percutaneous/
permucosal Vaccination +/- HBIG Appendix
-------------------------------------------------------------------------------
* HBIG = Hepatitis B immune globulin.
====================================================================================
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Table_3
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settings to landscape and use a small font size.
TABLE 3. Recommended schedule of hepatitis B immunoprophylaxis to prevent
perinatal transmission of hepatitis B virus infection
======================================================================================================
--------------------------------------------------------------------------------------
Infant born to mother known to be HBsAg * positive
Vaccine dose + Age of infant
First Birth (within 12 hours)
HBIG & Birth (within 12 hours)
Second 1 month
Third 6 months @
Infant born to mother not screened for HBsAg
Vaccine dose ** Age of infant
First Birth (within 12 hours)
HBIG & If mother is found to be HBsAg
positive, administer dose to
infant as soon as possible, not
later than 1 week after birth
Second 1-2 months ++
Third 6 months @
--------------------------------------------------------------------------------------
* HBsAg = Hepatitis B surface antigen.
+ See Table 1 for appropriate vaccine dose.
& Hepatitis B immune globulin (HBIG) -- 0.5 mL administered intramuscularly at a site different
from that used for vaccine.
@ If four-dose schedule (Engerix-B) is used, the third dose is administered at 2 months of age and
the fourth dose at 12-18 months.
** First dose = dose for infant of HBsAg-positive mother (see Table 1). If mother is found to be
HBsAg positive, continue that dose; if mother is found to be HBsAg negative, use appropriate
dose from Table 1.
++ Infants of women who are HBsAg negative can be vaccinated at 2 months of age.
======================================================================================================
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Table_4
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settings to landscape and use a small font size.
TABLE 4. Recommended schedules of hepatitis B vaccination for infants born to
HBsAg * -negative mothers
==============================================================================================
Hepatitis B vaccine Age of infant
----------------------------------------------------------------------------------
Option 1
Dose 1 Birth -- before hospital discharge
Dose 2 1-2 months +
Dose 3 6-18 months +
Option 2
Dose 1 1-2 months +
Dose 2 4 months +
Dose 3 6-18 months +
----------------------------------------------------------------------------------
* HBsAg = Hepatitis B surface antigen.
+ Hepatitis B vaccine can be administered simultaneously with diphtheria-tetanus-pertussis,
Haemophilus influenzae type b conjugate, measles-mumps-rubella, and oral polio vaccines at
the same visit.
==============================================================================================
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