Recommendations of the Immunization Practices Advisory Committee
Update: Prevention of Haemophilus influenzae Type b Disease
Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate)
has
recently been licensed for use in children 18 months of age or
older
for the prevention of Haemophilus influenzae type b (Haemophilus b)
disease. This vaccine consists of Haemophilus b capsular
polysaccharide covalently linked to diphtheria toxoid (conjugate
vaccine).
A previously developed vaccine consisting of the Haemophilus b
capsular polysaccharide alone (polysaccharide vaccine) was shown to
be
effective in Finnish children over 24 months of age (1), the age
group
in which approximately 20% of all invasive Haemophilus b infections
among U.S. children less than 5 years of age can be expected to
occur
(2). A similar, but not identical, polysaccharide vaccine was
licensed
for use in the United States in April 1985 on the basis of data
demonstrating biochemical characteristics and immunogenicity
comparable to the vaccine used in the original Finnish trial (3).
In
that Finnish trial, polysaccharide vaccine was not effective in
children less than 18 months of age. Because of the small sample
size,
efficacy could not be demonstrated in children 18 to 23 months of
age.
Polysaccharide vaccine was immunogenic (as measured by antibody
production) in children 18 to 23 months old, but less so than it
was
in older children (1).
Conjugate vaccine was developed with the ultimate goal of
providing an effective vaccine for infants and younger children.
Preliminary data from a new Finnish study suggest that conjugate
vaccine was 87% effective in preventing Haemophilus b disease when
administered in a three-dose regimen to infants 3 to 6 months of
age
(4). However, licensure of conjugate vaccine for use in infants in
the
United States cannot be considered until this and other efficacy
trials are further evaluated. Since antibody production after
vaccination with conjugate vaccine in children 18 months of age or
older is substantially greater than that after vaccination with
polysaccharide vaccine, conjugate vaccine has been licensed for use
in
these children.
Safety
When conjugate vaccine alone was given to over 1,000 adults and
vaccination with conjugate vaccine in children 18 months of age or
older is substantially greater than that after vaccination with
polysaccharide vaccine, conjugate vaccine has been licensed for use
in
these children.
Safety
When conjugate vaccine alone was given to over 1,000 adults and
children, no serious adverse reactions were observed (5-12). When
conjugate vaccine was given with diphtheria and tetanus toxoid and
pertussis vaccine (DTP) and inactivated polio vaccine (IPV) to
30,000
infants, the rate and extent of serious adverse reactions did not
differ from those seen when DTP was administered alone (4). In one
study of over 500 children 15 to 24 months of age, no significant
difference in local or systemic side effects occurred between
groups
of children vaccinated with either polysaccharide vaccine or
conjugate
vaccine (7). Local reactions were noted for 10.3% of children
receiving polysaccharide vaccine and 12.5% of children receiving
conjugate vaccine, while moderate fever (temperature greater than
39.0
degrees C (greater than 102.2 degrees F) occurred in 1.4% of
children
vaccinated with polysaccharide vaccine and 0.7% of children
vaccinated
with conjugate vaccine.
Immunogenicity
In several studies using different regimens of vaccine
administration, conjugate vaccine has shown greater immunogenicity
than polysaccharide vaccine (5-9,11,12). Response to a single dose
of
either polysaccharide vaccine or conjugate vaccine in children 15
to
24 months of age was specifically addressed in a randomized,
double-
blind study recently completed in the United States (7). More than
90%
of children vaccinated with conjugate vaccine responded with
antibody
levels considered to be protective (0.15 ug/mL), whereas less than
50%
of children vaccinated with polysaccharide vaccine had such a
response. Over 60% of children vaccinated with conjugate vaccine,
but
less than 30% of those vaccinated with polysaccharide vaccine,
produced levels of antibody considered to be indicative of
long-term
protection (1.0 ug/mL).* Children given conjugate vaccine at 15 to
24
months of age had significantly higher levels of antibody to
Haemophilus b polysaccharide 1 year after vaccination than did
children receiving polysaccharide vaccine (8). Conjugate vaccine
recipients responded to a booster dose of either polysaccharide
vaccine or conjugate vaccine with higher geometric mean antibody
levels than did those initially vaccinated with polysaccharide
vaccine
(8).
In another study, children with sickle cell syndromes who
received
conjugate vaccine had higher postvaccination levels of antibody to
Haemophilus b polysaccharide than did similar children given
polysaccharide vaccine (13). The studies to date showing increased
immunogenicity in children less than 18 months of age (5,6,9,11)
suggest that conjugate vaccine may be functioning as a T-cell
dependent antigen. This finding contrasts with the lack of
immunogenicity in infants and the absence of immunologic memory
characteristic of T-cell independent polysaccharide vaccines.
Biological Activity
Several investigators have demonstrated that conjugate vaccine
produces functional activity against Haemophilus b similar to that
produced by polysaccharide vaccine. In one randomized, double-blind
study, adults vaccinated with conjugate vaccine had serum
bactericidal
titers for Haemophilus b at least as high as those of adults
receiving
polysaccharide vaccine (12). In addition, sera from adults
vaccinated
with conjugate vaccine were protective in an infant rat model of
Haemophilus b disease, whereas similarly diluted sera from persons
receiving polysaccharide vaccine showed no protective activity. In
a
separate study, sera from 9- to 14-month-old children given
conjugate
vaccine showed greater opsonic activity against Haemophilus b
organisms than did sera from children vaccinated with
polysaccharide
vaccine (14). Both studies showed a correlation between functional
activity and serum levels of antibody to Haemophilus b
polysaccharide
and suggest that antibody produced in response to conjugate vaccine
is
biologically equivalent to that produced in response to
polysaccharide
vaccine.
The ACIP recommends that all children receive conjugate vaccine
at
18 months of age. The efficacy of conjugate vaccine in children
18
months of age or older has not been determined in field trials.
However, studies comparing antibody production in children
receiving conjugate vaccine with that in children receiving
polysaccharide vaccine suggest that conjugate vaccine is likely
to
be more effective than polysaccharide vaccine. The ACIP
therefore
recommends use of conjugate vaccine in all children vaccinated
against Haemophilus b disease.
While the duration of immunity after a single dose of conjugate
vaccine is unknown at this time, it is expected to be at least
1.5
to 3 years. Until further information is available,
revaccination
is not recommended for children receiving conjugate vaccine at
18
months of age or older.
Vaccination of children more than 24 months of age who have not
yet received Haemophilus b vaccine should be based on risk of
disease. Children considered at high risk for Haemophilus b
disease, including those attending day-care centers, those with
anatomic or functional asplenia (i.e., sickle cell disease or
splenectomy), and those with malignancies associated with
immunosuppression, should receive the vaccine. Although risk of
disease decreases with increasing age, physicians may wish to
vaccinate previously healthy children between 2 and 5 years of
age
to prevent disease that can occur in this group.
Because many children who received polysaccharide vaccine
between
the ages of 18 and 23 months may have had a less than adequate
response to the vaccine, they should be revaccinated with a
single
dose of conjugate vaccine. Revaccination should take place a
minimum of 2 months after the initial dose of polysaccharide
vaccine.
There is no need to routinely revaccinate children who received
polysaccharide vaccine at 24 months of age or older.
Children who had invasive Haemophilus b disease when they were
less than 24 months of age should still receive vaccine
according
to the above recommendations since most children less than 24
months of age fail to develop adequate immunity following
natural
infection (15).
Although increases in serum diphtheria anti-toxin levels can
follow administration of conjugate vaccine, this vaccine should
not be considered an immunizing agent against diphtheria. No
changes in the schedule for administration of diphtheria
toxoid,
customarily given as DTP, should be made secondary to the use
of
conjugate vaccine.
Vaccination with either polysaccharide vaccine or conjugate
vaccine probably does not inhibit asymptomatic carriage of
Haemophilus b organisms. Although vaccinated children may be
protected from invasive disease, they may pass the organism on
to
susceptible children. In addition, no vaccine is 100%
effective.
Therefore, chemoprophylaxis of household or day-care contacts
of
children with Haemophilus b disease should be directed at
vaccinated as well as unvaccinated contacts. Because of the
length
of time necessary to generate an immunologic response to the
vaccines, vaccination does not play a major role in the
management
of patients with Haemophilus b disease or their contacts.
Vaccine
may be given to previously unvaccinated children of appropriate
age to provide protection against future exposure.
Conjugate vaccine and DTP may be given simultaneously at
different
sites. Data are lacking on concomitant administration of
conjugate
vaccine and measles- mumps-rubella (MMR) or oral polio (OPV)
vaccines. However, if the recipient is unlikely to return for
further vaccination, simultaneous administration of all
vaccines
appropriate to the recipient's age and previous vaccination
status
is recommended (including DTP, OPV, MMR, and conjugate
vaccine).
References
Peltola H, Kayhty H, Virtanen M, Makela PH. Prevention of
Hemophilus influenzae type b bacteremic infections with the
capsular polysaccharide vaccine. N Engl J Med 1984;310: 1561-6.
Cochi SL, Broome CV, Hightower AW. Immunization of U.S.
children
with Hemophilus influenzae type b polysaccharide vaccine: a
cost-effectiveness model of strategy assessment. JAMA
1985;253:521-9.
Immunization Practices Advisory Committee. Polysaccharide
vaccine
for prevention of Haemophilus influenzae type b disease. MMWR
1985;34:201-5.
Eskola J, Peltola H, Takala AK, et al. Efficacy of Haemophilus
influenzae type b polysaccharide-diphtheria toxoid conjugate
vaccine in infancy. N Engl J Med 1987;317: 717-22.
Lepow ML, Samuelson JS, Gordon LK. Safety and immunogenicity of
Haemophilus influenzae type b-polysaccharide diphtheria toxoid
conjugate vaccine in infants 9 to 15 months of age. J Pediatr
1985;106:185-9.
Kayhty H, Eskola J, Peltola H, Stout MG, Samuelson JS, Gordon
LK.
Immunogenicity in infants of a vaccine composed of Haemophilus
influenzae type b capsular polysaccharide mixed with DPT or
conjugated to diphtheria toxoid. J Infect Dis 1987;155:100-6.
Berkowitz CD, Ward JI, Meier K, et al. Safety and
immunogenicity
of Haemophilus influenzae type b polysaccharide and
polysaccharide
diphtheria toxoid conjugate vaccines in children 15 to 24
months
of age. J Pediatr 1987;110:509-14.
Berkowitz CD, Ward JI, Hendley JO, et al. Persistence of
antibody
(AB) to Haemophilus influenzae type b (Hib) and response to PRP
and PRP-D booster immunization in children initially immunized
with either vaccine at 15 to 24 months (Abstract no. 889).
Pediatr
Res 1987;21:321A.
Eskola J, K|$$|Adayhty H, Peltola H, et al. Antibody levels
achieved in infants by course of Haemophilus influenzae type b
polysaccharide/diphtheria toxoid conjugate vaccine. Lancet
1985;1:1184-6.
Lepow ML, Barkin RM, Berkowitz CD, et al. Safety and
Res 1987;21:321A.
Eskola J, K|$$|Adayhty H, Peltola H, et al. Antibody levels
achieved in infants by course of Haemophilus influenzae type b
polysaccharide/diphtheria toxoid conjugate vaccine. Lancet
1985;1:1184-6.
Lepow ML, Barkin RM, Berkowitz CD, et al. Safety and
immunogenicity of Haemophilus influenzae type b
polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) in
infants. J Infect Dis 1987;156:591-6.
Lepow ML, Randolph M, Cimma R, et al. Persistence of antibody
and
response to booster dose of Haemophilus influenzae type b
polysaccharide diphtheria toxoid conjugate vaccine in infants
immunized at 9 to 15 months of age. J Pediatr 1986;108:882-6.
Granoff DM, Boies EG, Munson RS. Immunogenicity of Haemophilus
influenzae type b polysaccharide-diphtheria toxoid conjugate
vaccine in adults. J Pediatr 1984;105:22-7.
Frank AL, Labotka RJ, Frisone LR, et al. H. influenza b
immunization of children with sickle cell diseases (Abstract
no.
906). Pediatr Res 1987;21:324A.
Cates KL. Serum opsonic activity for Haemophilus influenzae
type b
in infants immunized with polysaccharide-protein conjugate
vaccines. J Infect Dis 1985;152:1076-7.
Immunization Practices Advisory Committee. Update: prevention
of
Haemophilus influenzae type b disease. MMWR
1986;35:170-4,179-80.
*It should be noted that three of four lots of polysaccharide
vaccine
used in this study had been heat-sized, a process which may reduce
immunogenicity. However, children receiving non-heat- sized
polysaccharide vaccine also had postimmunization levels of
antibodies
to Haemophilus b polysaccharide that were lower than those observed
in
children vaccinated with conjugate vaccine. In another study in
which
vaccine recipients were tested at 1 month and again at 1 year after
completion of the immunization series, 9- to 15-month-old children
who
had received two doses of conjugate vaccine had significantly
higher
titers of antibody to Haemophilus b polysaccharide than did similar
children who had received two doses of non-heat-sized
polysaccharide
vaccine (5).
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