Download 4.3 Haemophilus influenzae type b

4.3 HAEMOPHILUS INFLUENZAE TYPE B
4.3.1 Bacteriology
Haemophilus influenzae is a Gram-negative coccobacillus that is a normal part of upper respiratory tract flora. It can be
isolated in two forms: capsular and non-capsular. Strains isolated from respiratory tract specimens, such as sputum and
middle ear or sinus fluid, usually do not have a capsule, and are known as non-typeable Haemophilus influenzae
(NTHi). Six capsular types (a to f) have been described and, before the introduction of vaccination against Haemophilus
influenzae type b (Hib), almost all H. influenzae isolates from sterile sites (blood, cerebrospinal fluid, joint or pleural
fluid) were of the b capsular type.1
Before Hib immunisation, invasive disease caused by Hib rarely occurred after the age of 5 years. This was because the
prevalence of antibody to Hib progressively increased from the age of 2 years, thought to be related to exposure to Hib
(or cross-reacting organisms) colonising the nasopharynx or other sites. Children <2 years of age are usually unable to
mount an antibody response to the type b capsular polysaccharide, even after invasive disease. 2
4.3.2 Clinical features
Clinical categories of invasive disease caused by Hib include meningitis, epiglottitis and a range of other infections
such as septic arthritis, cellulitis and pneumonia.3 Hib is rarely isolated from the blood without a focal infection such as
the above being evident or developing subsequently. The classical clinical signs of meningitis – neck stiffness and
photophobia – are often not detected in infants, who present with drowsiness, poor feeding and high fever. Epiglottitis
(inflammation of the epiglottis) presents with respiratory obstruction, associated with soft stridor and often drooling in a
pale, febrile, anxious child who remains upright to maximise his or her airway. Meningitis and epiglottitis are almost
invariably fatal without appropriate treatment. The case-fatality rate for Hib meningitis in developed countries is at least
3% even with treatment, and 15 to 30% of survivors have permanent neurological sequelae. 1 There are no specific
clinical features of any of the focal infections due to Hib that enable them to be differentiated from those due to other
organisms. However, before the introduction of Hib vaccines, epiglottitis was due to Hib in over 95% of cases.4 Nontypeable Haemophilus influenzae strains may occasionally cause invasive disease, but are a common cause of otitis
media in children and bronchitis in adults.2 Hib vaccines are not effective in preventing NTHi infections.
4.3.3 Epidemiology
Since Hib vaccines were included in the routine vaccination schedule in 1993, there has been a reduction of more than
95% in notified cases of Hib disease. In 1992 alone, 549 Hib cases were reported; in contrast, during the 2 years from
January 2006 to December 2007, a total of 39 Hib infections were notified in Australia, giving an average annual
notification rate of 0.09 per 100 000 population.5-7 The reduction in the incidence of Hib disease following routine
vaccination has been particularly marked in Indigenous children, although absolute rates remain substantially higher
than those in the non-Indigenous population.8-10 Similar impressive reductions in Hib disease have been seen in other
countries with routine childhood vaccination.11,12 Since Hib disease has become relatively rare, cases of epiglottitis can
no longer be assumed to be due to H. influenzae type b and, moreover, even when H. influenzae is isolated from a
normally sterile site, it may not be type b. Thus, laboratory confirmation of H. influenzae infection and serotype should
always be sought before vaccination failure is assumed.13,14
4.3.4 Vaccines
Four types of conjugate Hib vaccines have been developed, each containing the Hib capsular polysaccharide
polyribosylribitol phosphate (PRP) conjugated to a different carrier protein. Of these, PRP-OMP (conjugated to the
outer membrane protein of Neisseria meningitidis), PRP-T (conjugated to tetanus toxoid) and HbOC (conjugated to a
mutant diphtheria toxoid) elicit antibody responses associated with protection of children against Hib. The fourth
vaccine type, PRP-D (conjugated to diphtheria toxoid), was less immunogenic and found to be poorly protective in
high-risk populations, such as Indigenous children.15 PRP-T has subsequently been included in a number of
combination vaccines including DTPa-hepB-IPV-Hib and Hib-MenCCV. Hib-MenCCV (which contains
meningococcal serogroup C and Haemophilus influenzae type b antigens) has been used under the NIP since July 2013.
The Hib PRP-T component in Hib-MenCCV has similar immunogenicity and safety to monovalent PRP-T Hib
vaccine.16-21
In Australia, the differing epidemiology of invasive Hib disease by ethnicity and region has determined the
recommendations for Hib vaccine choice (refer to 3.1 Vaccination for Aboriginal and Torres Strait Islander people).
There have been four distinct eras of implementation of the Hib vaccination program for Australian children, which are
described in detail elsewhere.10
Some Hib combination vaccines containing acellular pertussis are known to produce lower Hib antibody responses than
similar formulations containing whole-cell pertussis.22 When administered according to the United Kingdom’s schedule
as 3 primary doses at 2, 3 and 4 months of age without a booster, their use has been associated with an increased risk of
vaccine failure.23 In other European countries that routinely give a 4th dose around the time of the 1st birthday, as
Australia does, no loss of effectiveness has been observed. 24,25
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Monovalent Hib vaccines

Act-HIB – Sanofi-Aventis Australia Pty Ltd (PRP-T). Lyophilised powder in a monodose vial with a pre-filled
diluent syringe. Each 0.5 mL reconstituted dose contains 10 µg Hib capsular polysaccharide (polyribosyl-ribitolphosphate [PRP]) conjugated to 18–30 µg tetanus protein.

Hiberix – GlaxoSmithKline Australia Pty Ltd (PRP-T). Lyophilised pellet in a monodose vial with separate
diluent. Each 0.5 mL reconstituted dose contains 10 µg Hib capsular polysaccharide (PRP) conjugated to 30 µg
tetanus toxoid; lactose.

Liquid PedvaxHIB – CSL Limited/Merck & Co Inc (PRP-OMP). Each 0.5 mL monodose vial contains 7.5 µg
Hib capsular polysaccharide (PRP) conjugated to 125 µg Neisseria meningitidis outer membrane protein (OMP)
complex; 225 µg aluminium as aluminium hydroxide; 35 µg borax.
Combination vaccines that contain Hib

Hexaxim – Sanofi-Aventis Australia Pty Ltd (DTPa-hepB-IPV-Hib; diphtheria-tetanus-acellular pertussishepatitis B-inactivated poliovirus-Haemophilus influenzae type b). Each 0.5 mL pre-filled syringe contains
≥20 IU diphtheria toxoid, ≥40 IU tetanus toxoid, 25 µg pertussis toxoid (PT), 25 µg filamentous haemagglutinin
(FHA), 10 µg recombinant HBsAg, 40 D-antigen units inactivated poliovirus type 1 (Mahoney), 8 D-antigen
units type 2 (MEF-1), 32 D-antigen units type 3 (Saukett) and 12 µg purified Hib capsular polysaccharide (PRP)
conjugated to 22–36 µg tetanus toxoid, adsorbed onto 0.6 mg aluminium as aluminium hydroxide. May contain
traces of glutaraldehyde, formaldehyde, neomycin, streptomycin and polymyxin B.

Infanrix hexa – GlaxoSmithKline Australia Pty Ltd (DTPa-hepB-IPV-Hib; diphtheria-tetanus-acellular
pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b [PRP-T]). The vaccine consists of
both a 0.5 mL pre-filled syringe containing ≥30 IU diphtheria toxoid, ≥40 IU tetanus toxoid, 25 µg PT, 25 µg
FHA, 8 µg pertactin (PRN), 10 µg recombinant HBsAg, 40 D-antigen units inactivated poliovirus type 1
(Mahoney), 8 D-antigen units type 2 (MEF-1) and 32 D-antigen units type 3 (Saukett), adsorbed onto aluminium
hydroxide/phosphate; traces of formaldehyde, polysorbate 80, polysorbate 20, polymyxin and neomycin; and a
vial containing a lyophilised pellet of 10 µg purified Hib capsular polysaccharide (PRP) conjugated to 20–40 µg
tetanus toxoid. May contain yeast proteins.

Menitorix – GlaxoSmithKline Australia Pty Ltd (Hib-MenCCV; Haemophilus influenzae type b [PRP-T]meningococcal serogroup C–tetanus toxoid conjugate). Lyophilised powder in a monodose vial with a pre-filled
diluent syringe. Each 0.5 mL reconstituted dose contains 5 µg Hib capsular polysaccharide (PRP) conjugated to
12.5 µg tetanus toxoid, and 5 µg Neisseria meningitidis serogroup C polysaccharide conjugated to 5 µg tetanus
toxoid; traces of trometamol and sucrose.

Pediacel – Sanofi-Aventis Australia Pty Ltd (DTPa-IPV-Hib; diphtheria-tetanus-acellular pertussis-inactivated
poliovirus-Haemophilus influenzae type b [PRP-T]). Each 0.5 mL monodose vial contains ≥30 IU diphtheria
toxoid, ≥40 IU tetanus toxoid, 20 µg PT, 20 µg FHA, 3 µg PRN, 5 µg pertussis fimbriae (FIM) 2+3, 40 Dantigen units inactivated poliovirus type 1 (Mahoney), 8 D-antigen units type 2 (MEF-1) and 32 D-antigen units
type 3 (Saukett), 10 µg Hib capsular polysaccharide (PRP) conjugated to 20 µg tetanus protein; 1.5 mg
aluminium phosphate; ≤50 ng bovine serum albumin; phenoxyethanol as preservative; traces of formaldehyde,
glutaraldehyde, polysorbate 80, polymyxin, neomycin and streptomycin.
4.3.5 Transport, storage and handling
Transport according to National vaccine storage guidelines: Strive for 5.26 Store at +2°C to +8°C. Do not freeze. Protect
from light.
Act-HIB must be reconstituted by adding the entire contents of the diluent syringe to the vial and shaking until the
powder is completely dissolved. Reconstituted vaccine must be used immediately.
Hiberix must be reconstituted by adding the entire contents of the diluent container to the vial and shaking until the
pellet is completely dissolved. Reconstituted vaccine should be used as soon as practicable. If storage is necessary, hold
at +2°C to +8°C for not more than 24 hours.
Infanrix hexa must be reconstituted by adding the entire contents of the syringe to the vial and shaking until the pellet is
completely dissolved. Reconstituted vaccine should be used as soon as practicable. If storage is necessary, hold at room
temperature for not more than 8 hours.
Menitorix must be reconstituted by adding the entire contents of the diluent syringe to the vial and shaking until the
powder is completely dissolved. Reconstituted vaccine should be used as soon as practicable. If storage is necessary,
hold at +2°C to +8°C for not more than 24 hours.
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4.3.6 Dosage and administration
The dose of all Hib-containing vaccines is 0.5 mL to be given by IM injection.
Co-administration with other vaccines
All Hib-containing vaccines may be administered in separate sites on the same day as any of the other childhood
vaccines, such as pneumococcal conjugate, hepatitis B, DTPa-containing, inactivated poliomyelitis (IPV or IPVcontaining) and monovalent meningococcal C (MenCCV) vaccines. General catch-up vaccination principles outlined in
2.1.5 Catch-up should be followed when planning catch-up schedules for Hib that require the use of Hib-MenCCV.
No or minimal immunologic interference has been observed when children are vaccinated with pneumococcal
conjugate vaccines (7vPCV – Prevenar; 13vPCV – Prevenar 13; or 10vPCV – Synflorix) and PRP-T-containing
hexavalent vaccine (Infanrix hexa) at the same immunisation visit. 27-30
Interchangeability of Hib vaccines
Where possible, the same brand of Hib-containing vaccine should be used for all primary doses. If different Hibcontaining vaccines (i.e. PRP-OMP and PRP-T vaccines) are used in the primary series, then 3 doses (of any Hibcontaining vaccine) are required at 2, 4 and 6 months of age, with a booster of a Hib-containing vaccine at 12 months of
age. For booster doses and in children >15 months of age, regardless of previous Hib vaccinations, a single dose of any
Hib-containing vaccine is sufficient for protection.
4.3.7 Recommendations
Infants
A Hib-containing vaccine is recommended for all infants from 2 months of age. PRP-T-containing Hib vaccines require
3 primary doses, at 2, 4 and 6 months of age, followed by a booster dose at 12 months of age (refer to ‘Booster doses’
below). Immunisation using PRP-OMP-containing Hib vaccine only requires 2 primary doses, at ages 2 and 4 months,
followed by a booster at 12 months of age.
The 1st dose of a Hib-containing vaccine can be given as early as 6 weeks of age. If the 1st dose is given at 6 weeks of
age, the next scheduled doses should still be given at 4 months and 6 months of age.
Booster doses
A single booster dose of Hib-containing vaccine is recommended at 12 months of age (refer to ‘Infants’ above). This
can be provided as either the monovalent Hib vaccine or the combination vaccine Hib-MenCCV (refer to 4.10
Meningococcal disease).
Children aged >15 months and up to 59 months of age at presentation who have not received a primary course of a Hib
or Hib-containing vaccine will only require 1 dose of vaccine as catch-up, irrespective of the number of previous doses
administered. There should be a minimum 2-month interval between their last dose and the catch-up dose. Catch-up for
Hib vaccination for children up to 59 months of age is outlined in Table 2.1.8 Catch-up schedule for Hib vaccination
for children <5 years of age in 2.1.5 Catch-up.
Preterm infants
Preterm infants can be immunised according to their chronological age, without correction for prematurity (refer to
3.3.2 Vaccination of women who are planning pregnancy, pregnant or breastfeeding, and preterm infants). For PRP-Tcontaining Hib vaccines, including Infanrix hexa, no change in the usual schedule is required. Preterm infants have been
shown to produce good antibody responses to all the antigens in Infanrix hexa following administration at 2, 4 and 6
months of age, although the responses to hepatitis B and Hib are not quite as high as in full-term infants.31
If a PRP-OMP-containing Hib vaccine is used for the primary doses in an extremely preterm and/or low-birth-weight
baby (<28 weeks gestation or <1500 g birth weight), an additional dose should be given at 6 months of age; that is,
doses should be given at 2, 4, 6 and 12 months of age.
Persons with functional or anatomical asplenia
Hib is an uncommon cause of post-splenectomy sepsis in adults and children. A single dose of Hib vaccine is
recommended for persons with functional or anatomical asplenia who were not fully vaccinated in early childhood
according to the recommendations above and Table 2.1.8 Catch-up schedule for Hib vaccination for children <5 years
of age. If vaccination is required, the dose should, where possible, be given 2 weeks before a planned splenectomy or at
approximately 1 week following an emergency splenectomy. Subsequent booster doses of Hib vaccine are not
required.32 For all recommendations for persons with functional or anatomical asplenia, refer to 3.3.3 Vaccination of
immunocompromised persons, Table 3.3.5 Recommendations for vaccination in persons with functional or anatomical
asplenia.
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Allogeneic and autologous haematopoietic stem cell transplant recipients
Allogeneic and autologous haematopoietic stem cell transplant (HSCT) recipients should also be given Hib vaccine post
transplant. Three doses of Hib conjugate vaccine should be administered to HSCT recipients at 6, 8 and 12 months after
transplant. Refer to 3.3.3 Vaccination of immunocompromised persons, Table 3.3.3 Recommendations for revaccination
following HSCT in children and adults, irrespective of previous immunisation history.
4.3.8 Pregnancy and breastfeeding
Hib vaccine is not routinely recommended for pregnant or breastfeeding women. However, for women who have
functional or anatomical asplenia refer to ‘Persons with functional or anatomical asplenia’ above.
Refer to 3.3 Groups with special vaccination requirements, Table 3.3.1 Recommendations for vaccination in pregnancy
for more information.
4.3.9 Contraindications
The only absolute contraindications to Hib-containing vaccines are:

anaphylaxis following a previous dose of any Hib-containing vaccine

anaphylaxis following any vaccine component.
4.3.10 Adverse events
Swelling and redness at the injection site after the 1st dose are common and have been reported in up to 5% of
vaccinated children. Fever in up to 2% has also been reported. These adverse events usually appear within 3 to 4 hours
of vaccination and resolve completely within 24 hours. The incidence of these adverse events declines with subsequent
doses, so it is recommended that the course of vaccination be completed regardless.
4.3.11 Public health management of invasive Hib disease
Haemophilus influenzae type b is a notifiable disease in all states and territories in Australia.
Further instructions about the public health management of Hib, including management of cases of invasive Hib disease
and their contacts, should be obtained from state/territory public health authorities (refer to Appendix 1 Contact details
for Australian, state and territory government health authorities and communicable disease control).
4.3.12 Variations from product information
The product information for Infanrix hexa states that this vaccine is indicated for primary immunisation of infants from
the age of 6 weeks and as a booster dose for children 18 months of age if boosting is required for all antigens. The
ATAGI recommends that this vaccine may also be used for catch-up of the primary schedule in children <10 years of
age.
The product information for Infanrix hexa and Pediacel states that these vaccines are contraindicated in children with
encephalopathy of unknown aetiology or with neurologic complications occurring within 7 days following a vaccine
dose. The ATAGI recommends instead that the only contraindication is a history of anaphylaxis to a previous dose or to
any of the vaccine components.
The product information for Act-HIB, Hiberix and Liquid PedvaxHIB states that these vaccines are indicated for use in
children aged 2 months to 5 years. The ATAGI also recommends administration of Hib vaccine to older people with
asplenia or following either allogeneic or autologous haematopoietic stem cell transplantation.
The product information for Pediacel states that this vaccine is indicated for primary immunisation of infants from the
age of 6 weeks and may also be used as a booster dose for children from 15 to 20 months of age who have previously
been vaccinated against diphtheria, tetanus, pertussis, poliomyelitis and Haemophilus influenzae type b. The ATAGI
recommends that, when appropriate, this product may also be used for either catch-up of the primary schedule or as a
booster dose in children aged <10 years.
References
A full reference list is available on the electronic Handbook or website www.immunise.health.gov.au.
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