Abbreviations and acronyms .......................................................................................... v
Preface ............................................................................................................................. vii
1. The organism and the disease ............................................................................ 1
1.1 Introduction..................................................................................................... 1
1.2 Epidemiology .................................................................................................. 1
1.3 The surface of Hib .......................................................................................... 4
2. The Immunology of Hib ...................................................................................... 5
2.1 Response to infection ..................................................................................... 6
3. Hib vaccines ........................................................................................................... 7
3.1 Polysaccharide vaccine responses ................................................................ 7
3.2 Conjugate vaccine responses ........................................................................ 8
4. Response to vaccination ..................................................................................... 9
4.1 Polysaccharide vaccine responses ................................................................ 9
4.2 Conjugate vaccine responses ........................................................................ 9
4.3 Impact on Hib carriage ................................................................................ 12
4.4 Impact of host factors .................................................................................. 13
4.5 Hib conjugate vaccine efficacy ................................................................... 13
5. Vaccine formulation issues: Hib interchangeability and
administration in combination ........................................................................ 15
5.1 Interchanging different Hib conjugate vaccines ...................................... 15
5.2 Simultaneous administration of Hib conjugate vaccines with
other childhood vaccines ............................................................................. 16
5.3 Hib combination vaccines ........................................................................... 16
6. Vaccine schedule issues ..................................................................................... 17
6.1 Hib conjugate immunogenicity at 2/4/6 months (USA schedule)
and effect of booster at 12-14 months ....................................................... 18
6.2 Hib conjugate immunogenicity at 2/3/4 months and effect of
booster at 12-14 months .............................................................................. 18
6.3 Hib conjugate immunogenicity at 3/5/12 months
(Scandinavian schedule) ............................................................................... 19
6.4 Hib conjugate immunogenicity at 6/10/14 weeks (EPI schedule) ........ 19
7. Vaccine effectiveness ......................................................................................... 21
7.1 Developed country experience ................................................................... 22
7.2 Developing country experience .................................................................. 25
8. Future prospects ................................................................................................. 27
8.1 Hib conjugates in the EPI schedule ........................................................... 27
8.2 Hib conjugates in combination vaccines ................................................... 27
8.3 The role of a booster dose ........................................................................... 28
References ...................................................................................................................... 29
aP acellular pertussis
BCG bacille Calmette-Guérin (vaccine)
BPIG bacterial polysaccharide immune globulin
CDC Centers for Disease Control & Prevention (USA)
CDSC Communicable Disease Surveillance Centre
CVI Children's Vaccine Initiative
DTaP diphtheria-tetanus acellular pertussis
DTP diphtheria-tetanus-pertussis (vaccine);
DTwP diphtheria-tetanus whole-cell pertussis
ELISA enzyme-linked immunosorbent assay
EPI Expanded Programme on Immunization
GAVI Global Alliance for Vaccines and Immunization
HepB Hepatitis B
Hi Haemophilus influenzae
Hib Haemophilus influenzae type b
HIV human immunodeficiency virus
HRU Health Research Unit
IPV inactivated polio vaccine
MMR measles, mumps, and rubella (vaccine)
OMP outer membrane protein of polyribosyl-ribitol- phosphate
OPV oral polio vaccine
PHLS Public Health Laboratory Service
PRP polyribosyl-ribitoal -phosphate (carbohydrate of the Hib capsule)
PRP-CRM197 polyribosyl-ribitol- phosphate-CRM197 conjugate vaccine
PRP-OMP polyribosyl-ribitol- phosphate-outer membrane protein conjugate
PRP-T polyribosyl-ribitol- phosphate-tetanus toxoid conjugate vaccine
UCLA University of California at Los Angeles
UNICEF The United Nations Children's Fund
USA The United States of America
WHO The World Health Organization
wP whole-cell pertussis
This module is part of the Series “The Immunological Basis for Immunization”,
which was initially developed in 1993 as a set of eight modules focusing on the
vaccines included in the Expanded Programme on Immunization (EPI)1. In addition
to a general immunology module, each of the seven other modules covered one of
the vaccines recommended as part of the EPI programme, i.e. diphtheria, measles,
pertussis, polio, tetanus, tuberculosis and yellow fever. These modules have become
some of the most widely used documents in the field of immunization.
With the development of the Global Immunization Vision and Strategy (2005-2015)
the expansion of immunization programmes in general, as well as the large
accumulation of new knowledge since 1993, the decision has been taken to update
and extend this series.
The main purpose of the modules - which are published as separate disease/vaccine-
specific modules - is to give immunization managers and vaccination professionals a
brief and easily-understood overview of the scientific basis of vaccination, and also
of the immunological basis for the WHO recommendations on vaccine use that since
1998 are published in the Vaccine Position Papers. (http://www.who.int/
WHO would like to thank all the people who were involved in the development of
the initial “Immunological Basis for Immunization” Series, as well as those involved
in its updating, and the development of new modules.
This programme was established in 1974 with the main aim of providing immunization for children
in developing countries.
1.The organism and
Haemophilus influenzae (Hi) are a genus of gram-negative coccobacilli, members of
the Pasteurellaceae family that exist in both capsulated and nonencapsulated forms.
Encapsulated strains are further classified according to the chemical composition of
the polysaccharide forming the capsule, and six serotypes, designated a-f, have been
identified (Pittman, 1931). Hi are carried in the moist mucosa of the
human nasopharynx from where they can spread to cause both local and
systemic disease including meningitis, pneumonia, epiglottitis, orbital cellulitis,
septic arthritis, bacteraemia, osteomyelitis, pericarditis, sinusitis and otitis media
(reviewed in Barbour, 1996). Hi serotype b (Hib) is responsible for approximately
95% of all invasive disease due to Hi (invasive disease is defined as the isolation of
Hi from an otherwise sterile site such as the blood stream or cerebrospinal fluid),
although the other serotypes can also cause invasive disease in the normal host
(Kniskern, Marburg & Ellis, 1995). About 5% of children with Hib meningitis die,
in spite of appropriate clinical management, and 20% to 40% of survivors suffer
permanent disability. The sequelae of Hib meningitis include blindness, deafness and
learning disabilities. Antibiotic resistance to all Hi has steadily increased in recent
years (Gessner et al., 2002). Nonencapsulated strains are an important cause of
mucosal diseases such as otitis media, sinusitis and lower respiratory tract infection,
and in some clinical settings, such as an immunocompromised host, may cause invasive
Although invasive Hib disease may occur in any age group, it is predominantly a
disease of early childhood. Rarely occurring in infants under three months of age
(WHO, 1998) or after the age of six years, the disease burden is generally highest in
children aged between 4 and 18 months (See Figure 1), although the precise age at
which risk is highest varies from developing countries where there is an earlier peak
(Asturias et al., 2003) to developed countries, such as the Republic of Finland,
where the peak is later (Peltola, 1998).
Figure 1: Age distribution of Hib infection from
October 1990 to September 1991 in six regions in England and Wales
Number of cases
<1 1 2 3 4 5-14 15-44 45-64 65+ NK
Age group (years)
Age distribution of Hib infection from October 1990 to September 1991 in six regions in England and
Wales. Out of 433 reported cases, 362 (84%) were due to Hib, 54 (13%) were due to non-serotypable
Hi, and 13 cases were not serotyped. Adapted from (Nazareth et al. 1992).
In the pre-vaccine era in developed countries, meningitis accounted for approximately
half of all invasive Hib disease. In the United Kingdom for example, an analysis of
invasive Hib disease revealed that 56% of isolates were from patients with
meningitis, 13% from patients with epiglottitis, and 6% from patients with
pneumonia (Nazareth et al., 1992). Data from some countries with good
surveillance systems illustrates how incidence figures in childhood may vary.
For example, in the pre-vaccine era, reported incidence rates per 100 000 for invasive
Hib disease below five years of age ranged from 21 to 44 in the United Kingdom
(Booy et al., 1994; Anderson et al., 1995a; Hargreaves et al., 1996), 20 to 50 in the
United States of America (USA) excluding Alaska (Broome, 1987), and 42 in the
Federative Republic of Brazil (Bryan et al., 1990). In the Republic of the Gambia,
the pre-1990 incidence rates for Hib meningitis <five years of age was 60/100 000
and as high as 200 /100 000 for those <1 year of age (Bijlmer et al., 1990). In south-
east asia, the exact contribution of Hib to the overall burden of meningitis and
pneumonia remains unclear. The incidence of Hib meningitis among children aged 0
to 4 years in Hong Kong Special Administrative Region of China has been reported
to be as low as 1.75 per 100 000 per year (Lau et al., 1998) and also 3.22 per 100 000
under five years of age in China (Province of Taiwan) (Shao et al., 2004), although
the incidence of Hib disease among Vietnamese refugee children in Hong Kong,
SAR exceeds 42 per 100 000 (Lau, 1999). The overall burden of Hib pneumonia in
general is difficult to quantify because only a small percentage of Hib pneumonia is
accompanied by bacteraemia. Studies incorporating a wide range of diagnostic
2 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
techniques, including lung aspirates, which are often considered the gold standard
for identifying a pathogen in pneumonia, have suggested that the burden of
Hib pneumonia in children under five years of age in the Republic of the
Gambia may be as high as 42% (Vuori-Holopainen & Peltola, 2001), while a vaccine
probe study there found that at least 21% of pneumonia was caused by Hib
(Mulholland et al., 1997).
Not all individuals within a population are at equal risk and a number of factors have
been identified that are associated with an increased risk of Hib disease. Hib disease
in the United States has been noted to be 1.2-1.5 times higher in boys than in girls
(Cochi & Broome, 1986; Wenger, 1998) and to be 2-4 times higher for black than
for white children younger than five years of age (Tarr & Peter, 1978;
Wenger, 1998). Indigenous populations, such as those of Australia (Aboriginals),
and North America (Alaskan Eskimos, and Apache and Navajo Indians) have been
shown to have the greatest known endemic risk of invasive Hib disease
(Bulkow et al., 1993; Wenger, 1998; Singleton et al., 2000) with rates as high
as 408/100 000 described (Ward et al., 1981). The reason for these very high rates is
likely to be due to a combination of genetic and environmental interactions.
Environmental factors that affect exposure to Hib, such as nursery settings,
and increased population density, have been associated with an increased risk of
invasive disease (Tarr & Peter, 1978; Wenger, 1998), while pre-existing
conditions such as sickle cell disease, human immunodeficiency virus (HIV),
bone-marrow transplant and complement deficiencies, are also known to be important
individual risk factors.
Estimates of rates of nasopharyngeal carriage also reveal that carriage is related to
the age of the individual, presumably reflecting the relative immaturity of
the immune system in young children. In the pre-vaccine era about four in
every 100 children in the United Kingdom carried the Hib organism
(McVernon et al., 2004a). This compares to a similar rate of 3.5% in the Republic of
Finland (Takala et al., 1989) and 2%—5% in the United States (Millar et al., 2000).
Carriage studies in the Republic of the Gambia have suggested higher rates of carriage,
although rates have varied between villages studied and between studies, with rates
as high as 12% (Adegbola et al., 2005) or 33% reported (Bijlmer et al., 1989).
Recent reports of invasive Hi non-b capsular serotypes in the era since development
of conjugate vaccines have prompted concern about serotype replacement.
Unusual clusters of invasive infection due to Hi serotype a with clinical features
that resemble those of infection due to Hi serotype b have been described.
A unique feature often associated with more virulent Hi serotype a isolates is the
IS1016-bexA partial deletion, which was previously identified in the capsule locus
of Hi serotype b strains (Kapogiannis et al., 2005). The presence of the necessary
bexA gene deletion has also been demonstrated in the capsulation locus of a sizeable
proportion of Hi types f and a isolates from invasive infections in the Republic of the
Gambia (Kroll et al., 1994; Ogilvie et al., 2001). To date however no widespread
level of replacement disease is evident.
1.3 The surface of Hib
The surface of Hib is composed of a cell wall and polysaccharide capsule.
Polysaccharide capsules are common cell-surface components of bacterial
pathogens that cause systemic disease. Based on in vitro studies, it is known that
polysaccharide capsules mediate resistance to important host defence
mechanisms, including phagocytosis and complement-mediated killing
(Sukupolvi-Petty, Grass & St Geme, 2006). The Hib capsule is made up of repeating
polymers of ribosyl and ribitol-phosphate and is thus designated polyribosyl-ribitol-
phosphate (PRP). The repeating sugar has homology to a number of other
bacterial-derived capsules including that of E. coli K100 (Bradshaw et al., 1971).
The other Hi capsular serotypes are composed of hexose rather than pentose sugars,
and only occasionally cause invasive disease, although the reason for the differences
in pathogenicity are not well understood. Encapsulated organisms can penetrate the
epithelium of the nasopharynx and invade capillaries directly which accounts for the
invasive potential of Hib. The antiphagocytic capsule prevents the induction of the
alternative complement pathway by inhibiting or delaying complement proteins on
the cell surface (particularly C3b), so that the bacterium can invade the blood or
cerebrospinal fluid without attracting phagocytes or provoking an inflammatory
response and complement-mediated bacteriolysis (Hetherington, Patrick & Hansen,
1993). For this reason, anticapsular antibody which is able to bind to capsule and
which promotes both phagocytosis (via Fc interactions with other cells) and
bacteriolysis (by allowing complement to bind), is critical for protection against
encapsulated organisms (Tosi, 2005). Anti PRP antibodies have been shown to be
produced on exposure to Hib and are known to provide protection against disease
(CDC, 1998; Heath, 1998; Granoff, 2001).
The Hi cell wall contains several different outer membrane proteins (OMPs) that
may also be targets of human IgG. These OMPs include P1, P2, P4, P5, P6, a 98kD
surface protein, and a 42kD protein called protein D. Antibodies to P1, P4, and P6
have been shown to bind to proteins on the surface of diverse Hi strains.
Animal models have suggested that antibody to several different proteins may be
protective, and development of a Hi OMP vaccine to prevent otitis media has been
actively pursued. A recent study by Prymula and others (Prymula et al., 2006) using
a Hi protein D as a carrier for pneumococcal polysaccharide vaccines appeared to
demonstrate protection against both pneumococcal and Hi otitis media.
4 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
2. The Immunology of Hib
Studies of the epidemiology of invasive Hib disease coupled with animal experiments
have provided clues to the key components mediating immunity to Hib. The striking
age-dependent susceptibility to invasive disease was initially shown in the 1930's to
correlate with the absence of bactericidal activity in the blood (Fothergill & Wright,
1933). Antibodies to Hib capsule were identified as key mediators of this effect and
shown to confer type-specific protection of lethal Hib disease in a rabbit
model. Subsequent studies in humans on the bactericidal activity of blood
identified a discrepancy between bactericidal activity and anticapsular antibody titre
(Anderson & Smith, 1977). At the same time, anti-PRP IgG was shown to be inversely
correlated to the incidence of Hib meningitis (Peltola et al., 1977). The absence of
invasive Hib infections in children with X-linked agammaglobulinaemia on
replacement immunoglobulin therapy, provided further evidence for the protective
effect of serum IgG in humans (Siber et al., 1992) while a formal trial in the
United States of the efficacy of bacterial polysaccharide immune globulin (BPIG)
was conducted in White Mountain Apache Indian infants (a group with very high
incidence of invasive Hib disease) and shown to be protective (Santosham et al.,
The incidence of Hib disease is relatively low in the first few months of life
due to the transfer of maternal IgG specific for PRP across the placenta, although in
some indigenous populations incidence of early invasive disease is high despite this
antibody. Generally, once maternal antibodies wane, the incidence of disease
increases (peaking at different times in different populations, see Section 1.2), but by
the age of five years the incidence of disease is universally low and remains low
throughout adulthood with only a small increase in the incidence in the very elderly
(Farley et al., 1992). Like other bacterial-derived polysaccharides, PRP is classified
as a T-independent antigen stimulating B cells directly without the help of T cells,
and antigens of this type are known to be poorly immunogenic in childhood.
Thus one of the reasons that young children are so susceptible to invasive Hib disease
is that they are unable to mount robust responses to pure polysaccharide antigens
before approximately 18 months of age.
2.1 Response to infection
Hib is the most virulent of the Haemophilus genus and 95% of bloodstream and
meningeal Haemophilus infections in children are due to type b. Hib colonizes the
human upper respiratory tract, although only a fraction of those acquiring carriage
of the bacteria will subsequently develop clinical disease. The time between infection
and the appearance of symptoms is thought to be between two and ten days.
Symptoms of Hib meningitis can include headache, fever, vomiting, stiffness of the
neck, sensitivity to bright lights, joint pains, drowsiness, confusion, hypothermia
and coma (Herson & Todd, 1977). If Hib infection occurs in a previously healthy
unimmunized child over the age of 24 months, the child generally develops a robust
immune response (Pichichero, Hall & Insel, 1981). Both humoral and cellular immune
responses play an important role in individual protection against Hib disease.
IgG, IgM and IgA antibodies to PRP may all be induced by infection as well as
vaccination. Variable immunoglobulin isotype and IgG subclass responses to
PRP polysaccharide after natural Hib exposure, disease, and immunization,
have been described (Jennings, 1983; Barrett, 1985). Most individuals respond with
IgG antibodies after PRP immunization, although some children have predominantly
IgA or IgM responses (Ramadas et al., 1986). IgG2 is the IgG subclass that is
commonly found, along with IgG1, in the natural response to polysaccharide
antigens. There is an increased susceptibility to Hib disease in patients who are
immunosuppressed and in those who are deficient in IgG2 and IgG4
(Ambrosino et al., 1992b). Rising Hib anticapsular antibodies have been detected
within as little as 2-3 days of the diagnosis of Hib meningitis (Anderson et al., 2000),
and a role for mucosal antibodies in the initial defence against colonisation and infection
has been suggested. However, the majority of studies have focused on serum-derived
IgG with relatively few studies focussing on the role of mucosal antibodies.
Most of the studies of Hib have also focussed on PRP responses alone, and relatively
little is known about the immune response or relative importance of responses to
Hib proteins. Antibodies directed against the capsular PRP or the outer membrane
proteins of Hib promote bactericidal activity, complement 3 binding, and ingestion
by phagocytic cells (Heath, 1998; Granoff, 2001).
6 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
3. Hib vaccines
3.1 Polysaccharide vaccine responses
The first vaccine developed against Hib was produced in the early 1970s and was
composed of purified Hib capsular polysaccharide capsule (PRP). A double-blind
efficacy trial of PRP vaccine was conducted in the Republic of Finland in the early
1970s involving 60 000 vaccinees between the ages of three months and five years.
The vaccine showed short-term efficacy in children who received vaccine
aged 18 months or older, but no protection in younger children (Peltola et al., 1977).
The absence of efficacy in those less than 18 months of age was due to the poor
immunogenicity of the PRP in the infants. Furthermore, no boost in antibody titre
was observed with repeated doses of PRP, the antibody that was produced
was relatively low-affinity IgM with minimal IgG production, and the vaccine had
no effect on nasopharyngeal carriage of Hib (Stein, 1992; Barbour, 1996).
Follow-up of the vaccinated cohort indicated that protection overall for the children
vaccinated over the age of 18 months was approximately 90% (Kayhty et al., 1984;
Peltola et al., 1984).
On the basis of this and other efficacy studies (Lepow, Samuelson & Gordon, 1985;
Eskola et al., 1987), pure polysaccharide vaccines (see Table 1) were licensed in the
United States in 1985, and recommended for use in those between two and five
years of age, or those over 18 months of age attending day care.
Experience with this vaccine varied geographically with some states reporting
negative efficacy and an increased risk of disease in the weeks following receipt of
PRP (Black et al., 1991b). This increased susceptibility in the weeks after vaccination
was associated with a transient reduction of PRP antibody in the serum of vaccinated
infants (Institute of Medicine, 1994). Overall the vaccine was thought to
be 50%-60% effective (Harrison et al., 1988) and was used until 1988 when it was
superseded by conjugate vaccines.
3.2 Conjugate vaccine responses
In the 1920s the pioneering work of Avery and Goebel (Avery & Goebel, 1929)
established that the immunogenicity of carbohydrate antigens in rabbits could be
improved by the conjugation of the sugars to a protein carrier. This work laid the
foundation for the development of conjugate vaccines for use in humans, but it was
only in the 1970s that work began seriously on the prototype vaccine for use in
humans - a Hib conjugate (Lepow, 1987; Tai et al., 1987; Campion & Casto, 1988).
The chemical attachment (conjugation) of PRP to protein antigens, such as diphtheria
and tetanus toxoids, was the initial basis for the development of Hib conjugate vaccines
(Peltola, 1998) as these antigens were known to be capable of eliciting T cell help,
and in turn the T cells were able to provide appropriate signals to the carbohydrate-
specific B cell, thus improving both the immunogenicity and the quality of the immune
response to the PRP component of the vaccine.
The vaccines currently licensed for use against Hib disease are based on
PRP conjugated to a protein carrier, PRP conjugated to tetanus toxoid (PRP-T),
an oligosaccharide of PRP conjugated to a mutated non-toxic diphtheria toxin,
CRM-197 (HbOC), and PRP conjugated to a Neisseria meningitidis type b outer
membrane protein complex (PRP-OMP) (as reviewed in Santosham, 1993).
PRP conjugated to diphtheria toxoid (PRP-D) was one of the first vaccines to be
produced, but is no longer manufactured (Table 1). The conjugate vaccines differ in
their carrier protein, method of chemical conjugation, and by polysaccharide size,
giving them somewhat different immunological properties. These vaccines were first
licensed in 1987 (USA), and initially restricted to children aged 15 to 18 months,
but subsequently in 1990, the license was extended to include infants in the first year
of life (Shapiro & Ward, 1991).
Table 1: Hib polysaccharide and polysaccharide-protein conjugate vaccines
currently or previously licensed
Type b native polysaccharide None
Type b polysaccharide Diphtheria toxoid ('PRP-D')
Type b saccharide Mutant non-toxic diphtheria toxin
Type b saccharide Neisseria meningitidis outer membrane
protein in outer membrane vesicles
Type b polysaccharide Tetanus toxoid ('PRP-T')
8 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
4. Response to vaccination
4.1 Polysaccharide vaccine responses
Much of our understanding of the immunology of responses to PRP comes from the
pivotal studies of Porter Anderson and David Smith (Anderson, Johnston & Smith,
1972), as well as the subsequent PRP vaccine trial performed in the
Republic of Finland in the 1970s (Kayhty et al., 1984). These studies demonstrated
the poor immunogenicity of PRP in young children whose B cell immunity is not
well developed at that age, and consequently the absence of protection, along with
the fact that repeated doses of PRP vaccine failed to elicit a memory response.
In older children, >18 months, the maturation of the immune system is associated
with the acquisition of responsiveness to PRP, and thus as titres in children rise
naturally with age, presumably stimulated through natural encounter with Hib in
the nasopharynx, or encounter with cross-reactive antigens (Bradshaw et al., 1971),
the incidence of disease declines. It is likely that ongoing exposure to Hib resulting
in the maintenance of detectable circulating antibody to PRP is important in
maintaining long-term protection against Hib. Serum antibodies to PRP were initially
measured by radioimmunoassay (RIA) but have been superseded by the introduction
of a robust enzyme-linked immunosorbent assay (ELISA) which is now widely used
for the measurement of PRP-specific IgG (Madore et al., 1996).
4.2 Conjugate vaccine responses
The simultaneous development of four different conjugate vaccines started in the
1970s. PRP-D was the prototype vaccine and the first to go into clinical trials.
PRP-D was shown to be moderately immunogenic with typically only 40% of infants
receiving the primary immunisation series, achieving antibody concentrations of
1.0 µg/ml, and 70% achieving 0.15 µg/ml (Eskola et al., 1990), but it was shown to
be efficacious in clinical trials in the Republic of Finland (Takala et al., 1989;
Peter, 1998). However it had low efficacy and elicited a poor immune
response when tested in Alaskan Eskimos who are at high risk for Hib disease.
Although initially licensed in many countries, PRP-D is no longer licensed or
manufactured for use in infants below 18 months of age (Ward et al., 1988).
The development of PRP-OMP, HbOC and PRP-T continued simultaneously,
and early immunogenicity studies illustrated good antibody responses in infants from
two months onwards (Eskola et al., 1987; Lepow, 1987). The PRP-OMP vaccine
was the only vaccine not to use a diphtheria or tetanus-based carrier protein.
Immunogenicity studies revealed the unique properties of this formulation which
elicits an anti-PRP concentration of 0.15 µg/ml and 1.0 µg/ml, a level correlated
with short-term and long-term protection respectively in a larger proportion of
children after a single dose (Decker & Edwards, 1998; Watt, Levine & Santosham,
2003). For this reason, PRP-OMP was designated the vaccine of choice for use in
populations that had a high proportion of disease in the first six months of life.
However, the geometric mean titres elicited after the PRP-OMP primary series
(3 doses) were shown to be lower than those elicited after the PRP-T or HbOC
primary series, and booster responses appeared attenuated compared to those seen
with PRP-T and HbOC. HbOC contains a unique short Hi oligosaccharide
conjugated to a mutant toxin (CRM197) isolated from Corynebacterium diphtheria
and elicits high levels of anti-PRP antibody after a 3-dose primary series
(Decker & Edwards, 1998; Watt, Levine & Santosham, 2003). PRP-OMP and
HbOC both show a positive correlation between age and the IgG response
(Madore et al., 1990). PRP-T was the last Hib conjugate vaccine to be evaluated and
was licensed for use in 1992. It contains tetanus toxoid as the carrier protein, attached
to PRP via 6- carbon linkage or carbodimide condensation, and has no adjuvant.
Comparative immunogenicity of the four different Hib conjugate vaccines developed,
when administered at 2, 4 and 6 months of age together with routine childhood
immunizations, is illustrated in Figure 2. As can be seen, apart from PRP-OMP,
the majority of the antibodies induced to Hib occurred after the third dose administered
at six months of age.
Figure 2: Comparison of antibody responses to
four different Hib conjugate vaccines
Before After 1st dose After 2nd dose After 3rd dose
(in order from left to right)
PRP-D PRP-OMP PRP-CRM197 PRP-T
Doses were given at 2, 4, and 6 months of age. Adapted from (Watt et al. 2003)
10 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
In addition to the level of IgG responses induced by conjugate vaccines,
conjugates induce immune memory to the PRP component of the vaccine which is
not seen when pure PRP vaccines are administered. Memory can be measured by
administering pure PRP and eliciting a response in a primed but not an unprimed
individual (such as a toddler). An increase in antibody avidity following primary
immunization and boosting has also been demonstrated in Hib conjugate
immunogenicity trials (Goldblatt, Vaz & Miller, 1998; Anttila et al., 1999).
This phenomenon of avidity maturation is not seen following PRP vaccination.
Avidity measurements have thus been proposed as a surrogate marker for the
successful generation of immunological memory. The relative importance of memory
versus circulating antibody levels for clinical protection by conjugate vaccines is
unclear (see below).
Experiments with the administration of hyperimmune anti-PRP IgG in both
animal models (Ambrosino et al., 1983; Akkoyunlu et al., 1997) and in humans
(Shenep et al., 1983; Siber et al., 1992), illustrated that a level of 0.15 µg/ml was
associated with short-term protection from invasive Hib disease. By contrast,
experience from field studies of PRP vaccine illustrated good protection in children
mounting a response of at least 1 µg/ml one month after completion of vaccination.
Thus during the development and evaluation of Hib conjugate vaccines,
these two thresholds were used to define short and long-term protection respectively.
However, neither threshold takes cognisance of the fundamental difference in the
nature of the immune response to conjugate vaccine as compared to PRP.
Extensive use of Hib vaccines and observation of their clinical efficacy in practice
has questioned the relevance of the 0·15-1·0 µg/ml concentration as surrogates of
protection following conjugate vaccination (Eskola et al., 1999) although they are
still widely used today. The fact that conjugate vaccines induce memory,
suggests that irrespective of the titre achieved after vaccination, priming for memory
responses may provide protection of longer duration than that achieved after
PRP vaccine, particularly if ongoing exposure to Hib is able to maintain circulating
antibody titres. The demonstration of efficacy for the PRP-D vaccine in the
Republic of Finland, despite its relatively poor immunogenicity, suggested that there
may be a role for memory in protection against Hib disease. The experience in
Alaska however established that in a high risk setting, higher antibody titres are
required for protection. Protection against invasive Hib disease in the face of vaccine-
induced memory but the absence of circulating antibody is not clearly established
(Galil et al., 1999) and is described further when discussing the recent experience in
the United Kingdom in Section 7.
4.3 Impact on Hib carriage
Takala and colleagues (Takala et al., 1991) first showed that Hib conjugate vaccine,
unlike Hib polysaccharide vaccine, was able to prevent oropharyngeal colonisation
by Hib. Pure PRP vaccines are known not to impact on carriage, but reduction in
nasopharyngeal carriage of Hib has been demonstrated in several trials of
Hib conjugate administered at different schedules in the United States
(Lepow, Samuelson & Gordon, 1985; Takala et al., 1991; Black et al., 1991b),
the Republic of the Gambia (Adegbola et al., 1998), the Federative Republic of
Brazil (Forleo-Neto et al., 1999) and the United Kingdom (Barbour et al., 1995).
While baseline rates of carriage have differed in each country (see Section 1.2),
the widespread use of conjugate vaccines has led to decreases in disease
incidence that were greater than rates of vaccination coverage, as well as decreases
in Hib disease in unvaccinated individuals and groups (Barbour et al., 1995;
Barbour, 1996; Peltola, 1998; Adegbola et al., 1999). The impact of herd effect can
be seen by the tenfold reduction in Hib disease rates in the United Kingdom in
unvaccinated children <1 year of age in 1998 compared with rates in similarly aged
children before vaccination began (Heath et al., 2000b). Another reflection of herd
effect is the impact of childhood Hib vaccination on adult Hib disease. A review of
adult cases of Hib disease in five English regions between 1990 and 1995 showed a
halving of case numbers between the first three-year period and the last two-year
period (Sarangi et al., 2000). Ongoing surveillance for Hib disease by Moulton and
colleagues (Moulton et al., 2000) demonstrated that immunization of 40% of
Navajo Indian infants (USA) between the years 1988 to 1992 resulted in a 75%
reduction of Hib disease among infants that were living in the same community.
This demonstrates that countries that implement Hib immunization programmes
may receive greater benefits at the community level than those hitherto seen due to
the direct protection conferred on the individual through vaccination. Antibody levels
required for the protection against colonisation are thought to be higher than those
required for protection against invasive disease. A study suggests that protection
against nasopharyngeal Hib colonization requires serum antibody concentrations of
approximately 5 µg/ml (Fernandez et al., 2000) which is identical to the concentration
thought to protect against pneumococcal colonisation (Goldblatt et al., 2005),
while studies of passive administration of antibodies into the peritoneum of infant
rats has suggested that a titre of >7 micrograms/ml is able to prevent colonisation
(Kauppi, Saarinen & Kayhty, 1993).
12 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
4.4 Impact of host factors
Optimal interventions to reduce Hib disease and transmission are likely to
depend upon many factors, including vaccine type, schedule of vaccination,
the specific population epidemiology, and programme performance, as well as other
environmental factors. Hib conjugate vaccine is immunogenic in patients with
increased risk for invasive disease, e.g. those with sickle-cell disease
(Goldblatt, Johnson & Evans, 1996b; O'Brien et al., 2000), leukaemia
(Feldman et al., 1990), human immunodeficiency virus (HIV) infection
(De Sousa dos et al., 2004), and those who have had a splenectomy
(Ambrosino et al., 1992a). However in persons with HIV infection,
immunogenicity varies with stage of infection and degree of impaired immunity
(Rutstein, Rudy & Cnaan, 1996). Immunogenicity of the Hib conjugate vaccines is
not equal in all populations. Castillo de Febres and colleagues (Castillo de,
Febres et al., 1994) compared PRP-T vaccine responses in infants in Nashville,
Tenessee (USA) and those living in Valencia in the Bolivarian Republic of Venezuela,
and demonstrated a 10-fold increased response to an identical primary immunisation
series in the Venezuelan children. Greenberg and colleagues (Greenberg et al., 1994)
identified differences in the immunogenicity of Hib conjugates administered to
children resident in California (USA) when stratified by race, with the lowest
responses in white children and the highest in Asian children. In the same study,
responses were significantly correlated with gestational age and breastfeeding to
six months. Levine and colleagues (Levine et al., 1997) studied a subgroup of
Chilean children demonstrating a significant response after two Hib doses and showed
that low maternal education (adjusted OR 1.68 p=0.05), mean number of persons in
the house, and the mean number of children under the age of six years in the house,
all correlated with responses to Hib conjugate vaccine. The authors postulated that
indigenous South Americans might be overrepresented in this group and the improved
responses might thus be attributed to host genetics. Enhanced responses to PRP-T
compared to PRP-OMP and HbOC have been reported in Philippine infants
(Capeding et al., 1998).
4.5 Hib conjugate vaccine efficacy
Eight randomised placebo-controlled efficacy trials of Hib conjugate vaccines have
been performed and all have used invasive disease as the primary endpoint
(reviewed in Obonyo & Lau, 2006). All studies and all vaccines, with the exception
of PRP-D in Alaskan Eskimo (USA) infants, have demonstrated high efficacy.
The studies and efficacy endpoints are summarized in Table 2. Peltola and colleagues
(Peltola et al., 1994) also demonstrated in a randomised Finnish study that both
PRP-D and HbOC vaccines were safe and effective and that a 2-dose primary
vaccination schedule was appropriate in producing high antibody concentrations.
Table 2: Vaccine efficacy estimates from effectiveness trials of the Hib vaccine
(CI confidence interval)
Vaccine Vaccine 95% CI Endpoint Study site Reference
PRP-T 95 67-100 Invasive disease The Gambia (Mulholland et al., 1997)
100 55-100 Pneumoniae after 2 or 3 doses
21.1 4.6-34.9 Radiologically defined pneumonia
PRP-D 95 83-98 Invasive disease Finland (Eskola et al., 1990)
PRP-D 35 57-73 Invasive disease in Alaskan Natives USA (Ward et al., 1990)
PRP-T 90 50-99 Invasive disease UK (Booy et al., 1994)
PRP-T 90.2 74.5-100 Invasive disease Chile (Lagos et al., 1996)
PRP-OMP 95 72-99 Invasive disease, Navajo infants USA (Santosham et al., 1991)
93 53-98 Meningitis
HbOC 100 64-100 Invasive disease, California USA (Black et al., 1991a)
14 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
5. Vaccine formulation issues:
Hib interchangeability and
administration in combination
There are currently various formulations of Hib conjugate vaccine: liquid Hib
conjugate vaccine (monovalent); liquid Hib conjugate combined with diphtheria-
tetanus-pertussis vaccine (DTP) and hepatitis B (HepB); liquid Hib conjugate and
HepB combined vaccines; lyophilised (freeze-dried) Hib conjugate with saline diluent
(monovalent), and lyophilised Hib conjugate vaccine to be used with liquid DTP,
DTP-HepB, DTP-IPV, DTaP, or DTaP/IPV in combination. With so many products
on the market, there are clearly issues regarding the compatibility of vaccines during
simultaneous administration, and questions about the interchanging of products.
Hib conjugate vaccine can be given safely and effectively at the same time as bacille
Calmette-Guérin (BCG), DTP, measles, polio (OPV or IPV), HepB, yellow fever
vaccines, and vitamin A supplementation. If Hib conjugate vaccine is given as a
separate injection at the same time as other vaccines, it should be administered at a
different site. It should not be mixed in the vial or syringe with any other vaccine
unless it is manufactured as a combined product (e.g. DTP-Hib) as studies have
shown that the mixture induces an immune response that is inferior to separate
injections of the respective antigens.
5.1 Interchanging different Hib conjugate vaccines
In the past it has been considered ideal to finish a schedule of primary dosing and
boosting with the same licensed product. However for logistical reasons it has
been important to ascertain whether Hib conjugate vaccines from different
manufacturers using the same or different carriers could be interchanged.
Several studies have reported on the safety and immunogenicity of vaccines when
Hib conjugates are interchanged during the primary schedule. Goldblatt and colleagues
(Goldblatt et al., 1996a) found no significant changes in immunogenicity in a study
where infants in the United Kingdom were given PRP-T or HbOC in various
combinations at 2, 3 and 4 months. Here a greater number of infants receiving mixed
combinations of conjugates achieved long-term protective antibody titres
of >1µg/ml compared to those receiving three doses of the same conjugate
(91% versus 93%). Similar studies by Greenberg and colleagues (Greenberg et al.,
1995), and Anderson and colleagues (Anderson et al., 1995b) (PRP-OMP and HbOC)
and also Scheifele and colleagues (Scheifele et al., 1996) (PRP-T and HbOC),
provide reassuring evidence that interchanging Hib conjugate vaccines when
administered at 2, 4 and 6 months is safe, and as immunogenic as schedules of single
Hib conjugate vaccines. In certain circumstances interchanging vaccines may be
advantageous. In a study of the safety and immunogenicity of PRP-OMP and HbOC
administered as a booster dose in 12 to 15-month-old Navajo Indian (USA) infants
primed with PRP-OMP, a booster dose of HbOC produced a significantly higher
antibody response compared to PRP-OMP (Reid et al., 1993). Currently, any licensed
conjugate vaccine may be used for the booster dose, regardless of what was
administered in the primary series.
5.2 Simultaneous administration of Hib conjugate vaccines with other
Hib conjugate vaccines have been administered simultaneously with a
variety of antigens including DTwP (Bell et al., 1998; Joshi & Joshi, 2005;
Berrington et al., 2006), measles, mumps, and rubella (MMR) (Black et al., 2006),
pneumococcal vaccines (Obonyo & Lau, 2006), and meningococcal C conjugate
vaccines (Bramley et al., 2001; Buttery et al., 2005) without any significant impact
on the immune responses to the Hib conjugate vaccine or to the simultaneously
administered antigen. However some combination vaccines containing DTaP and
Hib have been shown to induce lower Hib responses when used in particular schedules
5.3 Hib combination vaccines
Hib conjugate vaccine is generally administered at the same time as diphtheria-
tetanus-pertussis (DTP) and other childhood vaccines, and this has led to the
development of combination vaccines. Combination vaccines have several advantages,
including programmatic simplification, and decreased number of injections, storage
space, and medical waste. However, interference between different components of
combination vaccines has been observed, particularly with vaccines that contain
Hib conjugates and acellular pertussis antigens (Watt, Levine & Santosham, 2003).
Hib conjugate vaccine has been combined with DTaP (quadrivalent), DTaP/IPV or
DTaP/HepB (pentavalent) and DTaP/IPV/HepB (hexavalent).
Attenuation of the Hib response when PRP-T is administered in combination with
DTPa-IPV compared to separate administration, was first noticed by Eskola and
colleagues (Eskola et al., 1996) and subsequently reported by several other studies
(Eskola et al., 1999; Vidor, Hoffenbach & Fletcher, 2001). Attenuation of the
Hib response was particularly prominent when the vaccine was given in an
accelerated schedule (e.g. at 2, 3 and 4 months of age) such as that used in the
United Kingdom (Goldblatt et al., 1999) compared to more extended schedules
(Vidor, Hoffenbach & Fletcher, 2001). The attenuation was thought to be due in part
to the effect of aluminium hydroxide affecting the integrity of the PRP-T as had
been previously demonstrated for Hib conjugates stored with aluminium hydroxide
(Claesson et al., 1988). As a result of these studies, the United States Food and Drug
Administration recommended that DTaP and Hib conjugate vaccines should not be
given as a combined injection to infants. Attempts to overcome the reduced Hib
response led to the development of DTaP-Hib combinations using aluminium
phosphate and these have been associated with less attenuation (Lee et al., 1999).
More recently it has become clear that the attenuation of the Hib response is also in
part due to an inhibition of the immune response as a result of excess tetanus
toxoid, a form of carrier-induced epitope suppression. Dagan and colleagues
(Dagan et al., 1998) showed that with the administration of increasing amounts of
tetanus there is a dose dependent effect on PRP-T responses. This effect is not as
marked with DTwP-containing combinations as it is likely that the adjuvant
effect of the wP masks this phenomenon. Recently a case-control study in the
United Kingdom has demonstrated an increased risk for invasive Hib disease in
children who received >2 doses of DTaP-Hib, which suggests that the reduced PRP
responses seen may be clinically relevant (McVernon et al., 2003) (see Section 7.1).
16 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
6. Vaccine schedule issues
Differences in the epidemiology of Hib disease and in public-health practices have
led to the adoption of several different schedules of immunization. Immunogenicity
is influenced by the schedule used, with intervals of two months between doses
giving better responses than intervals of one month (CDC, 1991). The mean titres
of antibody are directly correlated with increasing age at administration of the
first dose of Hib conjugate vaccine (Fritzell & Plotkin, 1992). Current vaccine
schedules in use in selected countries around the world are shown below in Table 3.
Table 3: Recommended schedules and Hib vaccines
used in childhood immunization
United kingdom 2, 3, 4 , 12-15 months
Slovenia risk groups only
Poland 2, 4, 12-15 months
Hungary 2, 4, 5 months
Italy 3, 5, 11-12 months
Israel 2, 4, 12 months
Iceland 3, 5, 12 months
Greece 2, 4, 6, 15-18 months
Germany 2, 3, 4 months, plus 11-14 months
France 2, 4, 18 months (vaccine with 5 antigens at 3 months)
Finland 4, 6 & 14-18 months
The czech republic 2, 3, 4 & 18-20 months
Australia 2, 4, 12 months
Canada 2, 4, 6, 15-18 months
The united states of America 2, 4, 6, 12-15 months
Chile 2, 4, 6 months
The gambia 2, 3, 4 months
Uganda 6, 10, 14 weeks
South africa 6, 10, 14 weeks
Tunisia 3, 4, 5 months
Bahrain 2, 4, 6, 18 months
Jamaica 6 weeks, 3, 5 months
(adapted from http://www.euibis.org/links.htm and http://www.who.int
immunization_monitoring) (2004) and WHO, http://www.who.int/immunization_monitoring/
6.1 Hib conjugate immunogenicity at 2/4/6 months (USA schedule) and
effect of booster at 12-14 months
Three Hib conjugate vaccines (PRP-T, PRP-OMP, HbOC) are currently licensed
for use in various countries. Original studies among Alaskan Eskimo infants,
and infants in California, USA, demonstrated that the three conjugate vaccines induce
markedly different immunologic responses. Only 60% of Alaskan Eskimo children
achieved an anti-PRP level of at least 1 µg/ml after a 3-dose series of PRP-OMP
(Bulkow et al., 1993), and low titres have been associated with higher susceptibility
to colonization (Fernandez et al., 2000). In 1997, a schedule for high-risk children
was introduced with PRP-OMP given as the first dose at two months followed by
HbOC at 4, 6, and 12 months. PRP-T and HbOC are administered in a 3-dose
primary series at 2, 4, and 6 months of age, with a booster dose recommended for all
infants at 12 to 15 months. Canada and the Kingdom of Belgium are also among the
countries using the same 2, 4 and 6-month schedule, with a booster dose in the
second year of life.
6.2 Hib conjugate immunogenicity at 2/3/4 months and effect of booster
at 12-14 months
An accelerated schedule of 2, 3 and 4 months with a booster in the second year of
life is in use in a number of European countries, including the French Republic,
the United Kingdom and the Kingdom of Belgium. In the United Kingdom,
Phase II studies of Hib conjugates showed good immunogenicity at the accelerated
schedule (Finn, 2004), and Hib conjugates were introduced in 1992, initially without
a booster dose. A study was performed to document the persistence of
vaccine-induced antibody in children in the United Kingdom, and this showed a
decline over the first five years of life. By 72 months of age, 32% of children
(95% CI 21% to 46%) had concentrations <0.15 µg/ml and so were apparently
unprotected (Heath et al., 2000a). The authors concluded that despite low measured
antibody concentrations, immunological memory was present in the population
studied, and this accounted for the ongoing reduced risk of contracting Hib in the
Pre-1996, Hib was given simultaneously (HbOC or PRP-T) with DTP in the
United Kingdom, but since then combination vaccines have been used exclusively so
that only PRP-T is administered in the primary series (combinations including
HbOC are not available). Evaluation of DTaP in the United Kingdom schedule has
revealed that Hib titres are reduced with such combination vaccines when
administered at the accelerated schedule (Bell et al., 1998), although even in the face
of poor primary responses, infants are primed for an excellent memory response
(Goldblatt et al., 1999). Due to an increase in Hib disease in the United Kingdom
(see Section 7.1) a routine Hib booster dose was introduced into the infant
immunization schedule with effect from September 2006. This is administered
simultaneously with meningococcal C conjugate vaccine at 12 months of age.
In the Kingdom of the Netherlands, Hib conjugate vaccine became part of the
primary course of childhood immunizations in 1993 at 3, 4, and 5 months of age,
with a booster given at the age of 11 months. In 1999, the primary infant vaccination
schedule was changed to 2, 3, and 4 months, with booster vaccination at 11 months
18 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
6.3 Hib conjugate immunogenicity at 3/5/12 months
In Scandinavian countries Hib disease occurs slightly later and a 2-dose schedule
at 3 and 5 months is used, followed by a booster third dose early in the second year
of life. In the Republic of Finland in 1990 and 1991, approximately 110 000 infants
received two doses of PRP-T at 4 and 6 months, with a booster dose at 14 to
18 months. This schedule was shown to be highly efficacious (Peltola, Kilpi & Anttila,
1992). In the Kingdom of Sweden it has been reported that the Hib vaccine has been
96% (95% CI) successful in reducing incidence after the first six years after its
introduction. One study (Garpenholt et al., 2000), during a six-year period found
six true vaccine failures, six apparent vaccine failures and one possible vaccine
failure in the 0-14 year age group in nearly two million vaccinated child-years
(Garpenholt et al., 2000; Farhoudi, Lofdahl & Giesecke, 2005). Another study in
the Kingdom of Sweden (Knutsson et al., 2001) found that mixing DTaP-IPV
(in which the pertussis vaccine consisted only of pertussis toxoid) with a Hib conjugate
vaccine led to an impaired antibody response to the Hib polysaccharide, but,
since protective levels of anti-Hib polysaccharide antibodies were achieved by all
subjects, the clinical relevance of this was probably of little clinical importance.
6.4 Hib conjugate immunogenicity at 6/10/14 weeks (EPI schedule)
The Expanded Programme on Immunization (EPI) schedule designed by the
World Health Organization (WHO) has been adopted by many different countries.
Hib conjugate vaccine is given in combination with DPwT at 6, 10 and 14 weeks of
age, at the same time as OPV, and this schedule has been found to be safe,
immunogenic and well tolerated. In the Republic of India, a study evaluated the
immune response to mixed or separate DTwP and Hib administered according to the
EPI schedule (Cherian et al., 2002), and found the mixed vaccines to be safe and
immunogenic and with the advantage of reducing the number of injections
administered per visit. DTPw-HBV/Hib vaccine was also reported in the
Republic of the Philippines (Gatchalian et al., 2005) to be immunogenic and well
tolerated when administered according to the EPI schedule. Capeding and
colleagues (Capeding et al., 1996) showed that all three Hib conjugate vaccines
(PRP-T, HbOC, and PRP-OMP) were immunogenic after three primary doses among
Philippine infants on the EPI schedule. Most infants immunised with Hib conjugates
according to the EPI schedules in the Republic of the Niger, and Cape Town in the
Republic of South Africa, achieved a level of anti-PRP antibodies >0.15 microgram/
ml, indicative of short-term protection, while over 70% achieved a level >1 g/ml,
indicative of long-term protection (Campagne et al., 1998; Hussey et al., 2002).
In the Republic of Kenya, introduction of Hib vaccine into the routine childhood
immunization EPI programme reduced Hib disease-incidence among children
younger than five years to 12% of its baseline level. This impact was observed by
the third year after vaccine introduction. (Cowgill et al., 2006).
Cost constraints have led to studies of fewer than the recommended numbers of
Hib conjugate doses or the administration of fractional doses of Hib. A study in the
Federative Republic of Brazil used a 2-dose regime and found that mean PRP antibody
titres were >1.0 µg/ml after two doses of PRP-T (Guimaraes et al., 2002). Nicol and
colleagues (Nicol et al., 2002) conducted a randomized trial comparing the use of
Hib conjugate vaccine diluted in a multidose vial of DTP with that of the full
Hib dose, to observe whether fractional dosing had an impact upon immunogenicity.
In this trial 168 South African infants received either the full dose Hib PRP-T vaccine
or a 1/10 dilution prepared by reconstituting the full dose in a 10-dose DTP vial.
Infants were vaccinated according to the EPI schedule at 6, 10 and 14 weeks of age
and received a full dose as a test of immunologic memory at nine months of age.
They showed that after the primary vaccination series, 95% of infants in the full
dose arm, and 94% of infants in the 1/10 dose arm achieved anti-PRP IgG antibody
concentrations of >1.0 µg/ml, and infants receiving the diluted vaccine also had
significantly higher titres of anti-PRP antibody in response to the booster dose.
In the Republic of Chile, a study of fractional dosing found that a mean of 91%
(83-96) to 100% (95-100) of infants immunized with one-half or one-third of a full
dose of Hib conjugate, developed protective antibody concentrations against Hib
(Levine et al., 1998). A recent study in the Republic of India showed similar findings
(Punjabi et al., 2006). However, it is unlikely that vaccine manufacturers will
reformulate their vaccines to produce substantially cheaper products, because a
66.7% reduction in antigen content is estimated to reduce costs by only 10% and
reformulation would also require companies to seek a new product licence
20 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
7. Vaccine effectiveness
Following introduction of Hib conjugate vaccines into routine childhood
immunization programmes in the 1990s, Hib disease has largely disappeared in
western Europe, Canada, the United States, Australia and New Zealand.
Re-emergence of invasive Hib disease in a well-vaccinated population in Alaska,
USA in 1997 (Galil et al., 1999) was attributed to ongoing carriage of Hib in the
context of a low prevalence of Hib antibody because of a change of Hib conjugate
vaccine. Vaccine efficacy has been shown in some cases to exceed 95% in infants
with a complete Hib vaccination schedule who are immunized starting from
two months of age (CDC, 2002). However, in some countries such as the
Republic of Finland (Eskola et al., 1999), high efficacy has been reported when the
vaccination schedule starts later, thereby showing that efficacy and effectiveness
depends on epidemiology.
Vaccine failures can however occur in a vaccinated population. Factors associated
with possible vaccine failure include prematurity (premature infants develop lower
antibody concentrations compared to full-term infants (Washburn et al., 1993;
Heath et al., 2003)), immunoglobulin deficiency, and clinical risk factors such as
malignancy and neutropaenia (Heath & McVernon, 2002).
While host factors might influence the risk of vaccine failure, there has also been an
interest in identifying bacterial factors that may play a role. Recently Cerquitti and
colleagues (Cerquetti et al., 2005) studied the frequency of a genetic duplication of
the capsulation locus frequently seen in invasive strains. The authors found that
strains containing amplified capb sequences were quite common among Hib strains,
and were significantly more frequent among strains from children with true vaccine
failure than among those from unvaccinated children, which suggests that the
amplification of the capb locus may contribute to vaccine failure because of the
increased virulence of the bacteria.
7.1 Developed country experience
The United States
Before the introduction of Hib conjugate vaccines, there were an estimated
20 000 cases of invasive Hib disease each year in the United States in children younger
than five years of age (Cochi, Broome & Hightower, 1985). Figure 3 shows that
after the introduction of Hib conjugate vaccines for toddlers in 1987 and for
infants in 1990, the incidence of invasive Hib disease declined by more than 99%
(Watt, Levine & Santosham, 2003). Hib conjugate vaccine has also been effective in
those populations within the United States who have a high incidence of Hib disease,
such as the American Indian and Alaskan Eskimo populations. The vaccination
policies in Alaska have changed several times over the past 10 years in response to
epidemiologic data and programmatic considerations. Routine Hib conjugate
vaccination was first implemented in 1991, with PRP-OMP being used statewide.
In 1996, Hib conjugate vaccine was changed to HbOC in combination with DTwP.
PRP-OMP continues to be the only Hib conjugate vaccine used in the Navajo
and Apache Indian populations in a schedule of 2, 4, and 12 to 15 months.
Coverage with Hib conjugate vaccine on the Navajo and White Mountain Apache
Indian reservations is higher than 90%.
Figure 3: Incidence of invasive Hib disease in the United States, 1990-2004
1990 1992 1994 1996 1998 2000 2002 2004
Doses were given at 2, 4, and 6 months with a booster at 12-15 months of age. x-axis: year; y-axis: cases
per 100 000 children <5 years of age. Reference: CDC, Pink Book: Haemophilus Influenzae Type b,
22 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
The United Kingdom
In the pre-vaccine era there were approximately 1500 annual cases of invasive
Hib disease in the United Kingdom, of which 900 were cases of meningitis and
60 resulted in death (Booy et al., 1995). Figure 4 shows the rapid decline of disease
after the introduction of Hib conjugate vaccines. When initially introduced in 1992,
the United Kingdom Hib conjugate vaccine programme had a number of unique
features, including an accelerated schedule with completion by four months of age,
the absence of a routine booster dose, and the inclusion of a catch-up component at
the beginning of the programme in which all children under the age of five years
were immunized within 12 months of the campaign starting. The rationale for the
United Kingdom approach was the belief that immunological memory after
three doses in infancy would be sufficient for protection through the early childhood
years when susceptibility was greatest (Heath & McVernon, 2002). The catch-up
campaign provided rapid protection for a large proportion of the susceptible
population and rapidly reduced rates of disease, protecting all of the at-risk group as
quickly as possible (Gay et al., 1997; Salisbury, 2001). As a result, the annual incidence
of Hib disease declined by 90%, falling to from 21/100 00 in the pre-vaccine era to
0.65 per 100 000 (Ramsay et al., 2003), and remained low throughout the 1990s.
Estimates of the efficacy of the vaccine suggested that seven to eight years after the
introduction of vaccine into the United Kingdom infant schedule, efficacy was still
in the order of 97% (McVernon et al., 2004b). Surveillance data also confirmed that
there was no compensatory increase in invasive disease due to non-typeable Hi.
Figure 4: Invasive Hib infections by age, 1990 to 2004,
England and Wales, combined PHLS HRU/CDSC data
300 5-14 yrs
250 15+ years
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
Data from the Health Protection Agency. http://www.hpa.org.uk/infections/topics_az/
However in the late 1990s the number of invasive Hib infections rose, with an increase
year-on- year in the number of cases in children born between 1996 and 2001.
By 2002 the disease incidence had reached 4.58 per 100 000 in those under
five years of age (Ramsay et al., 2003). Vaccine failures were occurring primarily in
children aged one to four years who completed the primary vaccination series,
but an increase in disease in those over 15 years of age was also seen.
An acellular pertussis combination vaccine (DTaP-Hib) was used briefly in
2001/2002 because of a shortage of the whole cell pertussis combination
(DTwP-Hib) vaccine, and this exacerbated the rise in the number of cases
(Heath & McVernon, 2002). A case-control study performed at the time demonstrated
an increased risk of vaccine failure in those who received the DTaP-Hib combination
(Ramsay et al., 2003). Despite intensive study and the supposition that Hib carriage
must have increased in the period, associated with increased disease,
adequately powered studies of Hib carriage in various age groups failed to reveal
significant Hib carriage in the United Kingdom population during this period
(Heath & McVernon, 2002). Trotter and colleagues (Trotter et al., 2003) studied
serum samples obtained from different birth cohorts and showed that Hib antibody
titres beyond the first year of life in cohorts immunized after the catch-up campaign
did not differ significantly from titres in similarly aged children in the pre-vaccine
era. McVernon and colleagues (McVernon et al., 2004b) analysed anti-PRP
IgG titres in the serum stored from adults in the United Kingdom, spanning the
period 1991 to 2003, and showed that titres in adults declined and remained low
following the introduction of Hib conjugate. This was presumably as a result of
reduced exposure to Hib due to the reduction in carriage associated with the
introduction of conjugate. Low circulating titres in toddlers and adults may thus
explain the increase in invasive disease in the United Kingdom between 1999 and
2002, which suggests that immune memory alone in a vaccinated child is unable to
provide robust protection against invasive Hib disease. A catch-up campaign was
undertaken in the United Kingdom in 2003 for all children under the age of
five years, and the incidence of invasive Hib disease reduced (Figure 4). A routine
Hib booster dose was introduced into the United Kingdom schedule in 2006.
Other European countries
In the Republic of Finland, Hib conjugate was introduced in 1986 at a 4, 6 and
15 month schedule and has proven to be highly efficacious (Eskola & Kayhty, 1996).
In the Kingdom of Norway, a routine infant vaccination programme (introduced at
3, 5 and 11-12 months), was accompanied by a catch-up programme for children up
to and including four years of age (Peltola et al., 1990). In the Kingdom of Sweden
following the introduction of routine Hib conjugate vaccination at 3, 5 and 12 months,
Hib epiglottis decreased from an incidence of 20.9 per 100 000 children <5 years old
in 1987 to 0.9 per 100 000 in 1996 (Garpenholt et al., 1999). The Kingdom of the
Netherlands, the French Republic and the Kingdom of Belgium have virtually
eliminated Hib disease, and the Republic of Iceland completely eliminated Hib disease
three years after the introduction of the vaccine.
24 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
7.2 Developing country experience
In July 1996, the Republic of Chile became the second non-industrialized nation,
after the Eastern Republic of Uruguay, to introduce Hib conjugate for routine use at
2, 4, and 6 months of age along with DTP and oral polio vaccine (Lagos et al., 1998).
Subsequently the Ministry of Health in the Republic of Chile decided to explore
ways to lower the cost of vaccination without compromising the vaccine's
effectiveness. Recent studies there have shown that two months after the
second dose of a primary vaccination series most patients have seroprotective
antibody titres and geometric mean titres are well above seroprotective thresholds
(Riedemann et al., 2002) suggesting that two doses may suffice, although this is not
yet Chilean government policy. Figure 5 shows the decline of Hib disease following
the introduction of Hib conjugate vaccine in the Republic of Chile and the Eastern
Republic of Uruguay.
A randomized, placebo-controlled trial of Hib conjugate was conducted in the
Western Region of the Republic of the Gambia between 1993 and 1995 and showed
that the vaccine provided 95% protective efficacy against all culture-confirmed,
invasive Hib disease, as well as 21% efficacy against radiographically-defined
pneumonia, and 60% protection against oropharyngeal carriage of Hib (Bijlmer &
Van, 1992; Mulholland et al., 1997). The Republic of the Gambia incorporated PRP-
T into its EPI in 1997, and since the introduction the incidence of Hib meningitis in
infants has declined from 200 per 100 000 to 21 per 100 000 (Adegbola et al., 1999).
Between 2001 and 2002, the Republic of Malawi, along with several other African
countries, introduced Hib conjugate vaccine with the assistance of the Vaccine Fund
of the Global Alliance for Vaccines and Immunization (GAVI), and the incidence of
Hib disease reduced by 88% in children <5 and 87% in children <2 (Hib Focus Vol
11, No. 4). Furthermore, vaccine effectiveness in preventing Hib meningitis among
HIV positive children with two or more doses while adjusting for age and residence
was close to 100%. Recently it has been reported that three years after introduction,
routine vaccination of infants against Hib in the Republic of Kenya showed invasive
Hib disease rates significantly reduced by 88% (Cowgill et al., 2006).
In other developing country settings, the perception of low burden of Hib disease
has meant that Hib conjugate introduction has not been perceived as a priority.
Lombok Island in the Republic of Indonesia was originally thought to have a low
incidence of Hib, although a recent study using Hib conjugate vaccine as a probe,
identified a high incidence of Hib meningitis with case-fatality proportions
between 12% and 18% (Gessner et al., 2005). The Lombok study showed that
Hib conjugate vaccine prevented a substantial amount of meningitis, but not
radiologically confirmed pneumonia, in young Indonesian children (Gessner et al.,
Despite the success of Hib conjugate vaccines it has been estimated that <8% of all
Hib disease worldwide is prevented by current vaccination coverage (Peltola, 2000),
with the highest disease burden in developing countries.
Figure 5: Impact of Hib vaccine by September 1997 in the
Eastern Republic of Uruguay and Republic of Chile
(adapted from: http://www.paho.org/English/HVP/HVI/hvp_hib_text.htm)
No. of isolates No. of isolates
1993 1994 1995 1996 1997 1996 1997
26 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
8. Future prospects
Three out of the four licensed Hib conjugate vaccines (PRP-HbOC, PRP-OMP,
PRP-T) have proven to be comparably efficacious in infancy, provided a complete
primary series is given. PRP-D performs less well in children below 18 months of
age, and is therefore no longer licensed or manufactured for use in infants.
All conjugate vaccines have an excellent safety record, and where tested,
do not interfere substantially with the immunogenicity of vaccines given
simultaneously. Furthermore, these vaccines are easily adapted to the routine schedule
of the national immunization programmes.
8.1 Hib conjugates in the EPI schedule
Recommendations of the Expanded Programme on Immunization of the
World Health Organization encourage simultaneous administration of several
childhood vaccines to attain comprehensive immunization as early as possible.
In addition, depending on the epidemiologic situation, the optimal immunization
schedule can vary from one country to another (WHO, 2006). A separate issue is
how to provide a new highly-effective vaccine in the existing EPI system. In common
with other newly developed vaccines, (including existing hepatitis B, and hepatitis A
vaccines, and imminent pneumococcal conjugate vaccines), Hib conjugate vaccines
are currently more expensive than those already in the EPI. WHO, the Children's
Vaccine Initiative (CVI), and others, are exploring approaches to reducing the cost
of these vaccines for non-industrialised countries.
Reduction in disease appears to occur more completely when a catch-up campaign is
instituted at the same time as routine immunization of infants is initiated.
An example of this impact can be seen by comparing the Eastern Republic of
Uruguay, which included a catch-up campaign, and the Republic of Chile, which did
not. In both countries cases declined by more than 90% compared to baseline,
but it took somewhat longer for the Republic of Chile to reach this goal
(Landaverde et al., 1999). In deciding whether to implement a catch-up campaign,
consideration must be given to the gain in disease prevented relative to the increased
cost of the vaccine and delivery operations.
8.2 Hib conjugates in combination vaccines
Hib conjugate combined with DTwP vaccines in a single injection are now widely
available for use in developing country settings. New combinations of higher valency
vaccines (such as DTPa-HBV-IPV/Hib) are licensed and used routinely in developed
countries but are likely to remain too costly for the foreseeable future for use in
8.3 The role of a booster dose
Most countries introducing Hib conjugate vaccine into routine vaccination
schedules have done so with the addition of a booster dose in the second year of life.
The major reason for this is the observation that vaccine-induced antibody wanes
over time (Heath et al., 2000a) leading to the concern that this may be accompanied
by an increase in susceptibility to disease. Infants who underwent the primary
schedule series and received a booster in the second year of life have shown elevated
antibody concentrations even at nine years of age (Claesson et al., 2005) or ten
(Makela et al., 2003). Although carriage has been low in the countries where these
studies were performed (the Kingdom of Sweden and the Republic of Finland
respectively), the persistence of high antibody concentrations reflects the probable
natural boosting due to cross reacting antigens. In the absence of vaccine boosting
and with little exposure to wild type Hib for natural boosting, anti-PRP antibody
levels induced by vaccination in infancy have been shown to wane over a period of
2-3 years (Heath et al., 2000a; Johnson et al., 2006), and experience in the
United Kingdom has shown that this may lead to a resurgence of Hib disease.
Booster doses are not routinely provided for in the EPI schedule. However,
it is unclear if the epidemiology of Hib in developing country settings using Hib
conjugates in infancy only, will mirror that seen in the United Kingdom. Further
surveillance of Hib in countries that have introduced Hib conjugate in the EPI
schedule is required. If boosting were required, it is important to study whether the
Hib conjugate could be administered at nine months of age when measles vaccine is
28 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
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42 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
The World Health Organization has provided The Quality, Safety and Standards team
technical support to its Member States in the focuses on supporting the use of vaccines,
field of vaccine-preventable diseases since other biological products and immunization-
1975. The office carrying out this function related equipment that meet current inter-
at WHO headquarters is the Department of national norms and standards of quality
Immunization, Vaccines and Biologicals (IVB). and safety. Activities cover: i ) setting norms
and standards and establishing reference
IVB’s mission is the achievement of a world preparation materials; ii ) ensuring the use of
in which all people at risk are protected quality vaccines and immunization equipment
against vaccine-preventable diseases. through prequalification activities and
The Department covers a range of activities strengthening national regulatory authorities;
including research and development, and iii ) monitoring, assessing and responding
standard-setting, vaccine regulation and to immunization safety issues of global
quality, vaccine supply and immunization concern.
financing, and immunization system
strengthening. The Expanded Programme on Immunization
focuses on maximizing access to high
These activities are carried out by three quality immunization services, accelerating
technical units: the Initiative for Vaccine disease control and linking to other health
Research; the Quality, Safety and Standards interventions that can be delivered during
team; and the Expanded Programme on immunization contacts. Activities cover:
Immunization. i ) immunization systems strengthening,
including expansion of immunization services
The Initiative for Vaccine Research guides,
beyond the infant age group; ii ) accelerated
facilitates and provides a vision for worldwide
control of measles and maternal and
vaccine and immunization technology
neonatal tetanus; iii ) introduction of new and
research and development efforts. It focuses
underutilized vaccines; iv ) vaccine supply
on current and emerging diseases of global
and immunization financing; and v ) disease
public health importance, including pandemic
surveillance and immunization coverage
influenza. Its main activities cover: i ) research
monitoring for tracking global progress.
and development of key candidate vaccines;
ii ) implementation research to promote The Director’s Office directs the work of
evidence-based decision-making on the these units through oversight of immunization
early introduction of new vaccines; and iii ) programme policy, planning, coordination and
promotion of the development, evaluation management. It also mobilizes resources and
and future availability of HIV, tuberculosis carries out communication, advocacy and
and malaria vaccines. media-related work.
Department of Immunization, Vaccines and Biologicals
Family and Community Health
World Health Organization
20, Avenue Appia
CH-1211 Geneva 27
Web site: http://www.who.int/immunization/en/
ISBN 978 92 4 159613 8