Haemophilus influenzae type B

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Sara E. Oliver, MD, MSPH; Pedro Moro, MD, MPH; and Amy E. Blain, MPH 

Haemophilus influenzae type b

● Causes severe bacterial

infection, particularly

among infants

● During late 19th century

believed to cause influenza

● Immunology and microbiology

clarified in 1930s

● Leading cause of bacterial

meningitis during

prevaccine era

Haemophilus influenzae

● Aerobic gram-negative bacteria

● Polysaccharide capsule

● Six different serotypes (a-f) of

polysaccharide capsule

● 95% of invasive disease caused

by type b during prevaccine era

Haemophilus influenzae is a bacterium that causes often-severe 

infections, particularly among infants. It was first described 

by Richard Pfeiffer in 1892. During an outbreak of influenza, 

he found H. influenzae in patients’ sputum and proposed a 

causal association between this bacterium and the clinical 

syndrome known as influenza. The organism was given the 

name Haemophilus by Charles-Edward Winslow, et al. in 1920. 

It was not until 1933 that it was established that influenza 

was caused by a virus and that H. influenzae was a cause of 

secondary infection. 

In the 1930s, Margaret Pittman demonstrated that H. 

influenzae could be isolated in encapsulated (typeable) and 

unencapsulated (nontypeable) forms. She observed that 

virtually all isolates from cerebrospinal fluid (CSF) and blood 

were of the capsular type b.

Before the introduction of effective vaccines, H. influenzae type 

b (Hib) was the leading cause of bacterial meningitis and other 

invasive bacterial disease, primarily among children younger 

than age 5 years; approximately one in 200 children in this 

age group developed invasive Hib disease. Approximately 

two-thirds of all cases occurred among children younger than 

age 18 months.

A pure polysaccharide vaccine was licensed for use in the United 

States in 1985 and was used until 1988. The first Hib conjugate 

vaccine was licensed in 1987.

Haemophilus influenzae

H. influenzae, a fastidious, pleomorphic, gram-negative

coccobacillus, requires hemin (X factor) and nicotinamideadenine-dinucleotide (NAD, also known as V factor) for in vitro

growth. It is generally aerobic, but can grow as an anaerobe

under certain conditions.

The outermost structure of encapsulated H. influenzae is 

composed of a polysaccharide, a key virulence factor. Six 

antigenically and biochemically distinct capsular polysaccharide 

types have been described; these are designated serotypes 

a through f. Hib capsule is composed of polyribosyl-ribitolphosphate (PRP), a polysaccharide used in Hib vaccines. There 

are currently no vaccines to prevent disease caused by non-b 

encapsulated or nontypeable strains. In the pre-Hib-vaccine era, 

type b organisms accounted for 95% of all H. influenzae strains 

that caused invasive disease.

Hib does not survive in the environment on inanimate surfaces.

https://www.cdc.gov/vaccines/pubs/pinkbook/hib.html Aug 2021
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Hib Pathogenesis

● Enters and colonizes 

nasopharynx

● May cause an invasive 

infection—invades bloodstream 

and infects distant sites in 

the body

● Incidence is age-dependent; 

peak occurrence was age 

6 to 11 months*

● Most children acquired 

immunity by age 5 or 6 years*

*Prevaccine era

Pathogenesis

H. influenzae enters the body through the nasopharynx. 

Organisms colonize the nasopharynx and may remain only 

transiently or for several months in the absence of symptoms 

(asymptomatic carrier). In the prevaccine era, Hib could be 

isolated from the nasopharynx of 0.5% to 3% of healthy infants 

and children, but was uncommon in adults. Nontypeable strains 

also frequently inhabit the human respiratory tract.

In some persons, H. influenzae causes an invasive infection. 

The exact mode of invasion of the bloodstream is unknown. 

A preceding viral or mycoplasma infection of the upper 

respiratory tract may be a contributing factor. The bacteria 

spread in the bloodstream to distant sites in the body. Meninges 

are especially likely to be affected.

Incidence is strikingly age-dependent. In the prevaccine era, 

up to 60% of invasive disease occurred before age 12 months, 

although some infants received passive protection from 

maternal IgG antibodies passed through the placenta and 

breastfeeding during the first 6 months of life. Peak occurrence 

was among children age 6 to 11 months. 

Antibodies to Hib capsular polysaccharide are protective. The 

precise level of antibody required for protection against invasive 

disease is not clearly established. However, a titer of 1 μg/mL 

3 weeks postvaccination correlated with protection in studies 

following vaccination with unconjugated, purified, PRP vaccine 

and suggested long-term protection from invasive disease.

In the prevaccine era, most children acquired immunity by age 

5 or 6 years through asymptomatic nasopharyngeal carriage 

of Hib bacteria. Since only a relatively small proportion of 

children carry Hib at any time, it has been assumed exposure 

to organisms that share common antigenic structures with the 

capsule of Hib (so-called “cross-reacting organisms”) may also 

stimulate the development of anticapsular antibodies against 

Hib. Natural exposure to Hib also induces antibodies to outer 

membrane proteins, lipopolysaccharides, and other antigens 

on the surface of the bacterium. The higher the age-specific 

incidence of Hib disease, the less likely there will be acquisition 

of both anticapsular and serum bactericidal antibody. 

The genetic constitution of the host may also be important 

in susceptibility to Hib infection. Risk for Hib disease has 

been associated with a number of genetic markers, but the 

mechanism of these associations is unknown. No single 

genetic relationship regulating susceptibility or immune 

responses to polysaccharide antigens has yet been 

convincingly demonstrated.
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Clinical Features

Hib can affect many organ systems. The most common types 

of disease are meningitis, bacteremia, epiglottitis, pneumonia, 

arthritis, and cellulitis.

Meningitis, an infection of the membranes covering the 

brain and spinal cord, is the most common clinical manifestation of invasive Hib disease, accounting for 50% to 

65% of cases in the prevaccine era. Hallmarks of meningitis 

are fever, decreased mental status, and stiff neck. Hearing 

impairment or other neurologic sequelae occur in 15% to 

30% of survivors. The case fatality ratio is 3% to 6%, despite 

appropriate antimicrobial therapy.

Epiglottitis is an infection and swelling of the epiglottis, 

the tissue in the throat that covers and protects the larynx 

during swallowing. Epiglottitis may cause life-threatening 

airway obstruction.

Septic arthritis, cellulitis, and pneumonia (which can be mild 

focal or severe empyema) are common manifestations of 

invasive Hib disease. Osteomyelitis and pericarditis are less 

common forms of invasive disease. 

Otitis media and acute bronchitis due to H. influenzae are 

generally caused by nontypeable strains. Hib strains account for 

only 5% to 10% of H. influenzae causing otitis media.

Non-type b encapsulated strains can cause invasive disease 

similar to type b infections. Nontypeable strains are generally 

less virulent than encapsulated strains among previously 

healthy individuals, but may cause invasive disease, particularly 

among neonates and those older than age 65 years.

Laboratory Testing

A Gram stain of an infected body fluid may demonstrate small, 

gram-negative coccobacilli suggestive of H. influenzae disease. 

CSF, blood, pleural fluid, joint fluid, and middle ear aspirates 

should be cultured on appropriate media. A positive culture 

for H. influenzae establishes the diagnosis. Detection of antigen 

or DNA may be used as an adjunct to culture, particularly in 

diagnosing H. influenzae infection in patients who have been 

partially treated with antimicrobial agents, in which case the 

organism may not be viable on culture.

All isolates of H. influenzae should be serotyped. This is an 

extremely important laboratory procedure that should be 

performed on every isolate of H. influenzae, especially those 

obtained from children younger than age 15 years. Two tests 

are available for serotyping isolates: slide agglutination and 

serotype-specific, real-time polymerase chain reaction (PCR). 

Slide agglutination is used to detect Hib capsular 

polysaccharide antigen in CSF, but a negative test does 

Hib Clinical Features

● Most common diseases 

resulting from Hib infection 

are meningitis, bacteremia, 

epiglottitis, pneumonia, 

arthritis, and cellulitis

● Generally requires 

hospitalization and 10 days 

of antimicrobial therapy

● Meningitis accounted for 

50% to 65% of cases with 

a fatality ratio of 3% to 6% 

(prevaccine era)
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not exclude the diagnosis, and false positive tests have 

been reported. Antigen testing of serum and urine is not 

recommended because of false positives. Serotype-specific, 

real-time PCR, currently available to detect the specific target 

gene of each serotype, can be used for detection of 

H. influenzae in blood, CSF, or other clinical specimens. 

Serotype-specific tests, usually done by a state health 

department or reference laboratory, indicate whether an 

isolate is type b, the only serotype that is potentially 

vaccine-preventable. 

Medical Management

Invasive Hib disease generally requires hospitalization. 

Antimicrobial therapy with an effective, third-generation 

cephalosporin (cefotaxime or ceftriaxone) should be started 

immediately. Chloramphenicol in combination with ampicillin 

could be used as an alternative. The treatment course is usually 

10 days. Ampicillin-resistant strains of Hib are now common 

throughout the United States. Children with life-threatening 

illness in which Hib may be the etiologic agent should not 

receive ampicillin alone as initial therapy.

Epidemiology 

Occurrence

Hib disease occurs worldwide. 

Reservoir

Humans are the only known reservoir. 

Transmission

H. influenzae colonizes the upper respiratory tract of humans 

and is transmitted person-to-person by inhalation of respiratory 

droplets or by direct contact with respiratory tract secretions. 

Neonates can acquire infection by aspiration of amniotic fluid or 

contact with genital tract secretions during delivery.

Temporal Pattern

Several studies in the prevaccine era described a bimodal 

seasonal pattern in the United States, with one peak during 

September through December and a second peak during March 

through May. The reason for this bimodal pattern is not known.

Communicability

The contagious potential of invasive Hib disease is considered 

to be limited. However, certain circumstances, particularly 

close contact with a case-patient (e.g., household, child care, or 

institutional setting) can lead to outbreaks or direct, secondary 

transmission of the disease.

Hib Epidemiology

● Reservoir

■ Human

● Transmission

■ Person-to-person through 

droplet inhalation or direct 

contact with respiratory tract 

■ Neonates can acquire during 

delivery through amniotic 

fluid or contact with genital 

tract secretions

● Temporal pattern

■ Bimodal: peaks in Sept–Dec 

and March–May 

● Communicability 

■ Generally limited but higher 

in some circumstances
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Risk Factors

Risk factors for Hib disease include both exposure factors and 

host factors. Exposure factors include household crowding, 

large household size, child care attendance, low socioeconomic 

status, low parental education levels, and school-age siblings. 

Host factors include age (youngest and oldest ages with 

elevated risk), race/ethnicity (Native Americans with an 

elevated risk, possibly confounded by socioeconomic variables 

associated with both race/ethnicity and Hib disease), and 

chronic disease (e.g., functional and anatomic asplenia, human 

immunodeficiency virus [HIV] infection, immunoglobulin 

deficiency, complement deficiency, receipt of chemotherapy or 

stem cell transplant). Protective factors (for infants younger than 

age 6 months) include breastfeeding and passively acquired 

maternal antibody.

Data are conflicting on the risk for secondary illness among 

child care contacts, but the risk is thought to be lower than 

among household contacts. Most studies suggest child care 

contacts are at relatively low risk for secondary transmission of 

Hib disease, particularly if contacts are appropriately vaccinated.

Secular Trends in the United States

Before the availability of national reporting data, several areas 

conducted active surveillance for H. influenzae disease, which 

allowed national estimates of disease. In the early 1980s, it was 

estimated that about 20,000 cases occurred annually in the 

United States, primarily among children younger than age 5 

years (40 to 50 cases per 100,000 population). The incidence of 

invasive Hib disease began to decline dramatically in the late 

1980s, coinciding with licensure of Hib conjugate vaccines, and 

has declined by more than 99% since the prevaccine era. 

Active Bacterial Core surveillance (ABCs) data includes serotype 

information on all invasive H. influenzae isolates. The number 

of cases and deaths of invasive H. influenzae infections in the 

United States increased from 3,400 in 1997 to 6,840 in 2018. 

Approximately 11.8% of cases died. While the rate of invasive 

H. influenzae infections increased from 1.23 per 100,000 

population in 1997 to 2.08 per 100,000 population in 2018 

in the surveillance areas, the rate of Hib infections decreased 

from 0.1 per 100,000 population in 1997 to 0.02 per 100,000 

population in 2018. Among children younger than age 5 years 

in 2018, the rate of invasive H. influenzae disease was 0.08 per 

100,000 population and 38 cases of invasive disease due to Hib 

were reported in the United States. An additional 9 cases of 

Hib are estimated to have occurred among the 175 reports of 

invasive H. influenzae infections with an unknown serotype. 

Hib Secular Trends in 

the United States

● About 20,000 cases of Hib 

annually before vaccine

● Incidence of Hib has declined 

99% since the prevaccine era

● From 2009-2018, 36 reported 

cases of Hib in patients 

younger than age 5 years

● Secondary cases of Hib are rare 

(illness occurring 1-60 days 

following contact with an 

ill person)
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From 2009–2018, 36 Hib cases in patients younger than age 

5 years were reported to ABCs. Two (5.6%) were too young to 

have received Hib vaccine, 12 (33.3%) were unvaccinated, and 

14 (38.9%) were undervaccinated (10 of 14 had received the 

3-dose primary series but were missing a booster dose at age 

12 through 15 months). Eight (22.2%) were age-appropriately 

vaccinated and had no reported underlying conditions; three of 

these were 3-month-old infants who had been age-eligible for 

only the first dose of Hib vaccine.

Secondary cases of Hib disease occur but are rare. Secondary 

Hib disease is defined as illness occurring 1 to 60 days following 

contact with an ill person, and accounts for less than 5% of all 

invasive Hib disease. Secondary attack rates are higher among 

household contacts younger than age 48 months (2.1%), 

especially those younger than age 12 months (6%) and younger 

than age 24 months (3%). In these household contacts, 64% of 

secondary cases occurred within the first week (excluding the 

first 24 hours) of disease onset in the index patient, 20% during 

the second week, and 16% during the third and fourth weeks.

Among children born during 2016–2017, 92.2% had received 

the Hib vaccine primary series (at least 2 or 3 doses, depending 

on product) and 79.9% had received the full series (primary 

series and booster; at least 3 or 4 doses, depending on product 

type) by age 24 months.

Haemophilus influenzae type b Vaccines 

A pure polysaccharide vaccine was licensed for use in the 

United States in 1985 and was used until 1988. The vaccine had 

low efficacy and is no longer available in the United States.

The characteristics of the Hib polysaccharide vaccine were 

similar to other polysaccharide vaccines. The response to the 

vaccine was typical of a T-independent antigen, most notably 

an age-dependent immune response and poor immunogenicity 

in children age 2 years or younger. In addition, no boost in 

antibody titer was observed with repeated doses, the antibody 

that was produced was relatively low-affinity IgM, and switching 

to IgG production was minimal.

The first Hib conjugate vaccine was licensed in 1987. 

Conjugation is the process of chemically bonding a 

polysaccharide to a more effective protein carrier. This process 

changes the polysaccharide from a T-independent to a 

T-dependent antigen and greatly improves immunogenicity, 

particularly in young children. In addition, repeat doses 

of conjugate vaccines elicit booster responses and allow 

maturation of class-specific immunity with predominance of 

IgG antibody. The conjugates also cause carrier priming and 

elicit antibody to “useful” carrier protein. 

Hib Vaccines

● Three conjugate vaccines

■ PRP-T (ActHIB)

■ PRP-T (Hiberix)

■ PRP-OMP (PedvaxHIB)

● Two combination vaccines 

containing Hib

■ DTaP-IPV/Hib (Pentacel)

■ DTaP-IPV-Hib-HepB (Vaxelis)
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Three monovalent Hib polysaccharide-protein conjugate 

vaccines (ActHIB, PedvaxHIB, and Hiberix) are currently licensed 

for use in the United States. 

Two combination vaccines containing Hib are currently 

licensed for use, DTaP-IPV/Hib (Pentacel) and DTaP-IPV-HibHepB (Vaxelis). 

Characteristics

Hib (PRP-T [ActHIB, Hiberix]) use a tetanus toxoid carrier protein, 

while Hib (PRP-OMP [PedvaxHIB]) uses a meningococcal outer 

membrane protein. DTaP-IPV/Hib (Pentacel) contains Hib (PRP-T) 

and DTaP-IPV-Hib-HepB (Vaxelis) contains Hib (PRP-OMP). Hib 

vaccines are administered by intramuscular injection. Each dose 

of Hib (PRP-OMP [PedvaxHIB]) vaccine contains aluminum as 

an adjuvant. Monovalent Hib vaccines contain no antibiotic 

or preservative. Specific ingredients to combination vaccines 

containing Hib vaccine differ. 

Vaccination Schedule and Use 

All infants should receive a primary series of Hib conjugate 

vaccine (monovalent or combination vaccine) beginning at 

age 2 months. The number of doses in the primary series 

depends on the type of vaccine used. A primary series of Hib 

(PRP-T) requires 3 doses, whereas Hib (PRP-OMP) requires 

2 doses. A booster dose is recommended at age 12 

through 15 months, regardless of which vaccine is used 

for the primary series. The recommended age for dose 4 of 

DTaP-IPV/Hib is age 15 through 18 months, but it can be 

administered as early as age 12 months, provided at least 

6 months have elapsed since dose 3.

Hib Vaccine Characteristics

● PRP-T use a tetanus toxoid 

carrier protein

● PRP-OMP uses a meningococcal 

outer membrane protein

● Administered by intramuscular 

injection

● PRP-OMP doses contain 

aluminum adjuvant
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Haemophilus influenzae type b (Hib) Routine 

Vaccination Schedule

Vaccine 

type

Vaccine 

Trade 

Names

2 months 4 months 6 months 12–15 

months

PRP-T

ActHIB Dose 1 Dose 2 Dose 3 Booster

Pentacel Dose 1 Dose 2 Dose 3 Booster*

Hiberix Dose 1 Dose 2 Dose 3 Booster†

PRP-OMP

PedvaxHIB Dose 1 Dose 2 — Booster

Vaxelis Dose 1 Dose 2 Dose 3§ Not 

indicated

* The recommended age for dose 4 of DTaP-IPV/Hib (Pentacel) is age 15 

through 18 months, but it can be administered as early as 12 months, 

provided at least 6 months have elapsed since dose 3.

† The recommended age for dose 4 of Hib (PRP-T) (Hiberix) is age 15 months, 

but to facilitate timely booster vaccination, it may be administered as early as 

age 12 months.

§The recommended minimum age for dose 3 of DTaP-IPV-Hib-HepB (Vaxelis) is 

24 weeks, the minimum age for completion of the hepatitis B vaccine series.

The recommended interval between doses in the primary series 

is 8 weeks, with a minimum interval of 4 weeks. At least 8 weeks 

should separate the booster dose from the previous (2nd or 3rd) 

dose. If DTaP-IPV/Hib is administered for the booster dose, at 

least 6 months need to have elapsed since dose 3. 

Hib vaccines should be given at the same visit as other 

recommended vaccines.

Limited data suggest Hib conjugate vaccines administered 

before age 6 weeks can induce immunologic tolerance, 

reducing the response to subsequent doses of Hib vaccine. 

Therefore, Hib vaccines, including combination vaccines 

containing Hib conjugate vaccine, should never be administered 

to a child younger than age 6 weeks.

The monovalent Hib conjugate vaccines are interchangeable. 

A series that includes vaccine of more than one brand will 

induce a protective antibody level. If a child receives different 

brands of Hib vaccine at age 2 and 4 months, a 3rd dose of any 

brand should be administered at age 6 months to complete 

the primary series. Any of these vaccines may be used for the 

booster dose, regardless of which vaccines were administered 

for the primary series. Data on the interchangeability of Hib 

combination vaccine with monovalent vaccines are limited. 

Whenever feasible, the same combination vaccine should be 

used for the subsequent doses. 

Hib Vaccination Schedule 

(Monovalent Vaccines)

● PRP-T (ActHIB and Hiberix) 

3-dose primary series at 

age 2, 4, and 6 months

● PRP-OMP (PedvaxHIB) 2-dose 

primary series at age 

2 and 4 months

● Booster dose at age 

12 through 15 months

● Recommended interval 

between primary series doses 

is 8 weeks and minimum 

interval is 4 weeks

● Minimum age for dose 1 is 

6 weeks

● Catch-up recommendations 

depend on child’s age

● Vaccines are interchangeable 

and should follow a 3-dose 

schedule if more than 1 brand 

is used
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Unvaccinated children age 7 months or older may not require a 

full series of 3 or 4 doses. The number of doses a child needs to 

complete the series depends on the child’s current age. 

Haemophilus influenzae type b Vaccine Schedule for 

Previously Unvaccinated Children

Vaccine

Age at 

1st Dose 

(months)

Primary series Booster

PRP-T

2–6 3 doses, each dose

8 weeks apart 12–15 months

7–11 2 doses, 

4 weeks apart 12–15 months

12–14 1 dose 8 weeks later

15–59 1 dose --

PRP-OMP

2–6 2 doses, 

8 weeks apart 12–15 months

7–11 2 doses, 

4 weeks apart 12–15 months

12–14 1 dose 8 weeks later

15–59 1 dose—

PRP-T (ActHIB, Hiberix)

Unvaccinated infants age 2 through 6 months should receive 

3 doses of vaccine, administered 2 months apart. The primary 

series should be followed by a booster dose at age 12 through 

15 months, administered at least 8 weeks after the last dose. 

A booster dose is only needed if 2 or 3 primary doses were 

administered before age 12 months. Unvaccinated children 

age 7 through 11 months should receive 2 doses of vaccine, 

4 weeks apart. Those 2 doses should be followed by a booster 

dose at age 12 through 15 months, administered at least 

8 weeks after the last dose. Unvaccinated children age 

12 through 14 months should receive 1 dose of vaccine, 

followed by a booster dose at least 8 weeks later. Any 

previously unvaccinated child age 15 through 59 months 

should receive a single dose of vaccine. 

PRP-OMP (PedvaxHIB)

Unvaccinated infants age 2 through 6 months should receive 

2 doses of vaccine, administered 2 months apart. Those 2 

doses should be followed by a booster dose at age 12 through 

15 months, administered at least 8 weeks after the last dose. 

Unvaccinated children age 7 through 11 months should receive 

2 doses of vaccine, 4 weeks apart, followed by a booster dose at 

age 12 through 15 months. The booster should be administered 
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at least 8 weeks after the last dose. Unvaccinated children 

age 12 through 14 months should receive 1 dose of vaccine, 

followed by a booster at least 8 weeks later. Any previously 

unvaccinated child age 15 through 59 months should receive a 

single dose of vaccine.

DTaP-IPV/Hib (Pentacel)

DTaP-IPV/Hib vaccine is approved for use as a 4-dose series 

for children age 6 weeks through 4 years. It is administered to 

infants at age 2, 4, 6, and 15 through 18 months. The minimum 

intervals for DTaP-IPV/Hib vaccine are determined by the 

DTaP component. The first 3 doses must be separated by at 

least 4 weeks between doses. Dose 4 must be separated from 

dose 3 by at least 6 months, and should not be administered 

before age 12 months. When DTaP-IPV/Hib vaccine is used 

to provide 4 doses at age 2, 4, 6, and between 15 through 18 

months (based on the DTaP and Hib schedules), an additional 

booster dose with IPV-stand alone or DTaP-IPV vaccine should 

be administered at age 4 through 6 years. This will result in a 

5-dose IPV vaccine series, which is acceptable.

DTaP-IPV-Hib-HepB (Vaxelis)

DTaP-IPV-Hib-HepB is approved for use as a 3-dose series 

for children age 6 weeks through 4 years. It is administered 

to infants at age 2, 4, and 6 months. The minimum intervals 

for DTaP-IPV-Hib-HepB vaccine are determined by the DTaP 

component. The 3 doses must be separated by at least 4 weeks 

between doses. Because the minimum age for the first dose of 

DTaP-IPV-Hib-HepB vaccine is 6 weeks, this vaccine cannot be 

used for the birth dose of hepatitis B (HepB) vaccine. The final 

dose of DTaP-IPV-Hib-HepB vaccine should be administered at 

age 24 weeks or older, the minimum age for completion of the 

hepatitis B vaccine series. When DTaP-IPV-Hib-HepB vaccine is 

used to provide 3 doses at age 2, 4, and 6 months (based on 

the DTaP and IPV schedules), this will result in a 4-dose HepB 

vaccine series, which is acceptable.

While single antigen PRP-OMP Hib vaccines are licensed as a 

2-dose primary series at age 2 and 4 months, DTaP-IPV-HibHepB is licensed as a 3-dose primary series. Therefore, three 

doses of a Hib conjugate-containing vaccine are needed to 

complete the primary series if DTaP-IPV-Hib-HepB is used for 

any doses. DTaP-IPV-Hib-HepB should not be used for the 

booster dose (given after completion of the 3-dose primary 

series). Any Hib conjugate vaccine licensed for a booster dose 

can be used. If DTaP-IPV-Hib-HepB is inadvertently given for 

the booster dose, the dose does not need to be repeated with 

another Hib-containing vaccine, if the proper spacing of prior 

doses is maintained. 
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Vaccination of Special Populations and 

Older Children

Children younger than age 24 months who develop invasive 

Hib disease should be considered susceptible and should 

receive Hib vaccine. Vaccination of these children should start 

as soon as possible during the convalescent phase of the illness. 

A complete series as recommended for the child’s age should 

be administered.

Children age 12 through 59 months who are at increased risk for 

Hib disease, including chemotherapy recipients and those with 

anatomic and functional asplenia (including sickle-cell disease), 

HIV infection, immunoglobulin deficiency, or early complement 

component deficiency, who have received either no doses or 

only 1 dose of Hib vaccine before age 12 months, should receive 

2 additional doses of Hib vaccine, 8 weeks apart. Children who 

received 2 or more doses of Hib vaccine before age 12 months 

should receive 1 additional dose. 

If a child younger than age 5 years undergoing chemotherapy 

or radiation treatment received a Hib vaccine dose(s) within 14 

days of starting therapy or during therapy, they should receive a 

repeat dose(s) at least 3 months following therapy completion.

In general, Hib vaccination of persons older than age 59 months 

is not recommended. The majority of older children are immune 

to Hib, probably from asymptomatic infection as infants. 

However, some older children and adults are at increased risk 

for invasive Hib disease and may be vaccinated if they were not 

vaccinated in childhood. A single dose of any Hib-containing 

vaccine should be administered to persons age 15 months or 

older undergoing an elective splenectomy if they are considered 

unimmunized. “Unimmunized” means they have not received 

a primary series and booster dose or at least 1 dose of Hib 

vaccine after age 14 months. If possible, the vaccine should be 

administered at least 14 days before the procedure. Hib vaccine 

should be administered to children age 5 years or older and 

adults who have anatomic or functional asplenia if they are 

considered unimmunized. Hib vaccine should be administered 

to children and adolescents age 5 through 18 years if they have 

HIV and are considered unimmunized. Adults with HIV do not 

need a dose of Hib vaccine. Hematopoietic stem cell transplant 

recipients of any age should receive 3 doses of Hib vaccine at 

least 4 weeks apart, beginning 6 to 12 months post-transplant, 

regardless of Hib vaccination history. 

For American Indians/Alaska Natives (AI/AN), the Advisory 

Committee on Immunization Practices (ACIP) recommends 

Hib (PRP-OMP) as the preferred vaccine for the primary series 

doses. Hib meningitis incidence peaks at a younger age among 

AI/AN infants, and Hib (PRP-OMP) produces a protective 

antibody response after the first dose, providing early protection. 

Hib Vaccination of Special 

Populations and Older Children

● Children younger than 

age 24 months who develop 

invasive Hib

■ Vaccinate as soon as possible 

during convalescent phase

■ Administer complete series 

for age

● Children age 12 through 

59 months at increased risk 

(chemotherapy, anatomic 

and functional asplenia, HIV 

infection, immunoglobulin 

deficiency, early complement 

component deficiency) 

■ If child received 0 or 1 dose 

before age 12 months, 

administer 2 doses, 8 weeks 

apart

■ If child received 2 or more 

doses before age 12 months, 

administer 1 dose

● Unimmunized persons age 15 

months or older undergoing an 

elective splenectomy

■ Administer 1 dose at least 14 

days before procedure

● Unimmunized persons age 5 

years or older with anatomic or 

functional asplenia

■ Administer 1 dose

● Unimmunized children and 

adolescents age 5 through 18 

years with HIV

■ Administer 1 dose

● Hematopoietic stem cell 

transplant recipients of any age

■ Administer 3 doses at least 4 

weeks apart, beginning 6 to 

12 months post-transplant

● American Indians/Alaska 

Natives

■ Administer PRP-OMP as 

preferred vaccine
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Immunogenicity and Vaccine Efficacy

Hib conjugate vaccines are highly immunogenic. More than 

95% of infants develop protective antibody levels after a 

primary series. Clinical efficacy has been estimated at 95% to 

100%. Invasive Hib disease is uncommon in children who are 

fully vaccinated.

Hib vaccine is also immunogenic in patients at increased risk for 

invasive disease, such as those with sickle-cell disease, leukemia, 

or those who have had a splenectomy. In persons with HIV 

infection, immunogenicity varies with stage of infection and 

degree of immunocompromise. Efficacy studies have not been 

performed in populations with increased risk of invasive disease.

Contraindications and Precautions 

to Vaccination

As with other vaccines, a history of a severe allergic reaction 

(anaphylaxis) to a vaccine component or following a prior 

dose is a contraindication to further doses. Moderate or severe 

acute illness with or without fever in a patient is considered a 

precaution to vaccination, although persons with minor illness 

may be vaccinated. 

Hib conjugate vaccines are contraindicated for children younger 

than age 6 weeks because of the potential for development of 

immunologic tolerance.

Contraindications to combination vaccines that contain Hib 

include the contraindications to the individual component 

vaccines, but specific ingredients might differ.

Vaccine Safety

Adverse reactions following Hib conjugate vaccines are not 

common. Swelling, redness, or pain have been reported in 5% 

to 30% of recipients and usually resolve within 12 to 24 hours. 

Systemic reactions such as fever and irritability are infrequent. 

Among reports to the Vaccine Adverse Event Reporting System 

(VAERS) following Hib vaccination, the most frequently reported 

adverse events were fever (31%), crying (11%), injection site 

erythema (11%), irritability (10%), and rash (9%). The median 

time from vaccination to onset of an adverse event was 1 day. 

The adverse event reporting frequencies for Hib vaccines are 

similar to those of other childhood vaccines; no unusual or 

unexpected safety concerns were observed in VAERS data for 

Hib vaccines.

Hib Vaccine Efficacy

● Highly immunogenic

● More than 95% of infants 

develop protective antibody 

levels after a primary series

Hib Vaccine Contraindications 

and Precautions

● Contraindication

■ Severe allergic reaction to 

a vaccine component or 

following a prior dose 

of vaccine

■ Children younger than age 

6 weeks

● Precaution

■ Moderate or severe 

acute illness

Hib Vaccine Safety

● Adverse reactions uncommon

● Swelling, redness, or pain 

■ 5%–30%

● Fever

■ 31%

● Crying

■ 11%

● Injection site erythema

■ 11%

● Irritability

■ 10%

● Rash

■ 9%
Haemophilus influenzae type B

123

8

In an observational study conducted by the Vaccine Safety 

Datalink of DTaP-IPV/Hib, children age 1 to 2 years who received 

DTaP-IPV/Hib had an elevated risk of fever compared to children 

who received DTaP-containing control vaccine (i.e., without 

Hib vaccine). DTaP-IPV/Hib was not associated with any other 

medically-attended adverse health event. 

Vaccine Storage and Handling

Hib vaccines should be maintained at refrigerator temperature 

between 2°C and 8°C (36°F and 46°F). Manufacturer package 

inserts contain additional information. For complete information 

on best practices and recommendations for vaccine storage and 

handling, please refer to CDC’s Vaccine Storage and Handling 

Toolkit, www.cdc.gov/vaccines/hcp/admin/storage/toolkit/

storage-handling-toolkit.pdf.

Surveillance and Reporting of Hib Disease

Reporting of H. influenzae varies by state. Invasive H. influenzae 

infections became nationally notifiable in 1991. Reporting 

of serotype information continues to be incomplete. For 

information on the case definition and guidance on case 

and contact investigations, please consult the Manual for the 

Surveillance of Vaccine-Preventable Diseases, www.cdc.gov/

vaccines/pubs/surv-manual/index.html. 
124

Haemophilus influenzae type B

 8

Acknowledgements

The editors would like to acknowledge Elizabeth Briere, Susan 

Hariri, and Heidi Soeters for their contributions to this chapter.

Selected References

American Academy of Pediatrics. Haemophilus influenzae

infections. In: Kimberlin D, Brady M, Jackson M, et al., eds. Red 

Book: 2018 Report of the Committee on Infectious Diseases. 31st 

ed. Itasca, IL: American Academy of Pediatrics; 2018:367–75. 

Bisgard K, Kao A, Leake J, et al. Haemophilus influenzae invasive 

disease in the United States, 1994–1995: near disappearance 

of a vaccine-preventable childhood disease. Emerg Infect Dis 

1998;4(2):229–37.

Blain A, MacNeil J, Wang X, et al. Invasive Haemophilus influenzae

disease in adults ≥65 years, United States, 2011. Open Forum 

Infect Dis 2014;1(2):ofu044.

CDC. Prevention and Control of Haemophilus influenzae Type 

b Disease: recommendations of the Advisory Committee on 

Immunization Practices (ACIP). MMWR 2014;63(No. RR-1):1–14.

CDC. Food and Drug Administration approval for use of Hiberix 

as a 3-Dose primary Haemophilus influenzae type b (Hib) 

vaccination series. MMWR 2016;65(16):418–9.

CDC. Haemophilus influenzae invasive disease among children 

aged <5 years—California, 1990–1996. MMWR 1998;47(35):737–40.

CDC. Prevention and Control of Haemophilus influenzae type b 

disease: recommendations of the ACIP, 2014. MMWR 2014;63

(RR-01):1–14.

CDC. Progress toward elimination of Haemophilus influenzae

type b disease among infants and children—United States, 

1998–2000. MMWR 2002;51(11):234–7.

Decker M, Edwards K. Haemophilus influenzae type b vaccines: 

history, choice and comparisons. Pediatr Infect Dis J 1998;17(9 

Suppl):S113–6.

Livorsi D, MacNeil J, Cohn A, et al. Invasive Haemophilus 

influenzae in the United States, 1999–2008: epidemiology and 

outcomes. J Infect 2012;65(6):496–504.

MacNeil J, Cohn A, Farley M, et al. Current epidemiology and 

trends in invasive Haemophilus influenzae disease–United States, 

1989–2008. Clin Infect Dis 2011;53(12):1230–6.

Nanduri S, Sutherland A, Gordon L, et al. Haemophilus influenzae

vaccines. In: Plotkin S, Orenstein W, Offit P, et al., eds. Plotkin’s 

Vaccines. 7th ed. Elsevier;2018:301–18.

Orenstein W, Hadler S, Wharton M. Trends in vaccinepreventable diseases. Semin Pediatr Infect Dis 1997;8(1):23–33.

Soeters H, Blain A, Pondo T, et al. Current epidemiology and 

trends in invasive Haemophilus influenzae disease — United 

States, 2009–2015. Clin Infect Dis 2018;67(6):881–9.

NOTES