Version May 2024
INTRODUCTION — Haemophilus influenzae serotype b (Hib) was once the most common cause of bacterial meningitis and a frequent cause of other invasive diseases (eg, epiglottitis, pneumonia, septic arthritis, bacteremia), particularly in early childhood. The widespread use of Hib conjugate vaccines in infancy has led to a dramatic decline in the incidence of invasive Hib disease in children. However, invasive Hib disease remains common in countries not using the vaccine. Other strains of H. influenzae, particularly nontypeable H. influenzae (NTHi), cause mucosal and respiratory infections throughout life.
Active immunization and chemoprophylaxis for prevention of Hib infections will be discussed here. The microbiology and epidemiology of Haemophilus infections and the clinical syndromes caused by H. influenzae (typeable and nontypeable) in children and adults are discussed separately:
●(See "Epidemiology, clinical manifestations, diagnosis, and treatment of Haemophilus influenzae".)
●(See "Bacterial meningitis in children older than one month: Clinical features and diagnosis" and "Clinical features and diagnosis of acute bacterial meningitis in adults".)
●(See "Epiglottitis (supraglottitis): Clinical features and diagnosis".)
●(See "Acute otitis media in children: Epidemiology, microbiology, and complications" and "Acute otitis media in children: Clinical manifestations and diagnosis" and "Acute otitis media in adults".)
●(See "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis" and "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis".)
●(See "Community-acquired pneumonia in children: Clinical features and diagnosis" and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)
HIB CONJUGATE VACCINES — Active immunization is the most important strategy for prevention of Hib infection. Licensed vaccines against nontype b strains and nontypeable strains of H. influenzae are not available [1].
Composition and storage — Hib conjugate vaccines consist of the type b capsular polysaccharide (polyribosylribitol phosphate [PRP)] conjugated to a protein carrier (eg, the outer membrane protein complex of Neisseria meningitidis [OMP] or tetanus toxoid) [1]. Conjugation of PRP to a protein carrier is necessary to induce T cell-dependent memory, which increases immunogenicity in young children. Antibodies against PRP activate complement, are opsonophagocytic and bactericidal, and protect from lethal Hib challenge in animal models [2-6]. The OMP and tetanus toxoid protein carriers do not provide protection against N. meningitidis or tetanus.
Several Hib conjugate vaccines are licensed in the United States (table 1). Hib conjugate vaccines licensed for use in the United States do not contain thimerosal [7].
A description of Hib conjugate vaccines for use in other countries is beyond the scope of this topic review. The World Health Organization maintains a database of vaccines that are prequalified for UNICEF and other United Nations agencies.
Hib conjugate vaccines (whether ready-to-use or freeze-dried) and diluents (if applicable) should be stored at 35 to 46°F (2 to 8°C) [8]. Freeze-dried polyribosylribitol phosphate conjugated to tetanus toxoid (PRP-T) powder should be protected from light; the diluent must not be frozen.
Efficacy/effectiveness — Prelicensure randomized trials of monovalent Hib conjugate vaccines demonstrated protective efficacy of ≥95 percent against invasive Hib disease after completion of the two- or three-dose primary series as recommended [9-11].
With routine infant immunization, invasive Hib disease has been virtually eliminated from the United States (figure 1) and other countries that routinely immunize infants against Hib [12-14]. The public health benefit of routine Hib immunization exceeded expectations based on efficacy trials alone. The added benefit appears to be due to reduced carriage and transmission in the community, which extends protection to the unimmunized (ie, "herd immunity").
Routine Hib immunization has not affected the burden of disease caused by other serotypes and nontypeable H. influenzae (NTHi). NTHi are an important cause of acute otitis media, acute sinusitis, bronchitis, and community-acquired pneumonia and an increasingly frequent cause of invasive disease [15]. Development of NTHi vaccines is an active area of investigation [16-18].
Adverse effects — Systemic reactions (eg, fever, irritability) are infrequent after Hib immunization [19]. Local reactions (eg, pain, redness, and/or swelling at the injection site) occur in approximately 25 percent of recipients. Local reactions usually are mild and resolve within 24 hours. The rate of adverse reactions with Hib-containing combination vaccines is similar to that when the component vaccines are administered separately [20-22].
In the United States, adverse events after vaccine administration should be reported to the Vaccine Adverse Event Reporting System (VAERS).
ROUTINE CHILDHOOD IMMUNIZATION IN THE UNITED STATES
Routine schedule — Hib conjugate vaccine is recommended for all infants in the United States [1,23]. The routine schedule consists of a two- or three-dose primary series (at age two and four months or two, four, and six months, depending upon the vaccine formulation) and a booster dose at 12 through 15 months of age (table 2) [1,23]. Hib conjugate vaccines can be administered at the same visit as other routine childhood immunizations (figure 2A) [24].
The minimum age for the first dose is six weeks; doses administered before six weeks should not be counted as valid. The recommended interval between doses in the primary series is eight weeks; however, doses separated by at least four weeks may be counted as valid [1]. The minimum age for the final dose is 12 months, and the minimum interval between the booster dose and the previous (second or third dose in the primary series) is eight weeks.
Protective levels of antibodies are achieved after two or three doses of conjugate Hib vaccines in young infants [9,25-29]. The booster dose is needed at 12 to 15 months to maximize long-term protection because of waning immunity and/or incomplete maturation of antibody by memory B cells [30-33]. Lack of a dose after 12 months of age has been associated with outbreaks of invasive Hib disease [33-35].
A 2013 systematic review of 21 randomized trials from 15 countries comparing different Hib vaccine schedules (eg, three primary doses with no booster, three primary doses with a booster, two primary doses with a booster) found little difference between schedules with respect to development of seroprotection [34]. However, children who received a booster dose were more likely to be seropositive than children of the same age who did not receive a booster dose. A separate 2013 systematic review of 30 observational studies of Hib vaccine effectiveness from 17 countries also found no particular schedule to be superior and some evidence to suggest that a booster dose provides additional protection [35].
Choice of vaccine
●Primary series – Most children can receive any of the licensed vaccines (table 1) for the primary series (table 2).
It is ideal to use the same Hib conjugate vaccine to complete the primary series. However, if it is unknown which vaccine was previously administered, or if the same vaccine is not available, the vaccines can be interchanged [23]. If two different preparations are used, a three-dose primary series is required.
Polyribosylribitol phosphate conjugated to outer membrane protein complex of N. meningitidis (PRP-OMP) is preferred for American Indian/Alaska Native infants, who are at increased risk for invasive Hib disease compared with non-American Indian/Alaska Native infants [1,23,36-38]. PRP-OMP induces high antibody responses after the first dose (usually given at age two months) [25-28,39,40]. After the second dose (usually given at age four months), more than 94 percent of infants mount an adequate antibody response [28,29].
●Booster dose – Any of the Hib conjugate vaccines except the combination diphtheria-tetanus toxoids-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate (Vaxelis) may be used for the booster dose (table 2); the vaccine need not be the same as the one used for the primary series [1,41].
Catch-up schedule
●Children <5 years – The catch-up schedule for Hib conjugate vaccine in children younger than five years (whether or not they are immune compromised) depends upon the age at which the series is initiated and the number of doses previously received (table 3) [42].
The Centers for Disease Control and Prevention has developed "job aids" to provide guidance for catch-up of Hib vaccine in children <5 years:
•Previous immunization with PedVaxHIB or Comvax (discontinued in 2014)
●Immune-competent children ≥5 years – Catch-up Hib vaccination is not indicated for immune-competent children ≥5 years of age. Natural immunity increases with age [43-46]. In the prevaccine era, invasive Hib disease occurred primarily in children younger than five years. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of Haemophilus influenzae", section on 'Hib invasive disease'.)
●Children ≥5 years at increased risk of invasive Hib disease – Recommendations for Hib immunization for persons ≥5 years of age who are at increased risk of invasive Hib disease are provided below. (See 'High risk of invasive Hib disease' below.)
Immunization in special circumstances
High risk of invasive Hib disease — The risk of invasive Hib disease is increased in [1,23]:
●Anatomic or functional asplenia (including sickle cell disease)
●HIV infection
●Immunoglobulin deficiency, including immunoglobulin G2 (IgG2) subclass deficiency
●Early component complement deficiency
●Recipients of hematopoietic stem cell transplant
●Recipients of chemotherapy or radiation therapy for malignant neoplasms
Recommendations for Hib conjugate immunization of children, adolescents, and adults at increased risk of invasive Hib disease vary according to age, number and timing of previous doses, and immune-compromising condition (table 4) [1,23,47].
Recommendations for Hib conjugate immunization in specific high-risk populations are discussed in greater detail separately:
●Individuals with anatomic or functional asplenia (or undergoing elective splenectomy) (see "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations')
●Individuals with HIV infection (see "Immunizations in persons with HIV", section on 'Haemophilus influenzae vaccine')
●Adults with cancer (see "Immunizations in adults with cancer", section on 'Haemophilus influenzae vaccine')
●Hematopoietic cell transplant candidates or recipients (see "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Haemophilus influenzae')
●Solid organ transplant candidates or recipients (see "Immunizations in solid organ transplant candidates and recipients", section on 'Haemophilus influenzae')
History of invasive Hib disease — The need for Hib immunization in children with a history of invasive Hib disease depends upon the age at the time of invasive infection:
●Before 24 months – Children who have invasive Hib disease before 24 months can remain at risk for a second episode of invasive Hib disease; natural infection at this age does not reliably result in protective antibody levels [1,23,48]. Such children should be immunized according to the age-appropriate schedule for unimmunized children (ie, as if they had never received Hib vaccine) [1,23]. Immunization should be initiated one month after the onset of invasive disease or as soon thereafter as possible. (See 'Catch-up schedule' above.)
●After 24 months – Children who have invasive Hib disease after 24 months of age virtually always develop a protective immune response and do not require immunization.
Children who develop invasive Hib disease despite two to three doses of Hib conjugate vaccine and those who have recurrent invasive Hib disease should undergo immunologic evaluation, particularly for IgG2 subclass deficiency [23,49,50]. (See "IgG subclass deficiency", section on 'IgG2 deficiency'.)
Preterm infants — Medically stable preterm infants should be vaccinated against Hib according to the routine schedule based on their chronologic age. (See "Care of the neonatal intensive care unit graduate", section on 'Immunizations'.)
Contraindications and precautions — Hib-containing vaccines are contraindicated in infants younger than six weeks and individuals with a severe allergy to any vaccine component (eg, latex if the vial stopper contains latex (table 1)) [1]. Administration of Hib conjugate vaccine before six weeks of age may induce immune tolerance and reduce the response to subsequent doses [51].
Moderate or severe acute illness (ie, illness more severe than upper respiratory infection, otitis media, gastroenteritis) with or without fever is a precaution to administration of Hib conjugate vaccine [52].
Administration — Each dose of Hib conjugate vaccine is 0.5 mL. Hib conjugate vaccine is administered intramuscularly, usually in the anterolateral thigh (for children <3 years) or deltoid (for children ≥3 years) (table 5). Hib conjugate vaccine may be administered at the same clinic visit as other routine childhood immunizations (figure 2A-B) [53].
ROUTINE IMMUNIZATION OUTSIDE THE UNITED STATES — The World Health Organization (WHO) recommends universal infant immunization against Hib [54]. Routine immunization schedules vary from country to country [55]. Schedules for individual countries are available through the WHO.
POSTEXPOSURE CHEMOPROPHYLAXIS — Chemoprophylaxis may be indicated for household (or close) contacts of a child with invasive Hib or H. influenzae type a disease, child care or preschool contacts, and the index patient, depending upon individual circumstances as described below [23]. Chemoprophylaxis generally is not indicated for contacts of people with invasive disease caused by nontype b strains of H. influenzae, nontype a strains of H. influenzae, or nontypeable H. influenzae.
Indications — We follow the indications for postexposure chemoprophylaxis provided by the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP), which are described below [1,23]. Guidance from Public Health England, Department of Health and NHS England uses a slightly different definition of close contact and considers children younger than 10 years (rather than four years) to be susceptible to invasive Hib disease [56].
Household/close contact — A household or close contact is defined as a person who resides with the index patient or who spent ≥4 hours with the index patient for at least five of the seven days before the day of hospital admission of the index case [23].
When there is a vulnerable household member, chemoprophylaxis is recommended for all household contacts (including the index case) [23]. This includes:
●Household with at least one contact <4 years of age who has not received an age-appropriate number of doses of Hib conjugate vaccine; in addition to chemoprophylaxis, the susceptible child(ren) should receive a dose of Hib conjugate vaccine and be scheduled for completion of Hib immunization if additional doses are necessary (see 'Routine childhood immunization in the United States' above)
●Household with a child <12 months of age who has not completed the primary Hib series (see 'Routine childhood immunization in the United States' above)
●Household with a contact <18 years who is immunocompromised, regardless of that child's Hib immunization status; chemoprophylaxis is not required for households with an immunocompromised adult [1]
For household/close contacts, chemoprophylaxis should be initiated as soon as possible [57]. Provision of chemoprophylaxis to household/close contacts soon after the index case is diagnosed with invasive Hib disease can eradicate nasopharyngeal carriage of Hib, thereby reducing the risk of developing invasive disease and interrupting transmission [58-62]. (See 'Regimen' below and "Pathogenesis and pathophysiology of bacterial meningitis".)
In observational studies from the prevaccine era, secondary attack rates were higher among household contacts younger than four years, and particularly those younger than one year [63-65]. In a large prospective study, the overall risk of invasive Hib disease among household contacts of an index patient with Hib meningitis was 0.21 percent, many times greater than the age-adjusted risk in the general population [64]. The risk was 6 percent among infants younger than one year, 2.1 percent in children younger than four years, and 0 percent in persons ≥6 years.
Child care or preschool contacts — Clinicians should follow local public health requirements regarding chemoprophylaxis of child care or preschool contacts of a child with invasive Hib disease.
Chemoprophylaxis for child care or school contacts after one case of invasive Hib disease is controversial. Epidemiologic studies have reached different conclusions regarding the risk among child care contacts compared with household contacts [66]. The risk among child care contacts appears to be increased relative to the general population but lower than in household/close contacts [65,67,68].
The AAP and CDC Advisory Committee on Immunization Practices recommend chemoprophylaxis for child care and preschool contacts (regardless of age or vaccine status) when unimmunized or incompletely immunized children attend the facility and two or more cases of Hib invasive disease have occurred among attendees within 60 days [1,23].
Index patient — Chemoprophylaxis is indicated to eradicate nasopharyngeal carriage of Hib from the index patient if they did not receive treatment for their infection with either ceftriaxone or cefotaxime, and the index patient either [1,23,69-71]:
●Is <2 years of age, or
●Lives in a household with a child <4 years of age who has not received an age-appropriate number of doses of Hib conjugate vaccine or an immunocompromised child <18 years of age (see 'Routine childhood immunization in the United States' above)
Prophylaxis for the index patient if indicated as above should be initiated within two weeks of the onset of disease and may be initiated immediately at the end of their therapy for invasive disease.
Drugs other than ceftriaxone and cefotaxime that may be used to treat Hib infections (eg, ampicillin, cefaclor) do not reliably eradicate Hib from the nasopharynx [72-77].
Regimen — Rifampin 20 mg/kg orally (maximum dose 600 mg) once per day for four days is the regimen of choice for Hib chemoprophylaxis in individuals ≥1 month [23]. The dose of rifampin for infants <1 month of age has not been established; we suggest 10 mg/kg once per day for four days.
Consultation with an expert in infectious diseases is recommended for contacts in whom rifampin is contraindicated.
In placebo-controlled randomized trials and observational studies, rifampin eliminated nasopharyngeal carriage of Hib in greater proportions of household or day care contacts of patients with invasive Hib disease (≥95 percent versus <30 percent) [58-62].
Drugs other than ceftriaxone and cefotaxime that may be used to treat Hib infections, such as ampicillin [72-74], cefaclor [75,76], and TMP-SMX [77], are not effective for chemoprophylaxis because they do not reliably eradicate Hib from the nasopharynx. We recommend not using these agents for antimicrobial prophylaxis against invasive Hib disease.
Monitoring contacts for illness — In addition to receiving chemoprophylaxis, exposed unimmunized or incompletely immunized children who are household, child care, or preschool contacts of patients with invasive Hib disease must be observed for signs of illness [23]. Exposed children in whom febrile illness develops should receive prompt medical attention. This is especially true for twins in which a co-primary or secondary case may occur in up to 25 percent of twin pairs [41].
The child should be examined for a focus of infection; lumbar puncture may be warranted based upon clinical presentation and risk factors (eg, age, immune competence). (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Clinical features'.)
Infections should be treated as indicated after appropriate cultures have been obtained. Parenteral antibiotics should be administered pending blood culture results if occult bacteremia is suspected. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of Haemophilus influenzae", section on 'Empiric treatment' and "Fever without a source in children 3 to 36 months of age: Evaluation and management", section on 'Bacteremia'.)
INFECTION CONTROL
Hospitalized patients — Hospitalized patients with known or suspected Hib infections should be in private rooms, and hospital personnel should wear a face mask when they are within 3 feet (1 meter) of the patient (ie, droplet precautions) for 24 hours after the initiation of parenteral antimicrobial therapy [23]. The doors of rooms used to house these patients may remain open. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Droplet precautions'.)
RESOURCES — Resources related to Hib immunization include:
●The American Academy of Pediatrics
●The Centers for Disease Control and Prevention
●Vaccine information statement for Hib
●The World Health Organization
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunizations in children and adolescents" and "Society guideline links: Haemophilus influenzae type b vaccination".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)
●Beyond the Basics topic (see "Patient education: Vaccines for infants and children age 0 to 6 years (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Hib vaccine recommendations and efficacy – We recommend immunization of all infants with a Haemophilus influenzae type b (Hib) conjugate vaccine (Grade 1A). In randomized trials, Hib conjugate vaccines prevented ≥95 percent of invasive Hib disease. (See 'Hib conjugate vaccines' above.)
●Routine Hib immunization in the United States
•Schedule – The routine schedule consists of a two-or three-dose primary series (at age two and four months or two, four, and six months, depending upon the vaccine formulation) and a booster dose at 12 to 15 months of age (table 2). (See 'Routine childhood immunization in the United States' above.)
•Choice of vaccine – Hib conjugate vaccines (table 1) are generally interchangeable. However, we prefer polyribosylribitol phosphate conjugated to outer membrane protein complex of Neisseria meningitidis (PRP-OMP) for American Indian/Alaska Native infants. (See 'Choice of vaccine' above.)
•Catch-up schedule – The routine catch-up schedule for Hib conjugate vaccine depends upon the age at which the series in initiated and the number of doses previously received (table 3). (See 'Catch-up schedule' above.)
●Routine Hib immunization in other countries – Routine schedules for other countries are available through the World Health Organization. (See 'Routine immunization outside the United States' above.)
●Immunization of high-risk individuals – Recommendations for Hib immunization of children, adolescents, and adults at increased risk of invasive Hib disease vary according to age, number and timing of previous doses, and immune-compromising condition (table 4). (See 'High risk of invasive Hib disease' above.)
●Vaccine administration – Hib vaccine is contraindicated in infants younger than six weeks and individuals with a severe allergy to any vaccine component.
The dose of Hib conjugate vaccine is 0.5 mL. Hib conjugate vaccine is administered intramuscularly, usually in the anterolateral thigh (for children <3 years) or deltoid (for children ≥3 years).
Hib conjugate vaccine may be administered at the same clinic visit as other routine childhood immunizations (figure 2A-B). (See 'Contraindications and precautions' above and 'Administration' above.)
●Postexposure chemoprophylaxis – Postexposure chemoprophylaxis of household and close contacts reduces the risk of developing invasive disease and/or transmission. (See 'Postexposure chemoprophylaxis' above and "Pathogenesis and pathophysiology of bacterial meningitis".)
•Household contacts – We suggest chemoprophylaxis for household and close contacts of patients with invasive Hib disease who live in a household with individuals susceptible to invasive Hib disease (Grade 2B). We provide chemoprophylaxis to all members of households that include (see 'Household/close contact' above and 'Regimen' above):
-A child <4 years who has not received an age-appropriate number of doses of Hib conjugate vaccine
-A child <12 months who has not completed the primary series of Hib conjugate vaccine
-An immunocompromised child (<18 years)
•Child care or preschool contacts – Clinicians should follow local public health requirements regarding chemoprophylaxis of child care or preschool contacts of a child with invasive Hib disease. (See 'Child care or preschool contacts' above.)
•Index patient – Chemoprophylaxis is indicated for index patients who did not receive at least one dose of ceftriaxone or cefotaxime if either (see 'Index patient' above):
-They are <2 years of age, or
-They live in a household with a child <4 years of age who has not received an age-appropriate number of doses of Hib conjugate vaccine or an immunocompromised child <18 years of age
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