Rx only

Haemophilus b Conjugate Vaccine (Diphtheria CRM ₁₉₇ Protein Conjugate) HibTITER® is a sterile solution of a conjugate of oligosaccharides of the capsular antigen of Haemophilus influenzae type b (Haemophilus b) and diphtheria CRM ₁₉₇ protein (CRM ₁₉₇ ) dissolved in 0.9% sodium chloride. The oligosaccharides are derived from highly purified capsular polysaccharide, polyribosylribitol phosphate, isolated from Haemophilus b strain Eagan grown in a chemically defined medium (a mixture of mineral salts, amino acids, and cofactors). The oligosaccharides are purified and sized by diafiltrations through a series of ultrafiltration membranes, and coupled by reductive amination directly to highly purified CRM ₁₉₇ . ^1,2 CRM ₁₉₇ is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae C7 ((beta) ₁₉₇ ) grown in a casamino acids and yeast extract-based medium that is ultrafiltered before use. CRM ₁₉₇ is purified through ultrafiltration, ammonium sulfate precipitation, and ion-exchange chromatography to high purity. The conjugate is purified to remove unreacted protein, oligosaccharides, and reagents; sterilized by filtration; and filled into vials. HibTITER is intended for intramuscular use.

The vaccine is a clear, colorless solution. Each single dose of 0.5 mL is formulated to contain 10 µg of purified Haemophilus b saccharide and approximately 25 µg of CRM ₁₉₇ protein. Multidose vials contain thimerosal (mercurial derivative) 1:10,000 as a preservative. The potency of HibTITER is determined by chemical assay for polyribosylribitol.

For several decades Haemophilus influenzae type b (Haemophilus b) was the most common cause of invasive bacterial disease, including meningitis, in young children in the United States. Although nonencapsulated H. influenzae are common and six capsular polysaccharide types are known, strains with the type b capsule caused most of the invasive Haemophilus diseases. ³

Haemophilus b diseases occurred primarily in children under 5 years of age prior to immunization with Haemophilus influenzae type b vaccines. In the US, the cumulative risk of developing invasive Haemophilus b disease during the first 5 years of life was estimated to be about 1 in 200. Approximately 60% of cases were meningitis. Cellulitis, epiglottitis, pericarditis, pneumonia, sepsis, or septic arthritis made up the remaining 40%. An estimated 12,000 cases of Haemophilus b meningitis occurred annually prior to the routine use of conjugate vaccines in toddlers. ^3,4 The mortality rate can be 5%, and neurologic sequelae have been observed in up to 38% of survivors. ⁵

The incidence of invasive Haemophilus b disease peaks between 6 months and 1 year of age, and approximately 55% of disease occurs between 6 and 18 months of age. ³ Interpersonal transmission of Haemophilus b occurs and risk of invasive disease is increased in children younger than 4 years of age who are exposed in the household to a primary case of disease. Clusters of cases in children in day care have been reported and recent studies suggest that the rate of secondary cases may also be increased among children exposed to a primary case in the day-care setting. ^3,6

The incidence of invasive Haemophilus b disease is increased in certain children, such as those who are native Americans, black, or from lower socioeconomic status, and those with medical conditions such as asplenia, sickle cell disease, malignancies associated with immunosuppression, and antibody deficiency syndromes. ^3,4,6

The protective activity of antibody to Haemophilus b polysaccharide was demonstrated by passive antibody studies in animals and in children with agammaglobulinemia or with Haemophilus b disease ⁷ and confirmed with the efficacy study of Haemophilus b polysaccharide (HbPs) vaccine. ⁸ Data from passive antibody studies indicate that a preexisting titer of antibody to HbPs of 0.15 µg/mL correlates with protection. ⁹ Data from a Finnish field trial in children 18 to 71 months of age indicate that a titer of >1.0 µg/mL 3 weeks after vaccination is associated with long-term protection. ^10,11

Linkage of Haemophilus b saccharides to a protein such as CRM ₁₉₇ converts the saccharide (HbO) to a T-dependent (HbOC) antigen, and results in an enhanced antibody response to the saccharide in young infants that primes for an anamnestic response and is predominantly of the IgG class. ¹² Laboratory evidence indicates that the native state of the CRM ₁₉₇ protein and the use of oligosaccharides in the formulation of HibTITER® enhances its immunogenicity. ^{13 - 15} Haemophilus b conjugate vaccines with other carrier proteins will be recognized differently by the immune system.

Prior to licensure, the immunogenicity of HibTITER was evaluated in US infants and children. ¹⁵ Infants 1 to 6 months of age at first immunization received three doses at approximately 2-month intervals. ¹⁶ Children 7 to 11 and 12 to 14 months of age received 2 doses at the same interval. ¹⁵ Children 15 to 23 months of age received a single dose. ¹⁷ HibTITER was highly immunogenic in all age groups studied, with 97% to 100% of 1,232 infants attaining titers of >/=1 µg/mL and 92% to 100% for bactericidal activity. ^{15 - 17}

Long-term persistence of the antibody response was observed. More than 80% of the 235 infants who received three doses of vaccine had an anti-HbPs antibody level >/=1 µg/mL at 2 years of age. ¹⁸

The vaccine generated an immune response characteristic of a protein antigen. IgG anti-HbPs antibodies of IgG ₁ subclass predominated and the immune system was primed for a booster response to HibTITER. There is some evidence suggesting natural increases in antibody levels over time after vaccination, most probably the result of contact with Haemophilus type b organisms or cross-reactive antigens. ¹⁸ These studies were carried out at a time when significant levels of Haemophilus b disease were still present in the community.

Antibody generated by HibTITER has been found to have high avidity, a measure of the functional affinity of antibody to bind to antigen. High-avidity antibody is more potent than low-avidity antibody in serum bactericidal assays. ¹⁹ The contribution to clinical protection is unknown.

Immunogenicity of HibTITER was evaluated in 26 children 22 months to 5 years of age who had not responded to earlier vaccination with Haemophilus b polysaccharide vaccine. One dose of HibTITER was immunogenic in all 26 children and generated titers of >/=1 µg/mL in 25 of the 26 infants. ²⁰ HibTITER has been found to be immunogenic in children with sickle cell disease, a condition that may cause increased susceptibility to Haemophilus b disease. ²¹ HibTITER has also been shown to be immunogenic in native American infants, such as the group of 50 studied in Alaska who received three doses at 2, 4, and 6 months of age. ²⁰ Antibody levels achieved were comparable to those seen in healthy US infants who received their first dose at 1 to 2 months of age and subsequent doses at 4 to 6 months of age. ^15,16,20

Postlicensure surveillance of immunogenicity was conducted during the distribution of the first 30 million doses of HibTITER and during the time period over which Haemophilus b disease in children has been decreasing significantly in areas of extensive vaccine usage. ^{20, 22 - 29} After three doses, titers ranged from 2.37 to 8.45 µg/mL with 67% to 94% attaining >/=1 µg/mL. ^20,24,25

Persistence of antibody was examined in several cohorts of subjects that received either a selected commercial lot or that were part of the initial efficacy trial in northern California. Geometric mean titers for these cohorts were between 0.51 and 1.96 just prior to boosting at 15 to 18 months. These lots not only induced persistent antibody but also provided effective priming for a booster dose with commercial lots, with postboosting titers greater than 1.0 µg/mL in 80% to 97% of subjects. ²⁰

HibTITER (HbOC) was shown to be effective in a large-scale controlled clinical trial in a multiethnic population in northern California carried out between February 1988 and June 1990. ^30,31 There were no (0) vaccine failures in infants who received three doses of HibTITER and 12 cases of Haemophilus b disease (6 cases of meningitis) in the control group. The estimate of efficacy is 100% ( P = .0002) with 95% confidence intervals of 68% to 100%. Through the end of 1991, with an additional 49,000 person-years of follow-up, there were still no cases of Haemophilus b disease in fully vaccinated infants less than 2 years of age. ^22,23 One case of disease has been reported in a 3 ¹ / ₂ -year-old child who did not receive a booster dose as recommended.

A comparative clinical trial was performed in Finland where approximately 53,000 infants received HibTITER at 4 and 6 months of age and a booster dose at 14 months in a trial conducted from January 1988 through December 1990. Only two children developed Haemophilus b disease after receiving the two-dose primary immunization schedule. One child became ill at 15 months of age and the other at 18 months of age; neither child received the scheduled booster at 14 months of age. No vaccine failure has been reported in children who received the two-dose primary series and the booster dose at 14 months of age. Based on more than 32,000 person-years of follow-up time, the estimate of efficacy is about 95% when compared to historical control groups followed between 1985 and 1988. ²⁰ Historical controls were used since all infants received one of two Haemophilus b conjugate vaccines during the period of the trial.

Evidence of efficacy postlicensure includes significant reductions in Haemophilus b disease that are closely associated with increases in the net doses of Haemophilus b Conjugate Vaccine distributed in the US. ^{20,22 -29} In the northern California Kaiser Permanente there has been a 94% decrease in Haemophilus disease incidence in 1991 for children younger than 18 months of age, compared to 1984-1988, when HibTITER was not available for this age group. ^22,23 Furthermore, active surveillance by the Centers for Disease Control and Prevention (CDC) has shown a 71% decrease in Haemophilus b disease in children less than 15 months old, between 1989 and 1991, which corresponds temporally and geographically with increases in net doses of Haemophilus b conjugate vaccine distributed in the US. ²⁶ As with all vaccines, this conjugate vaccine cannot be expected to be 100% effective. There have been rare reports to the Vaccine Adverse Event Reporting System (VAERS) of Haemophilus b disease following full primary immunization.

Haemophilus b Conjugate Vaccine (Diphtheria CRM ₁₉₇ Protein Conjugate) HibTITER® is indicated for the immunization of children 2 months to 71 months of age against invasive diseases caused by H. influenzae type b.

As with any vaccine, HibTITER may not protect 100% of individuals receiving the vaccine.

HibTITER may be administered simultaneously but at different sites from other routine pediatric vaccines, eg, Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed (DTP), Oral Poliovirus Vaccine (OPV), and Measles-Mumps-Rubella Vaccine (MMR). ^32,33

CONTRAINDICATIONS

Hypersensitivity to any component of the vaccine, including diphtheria toxoid, or thimerosal in the multidose presentation, is a contraindication to use of HibTITER®.

HibTITER® WILL NOT PROTECT AGAINST H. INFLUENZAE OTHER THAN TYPE b STRAINS, NOR WILL HibTITER PROTECT AGAINST OTHER MICROORGANISMS THAT CAUSE MENINGITIS OR SEPTIC DISEASE.

AS WITH ANY INTRAMUSCULAR INJECTION, HibTITER SHOULD BE GIVEN WITH CAUTION TO INFANTS OR CHILDREN WITH THROMBOCYTOPENIA OR ANY COAGULATION DISORDER THAT WOULD CONTRAINDICATE INTRAMUSCULAR INJECTION (SEE DRUG INTERACTIONS ).

ANTIGENURIA HAS BEEN DETECTED FOLLOWING RECEIPT OF HAEMOPHILUS b CONJUGATE VACCINE ³⁴ AND THEREFORE ANTIGEN DETECTION IN URINE MAY NOT HAVE DIAGNOSTIC VALUE IN SUSPECTED HAEMOPHILUS b DISEASE WITHIN 2 WEEKS OF IMMUNIZATION.

Health care professionals should administer HibTITER with caution to patients with a possible history of latex sensitivity, since its packaging contains dry natural rubber.

PRECAUTIONS

GENERAL

1. CARE IS TO BE TAKEN BY THE HEALTH CARE PROVIDER FOR SAFE AND EFFECTIVE USE OF THIS PRODUCT.
2. PRIOR TO ADMINISTRATION OF ANY DOSE OF HibTITER, THE PARENT OR GUARDIAN SHOULD BE ASKED ABOUT THE PERSONAL HISTORY, FAMILY HISTORY, AND RECENT HEALTH STATUS OF THE VACCINE RECIPIENT. THE HEALTH CARE PROVIDER SHOULD ASCERTAIN PREVIOUS IMMUNIZATION HISTORY, CURRENT HEALTH STATUS, AND OCCURRENCE OF ANY SYMPTOMS AND/OR SIGNS OF AN ADVERSE EVENT AFTER PREVIOUS IMMUNIZATION IN THE CHILD TO BE IMMUNIZED, IN ORDER TO DETERMINE THE EXISTENCE OF ANY CONTRAINDICATION TO IMMUNIZATION WITH HibTITER AND TO ALLOW AN ASSESSMENT OF BENEFITS AND RISKS.
3. BEFORE THE INJECTION OF ANY BIOLOGICAL, THE HEALTH CARE PROVIDER SHOULD TAKE ALL PRECAUTIONS KNOWN FOR THE PREVENTION OF ALLERGIC OR ANY OTHER SIDE REACTIONS. This should include: a review of the patient' history regarding possible sensitivity; the ready availability of epinephrine 1:1,000 and other appropriate agents used for control of immediate allergic reactions; and a knowledge of the recent literature pertaining to use of the biological concerned, including the nature of side effects and adverse reactions that may follow its use.
4. Children with impaired immune responsiveness, whether due to the use of immunosuppressive therapy (including irradiation, corticosteroids, antimetabolites, alkylating agents, and cytotoxic agents), a genetic defect, human immunodeficiency virus (HIV) infection, or other causes, may have reduced antibody response to active immunization procedures. ^35,36 Deferral of administration of vaccine may be considered in individuals receiving immunosuppressive therapy. ³⁵ Other groups should receive this vaccine according to the usual recommended schedule. ^{35 - 37} (See DRUG INTERACTIONS .)
5. This product is not contraindicated based on the presence of human immunodeficiency virus infection. ³⁸
6. Any acute infection or febrile illness is reason for delaying use of HibTITER® except when in the opinion of the physician, withholding the vaccine entails a greater risk. A minor afebrile illness, such as a mild upper respiratory infection, is not usually reason to defer immunization.
7. As reported with Haemophilus b polysaccharide vaccine, cases of Haemophilus b disease may occur prior to the onset of the protective effects of the vaccine. ^3,39
8. The vaccine should not be injected intradermally since the safety and immunogenicity of this route have not been evaluated. The vaccine should be given intramuscularly.
9. A separate sterile syringe and needle or a sterile disposable unit should be used for each individual patient to prevent transmission of infectious agents from one person to another. Needles should be disposed of properly and should not be recapped.
10. Special care should be taken to prevent injection into a blood vessel.

The US Department of Health and Human Services has established a new Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine, including but not limited to the reporting of events required by the National Childhood Vaccine Injury Act of 1986. ⁴⁰ The VAERS toll-free number for VAERS forms and information is 800-822-7967.

ALTHOUGH SOME ANTIBODY RESPONSE TO DIPHTHERIA TOXIN OCCURS, IMMUNIZATION WITH HibTITER DOES NOT SUBSTITUTE FOR ROUTINE DIPHTHERIA IMMUNIZATION.

Packaging for HibTITER contains dry natural rubber. Health care professionals should administer HibTITER with caution to patients with a possible history of latex sensitivity

INFORMATION FOR PATIENT

PRIOR TO ADMINISTRATION OF HibTITER®, HEALTH CARE PERSONNEL SHOULD INFORM THE PARENT, GUARDIAN OR OTHER RESPONSIBLE ADULT, OF THE RECOMMENDED IMMUNIZATION SCHEDULE FOR PROTECTION AGAINST HAEMOPHILUS b DISEASE AND THE BENEFITS AND RISKS TO THE CHILD RECEIVING THIS VACCINE. GUIDANCE SHOULD BE PROVIDED ON MEASURES TO BE TAKEN SHOULD ADVERSE EVENTS OCCUR, SUCH AS, ANTIPYRETIC MEASURES FOR ELEVATED TEMPERATURES AND THE NEED TO REPORT ADVERSE EVENTS TO THE HEALTH CARE PROVIDER. Parents should be provided with vaccine information pamphlets at the time of each vaccination, as stated in the National Childhood Vaccine Injury Act. ⁴⁰

PATIENTS, PARENTS, OR GUARDIANS SHOULD BE INSTRUCTED TO REPORT ANY SERIOUS ADVERSE REACTIONS TO THEIR HEALTH CARE PROVIDER.

DRUG INTERACTIONS

No impairment of the antibody response to the individual antigens was demonstrated when HibTITER® was given at the same time but at separate sites as DTP plus OPV to children 2 to 20 months of age or MMR to children 15 ± 1 month of age. ^20,41

As with other intramuscular injections, HibTITER should be given with caution to children on anticoagulant therapy.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

HibTITER® has not been evaluated for its carcinogenic, mutagenic potential, or impairment of fertility.

PREGNANCY

REPRODUCTIVE STUDIES--PREGNANCY CATEGORY C

Animal reproduction studies have not been conducted with HibTITER®. It is also not known whether HibTITER can cause fetal harm when administered to a pregnant woman or can affect reproduction capability. HibTITER is NOT recommended for use in a pregnant woman.

GERIATRIC USE

This vaccine is NOT recommended for use in adult populations.

PEDIATRIC USE

The safety and effectiveness of HibTITER® in children below the age of 6 weeks have not been established.

ADVERSE REACTIONS

Adverse reactions associated with HibTITER® have been evaluated in 401 infants who were vaccinated initially at 1 to 6 months of age and were given 1,118 doses independent of DTP vaccine. Observations were made during the day of vaccination and days 1 and 2 postvaccination. A temperature >38.3°C was recorded at least once during the observation period following 2% of the vaccinations. Local erythema, warmth, or swelling (>/= 2 cm) was observed following 3.3% of vaccinations. The incidence of temperature > 38.3°C was greater during the first postvaccination day than during the day of vaccination or the second postvaccination day. The incidence of local erythema, warmth, or swelling was similar during the day of vaccination and the first postvaccination day; it was lower during the second postvaccination day. All side effects have been infrequent, mild, and transient with no serious sequelae (Table 1). No difference in the rates of these complaints was reported after dose 1, 2, or 3.

The following complaints were also observed after 1,118 vaccinations with HibTITER: irritability (133), sleepiness (91), prolonged crying [>/= 4 hours] (38), appetite loss (23), vomiting (9), diarrhea (2), and rash (1).

Additional safety data with HibTITER are available from the efficacy studies conducted in young infants. ³⁰ There were 79,483 doses given to 30,844 infants at approximately 2, 4, and 6 months of age in California, usually at the same time as DTP (but at a separate injection site) and OPV; approximately 100,000 doses have been given to 53,000 infants at 4 and 6 months in Finland at the same time as a combined DTP and inactivated polio (IPV) vaccine (but at a separate injection site). The rate and type of reactions associated with the vaccinations were no different from those seen when DTP or DTP-IPV was administered alone. These included fever, local reactions, rash, and one hyporesponsive episode with a single seizure. The safety of HibTITER was also evaluated in the California study by direct phone questioning of the parents or guardians of 6,887 vaccine recipients. The incidence and type of side effects reported within 24 hours of vaccination were similar to those cited in Table 1. In addition, analysis of emergency room (ER) visits within 30 days and hospitalization within 60 days after receipt of 23,800 doses of HibTITER showed no increase in the rates of any type of ER visit or hospitalization.

Table 2 details the side effects associated with a single vaccination of HibTITER given (without DTP) to infants of 15 to 23 months of age.

Similar results have been observed in the analysis of 2,285 subjects of 18 to 60 months of age, vaccinated as part of a postmarketing safety study of HibTITER. ²⁰ These data were collected by telephone survey 24 to 48 hours postvaccination. Additional observations included irritability, restless sleep, and GI symptoms (diarrhea, vomiting, and loss of appetite) in the group that received HibTITER alone. A cause and effect relationship between these observations and the vaccinations has not been established.

Rash, hives (urticaria), erythema multiforme, convulsions, ⁴² vomiting/diarrhea, ⁴² and Guillain-Barré syndrome ⁴³ have been observed following the administration of Haemophilus b polysaccharide and Haemophilus b conjugate vaccines. However, a cause and effect relationship among any of these events and the vaccination has not been established.

DOSAGE AND ADMINISTRATION

HibTITER® is for intramuscular use only.

Any parenteral drug product should be inspected visually for extraneous particulate matter and/or discoloration prior to administration whenever solution and container permit. If these conditions exist, HibTITER should not be administered.

Before injection, the skin over the site to be injected should be cleansed with a suitable germicide. After insertion of the needle, aspirate to help avoid inadvertent injection into a blood vessel.

The vaccine should be injected intramuscularly, preferably into the midlateral muscles of the thigh or deltoid, with care to avoid major peripheral nerve trunks.

HibTITER is indicated for children 2 months to 71 months of age for the prevention of invasive Haemophilus b disease. For infants 2 to 6 months of age, the immunizing dose is three separate injections of 0.5 mL given at approximately 2-month intervals. Previously unvaccinated infants from 7 through 11 months of age should receive two separate injections approximately 2 months apart. Children from 12 through 14 months of age who have not been vaccinated previously receive one injection. All vaccinated children receive a single booster dose at 15 months of age or older, but not less than 2 months after the previous dose. Previously unvaccinated children 15 to 71 months of age receive a single injection of HibTITER. ^32,33 Preterm infants should be vaccinated with HibTITER according to their chronological age, from birth. ³²

Interruption of the recommended schedules with a delay between doses does not interfere with the final immunity achieved nor does it necessitate starting the series over again, regardless of the length of time elapsed between doses. ^32,33

NO DATA ARE AVAILABLE TO SUPPORT THE INTERCHANGEABILITY OF HibTITER OR OTHER HAEMOPHILUS b CONJUGATE VACCINES WITH ONE ANOTHER FOR THE PRIMARY IMMUNIZATION SERIES. THEREFORE, IT IS RECOMMENDED THAT THE SAME CONJUGATE VACCINE BE USED THROUGHOUT EACH IMMUNIZATION SCHEDULE, CONSISTENT WITH THE DATA SUPPORTING APPROVAL AND LICENSURE OF THE VACCINE.

Each dose of 0.5 mL is formulated to contain 10 µg of purified Haemophilus b saccharide and approximately 25 µg of CRM ₁₉₇ protein

STORAGE

Stability studies indicate that HibTITER® can be shipped at ambient temperatures and stored at 2°-8°C (36°-46°F). DO NOT FREEZE.

HOW SUPPLIED

Vial, 1 Dose (4 per package)          --Product No. 0005-0104-41
Vial, 10 Dose                                 --Product No. 0005-0201-10

REFERENCES

1. United States Patent Number 4,902,506 by Anderson PW, Eby RJ filed May 5, 1986 issued February 20, 1990.
2. Seid RC Jr, Boykins RA, Liu DF, et al. Chemical evidence for covalent linkage of a semi-synthetic glycoconjugate vaccine for Haemophilus influenzae type b disease. Glycoconjugate J. 1989;6:489-498.
3. Wenger JD, Ward JL, Broome CV. Prevention of Haemophilus influenzae type b disease: vaccines and passive prophylaxis. In: Remington JS, Swartz MS, eds. Current Clinical Topics in Infectious Diseases. New York, NY: McGraw-Hill Inc; 1989;10:306-339.
4. Recommendation of the Immunization Practices Advisory Committee (ACIP)-polysaccharide vaccine for prevention of Haemophilus influenzae type b disease. MMWR. 1985;34:201-205.
5. Sell SH. Long term sequelae of bacterial meningitis in children. Pediatr Infect Dis J. 1983;2:90-93.
6. Broome CV. Epidemiology of Haemophilus influenzae type b infections in the United States. Pediatr Infect Dis J. 1987;6:779-782.
7. Alexander HE. The productive or curative element in type b Haemophilus influenzae rabbit serum. Yale J Biol Med. 1944;16:425-434.
8. Peltola H, Kayhty H, Sivonen A. Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics 1977;60:730-737.
9. Robbins JB, Parke JC Jr, Schneerson R. Quantitative measurement of "natural" and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res. 1973;7:103-110.
10. Kayhty H, Peltola H, Karanko V, et al. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis. 1983;147:1100.
11. Kayhty H, Karanko, V, Peltola H, et al. Serum antibodies after vaccination with Haemophilus influenzae type b capsular polysaccharide and responses to reimmunization: no evidence of immunologic tolerance or memory. Pediatrics. 1984;74:857-865.
12. Weinberg GA, Granoff DM. Polysaccharide-protein conjugate vaccines for the prevention of Haemophilus influenzae type b disease. J Pediatr. 1988;113:621-631.
13. Makela O, Péterfy F, Outshoorn IG, et al. Immunogenic properties of (alpha) (1-6) dextran, its protein conjugates, and conjugates of its breakdown products in mice. Scand J Immunol. 1984;19:541-550.
14. Anderson P, Pichichero ME, Insel RA. Immunogens consisting of oligosaccharides from Haemophilus influenzae type b coupled to diphtheria toxoid or the toxin protein CRM ₁₉₇ . J Clin Invest. 1985;76:52-59.
15. Madore DV, Phipps DC, Eby R, et al. Immune response of young children vaccinated with Haemophilus influenzae type b conjugate vaccines. In: Cruse JM, Lewis RE, eds. Contributions to Microbiology and Immunology: Conjugate Vaccines. New York, NY: Karger Medical and Scientific Publishers: 1989;10:125-150.
16. Madore DV, Phipps DC, Eby R, et al. Safety and immunologic response to Haemophilus influenzae type b oligosaccharide CRM ₁₉₇ conjugate vaccine in 1- to 6-month-old infants. Pediatrics 1990;85:331-337.
17. Madore DV, Johnson CL, Phipps DC, et al. Safety and immunogenicity of Haemophilus influenzae type b oligosaccharide CRM ₁₉₇ conjugate vaccine in infants aged 15-23 months. Pediatrics 1990;86:527-534.
18. Rothstein EP, Madore DV, Long S. Antibody persistence four years after primary immunization of infants and toddlers with Haemophilus influenzae type b CRM ₁₉₇ conjugate vaccine. J Pediatr. 1991;119:655-657.
19. Schlesinger Y, Granoff DM. Avidity and bactericidal activity of antibodies elicited by different Haemophilus influenzae type b conjugate vaccines. JAMA. 1992; 267:1489-1494.
20. Unpublished data available from Lederle Laboratories.
21. Gigliotti F, Feldman S, Wang WC, et al. Immunization of young infants with sickle cell disease with a Haemophilus influenzae type b saccharide-diphtheria CRM ₁₉₇ protein conjugate vaccine. J Pediatr. 1989;114:1006-1010.
22. Black SB, Shinefield HR, The Kaiser Permanente Pediatric Vaccine Study Group. Immunization with oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine on a large health maintenance organization population: extended follow-up and impact on Haemophilus influenzae disease epidemiology. Pediatr Infect Dis J. 1992;11:610-613.
23. Black SB, Shinefield HR, Fireman B, et al. Safety, immunogenicity, and efficacy in infancy of oligosaccharide conjugate Haemophilus influenzae type b vaccine in a United States Population: possible implications for optimal use. J Infect Dis. 1992;165 (suppl 1):S139-S143.
24. Granoff DM, Anderson EL, Osterholm MT, et al. Differences in the immunogenicity of three Haemophilus influenzae type b conjugate vaccines in infants. J Pediatr. 1992;121:187-194.
25. Decker MD, Edwards KM, Bradley R, et al. Comparative trial in infants of four conjugate Haemophilus influenzae type b vaccines. J Pediatr. 1992;120:184-189.
26. Adams WG, Deaver KA, Cochi SL, et al. Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era. JAMA. 1993;269:221-226.
27. Murphy TV, White KE, Pastor P, et al. Declining incidence of Haemophilus influenzae type b disease since introduction of vaccination. JAMA. 1993;269:246-248.
28. Broadhurst LE, Erickson RL, Kelley PW. Decreases in invasive Haemophilus influenzae diseases in US Army children, 1984 through 1991. JAMA. 1993;269:227-231.
29. Shapiro ED. Infections caused by Haemophilus influenzae type b: the beginning of the end? JAMA. 1993;269:264-266.
30. Black SB, Shinefield HR, Lampert D, et al. Safety and immunogenicity of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in infancy. Pediatr Infect Dis J. 1991;10:92-96.
31. Black SB, Shinefield HR, Fireman B, et al. Efficacy in infancy of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in a United States Population of 61,080 children. Pediatr Infect Dis J. 1991;10:97-104.
32. Recommendations of the AAP: Haemophilus influenzae type b conjugate vaccines: recommendations for immunization of infants and children 2 months of age and older: update. Pediatrics 1991;88:169-172.
33. Recommendation of the ACIP: Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. MMWR. 1991;40:1-7.
34. Jones RG, Bass JW, Weisse ME, et al. Antigenuria after immunization with Haemophilus influenzae oligosaccharide CRM ₁₉₇ conjugate (HbOC) vaccine. Pediatr Infect Dis J. 1991;10:557-559.
35. American Academy of Pediatrics: Report of the Committee on Infectious Diseases. 22nd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1991.
36. Recommendation of the ACIP--immunization of children infected with human T-lymphotrophic virus type III/lymphadenopathy-associated virus. MMWR. 1986;35(38):595-606.
37. Immunization of children infected with human immunodeficiency virus--supplementary ACIP statement. MMWR. 1988;37(12):181-183.
38. General Recommendations on Immunization--recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR. 1989;38(13):221.
39. Spinola SM, Sheaffer CI, Philbrick KB, et al. Antigenuria after Haemophilus influenzae type b polysaccharide immunization: a prospective study. J Pediatr. 1986;109:835-837.
40. CDC. Vaccine Adverse Event Reporting System--United States. MMWR. 1990;39:730-733.
41. Paradiso PR. Combined childhood immunizations. JAMA. 1992;268:1685.
42. Milstein JB, Gross TP, Kuritsky JN. Adverse reactions reported following receipt of Haemophilus influenzae type b vaccine: an analysis after one year of marketing. Pediatrics 1987;80:270-274.
43. D'Cruz DF, Shapiro ED, Spiegelman KN, et al. Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome) after immunization with Haemophilus influenzae type b conjugate vaccine. J Pediatr. 1989;115:743-746.

Manufactured by:

LEDERLE LABORATORIES

Division American Cyanamid Company

Pearl River, NY 10965 USA

US Gov't. License No. 17

Marketed by:

WYETH-LEDERLE VACCINES AND PEDIATRICS

Wyeth-Ayerst Laboratories

Philadelphia, PA 19101

CI 6100-1  Issued September 29, 1999

PRODUCT PHOTO(S):