These recommendations include information on two vaccines recently licensed for use among infants: Haemophilus b Conjugate Vaccine (PRP-T ), manufactured by Pasteur Merieux Vaccins, and TETRAMUNE TM , manufactured by Lederle Laboratories/Praxis Biologics. This statement also updates recommendations for use of other available Haemophilus b vaccines (PRP-D ; HbOC ; and PRP-OMP ) for infants and children.# INTRODUCTION
The incidence of Haemophilus influenzae type b (Hib) disease in the United States has declined since the mid-1980s (1 ). Before the introduction of effective vaccines, Hib was the leading cause of bacterial meningitis and other invasive bacterial disease among children <5 years of age; approximately one in 200 children developed invasive Hib disease before the age of 5 years. Nearly all infections occurred among children <5 years of age, and approximately two thirds of all cases occurred among children <18 months of age. Meningitis occurred in approximately two thirds of children with invasive Hib disease, resulting in hearing impairment or neurologic sequelae in 15%-30%. The case-fatality rate was 2%-5% (2 ).
In 1985, the first Hib vaccines were licensed for use in the United States. These vaccines contained purified polyribosylribitol phosphate (PRP) capsular material from type b strains. Antibody against PRP was shown to be the primary component of serum bactericidal activity against the organism. Although the vaccine was highly effective in trials in Finland among children 18 months of age (3 ), postmarketing efficacy studies in the United States demonstrated variable efficacy (4,5 ). PRP vaccines were ineffective in children <18 months of age because of the T-cell-independent nature of the immune response to PRP polysaccharide (3 ).
Conjugation of the PRP polysaccharide with protein carriers confers T-celldependent characteristics to the vaccine and substantially enhances the immunologic response to the PRP antigen. By 1989, Hib conjugate vaccines (PRP-D ; HbOC ; and PRP-OMP ) were licensed for use among children 15 months of age. In late 1990, following two prospective studies, PRP-OMP (6 ) and HbOC (7 ) were licensed for use among infants. On the basis of findings establishing comparable immunogenicity, a third conjugate vaccine, PRP-T (ActHIB TM , OmniHIB TM ) has now been licensed for use among infants. Specific characteristics of the four conjugate vaccines available for infants and children vary (e.g., the type of protein carrier, the size of the polysaccharide, and the chemical linkage between the polysaccharide and carrier) (Table 1).
Current recommendations for universal vaccination of infants require parenteral administration of three different vaccines (diphtheria-tetanus-pertussis , Hib conjugate, and hepatitis B) during two or three different visits to a health-care provider. Combination vaccines were developed to reduce the number of injections at each visit. TETRAMUNE TM is the first licensed combination vaccine that provides protection against diphtheria, tetanus, pertussis, and Hib disease.
This statement a) summarizes current immunogenicity and efficacy data regarding Hib conjugate vaccines, including PRP-T; b) summarizes available information regarding the safety and immunogenicity of TETRAMUNE TM ; and c) provides updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for use of conjugate Hib vaccines and TETRAMUNE TM for infants and children.

# HIB CONJUGATE VACCINES Immunogenicity
Studies have been performed with all four Hib conjugate vaccines to determine immunogenicity in infants 2-6 months of age. Direct comparison of studies is complicated by differing vaccination and blood collection regimens and interlaboratory variation in assays for measurement of PRP antibody. Also, the precise level of antibody required for protection against invasive disease is not clearly established. However, a geometric mean titer (GMT) of 1 g/mL 3 weeks postvaccination correlated with protection in studies following vaccination with unconjugated PRP vaccine and suggests long-term protection from invasive disease (8 ). After three vaccinations at ages 2, 4, and 6 months, each of three Hib conjugate vaccines-HbOC, PRP-OMP, and PRP-T-produced protective levels of anticapsular antibody (9)(10)(11)(12)(13). One study reported comparative immunogenicity with PRP-OMP, HbOC, and PRP-T (12 ), and two other studies compared immunogenicity with all four conjugate vaccines (11,13 ) (Table 2). In this age group, only PRP-OMP vaccine produced a substantial increase in antibody after one dose (12,13 ). Antibody response among infants following a series of three infant vaccinations with PRP-D is limited (only 15%-45% of infants develop a GMT 1 g/mL after 3 doses) (11,13,14 ) and is lower than with HbOC, PRP-OMP, or PRP-T.
With each conjugate vaccine, antibody levels decline after administration of the primary series. Regardless of the conjugate vaccine used in the primary series for infants, booster vaccination of children 12 months of age with any of the licensed conjugate vaccines will likely elicit an adequate response, as studies indicate that a) unconjugated PRP (administered at 12-14 months of age) elicits a good booster response in infants who are administered PRP-OMP (15 ), HbOC (15,16 ), or PRP-T (15,16, ) during infancy; b) PRP-D administered as a booster at age 15 months induces adequate immunologic response regardless of the Hib conjugate administered in the initial series (17 ); and c) each conjugate vaccine demonstrates adequate immunogenicity when administered as a single vaccination to children 15 months of age (18,19 ).
Limited information is available regarding the interchangeability of different Hib vaccines for the primary series at 2, 4, and 6 months of age (Table 3). Preliminary findings from two studies suggest that the vaccination series consisting of PRP-OMP at 2 months, followed by either PRP-T (20,21 ) or HbOC (20,22 ) at 4 months and 6 months, induces adequate anti-PRP antibody response. The sequence HbOC, PRP-T, PRP-T was also immunogenic (20 ) after the complete primary series was administered. This information suggests that any combination of three doses of Hib conjugate vaccines licensed for use among infants will provide adequate protection.
The carrier proteins used in PRP-T, PRP-D, and HbOC (but not PRP-OMP) are derived from the toxoids used in DTP vaccine (Table 1). Limited data have indicated that prior or concurrent administration of DTP vaccine may enhance anti-PRP antibody response following vaccination with these Hib vaccines (23)(24)(25)(26). It has been suggested that priming T-cells to the carrier proteins may be important for optimal antibody response to the conjugated vaccine. For infants, the immunogenicity of PRP-OMP (which has a carrier derived from the meningococcal outer membrane protein) appears to be unaffected by the absence of prior or concurrent DTP vaccination (24 ).

# Efficacy
Efficacy studies of PRP-D, PRP-OMP, HbOC, and PRP-T vaccines administered to infants 2-6 months of age are summarized in this report (Table 4). Two randomized, double-blind trials evaluating PRP-T vaccine efficacy were discontinued in the United States in October 1990 after licensure was granted to HbOC and PRP-OMP vaccines. A third efficacy trial of PRP-T in England has recently been completed.
Efficacy of the PRP-D conjugate has varied with the age of the population studied. Postlicensure studies performed in the United States among children aged 15-60 months demonstrated point estimates of efficacy ranging from 74%-96%. Two studies have prospectively evaluated efficacy of PRP-D administered to children <12 months of age. In a trial in Finland involving 114,000 infants vaccinated at 3, 4, and 6 months of age, the point estimate of efficacy was 89% (95% confidence interval  = 70-96) (27 ). In comparison, among Alaskan Natives vaccinated at ages 2, 4, and 6 months, the point estimate of efficacy was 35% (95% CI = -57-73) and not significantly different from zero (28 ). PRP-OMP was shown to be 93%-100% efficacious in Navajo infants (a population at particularly high risk of disease) vaccinated at 2 and 4 months of age (6 ). Two studies have indicated a point estimate of efficacy of 97% following the administration of two doses of HbOC (in Finland) (29 ) or three doses of vaccine (in the United States) (7 ) to infants.
Although the trials evaluating PRP-T vaccine efficacy among infants in the United States were terminated early, no cases of invasive Hib disease were reported among more than 6,200 vaccinees at the time of termination (30 , J.C. Parke, Carolinas Medical Center, unpublished data). In a trial in Great Britain, PRP-T was protective in infants vaccinated at ages 2, 3, and 4 months (31 ). Efficacy of PRP-T was also suggested in a nationwide immunization program that was implemented in Finland in January 1990. There were no reported cases of invasive Hib disease among more than 97,000 infants who received 2 doses of PRP-T. Two children developed disease after one dose of vaccine (32 ).
In the United States, 30-50 cases of invasive Hib disease have been reported among children who had received appropriate vaccination with the Hib conjugate vaccine and therefore were expected to have had adequate levels of protective antibody (33)(34)(35). These cases may represent vaccine failure. Results of immunologic evaluation of children who had vaccine failure vary with the age of the child. In a study of children vaccinated with Hib conjugate vaccine at age 15 months, subnormal immunoglobulin concentrations were present in approximately 40% of those who developed invasive Hib disease (33 ). However, in a separate study that evaluated fully vaccinated children <12 months of age who developed invasive Hib disease, only 9% had evidence of low immunoglobulin levels (34 ).

# COMBINATION VACCINES TETRAMUNE TM
On March 30, 1993, the Food and Drug Administration licensed TETRAMUNE TM , a vaccine manufactured by Lederle Laboratories/Praxis Biologics by combining a licensed DTP vaccine (TRI-IMMUNOL  ) and HbOC (HibTITER  ). TETRAMUNE TM contains 12.5 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid, an estimated 4 protective units of pertussis vaccine, 10 g of purified Hib polysaccharide, and approximately 25 g of CRM197 protein. The single-dose volume is 0.5 mL to be administered intramuscularly.

# Safety and Immunogenicity
The safety of TETRAMUNE TM vaccine was evaluated in a study of 6,497 infants in California who received doses at ages 2, 4, and 6 months, compared with 3,935 infants who received DTP (TRI-IMMUNOL  ) and HbOC vaccines as separate concurrent injections (36, Lederle Laboratories/Praxis Biologics, unpublished data). Based on follow-up of a randomized subset of 1,411 infants (for whom 1,347 parents were interviewed), the risk for local and systemic reactions was similar for infants who received the combination product when compared with those who received two separate injections of DTP and HbOC. The infants who received the combination vaccine, however, experienced a higher likelihood of restless sleep following the second dose and 1 inch of swelling at the injection site after administration of the first dose of the combination vaccine (Table 5).
Immunogenicity studies among infants who received TETRAMUNE TM at ages 2, 4, and 6 months (37, Lederle Laboratories/Praxis Biologics, unpublished data) indicated that antibody responses to Hib PRP, diphtheria, and tetanus toxins were comparable to or higher than those in persons who received separate, but concurrent administration of DTP and HbOC vaccines. Similarly, antibody responses to pertussis toxin, filamentous hemagglutinin, 69-kd outer-membrane protein (pertactin), and pertussis agglutinins were comparable to or higher than those following separate concurrent administration of DTP and HbOC vaccines (Table 6). Comparable immunogenicity results also were reported for children aged 15-18 months (who had received prior doses of DTP, but not Hib vaccine) following a dose of TETRAMUNE TM when compared with separate but concurrent administration of DTP and HbOC vaccines.

# Efficacy
No efficacy information is available for TETRAMUNE TM , but the immunogenicity information suggests TETRAMUNE TM will provide similar protection against Hib disease and diphtheria, tetanus, and pertussis as will the separate administration of HbOC or DTP vaccines.

# Other combination vaccines
Published studies have evaluated the safety and immunogenicity of other vaccines that combine DTP (or DTaP ) and Hib in the same formulation or the same syringe. However, none of these formulations (PRP-D-DTaP , HbOC-DTaP , or PRP-T-DTP ) have been licensed for use. Two studies have shown a slight reduction in the immune response to pertussis when certain Hib vaccines were combined with DTP (42,43 ), but the magnitude of the effect is unlikely to be clinically relevant.

# Simultaneous vaccination
Large prelicensure and postlicensure studies have demonstrated the safety, immunogenicity, and efficacy of each of the licensed Hib conjugate vaccines administered to infants concurrently with DTP vaccine and oral polio vaccine (OPV) (6,7,9,32 ) as well as the safety and immunogenicity of TETRAMUNE TM when administered concurrently with OPV in recommended schedules (36,37 ). More limited data also support the safety and immunogenicity of Hib conjugate vaccines when administered simultaneously with hepatitis B vaccine to infants, and with DTP, OPV, measles, mumps, and rubella (MMR) and/or hepatitis B vaccine when administered at ages 12-18 months.

# Recommendations for Hib Vaccination General
All infants should receive a conjugate Hib vaccine (separate or in combination with DTP ), beginning at age 2 months (but not earlier than 6 weeks). If the first vaccination is delayed beyond age 6 months, the schedule of vaccination for previously unimmunized children should be followed (Table 7). When possible, the Hib conjugate vaccine used at the first vaccination should be used for all subsequent vaccinations in the primary series. When either Hib vaccines or TETRAMUNE TM is used, the vaccine should be administered intramuscularly using a separate syringe and administered at a separate site from any other concurrent vaccinations.

# HbOC or PRP-T
Previously unvaccinated infants aged 2-6 months should receive three doses of vaccine administered 2 months apart, followed by a booster dose at age 12-15 months, at least 2 months after the last vaccination. Unvaccinated children ages 7-11 months should receive two doses of vaccine, 2 months apart, followed by a booster dose at age 12-18 months, at least 2 months after the last vaccination. Unvaccinated children ages 12-14 months should receive two doses of vaccine, at least 2 months apart. Any previously unvaccinated child aged 15-59 months should receive a single dose of vaccine.

# PRP-OMP
Previously unvaccinated infants ages 2-6 months should receive two doses of vaccine administered at least 2 months apart. Although PRP-OMP induces a substantial antibody response after one dose, all children should receive all recommended doses of PRP-OMP. Because of the substantial antibody response after one dose, it may be advantageous to use PRP-OMP vaccine in populations that are known to be at increased risk for disease during early infancy (e.g., Alaskan Natives). A booster dose should be administered to all children at 12-15 months of age at least 2 months after the last vaccination. Unvaccinated children ages 7-11 months should receive two doses of vaccine, 2 months apart, followed by a booster dose at 12-18 months of age, at least 2 months after the last dose. Unvaccinated children ages 12-14 months should receive two doses of vaccine, 2 months apart. Any previously unvaccinated child 15-59 months of age should receive a single dose of vaccine.

# PRP-D
One dose of PRP-D may be administered to unvaccinated children aged 15-59 months. This vaccine may be used as a booster dose at 12-18 months of age following a two-or three-dose primary series, regardless of the vaccine used in the primary series. This vaccine is not licensed for use among infants because of its limited immunogenicity and variable protective efficacy in this age group.

# TETRAMUNE TM
The combination vaccine TETRAMUNE TM may be used for routine vaccination of infants, beginning at age 2 months, to prevent diphtheria, tetanus, pertussis, and invasive Hib disease. Previously unvaccinated infants aged 2-6 months should receive three doses administered at least 2 months apart. An additional dose should be administered at 12-15 months of age, after at least a 6-month interval following the third dose. Alternatively, acellular DTP and Hib vaccine can be administered as separate injections at 12-15 months of age. Acellular DTP is preferred for doses four and five of the five-dose DTP series. For infants who begin both Hib and DTP vaccinations late (after 2 months of age), TETRAMUNE TM may be used for the first and second doses of the vaccine series. However, because delay in initiation of the DTP series does not reduce the number of required doses of DTP, additional doses of DTP without Hib are necessary to ensure that all four doses are administered. Infants ages 7-11 months who have not previously been vaccinated with DTP or Hib vaccines should receive two doses of TETRAMUNE TM , administered at least 2 months apart, followed by a dose of DTP vaccine 4-8 weeks after the second dose of TETRAMUNE TM . An additional dose of DTP and Hib vaccines should then be administered: DTP vaccine at least 6 months after the third immunizing dose against diphtheria, tetanus, and pertussis; and Hib vaccine at 12-18 months of age, at least 2 months after the last Hib dose.
TETRAMUNE TM may be used to complete an infant immunization series started with any Hib vaccine (licensed for use in this age group) and with any DTP vaccine if both vaccines are to be administered simultaneously. Completion of the primary series using the same Hib vaccine, however, is preferable. Conversely, any DTP vaccine may be used to complete a series initiated with TETRAMUNE TM (see the general ACIP statement on Diphtheria, Tetanus and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures  for further information).

# Other considerations for Hib vaccination
Other considerations for Hib vaccination are discussed in the following section:
1) Although an interval of 2 months between doses of Hib vaccine in the primary series is recommended, an interval of 1 month is acceptable, if necessary.

# Adverse reactions
Adverse reactions to each of the four Hib conjugate vaccines are generally uncommon. Swelling, redness, and/or pain have been reported in 5%-30% of recipients and usually resolve within 12-24 hours. Systemic reactions such as fever and irritability are infrequent. Available information on side effects and adverse reactions suggests that the risks for local and systemic events following TETRAMUNE TM administration are similar to those following concurrent administration of its individual component vaccines (i.e., DTP and Hib vaccines), and may be due largely to the pertussis component of the DTP vaccine (52 ).
Surveillance regarding the safety of TETRAMUNE TM , PRP-T, and other Hib vaccines in large-scale use aids in the assessment of vaccine safety by identifying potential events that may warrant further study. The Vaccine Adverse Event Reporting System (VAERS) of the U.S. Department of Health and Human Services encourages reports of all serious adverse events that occur after receipt of any vaccine.- Invasive Hib disease is a reportable condition in 43 states. All health-care workers should report any case of invasive Hib disease to local and state health departments.

# Contraindications and Precautions
Vaccination with a specific Hib conjugate vaccine is contraindicated in persons known to have experienced anaphylaxis following a prior dose of that vaccine. Vaccination should be delayed in children with moderate or severe illnesses. Minor illnesses (e.g., mild upper-respiratory infection) are not contraindications to vaccination.
Contraindications and precautions of the use of TETRAMUNE TM are the same as those for its individual component vaccines (i.e., DTP or Hib) (see the general ACIP statement on Diphtheria, Tetanus, and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures  for more details on the use of vaccines containing DTP).
The following CDC staff members prepared this report:

# Advisory Committee on Immunization Practices
Membership List, October 1993 -Continued