haemophilus influenzae type b conjugate vaccines

480 PEDIATRICS Vol. 92 No. 3 September 1993

Haemophilus Influenzae Type b Conjugate Vaccines: Recommendations for

Immunization With Recently and Previously Licensed Vaccines

Committee on Infectious Diseases

This updated statement on Haemophilus influenzaetype b conjugate vaccines includes recommendationsfor use of a newly licensed Haemophilus conjugatevaccine, and a newly licensed combination vaccinethat combines one of the Haemophilus conjugate vac-cines and diphtheria, tetanus toxoids, and pertussis(DTP). The statement also includes revised guide-lines for the use of all conjugate vaccines. The

changes concern use of different vaccine products inchildren younger than 15 months of age; timing forbooster doses for completion of the immunization

schedule in children 12 months of age and older;schedules for children in whom vaccination has beendelayed in initiation, or has lapsed; choice of vaccine

in children in whom vaccination against DTP ordiphtheria and tetanus toxoids (DT) is deferred;number of doses for children with immunologic im-

pairment associated with increased risk of H influen-zae type b disease; and indications for rifampin pro-phylaxis in households where contacts have beenvaccinated. Related information on the basis forthese new recommendations also is given.

As of 1993, four H influenzae type b conjugate vac-

cines, and a combination vaccine that combines oneof these vaccines with DTF� are licensed in the UnitedStates. The newly licensed conjugate vaccine consistsof polyribosylribitol phosphate (PRP) conjugated totetanus toxoid (PRP-T; ActHIB/OmniHib, preparedby Institut Meneux and distributed in the UnitedStates by Connaught Laboratories and SmithKlineBeecham). The combination vaccine consists of a li-censed conjugate of PRP oligomers covalently linkedto diphthena-CRM,97 protein (HbOC; HIBTITER)with DiP (TRI-IMMUNOL), and is referred to as

HbOC-DTP (TETRAMUNE; manufactured by Leder-le-Praxis). Both new vaccines are approved for usebeginning at 2 months of age.

The four licensed vaccines are summarized in

Table I . Their composition differs in several impor-

The recommendations in this policy statement do not indicate an exclusive

course of treatment or serve as a standard of medical care. Variations, takinginto account individual circumstances, may be appropriate.This policy statement supercedes previous Academy policy statements on

Haemophilus influenzae conjugate vaccines. The following statements have

been retired: Haeinophilus influenzae Type b Conjugate Vacdne (June 1988);

Haemophilus influenzae Type b Conjugate Vaccines: Update (August 1989);

Haemophilus influenzae Type b Conjugate Vaccines: Immunization of Chil-

dren at 15 Months of Age (November 1990); Haemophilus influenzae Type b

Conjugate Vaccines: Immunization of Children at 2-15 Months of Age (No-

vember 1990); Haemophilus Influen.zae Type b Conjugate Vaccines: Recom-mendations for Immunization of Infants and Children at 2 Months of Age

and Older - Update (July 1991).PEDIATRICS (ISSN 0031 4005). Copyright © 1993 by the American Acad-

emy of Pediatrics.

tant respects, including the carrier protein used, the

polysaccharide molecular size, and the method ofconjugating the saccharide to the protein. Thesechemical differences result in different immunologicproperties. The evaluation of H influenzae type b con-jugate vaccines has included studies of immunoge-nicity (the ability to elicit antibody responses), effi-cacy (the ability of vaccination to decrease theincidence of disease), and safety.

Healthy Infants

IMMUNOGENICITY

The relationship between protection and the mag-nitride of the antibody response following vaccina-tion is complex. Some infants with low antibody re-sponses may be protected against disease whenexposed to H influenzae type b because conjugatevaccination primes infants’ and provides them withan ability to mount a serum antibody response rap-idly upon encountering the organism. Qualitative

differences in the avidity (a measure of the functionalaffinity of serum antibody to bind to antigen) of an-

tibody elicited by different conjugate vaccines alsosuggest that the concentration of anti-PRP antibodyis not the only determinant of protection.2 Postvac-cination sera with high antibody avidity requiremuch lower antibody concentrations for in vitro bac-terial killing than sera with low antibody avidity inwhich higher antibody concentrations are required.2

The clinical importance of these differences in anti-body avidity has yet to be determined.

The four licensed H influenzae type b conjugatevaccines elicit different patterns of serum antibodyresponse in infants vaccinated at 2, 4, and 6 months

of age (Figure).3’4 The PRP-OMP (PedvaxHlB) elicitssignificant increases in antibody concentration after asingle injection at 2 months of age, whereas the otherthree conjugates do not. After a second injection ofPRP-OMP at 4 months of age, modest increases inantibody concentration occur. Because of the low re-sponses to the first injection of PRP-T or HbOC at 2months of age, the fold increases in antibody concen-tration to the second injection of these vaccines arehigher than those with PRP-OMP.4 However, aftertwo injections, the geometric mean antibody concen-tration is highest in PRP-OMP recipients, followedby that in recipients of PRP-T, HbOC, and PRP-D (seeFigure).3’4

For infants vaccinated at 2 and 4 months of age, athird injection of conjugate vaccine is recommendedat 6 months of age for infants receiving HbOC or

PRP-T. A third dose at this age is not recommended

by guest on October 26, 2021www.aappublications.org/newsDownloaded from

. PRP.OMP,

� HbOC, N=167

� PRP-T, N=142. PRP.D,

Figure. Immunogenicity of four

Haemophilus influenzae type b conju-

gate vaccines in infants vaccinated at

2, 4, and 6 months of age. Data are

from a randomized, comparative im-

munogenicity trial performed in

Minneapolis, St Louis, and Dallas.4

Data from the PRP-D group were ob-

tamed as part of the randomized

trial but were not included in the

published report.

40

10

1

0.1PRE POST.2 POST-3

TABLE 1. Haemophilus influenzae Type b Conjugate Vaccines*

AMERICAN ACADEMY OF PEDIATRICS 481

Manufacturer Abbreviation Trade Name Carrier Protein

Connaught Laboratories PRP-D Prohibit Diphtheria toxoid

Lederle-Praxis HbOCt HIBTITER CRM197 (a nontoxic mutant diphtheriatoxin)

Merck, Sharp & Dohme PRP-OMP PedvaxHlB OMP (an outer membrane protein com-plex of Neisseria meningitidis)

Pasteur Merieux Vaccins PRP-T ActHIB/OmniHib Tetanus toxoid(Distributed by SmithKline

Beecham, and Connaught

Laboratories)

* PRP-D is recommended by the Academy only for infants 12 months of age or older. The HbOC, PRP-OMP, and PRP-T are recommended

for infants beginning at approximately 2 months of age.

i. HbOC is also available as a combination vaccine with DTP (TETRAMUNE).

for PRP-OMP because the antibody concentrationsare high after two doses of this vaccine and there isonly a minimal increase after a third dose given at 6months of age (Figure). The anti-PRP antibody re-sponses of infants vaccinated at 2, 4, and 6 months ofage with HbOC-DTP are similar to those observed ininfants given HbOC and DTP as separate injections(see “Combination Vaccines”). For infants scheduledto receive separate injections of HbOC and DTP,HbOC-DTP can be substituted. The Academy con-siders that this combination vaccine and all three ofthe individual conjugate vaccines are likely to beequivalent in the protection achieved against H in-fi uenzae type b disease after completing the recom-mended primary series of two or three doses (de-pending on the product).

Until recently, immunogenicity studies conductedin infants younger than 12 months of age used thesame conjugate vaccine product for all doses. Be-cause conjugate vaccines differ chemically and im-munologically, how infants given sequential doses ofdifferent vaccines would respond is not known. Sev-eral ongoing studies are addressing this question.Until additional data from these studies are avail-able, the Academy recommends that when feasiblethe same conjugate vaccine should be used for sub-sequent doses for infants younger than 12 months ofage as was used for the initial dose. However, for

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infants given doses of different conjugate vaccines, itis not necessary to give more than three doses of anyvaccine to complete the primary series.

After administration of the recommended initialtwo doses of PRP-OMP at 2 and 4 months of age, orthe initial three doses of HbOC or PRP-T at 2, 4, and6 months of age, serum antibody concentrations de-dine rapidly. At 12 months of age, the antibody con-centrations have decreased approximately three- tosix-fold compared with the respective peak concen-trations.’ Therefore, a booster dose of conjugate vac-cine is recommended at 12 to 15 months of age. Forthis dose, any conjugate vaccine (PRP-D, HbOC,PRP-OMP, or PRP-T) is acceptable, regardless ofwhich vaccine was used for the primary series. Thereasons are several: (1) Unconjugated PRP (no longercommercially available in the United States) whengiven at 12 months of age elicits a memory antibodyresponse in infants previously given PRP-OMP,HbOC, or PRP-T.’ (2) PRP-D given as a booster doseat 15 months of age is as or more immunogenic thana booster dose of the conjugate vaccine used for theinitial series.5 (3) In previously unvaccinated 15-month-olds, a single dose of any of the licensed con-jugate vaccines confers protection. Similar protectioncan be expected in previously vaccinated childrenreceiving a booster or reinforcing dose at 12 to 15months of age.


482 H INFLUENZAE Type b Conjugate Vaccines

At 15 months of age, HbOC-DTP may be used in

children scheduled to receive DTP and a booster in-jection of conjugate vaccine. However, at this age,DTaP vaccines, containing acellular pertussis, are ap-proved for use, and are associated with fewer local,febrile, and minor systemic reactions than DTP vac-

cine containing whole-cell pertussis.6 Currently, a li-censed combination conjugate vaccine containingDTaP is not available. Therefore, in children 15

months of age or older, separate injections of any H

influenzae type b conjugate vaccine and DTaP, DTP, ora dose of HbOC-DTP, are acceptable.

For children whose initial vaccination is given at12 to 14 months of age, the Academy considers thatany conjugate vaccine (PRP-D, HbOC, PRP-OMP, orPRP-T) also is acceptable. Currently, the Food and

Drug Administration (FDA) has approved labelingfor PRP-D for use beginning at 15 months of age. Therationale for the Academy recommending use ofPRP-D beginning at 12 months of age is as follows:(1) At 12 to 14 months of age, two doses of conjugatevaccine are recommended, separated by 2 months.(2) At this age, two doses of PRP-D elicited higher

serum antibody concentrations, and higher bacteri-cidal titers, than one dose given at 18 months.7 (3)Therefore, similar protection can be expected in chil-

dren receiving two doses at 12 to 15 months of agecompared with those receiving the recommendedone dose at 15 to 18 months.

Children in Whom DTP or DT Vaccination Is Deferred

The carrier proteins used in PRP-T, PRP-D, andHbOC (but not PRP-OMP) are chemically and im-munologically related to toxoids contained in DTP(Table 1). In most published immunogenicity studies,H influenzae type b conjugate vaccines were admin-istered to infants who received DTP before or simul-taneously with the conjugate vaccination. Data fromexperiments in infant animals8’9 and humans’#{176} mdi-

cate that, in the absence of previous or simultaneousvaccination with DTP, vaccination with conjugatevaccines is insufficient to elicit consistent antibodyresponses to the carrier protein. Previous or simulta-neous vaccination with DTP also may be required to

elicit maximal anti-PRP antibody responses to PRP-T,

PRP-D, or HbOC,8-10 but not to PRP-OMP.9”#{176} Thus,in infants vaccinated with a Haemophilus conjugatevaccine in whom DTP or DT vaccination is deferred,

PRP-OMP may be advantageous.

Children With Immunologic Impairment

Children with chronic ifinesses associated with in-

creased risk of H influenzae type b disease may have

impaired antibody responses to conjugate vaccina-tion. Examples include children with human immu-nodeficiency virus (HIV) infection, immunoglobulindeficiency, bone marrow transplants, anatomic orfunctional asplenia, and recipients of chemotherapy

for malignancy.”’5 Although most infants withsickle cell disease who are vaccinated with Haemo-philus conjugate vaccine in the first year of life ap-

pear to respond with protective antibody,’6 some

children in whom vaccination is initiated in the sec-ond or third year of life after development of func-tional hyposplenia show subnormal antibody re-

sponses.l3”�’8 However, these children usually willrespond if given an additional dose. Infants with se-lective IgG2 subclass immunoglobulin deficiency

also frequently have impaired antibody responses toconjugate vaccination, but many will respond toadditional doses as they get olderY1”2 Thus, somechildren with immunologic impairment may benefitfrom additional doses of conjugate vaccine beyondthose normally indicated.

CONJUGATE VACCINE EFFICACY

Summary of Clinical Trials

Results of the prelicensure conjugate vaccine effi-cacy studies are summarized in Table 2. PRP-D pro-tected Finnish infants vaccinated at 3, 4, and 6months of age,’9 but this vaccine did not providesignificant protection to native Alaskan infants vac-

cinated at 2, 4, and 6 months.2#{176} In contrast, in Navajoinfants, another population with an increased risk ofH influenzae type b disease, vaccination with PRP-

OMP was highly efficacious when administered at 2

and 4 months of age2’ (Table 2). Short-term protec-tion also was observed after a single dose of PRP-

OMP given at 2 months of age, a finding that corre-lates with the ability of this vaccine at that age toelicit serum antibody responses after one injection(Figure).

The efficacy of HbOC was evaluated in a trial per-formed in Northern California?� After a three-doseschedule vaccine efficacy was high (Table 2). Thevaccine also may be protective after two doses, butthe small number of patient-months of follow-up be-tween the second and third doses and the cone-

sponding small number of cases observed in the un-vaccinated controls in this period limited theanalysis. No significant protection was observed in

this trial after one dose of HbOC.Two randomized, controlled trials to evaluate the

efficacy of PRP-T vaccine given at 2, 4, and 6 monthsof age were terminated before completion23 becauseFDA approval (October 1990) of Haemophilus conju-

TABLE 2. Summary of Pre licensure Conjugate Vaccine Efficacy Studies*

Location or

Population

Vaccine Design Age, mo % Efficacy

(95% CI)t

Finland’9

Alaskan natives20

Northern Californian

Navajo21

PRP-D

PRP-D

HbOC

PRP-OMP

Open randomizedPlacebo-controlled randomized

Open quasirandomizedPlacebo-controlled randomized

3,4,62,4,6

2,4,62,4

89 (70 to 96)35 (-57-73)

100 (68-100)93 (53-98)

* PRP-T was evaluated in two US efficacy studies that could not be completed (see text).23 PRP-T was found to be efficacious in an open

trial in the United Kingdom, where infants were y�ccjnated � 2, 3, and 4 months of age.24t CI = confidence interval.



gate vaccine for 2-month-old infants precluded thecontinued use of placebo controls. Therefore, the li-

censure of PRP-T was based principally on immuno-genicity data (Figure).23 However, in the two incom-plete trials, no cases of invasive H influenzae type bdisease occurred in approximately 6 000 infants vac-cinated with PRP-T.23 The results of another efficacytrial done in the United Kingdom suggest that PRP-T

is protective when given at 2, 3, and 4 months ofage.24

Postlicensure Surveillance

Since 1988, when H influenzae type b conjugatevaccines were introduced in the United States forinfants 18 months of age or older, the protective ef-ficacy of vaccination generally has been high; thesefindings have been summarized by Loughlin et al.25Population-based surveillance in several regions of

the country also has documented a dramatic declinein the incidence of invasive H influenzae type b dis-

ease in infants and children of all ages.26’27 This de-dine was noted not only in the age group vaccinatedbut also in younger infants who, before 1991, werenot targeted for vaccination. The factors responsiblefor the decline in incidence in the unvaccinated agegroup are incompletely understood but conjugatevaccination may decrease nasopharyngeal H influen-

zae type b colonization28’29 and result in lower rates

of acquisition of H influenzae type b colonization by

unvaccinated infants.

Vaccine Failure

Despite receiving conjugate vaccination, H influen-

zae type b disease can still occurY1’3#{176}In some chil-dren, onset of disease occurred within a week of

conjugate vaccination but, because it takes I to 2weeks for vaccination to elicit serum antibody re-

sponses, infants are not expected to be protected dur-ing this immediate postvaCcination period. There is

no evidence, to date, of any increased risk of diseaseduring the 1 to 2 weeks after conjugate vaccination.

Cases of Haemophilus disease also have occurredmore than 2 weeks after vaccination.’1’30 In one

study, more than one third of children vaccinatedwith conjugate vaccine at 15 months of age or olderwho subsequently developed Haemophilus disease

had subnormal serum immunoglobulin concentra-tions, particularly IgG2Y1 In contrast, immunoglob-

ulin deficiency may be less common in infants failingvaccination at younger than 12 months of age.3#{176}However, longer follow-up is needed in this agegroup, because it is possible that vaccination failuremay be a marker for an evolving immunodeficiencythat is not yet reflected in abnormal serum immuno-globulin concentrations. Children who develop dis-

ease despite vaccination at 15 months of age or older

may benefit from immunologic evaluation. Consid-eration also should be given for evaluation of infantsfailing vaccination at a younger age if there are otherfactors present suggesting increased susceptibility toinfection.

Rifampin Prophylaxis.. Despite the occurrence ofdisease in a few vaccinated children, available dataindicate that conjugate vaccination is highly effectivein preventing disease, particularly in fully vaccinated

children (defined as at least one dose of conjugatevaccine given at 15 months of age or older, or twodoses at 12 to 14 months, or two or more doses whenyounger than 12 months of age with a booster orreinforcing dose at 12 months of age or older (see

Tables 3, 4, and 5). Previously, the Academy sug-gested: “Rifampin prophylaxis is recommended forall household contacts, irrespective of age, in house-

holds with at least one contact younger than 48months, regardless of the immunization status of the

contacts.” (See recommendations in the 1991 Reportof the Committee on Infectious Diseases.31) House-holds without such a member were excluded fromthat recommendation. The Academy now considers

that an otherwise healthy child who is fully immu-nized is at minimal risk of acquiring disease, even if

exposed to a child with H influenzae type b disease.Therefore, rifampin prophylaxis is no longer mdi-cated for management of households where all con-tacts younger than 48 months are fully immunizedaccording to the above definitions.

COMBINATION VACCINES

The FDA recently licensed HbOC-DTP (TETRA-MUNE) for use in infants as young as 2 months ofage. The vaccine is administered intramuscularly in a

dose of 0.5 mL, which contains the same quantities of

TABLE 3. Recommendations for Hacrnophi!us

ginning at 2 to 6 Months of AgeConjugate Vaccination in Children Immunized Be-

Vaccine Product Total No. of Currently Recommended

at Initiation Doses to Be Vaccine Regimens*

Administered

H�bOC or PRP-T 4 Three doses at 2-mo intervalsWhen feasible same vaccine for doses 1-3

Fourth dose at 12-15 mo of age

Any conjugate vaccine for dose 4+

PRP-OMP 3 Two doses at 2-mo intervalsWhen feasible same vaccine for doses 1-2

Third dose at 12-15 mo of age

Any conjugate vaccine for dose 3+

* See text. The HbOC, PRP-T, or PRP-OMP should be given in a separate syringe and at a separate site

from other immunizations. HbOC is also available as a combination vaccine with DTP (HbOC-DTP).

This combination can be used in infants scheduled to receive separate injections of DTP and HbOC.

t The safety and efficacy of PRP-OMP, PRP-D, PRP-T, and HbOC are likely to be equivalent in children

12 months of age and older.



TABLE 4. Recommendations for Haemophilus Conjuga

Vaccination is Delayed Until 7 Months of Age or Olderte Vaccination in Children in Whom Initial

Age at Initiation of Vaccine Product Total No. of Currently RecommendedImmunization, mo at Initiation Doses to be Vaccine Regimens*

Administered

7-11 HbOC, PRP-T, 3 Two doses at 2-mo intervaist

or PRP-OMP When feasible, same vaccine for doses I

and 2

Third dose at 12-18 mo of age with dose

3 given at least 2 mo after dose 2

Any conjugate vaccine for dose 31

12-14 HbOC, PRP-T, 2 2-mo interval between dosest

PRP-OME or Any conjugate vaccine for dose 21PRP-D

15-59 HbOC, PRP-T, I� Any conjugate vaccine

PRP-OMP, orPRP-D

60 and older1j HbOC, PRP-T, I-2� Any conjugate vaccinePRP-OMP, or

PRP-D

* See text. HbOC, PRP-T, or PRP-OMP should be given in a separate syringe and at a separate site from

other immunizations. HbOC is also available as a combination vaccine with Dl? (HbOC-DTP). This

combination can be used in infants scheduled to receive separate injections of DIP and HbOC.

However, in children 15 months of age or older eligible to receive DTaP (containing acellular pertussisvaccine), HbOC-DTP, or separate injections of conjugate vaccine and DTaP, are acceptable because of

the lower rate of febrile and minor local and systemic reactions associated with DTaP.

f For catch-up, a minimum of 1-month interval between doses may be used.

I The safety and efficacy of PRP-OMP, PRP-D, PRP-T, and HbOC are likely to be equivalent for use asa booster dose in children 12 months of age and older.

� Iwo doses separated by 2 months are recommended by some experts for children with certain

underlying diseases associated with increased risk of disease and impaired antibody responses to H

influenzae type b conjugate vaccination (see text).

#{182}Only for children with chronic illness known to be associated with an increased risk for H influenzae

type b disease (see text).

diphtheria toxoid, tetanus toxoid, whole cell pertus-sis vaccine, and diphtheria-CRM,97 protein conju-gated to PRP oligosaccharide, as DTP and HbOCvaccines.

The anti-PRP antibody responses of infants vacci-nated at 2, 4, and 6 months of age with HbOC-DTPwere similar to those observed in infants givenHbOC and DTP as separate injections.32 Similarly,the antibody responses to diphtheria and tetanus tox-oids, and to the components of whole-cell pertussisvaccine, were similar to or enhanced in the group

given the combination vaccine compared with thosegiven separate injections of HbOC and DW32 Forthese reasons, although efficacy data are not avail-able, HbOC-DTP is expected to provide equivalentprotection against H influenzae type b disease, and

against diphtheria, tetanus, and pertussis, as whenthe vaccines are administered as separate injections.Therefore, in infants scheduled to receive separateinjections of DTP and HbOC, HbOC-DTP can be sub-

stituted.Physicians should not mix H influenzae conjugate

vaccines in the same syringe with other vaccines un-less specific combinations are approved by the FDA.Studies are underway to evaluate both additionalfixed combination vaccines and some specific com-

binations that may be mixed together just before vac-cination.

SAFETY

Adverse reactions to the four licensed H influenzaetype b conjugate vaccines are few. Pain, redness,

and/or swelling at the injection site occur in about25% of recipients, but these symptoms typically aremild and last less than 24 hours.� Systemic reactionssuch as fever and irritability are infrequent.3 When

conjugate vaccines are administered during the samevisit as when DTP vaccine is given, the rates of sys-temic reactions do not differ from those observedwhen only DTP vaccine is administered.3 Similarly,when the combination DTP-HbOC vaccine is admin-istered, no clinically important differences in the re-

spective rates of systemic or local reactions have beenobserved in comparison with those of infants givenHbOC and DTP as separate injections.32

RECOMMENDATIONS

1 . All children should be immunized with an H in-fi uenzae type b conjugate vaccine beginning at ap-proximately 2 months of age or as soon as possiblethereafter (Table 3). Only HbOC, PRP-OMP, orPRP-T should be given to children younger than12 months of age.

a. The H influenzae type b conjugate immuniza-tion can be initiated as early as 6 weeks of age.

b. When DT or DTP vaccination is deferred, use

of PRP-OMP may be advantageous (see Rec-ommendation 4c).

c. H influenzae type b conjugate vaccination can begiven during visits when vaccines for DTP,DTaP, polio, hepatitis B, or measles, mumps,

rubella (MMR) are given.d. HbOC, PRP-T, or PRP-OMP should be given in

a separate syringe and at a separate site from



TABLE 5. Recommendations for Haeinophilus Conjugate Vaccination in Children With a Lapse in

Vaccination

Age at Previous Vaccination Recommended RegimenPresentation, History

mo

7-11 1 dose*

2 doses of HbOC or

PRP-T

One dose of conjugate at 7-Il mo, with a booster

dose given at least 2 mo later, at 12-15 mot

Same as above

12-14 2 doses before 12 mo* A single dose of any licensed conjugates

12-14 1 dose before 12 mo* Two additional doses of any licensed conjugate,

separated by 2 mol

15-59 Any incomplete sched-

ule

A single dose of any licensed conjugates

* PRP-OMP, PRP-T, or HbOC. HbOC is also available as a combination vaccine with DIP (HbOC-

DIP). This combination can be used in infants scheduled to receive separate injections of DIP and

HbOC. In children 15 months of age or older eligible to receive DIaP (containing acellular pertussis),

HbOC-DTP or separate injections of conjugate vaccine and DTaP can be given, because of the lowerrate of febrile and minor local and systemic reactions associated with DIaP.

t For the dose given at 7 to II months, when feasible, the same vaccine should be given as was used

for the dose given at 2 to 6 months. For the dose given at 12 to 15 months, any licensed conjugate can

be used (see below).

I The Academy considers that safety and efficacy of PRP-OMP, PRP-D, PRP-T, or HbOC are likely tobe equivalent when used in children � 12 months of age.

DTP or other vaccinations unless specific com-binations are approved by the FDA (see be-low).

e. In infants scheduled to receive both HbOC andDTP, a single injection of the combination vac-cine, HbOC-DTP, can be substituted for the two

injections.2. For routine immunization of children younger

than 7 months of age.a. Primary series. Either a three-dose series of

HbOC, or PRP-T, or a two-dose series of PRP-OMP, should be administered (Table 3). Dosesare given at approximately 2-month intervals.When feasible, the conjugate vaccine productused for the first dose should be used for sub-

sequent doses in children younger than 12months of age. When sequential doses of dif-ferent vaccine products are given, it is not con-sidered necessary to administer more than atotal of three doses of any conjugate vaccine to

complete the primary series. In infants sched-uled to receive separate injections of DTP andHbOC, the combination HbOC-DTP vaccine

can be used in infants previously given anyDTP vaccine. The safety and efficacy of the dif-

ferent vaccines given in their recommendedschedules appear to be equivalent.

b. Reinforcing/booster vaccination at 12 to 15

months of age. For children who have com-pleted a primary series, an additional dose of

conjugate vaccine is recommended at 12 to 15

months of age, or as soon as possible thereafter.Any conjugate vaccine (PRP-D, HbOC, PRP-OMP, or PRP-T) is acceptable for this dose re-

gardless of the vaccine used previously. Forinfants scheduled to receive both HbOC andDTP, a single injection of the combination vac-

cine, I-IbOC-DTP, can be substituted. However,for this dose in children 15 months of age or

older, separate injections of Haemophilus b con-jugate and DTaP vaccines are acceptable, be-

cause of the lower frequency of local and minorsystemic reactions associated with use of acel-lular pertussis vaccine.

The MMR vaccination can be given at the

same time as H influenzae type b conjugate vac-cine, but it should be given at a separate siteand in a separate syringe. Some physiciansmay choose to give these injections in morethan one visit. In this circumstance, for patientswho have not been immunized previously

against measles, priority should be given toadministration of the MMR vaccination whenthe age of the patient is appropriate.

3. Children younger than 5 years of age who did notreceive Haemophilus conjugate vaccine in the first 6months of life should be immunized according tothe following recommended schedules (Table 4):

a. For children in whom immunization is initiatedat 7 to 11 months of age, the recommended

schedules for HbOC, PRP-OMP, and PRP-T areidentical and require three doses. The first twodoses are given at 2-month intervals using the

same vaccine product, when feasible, for bothdoses. The third (booster) dose should be givenat 12 to 18 months of age, preferably 2 monthsafter the second dose. For the third dose, anylicensed conjugate vaccine is acceptable.

b. For children in whom immunization is initi-ated at 12 to 14 months of age, the recom-mended regimens for PRP-D, HbOC, PRP-

OMP, or PRP-T are identical and require twodoses given at a 2-month interval.

c. For children in whom immunization is initiatedat 15 months of age or older, and who have not

yet reached their fifth birthday (ie, 59 months ofage or younger), the recommended regimen is asingle dose of any licensed conjugate vaccine.

d. Circumstances may suggest a need for morerapid “catch-up” immunization in which case a1-month interval between doses is the mini-

mum.



e. For infants in whom immunization with bothDTP and conjugate vaccination is initiated late,the HbOC-DTP combination can be substituted

for separate injections of the two vaccines.However, additional doses of DTP alone may

be necessary to complete the primary DTP im-

munization because, in contrast to Haemophilustype b vaccination, delay in DTP vaccination

does not decrease the total number of required

injections.4. Special Circumstances

a. Lapsed immunizations. Recommendations forvaccination of children who have had a lapse in

the schedule of immunizations are based onlimited data. The interim recommendations are

summarized in Table 5.b. Premature infants. For infants born prematurely,

immunization should be based on chronologic

age and initiated at 2 months of age according

to recommendations in Table 3. Data areneeded on responses of these infants to Haemo-

philus conjugate vaccines. However, experi-

ences with other antigens that are T-cell depen-dent such as diphtheria and tetanus toxoids

justify this interim recommendation.c. Deferring DTP or DT vaccination. Infants with

certain neurologic disorders occasionally haveDTP and DT vaccination deferred until the firstbirthday. (See current Report of the Committeeon Infectious Diseases.31’PP367369) Use of PRP-OMP may be advantageous in this circum-stance because PRP-OMP conjugate vaccine is

immunogenic in the absence of vaccinationwith diphtheria or tetanus toxoids.9’1#{176} Simulta-neous or previous vaccination with diphtheria

or tetanus toxoids may be required for an op-timal anticapsular antibody response to PRP-T

or HbOC.�’� In infants in whom a decision hasbeen made to use DT vaccine instead of DTP,

these considerations do not apply and any H

influenzae type b conjugate vaccine may be

used.d. In infants in whom pertussis vaccination is con-

traindicated, HbOC-DTP should not be used.

These contraindications include a history of animmediate anaphylactic reaction after admin-istration of DTP, or development of encephal-

opathy within 7 days after DTF� defined as asevere acute central nervous system disorderthat may manifest by major alterations of con-

sciousness or generalized focal seizures thatpersist more than a few hours without recoverywithin 24 hours. Similarly, all the “precau-

tions” that apply to pertussis vaccination alsoapply to the use of HbOC-DTP (see 1991Report of the Committee on Infectious Di-

seases.3’ ‘PP367369).

e. Immunologic impairment associated with increasedrisk of invasive H influenzae type b disease (eg,

patients with HP! infection, IgG2 subclass defi-ciency, bone marrow transplants, sickle cell disease,

splenectomy, and those receiving chemotherapy for

malignancies). When children with splenectomy

or sickle cell disease have completed a primary

series of immunizations and have received abooster dose at 12 months of age or older, ad-ditional doses are not needed. For children with

malignancies, some experts recommend an ad-ditional dose of conjugate vaccine be given be-fore undergoing chemotherapy and/or sple-

nectomy. The currently available data on theantibody responses of children with HIV infec-

tion or IgG2 deficiency are limited. Whetherchildren with these conditions will benefit fromadditional doses if they have completed a pri-mary series of immunizations and have re-ceived a booster dose at 12 months of age or

older is not known.For those children 12 to 59 months of age

with one of these underlying conditions predis-

posing to H influenzae type b disease who areunvaccinated, or who received only one dose ofconjugate vaccine before 12 months of age, twodoses of any conjugate vaccine, separated by 2months, are recommended. For those in this

age group who received two doses before 12months of age, one additional dose of conjugatevaccine is recommended.

Unvaccinated children with underlying dis-eases predisposing to H influenzae type b dis-

ease who are older than 59 months of age

should be vaccinated with any licensed conju-gate vaccine. One dose appears sufficient in this

age group for children with sickle cell diseaseor asplenia.’3’17 Two doses separated by 1 to 2months are suggested, based on limited data,

for children with HIV infection, IgG2 defi-ciency, bone marrow transplants, or malig-

nancies.’�’4 Because DTP vaccination is notrecommended routinely for persons 7 years of

age or older, HbOC-DTP also is not recom-mended for use at this age.

No known contraindications exist to simul-

taneous administration of Haemophilus conju-gate vaccine with pneumococcal vaccine ormeningococcal vaccine when given in separatesyringes at different sites.

f. Prior H influenzae type b disease. Children whohad invasive H influenzae type b disease whenyounger than 24 months of age frequently havelow anticapsular antibody concentrations inconvalescent sera and may remain at risk of

developing a second episode of disease.33 Anyconjugate vaccination given before developingdisease should be ignored, and conjugate vac-cination in these patients should be readminis-tered during convalescence according to theage-appropriate schedule for unvaccinated chil-dren (Tables 3 through 5). Revaccination shouldbe initiated I month after onset of disease, or as

soon as possible thereafter.Children whose disease occurred at age 24

months or older do not need immunization, ir-respective of previous vaccination status, be-cause the disease most likely induced a protec-five immune response and second episodes ofdisease at this age are rare.

Immunized children who experience inva-



sive H influenzae type b disease after receiving adose of a conjugate vaccine at 15 months of age

or older have a high frequency of IgG2 defi-ciency and, therefore, should be considered forimmunologic evaluation.� Children who com-pleted the recommended vaccination schedule

before 15 months of age (ie, final dose given at12 to 14 months of age) and who develop inva-sive disease also should be considered for im-munologic evaluation. Whether immunologicevaluation should be performed for children

who experience invasive H influenzae type b dis-

ease after conjugate immunization given at

younger than 12 months of age is uncertain.30Nevertheless, evaluation of immunoglobulin

concentrations in such patients, particularlythose with a history of recurrent infection,

should be considered.5. Rifampin chemoprophylaxis of contacts of pa-

tients with H influenzae disease. Based on the highefficacy of conjugate vaccination, householdmembers do not require rifampin prophylaxiswhen all the contacts younger than 48 months are

fully immunized: defined as at least one dose ofconjugate vaccine at 15 months of age or older, or

two doses at 12 to 14 months, or two or moredoses when younger than 12 months of age with a

booster dose at 12 months of age or older (seeTables 3, 4, and 5). All members of a householdwith a child younger than 12 months of age (eg,children who have not yet received the booster/reinforcing dose) should receive rifampin prophy-laxis, irrespective of the vaccination status of the

child, although the risk of secondary disease isvery low in a child of this age who has completed

the primary two- or three-dose series. Members ofhouseholds with a fully vaccinated immunocom-promised child should receive rifampin because ofconcern that the vaccination may have been inef-

fective.6. Reporting of H influenzae disease and adverse re-

actions after immunization. All important adversereactions occurring at any time after immuniza-tion, including cases of disease occurring in fullyor partially immunized children, should be re-

ported promptly to the Vaccine Adverse EventReporting System (VAERS) of the Department ofHealth and Human Services. (For reporting form,

call 1-800-822-7967.) In addition, all cases of in-vasive H influenzae type b disease, including those

in fully or partially vaccinated children, should bereported to the Centers for Disease Control (CDC)through the state and local health department.The time after immunization when protection canbe anticipated is not known with precision andprobably differs depending on the number of pre-

vious doses. Providers should be aware of thisuncertainty and not expect protection simulta-neously with vaccine administration.

FUTURE DEVELOPMENTS

Studies are in progress to assess the safety and

immunogenicity of H influenzae type b conjugate vac-cines when combined with DTP, hepatitis B, en-

hanced potency inactivated polio vaccine, or MMR in

the same syringe, and to evaluate the safety andimmunogenicity of regimens employing several con-

jugate vaccines.

COMMI-I-EEE ON INFECTIOUS DISEASES, 1992 to 1993

Caroline B. Hall, MD, ChairpersonDan M. Granoff, MDDonald S. Gromisch, MDNeal A. Halsey, MD

Steve Kohl, MD

Edgar K. Marcuse, MD

Melvin I. Marks, MD

George A. Nankervis, MDLarry K. Pickering, MD

Gwendolyn B. Scott, MDRussell W. Steele, MD

Ram Yogev, MD

Ex-OmCI0

Georges Peter, MD

Liaison RepresentativesKenneth J. Bart, MD, MPH, National

Vaccine ProgramClaire Broome, MD, Centers for Disease

ControlM. Carolyn Hardegree, MD, Food and Drug

AdministrationRichard F. Jacobs, MD, American Thoracic

SocietyNoni E. MacDonald, MD, Canadian

Paediatric SocietyWalter A. Orenstein, MD, Centers for

Disease Control

Gina Rabinovich, MD, National Institutes ofHealth

ConsultantRobert S. Daum, MD, University of Chicago

AAP StaffEdgar 0. Ledbetter, MD, Director,

Department of Maternal, Child and

Adolescent Health

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1993;92;480Pediatrics Immunization With Recently and Previously Licensed Vaccines

Type b Conjugate Vaccines: Recommendations forHaemophilus Influenzae

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