AMERICAN ACADEMY OF PEDIATRICS

Combination Vaccines for Childhood Immunization: Recommendations ofthe Advisory Committee on Immunization Practices (ACIP), the American

Academy of Pediatrics (AAP), and the American Academy of FamilyPhysicians (AAFP)*

SUMMARY. An increasing number of new and im-proved vaccines to prevent childhood diseases are beingintroduced. Combination vaccines represent one solutionto the problem of increased numbers of injections duringsingle clinic visits. This statement provides general guid-ance on the use of combination vaccines and relatedissues and questions.

To minimize the number of injections children re-ceive, parenteral combination vaccines should be used, iflicensed and indicated for the patient’s age, instead oftheir equivalent component vaccines. Hepatitis A, hepa-titis B, and Haemophilus influenzae type b vaccines, ineither monovalent or combination formulations from thesame or different manufacturers, are interchangeable forsequential doses in the vaccination series. However, us-ing acellular pertussis vaccine product(s) from the samemanufacturer is preferable for at least the first threedoses, until studies demonstrate the interchangeabilityof these vaccines. Immunization providers should stocksufficient types of combination and monovalent vaccinesneeded to vaccinate children against all diseases forwhich vaccines are recommended, but they need notstock all available types or brand-name products. Whenpatients have already received the recommended vacci-nations for some of the components in a combinationvaccine, administering the extra antigen(s) in the combi-nation is often permissible if doing so will reduce thenumber of injections required.

To overcome recording errors and ambiguities in thenames of vaccine combinations, improved systems areneeded to enhance the convenience and accuracy oftransferring vaccine-identifying information into medi-cal records and immunization registries. Further scien-tific and programmatic research is needed on specificquestions related to the use of combination vaccines.

ABBREVIATIONS. For a complete list of abbreviations, see page1071.

The introduction of vaccines for newly prevent-able diseases poses a challenge for their incor-poration into an already complex immuniza-

tion schedule. To complete the 1999 RecommendedChildhood Immunization Schedule in the UnitedStates,1,2 a minimum of 13 separate injections areneeded to immunize a child from birth to age 6 years,

using vaccines licensed in the United States as ofApril 10, 1999. During some office or clinic visits, theadministration of three or four separate injectionscan be indicated.

Combination vaccines merge into a single prod-uct antigens that prevent different diseases or thatprotect against multiple strains of infectious agentscausing the same disease. Thus, they reduce thenumber of injections required to prevent some dis-eases. Combination vaccines available for manyyears include diphtheria and tetanus toxoids andwhole-cell pertussis vaccine (DTwP); measles-mumps-rubella vaccine (MMR); and trivalent inac-tivated polio vaccine (IPV). Combinations licensedin recent years in the United States include diph-theria and tetanus toxoids and acellular pertussisvaccine (DTaP),3– 6 DTwP-Haemophilus influenzaetype b (Hib) vaccine (DTwP-Hib),7,8 DTaP-Hib‡1,9

and Hib-hepatitis B (HepB) vaccine (Hib-Hep B).10

In the future, combination vaccines might includeincreasing numbers of components in different ar-rays to protect against these and other diseases,including hepatitis A, Neisseria meningitidis, Strep-tococcus pneumoniae, and varicella (Appendix A).11

Combination vaccines have some drawbacks.Chemical incompatibility or immunologic interfer-ence when different antigens are combined intoone vaccine could be difficult to overcome.12–16

Vaccine combinations that require different sched-ules might cause confusion and uncertainty whenchildren are treated by multiple vaccine providerswho use different products. The trend to developcombination products could encourage vaccinecompanies to merge to acquire the needed intellec-tual property.17 Competition and innovation mightbe reduced if companies with only a few vaccineantigens are discouraged from developing newproducts.

This report, published simultaneously by the Ad-visory Committee on Immunization Practices(ACIP),18 the American Academy of Pediatrics,19 andthe American Academy of Family Physicians,20 pro-vides general recommendations for the optimal useof existing and anticipated parenteral combinationvaccines, along with relevant background, rationale,and discussion of questions raised by the use of theseproducts. Principal recommendations are classified

*The following CDC staff member prepared this report: Bruce G. Weniger,MD, MPH, Epidemiology and Surveillance Division, National Immuniza-tion Program.PEDIATRICS (ISSN 0031 4005). Copyright © 1999 by the American Acad-emy of Pediatrics.

‡As of April 10, 1999, DTaP-Hib vaccine was licensed only for the fourthdose recommended at age 15–18 months in the vaccination series.

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by the strength and quality of evidence supportingthem (Appendix B).21–24

PREFERENCE FOR COMBINATION VACCINESThe use of licensed combination vaccines is pre-

ferred over separate injection of their equivalentcomponent vaccines. Only combinations approvedby the US Food and Drug Administration (FDA)should be used.

RationaleThe use of combination vaccines is a practical way

to overcome the constraints of multiple injections,especially for starting the immunization series forchildren behind schedule. The use of combinationvaccines might improve timely vaccination coverage.Some immunization providers and parents object toadministering more than two or three injectable vac-cines during a single visit because of a child’s fear ofneedles and pain25–30 and because of unsubstantiatedconcerns regarding safety.31,32

Other potential advantages of combination vac-cines include a) reducing the cost of stocking andadministering separate vaccines, b) reducing the costfor extra health-care visits, and c) facilitating theaddition of new vaccines into immunization pro-grams. The price of a new combination vaccine cansometimes exceed the total price of separate vaccinesfor the same diseases. However, the combinationvaccine might represent a better economic value ifone considers the direct and indirect costs of extrainjections, delayed or missed vaccinations, and addi-tional handling and storage.11

Combining Separate Vaccines Without FDA ApprovalImmunization providers should not combine sep-

arate vaccines into the same syringe to administertogether unless such mixing is indicated for the pa-tient’s age on the respective product label insertsapproved by the FDA. The safety, immunogenicity,and efficacy of such unlicensed combinations areunknown.33

INTERCHANGEABILITY OF VACCINE PRODUCTSIn general, vaccines from different manufacturers

that protect against the same disease may be admin-istered interchangeably in sequential doses in theimmunization series for an individual patient (eg,hepatitis A vaccine [HepA], HepB, and Hib). How-ever, until data supporting interchangeability of acel-lular pertussis vaccines (eg, DTaP) are available, vac-cines from the same manufacturer should be used,whenever feasible, for at least the first three doses inthe pertussis series. Immunization providers whocannot determine which DTaP vaccine was previ-ously administered, or who do not have the samevaccine, should use any of the licensed acellular per-tussis products to continue the immunization series.

Interchangeability of FormulationsThe FDA generally licenses a combination vaccine

based on studies indicating that the product’s immu-nogenicity (or efficacy) and safety are comparablewith or equivalent to monovalent or combination

products licensed previously.16,34 FDA approval alsogenerally indicates that a combination vaccine maybe used interchangeably with monovalent formula-tions and other combination products with similarcomponent antigens produced by the same manufac-turer to continue the vaccination series. For example,DTaP, DTaP-Hib, and future DTaP-combination vac-cines (Appendix A) that contain similar acellular per-tussis antigens from the same manufacturer may beused interchangeably, if approved for the patient’sage.

Interchangeability of Vaccines From DifferentManufacturers

The licensure of a vaccine does not necessarilyindicate that interchangeability with products ofother manufacturers has been demonstrated. Suchdata are ascertained and interpreted more easily fordiseases with known correlates of protective immu-nity (eg, specific antibodies). For diseases withoutsuch surrogate laboratory markers, field efficacy(phase III) trials, or postlicensure surveillance gener-ally are required to determine protection.35,36

Diseases With Serologic Correlates of ImmunityStudies of serologic responses that have been cor-

related with protection against specific diseases sup-port the interchangeability of vaccines from differentmanufacturers for HepA, HepB, and Hib.

Preliminary data indicate that the two hepatitis Avaccine products currently licensed in the UnitedStates37 may be used interchangeably38 (Merck & Co,Inc, unpublished data, 1998). Hepatitis B vaccineproducts (ie, HepB and Hib-HepB if age-appropri-ate) also may be interchanged for any doses in thehepatitis B series.39

Based on subsequent data,40 – 42 the guidelines forHaemophilus influenzae type b disease7,43 were up-dated in the 1998 Recommended Childhood Im-munization Schedule44 – 47 to indicate that differentHib vaccine products from several manufacturersmay be used interchangeably for sequential dosesof the vaccination series. A PRP-OMP Hib (Hibvaccine with a polyribosylribitol phosphate poly-saccharide conjugated to a meningococcal outermembrane protein) or a PRP-OMP Hib-HepB vac-cine might be administered in a series with HbOCHib (Hib vaccine with oligosaccharides conjugatedto diphtheria CRM197 toxin protein) or withPRP-T Hib (polyribosylribitol phosphate polysac-charide conjugated to tetanus toxoid). In suchcases, the recommended number of doses to com-plete the series is determined by the HbOC orPRP-T product, not by the PRP-OMP vaccine.1,2 Forexample, if PRP-OMP Hib is administered for thefirst dose at age 2 months and another product isadministered at age 4 months, a third dose of anyof the licensed Hib vaccines is recommended atage 6 months to complete the primary series.

Diseases Without Serologic Correlates of ImmunityDespite extensive research, no serologic corre-

lates of immunity have been identified for pertus-sis. Limited data exist concerning the safety,

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immunogenicity, or efficacy of administering acel-lular pertussis vaccines (eg, DTaP or DTaP-Hib)from different manufacturers between the fourth(at age 15–18 months) and fifth (at age 4 – 6 years)doses in the vaccination series.48 No data are avail-able regarding the interchangeability of acellularpertussis products from different manufacturersfor the first three pertussis doses scheduled at ages2, 4, and 6 months. Thus, use of the same manu-facturer’s acellular pertussis vaccine product(s) ispreferred for at least the first three doses in theseries.5,49

VACCINE SUPPLYImmunization clinics and providers should main-

tain a supply of vaccines that will protect childrenfrom all diseases specified in the current Recom-mended Childhood Immunization Schedule.1,2 Thisresponsibility can be fulfilled by stocking severalcombination and monovalent vaccine products.However, not stocking all available combination andmonovalent vaccines or multiple products of each isacceptable.

New and potential combination vaccines cancontain different but overlapping groups of anti-gens (Appendix A). Thus, not all such vaccineswould need to be available for the age-appropriatevaccination of children. Those responsible forchildhood vaccination can stock several vaccinetypes and products, or they may continue to stocka limited number, as long as they prevent all dis-eases recommended in the immunization sched-ule.1,2 Potential advantages of stocking a limitednumber of vaccines include reducing a) confusionand potential errors when staff must handle re-dundant products and formulations, b) wastagewhen less commonly used products expire, c) coldstorage capacity requirements, and d) admini-strative overhead in accounting, purchasing, andhandling.

EXTRA DOSES OF VACCINE ANTIGENSUsing combination vaccines containing some anti-

gens not indicated at the time of administration to apatient might be justified when a) products that con-tain only the needed antigens are not readily avail-able or would result in extra injections, and b) po-tential benefits to the child outweigh the risk ofadverse events associated with the extra antigen(s).An extra dose of many live-virus vaccines and Hib orHepB vaccines has not been found to be harmful.However, the risk of adverse reactions might in-crease when extra doses are administered earlierthan the recommended interval for certain vaccines(eg, tetanus toxoid vaccines and pneumococcal poly-saccharide vaccine).22,50

General Immunization PracticePatients commonly receive extra doses of vaccines

or vaccine antigens for diseases to which they areimmune. For example, some children receiving rec-ommended second or third doses of many vaccinesin the routine immunization series will already haveimmunologic protection from previous dose(s). Be-

cause serologic testing for markers of immunity isusually impractical and costly, multiple doses for allchildren are justified for both clinical and publichealth reasons to decrease the number of susceptiblepersons, which ensures high overall rates of protec-tion in the population.

Extra vaccine doses also are sometimes adminis-tered when an immunization provider is unawarethat the child is already up-to-date for some or all ofthe antigens in a vaccine (see Improving Immuniza-tion Records). During National Immunization Daysand similar mass campaigns, millions of children incountries around the world are administered poliovaccine51,52 and/or measles vaccine,53,54 regardless ofprior vaccination status.

Extra Doses of Combination Vaccine AntigensACIP, AAP, and AAFP recommend that combina-

tion vaccines may be used whenever any compo-nents of the combination are indicated and its othercomponents are not contraindicated.1,2 An immuni-zation provider might not have vaccines availablethat contain only those antigens indicated by achild’s immunization history. Alternatively, the indi-cated vaccines might be available, but the providernevertheless might prefer to use a combination vac-cine to reduce the required number of injections. Insuch cases, the benefits and risks of administeringthe combination vaccine with an unneeded antigenshould be compared.

Live-Virus VaccinesAdministering an extra dose of live, attenuated

virus vaccines to immunocompetent persons whoalready have vaccine-induced or natural immunityhas not been demonstrated to increase the risk ofadverse events. Examples of these include MMR,varicella, rotavirus, and oral polio vaccines.

Inactivated VaccinesWhen inactivated (killed) or subunit vaccines

(which are often adsorbed to aluminum-salt adju-vants) are administered, the reactogenicity of thevaccine must be considered in balancing the ben-efits and risks of extra doses. Because clinical ex-perience suggests low reactogenicity, an extra doseof Hib or HepB vaccine may be administered aspart of a combination vaccine to complete a vacci-nation series for another component of the combi-nation. Administration of extra doses of tetanustoxoid-containing vaccines earlier than the recom-mended intervals can increase the risk of hyper-sensitivity reactions.55– 61 Examples of such vac-cines include DTaP, DTaP-Hib, diphtheria andtetanus toxoids for children (DT), tetanus anddiphtheria toxoids for adolescents and adults (Td),and tetanus toxoid. Extra doses of tetanus toxoid-containing vaccines might be appropriate in cer-tain circumstances, including for children who re-ceived prior DT vaccine and need protection frompertussis (in DTaP) or for immigrants with uncer-tain immunization histories.

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Impact of Reimbursement PoliciesAdministering extra antigens contained in a com-

bination vaccine, when justified as previously de-scribed, is acceptable practice and should be reim-bursed on the patient’s behalf by indemnity healthinsurance and managed-care systems. Otherwise,high levels of timely vaccination coverage might bediscouraged.

Conjugate Vaccine Carrier ProteinsSome carrier proteins in existing conjugated Hib

vaccines62 also are used as conjugates in new vac-cines in development (eg, for pneumococcal and me-ningococcal disease).63 Protein conjugates used inHib conjugate vaccines include a mutant diphtheriatoxin (in HbOC), an outer membrane protein fromNeisseria meningitidis (in PRP-OMP), and tetanus anddiphtheria toxoids (in PRP-T and PRP-D [polyribo-sylribitol phosphate polysaccharide conjugated to adiphtheria toxoid], respectively). Administeringlarge amounts of tetanus toxoid carrier protein si-multaneously with PRP-T conjugate vaccine hasbeen associated with a reduction in the response toPRP64 (see Future Research and Priorities).

IMPROVING IMMUNIZATION RECORDSImproving the convenience and accuracy of trans-

ferring vaccine-identifying information into medicalrecords and immunization registries should be a pri-ority for immunization programs. Priority alsoshould be given to ensuring that providers havetimely access to the immunization histories of theirpatients.

As new combination vaccines with longer genericnames and novel trade names are licensed (Appen-dix A), problems with accurate recordkeeping inmedical charts and immunization registries willlikely be exacerbated.

Monitoring Vaccine Safety, Coverage, and EfficacyAll health-care providers are mandated by law

to document in each patient’s medical record theidentity, manufacturer, date of administration, andlot number of certain specified vaccines, includingmost vaccines recommended for children.65,66 Al-though such data are essential for surveillance andstudies of vaccine safety, efficacy, and coverage,these records are often incomplete and inaccurate.Two major active67 and passive68,69 surveillancesystems monitoring vaccine safety in the UnitedStates have detected substantial rates of missingand erroneous data ($10%) in the recording ofvaccine type, brand, or lot number in the medicalrecords of vaccine recipients (CDC, unpublisheddata, 1997). Similar rates of incomplete and incor-rect vaccination medical records were encounteredby the National Immunization Survey and the Na-tional Health Interview Survey (CDC, unpublisheddata, 1997).

Patient Migration Among Immunization ProvidersChanging immunization providers during the

course of a child’s vaccination series is common in

the United States. The 1994 National Health Inter-view Survey documented that approximately 25%of children were vaccinated by more than oneprovider during the first 2 years of life (CDC,unpublished data, 1997). Eligibility for Medicaidand resulting enrollment in Medicaid managed-care health plans tend to be sporadic, with anaverage duration of 9 months and a median of ,12months in 1993 (Health Care Financing Adminis-tration, unpublished data, 1998).

The vaccination records of children who havechanged immunization providers are often unavail-able and incomplete. Missing or inaccurate informa-tion regarding the vaccines received previouslymight preclude accurate determination of which vac-cines are indicated at the time of a visit, resulting inthe administration of extra doses.

Strategies for Accurate Vaccine IdentificationPotential strategies to improve the accuracy and

timely availability of vaccination information includethe following:

• Designing and adopting a recommended, nation-ally standardized, uniform vaccination medicalrecord form. A copy provided to parents couldserve as a record of vaccination history for subse-quent immunization providers and satisfy schoolentry requirements. Immunization registries couldgenerate printouts to document vaccinations re-ceived from multiple providers and to replacemisplaced forms.

• Expanding and coordinating immunization regis-tries, which track vaccinations received by childrenand make the information available in a convenientand timely manner to parents and authorized im-munization providers with a need to know, whileprotecting confidentiality and privacy.

• Developing technologies, standards, and guide-lines to improve the accuracy and convenience ofrecording and transferring information from thevaccine package or vial into a patient’s medicalrecord, compatible with both manual and comput-erized medical record systems. These methodscould include standardized, peel-off identificationstickers on vaccine packaging and standardizedcoding of vaccine identity, expiration date, and lotnumber. Machine-readable bar codes followingUniform Code Council standards70 on vaccinepackaging and/or stickers could facilitate accurateelectronic transfer of this information into comput-erized medical record systems and immunizationregistries.

FUTURE RESEARCH AND PRIORITIESFurther efforts are needed to study and obtain

more data on the following key subjects related tocombination vaccines:

• The interchangeability of vaccines produced bydifferent manufacturers to prevent the same dis-ease, particularly those that differ in the nature orquantity of one or more component antigens.

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• The safety and efficacy of administering combina-tion vaccines to patients who might already be fullyimmunized for one or more of the components.

• Economic and operations research on a) the fre-quency of delayed or missed vaccinations becauseof objections to multiple injections; b) the costs ofany increased disease burden caused by suchmissed vaccinations; c) the costs of extra visitsneeded to comply with the routine immunizationschedule; and d) the administrative overhead andcost of errors and confusion that might resultwhen handling a greater number of products.

• The effects on immunogenicity and safety of si-multaneous or repeated exposures to the sameproteins used as antigens (eg, tetanus and diph-theria toxoids) and/or as carrier components inexisting and future conjugated vaccines.

• Research to develop and evaluate alternativemeans of antigen delivery by the mucosal,71,72 par-enteral,73 and cutaneous routes,74–77 which wouldallow new and existing vaccines to be adminis-tered less painfully and more safely than withneedles and syringes.78–80

Committee on Infectious Diseases, 1998–1999Neal A. Halsey, MD, ChairpersonJon S. Abramson, MD

P. Joan Chesney, MDMargaret C. Fisher, MDMichael A. Gerber, MDS. Michael Marcy, MDDennis L. Murray, MDGary D. Overturf, MDCharles G. Prober, MDThomas N. Saari, MDLeonard B. Weiner, MDRichard J. Whitley, MD

Ex-OfficioGeorges Peter, MDLarry K. Pickering, MDCarol J. Baker, MD

Liason RepresentativesAnthony Hirsch, MD

AAP Council on Pediatric PracticeRichard F. Jacobs, MD

American Thoracic SocietyNoni E. MacDonald, MD

Canadian Paediatric SocietyBen Schwartz, MD

Centers for Disease Control and PreventionWalter A. Orenstein, MD

Centers for Disease Control and PreventionM. Carolyn Hardegree, MD

Food and Drug AdministrationN. Regina Rabinovich, MD

National Institutes of HealthRobert F. Breiman, MD

National Vaccine Program Office

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