A practical guide to using the new combination vaccines


With a combination vaccine that protects against five diseases now approved for use in the US--and other such vaccines on the horizon--pediatricians need answers to new questions: How should these vaccines be used for infants at various stages of immunization? Is it safe to give extra doses?


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A practical guide to using the new combination vaccines

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Choose article section... Implementation issues Administrative issues Educating parents

By Sharon G. Humiston, MD, MPH, and Richard G. Judelsohn, MD

With a combination vaccine that protects against five diseases now approved for use in the US—and other such vaccines on the horizon—pediatricians need answers to new questions: How should these vaccines be used for infants at various stages of immunization? Which vaccines can be used interchangeably? Is it safe to give extra doses? Administrative issues and parent education also need to be addressed.

In 1960, routine childhood vaccination—with diphtheria-tetanus-pertussis (DTP), inactivated poliovirus (IPV), and smallpox vaccines—prevented five diseases and necessitated eight injections before the age of 2 years. Today, routine childhood vaccination prevents 11 diseases and requires as many as 20 injections—excluding influenza and hepatitis A vaccines—before the age of 2 years.1-3 (See the 2003 recommended childhood immunization schedule in the January issue of Contemporary Pediatrics.)

The increase in the number of vaccines, and the definitive success of those vaccines, has resulted in a remarkable decline in the incidence of the 11 targeted vaccine-preventable diseases in the United States (Table 1).4 But the growing number of vaccines also has created challenges. Keeping children's immunization status and records up to date may be daunting for health-care professionals and parents alike. Nurses, physicians, and parents may resist administering four or five injections to an infant at a well-child visit; some now even object to administrating more than two vaccines at a single visit.5–8 As a result, completion of vaccination may be delayed, possibly compromising protection, or families may be asked to make additional office visits solely for vaccinations, a policy that inconveniences families and is abjured by many insurance companies. What's more, many parents, unaware that the number of antigens in vaccines has dropped (Table 2), have become concerned by the number of injections: 23% of parents believe that the large number of immunizations children receive may have adverse consequences, and 25% believe that a child's immune system can be weakened as a result of too many immunizations.8


The decline of vaccine-preventable diseases in the US

Annual morbidity, 20th century
2001 morbidity (provisional total)
Polio (paralytic)
Congenital rubella
Haemophilus influenzae
20,000 (approximate)
Hepatitis B



In 1999, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) stated that "the use of licensed combination vaccines is preferred over separate injections of their equivalent component vaccines" if an antigen in the combination is indicated and no antigen in it is contraindicated.9 Several licensed combination vaccines are already in use in the US. The vaccines against hepatitis B (Hep B) and Haemophilus influenzae type b (Hib); measles, mumps, and rubella (MMR); and diphtheria, tetanus, and acellular pertussis (DTaP) are commonly recognized as combination vaccines. Practitioners may overlook the fact that inactivated poliovirus vaccine contains protective antigens against three different poliovirus strains, and influenza vaccine is, likewise, trivalent.

Combination vaccines containing antigens that protect against five or six diseases are already in use in Canada, Mexico, and Europe. In December 2002, one such vaccine—DTaP-Hep B-IPV (Pediarix, GlaxoSmithKline Biologicals, Rixensart, Belgium)— received approval from the US Food and Drug Administration ( www.fda.gov/bbs/topics/ANSWERS/2002/ANS01181.html ). Another combination vaccine—DTaP-Hib-IPV (Pentacel, Aventis Pasteur, Swiftwater, Pa.)10—is seeking FDA approval.

Although new combination vaccines have been eagerly awaited because they will decrease the number of injections infants receive, they also will raise questions about timing and scheduling, vaccine safety, record keeping, costs, and parent education.

Implementation issues

Many different administration scenarios are possible for each combination vaccine. The "common scenario" in Table 3 shows a typical office schedule for currently used, routine vaccines. As examples of the use of vaccines that protect against five diseases, Table 3, Scenario A, shows schedules incorporating one, two, or three doses of DTaP-Hep B-IPV combined vaccine. Scenario B shows schedules incorporating one, two, or three doses of DTaP-Hib-IPV combined vaccine.



Each scenario shows the number of injections for full and timely protection against these diseases when given over the course of well-child-care visits for a 6-month-old infant, including a birth dose of hepatitis B vaccine as recommended by ACIP.1 The total number of doses of each antigen is highlighted. This table provides insight into some of the issues that clinicians face when incorporating such combination vaccines into their practice.

How many fewer injections will a child be given if pediatricians switch to combination vaccines now?

Children today commonly receive 15 injections in the first six months of life. Providers may choose to reduce this number by using the combination vaccine Hep B-Hib (Comvax, Merck & Co., Whitehouse Station, N.J.), which would decrease the number of injections to 12, or by delaying the third doses of IPV or Hep B vaccines. Once pediatricians begin using vaccines that protect against five diseases for the primary series, as few as nine, or as many as 13, injections will be needed in the first six months of life. Parents will need to be advised, however, that, even with the use of these combination vaccines, most visits will include at least three injections. So, providers should not begin to disparage the practice of giving multiple injections of vaccines at a single visit.

The reduction in the number of injections afforded by the use of combination vaccines will take on increasing importance as new immunizations (for instance, a conjugated meningococcal vaccine) become licensed and are recommended for routine use in the US.

Are the different brands of vaccine interchangeable?

In Table 3, Schedule 1 for Scenarios A and B, a patient receives combination vaccines only at age 6 months. Suppose that, from birth to 4 months of age, that child received vaccines manufactured by companies other than the one that produced the combination vaccine. Could the combination vaccine be used for the 6-month dose? That is, can a combination vaccine manufactured by one company be used to complete an immunization series initiated with separate vaccines manufactured by other companies?

Generally, vaccines against the same disease that are produced by different manufacturers can be administered interchangeably in an immunization series.9 Evidence supports the interchangeability of vaccines with measurable serologic correlates of efficacy, such as Hep B,11,12 Hib,13–16 and IPV.17

For DTaP, the interchangeability of products is less clear because there are no clearly established markers of protective immunity for pertussis. For this reason, DTaP vaccine from a single manufacturer is preferred for the series, but ACIP recommendations emphasize that, if a health-care provider cannot ascertain which brand of DTaP was administered previously, or, if the brand used previously is not available, any of the licensed products can be used to continue the series.9

Data supporting this ACIP recommendation have become available from a multicenter, randomized trial that evaluated the safety and immunogenicity of a mixed sequence of the two DTaP products available in the US.18 In this study, 449 infants were randomized into one of three groups and vaccinated at 2, 4, and 6 months of age. Infants received either Tripedia (Aventis Pasteur) for all three doses, Tripedia for the first dose followed by Infanrix (GlaxoSmithKline Biologicals) for the second and third doses, or Tripedia for the first two doses and Infanrix for the third dose. One month after the third dose, infants in all groups had developed a significant antibody response to the diphtheria, pertussis, and tetanus antigens. Although Greenberg and colleagues studied only three different sequences of DTaP vaccine,18 the data suggest that the two DTaP vaccines studied can be used interchangeably.

In clinical settings, product shifting for many vaccines is already common; many children finish their vaccine series with vaccine brands different from the one with which their series was initiated. Patients move between communities or between insurance carriers and, in a new location or under a new formulary, may receive a different brand of vaccine. Recent vaccine shortages also have necessitated use of brands different from the brand used to initiate the series. Primary care offices cannot, with practical economic sense, stock all brands of all vaccines.

There are, however, exceptions to the acceptability of brand shifting. For example, the two-dose adolescent schedule for Hep B vaccine is FDA–approved for one licensed Hep B vaccine (Recombivax HB, Merck & Co.), but not the other (Engerix-B, GlaxoSmithKline). Also, current ACIP and American Academy of Pediatrics (AAP) recommendations indicate that a timely Hib vaccine series can be completed in three (instead of four) doses only when the first two are the Hib capsular polysaccharide polyribosyl-ribitol phosphate (PRP) conjugated to the meningococcal outer-membrane protein (OMP) complex (PRP-OMP; PedvaxHIB, Merck & Co). If either of the other licensed Hib vaccines (HibTITER, Lederle Laboratories, Pearl River, N.Y.; ActHIB, Aventis Pasteur) is used for the first two doses, a total of four Hib vaccine doses is recommended.

To summarize, Table 3, Schedules 1 and 2 for Scenarios A and B, in which a combination vaccine is introduced after the series has been initiated, are acceptable alternatives, even if the switch to the combination vaccine requires a change in manufacturer.

Does the risk of adverse reactions increase if extra doses of vaccines are used?

In Table 3, Schedule 3 for Scenario A, the use of a birth dose of Hep B vaccine and three doses of DTaP-Hep B-IPV leads to four (instead of the routinely recommended three) total doses of Hep B vaccine. In this and other cases, the use of combination vaccines may lead to the administration of extra doses of vaccine antigens. Generally, an extra vaccine dose has not been found harmful. Administering an extra dose of live, attenuated virus vaccine, such as MMR and varicella vaccines, does not increase the risk of adverse events.9 Similarly, because Hib and Hep B vaccines are associated with low reactogenicity, the ACIP finds it acceptable to administer an extra dose of Hib or Hep B as part of a combination vaccine. Although extra doses of tetanus toxoid-containing vaccines (DTaP and diphtheria-tetanus [DT] toxoid, for instance) can, in certain circumstances, increase the risk of hypersensitivity reactions, especially if administered earlier than the recommended interval,9 extra doses of tetanus toxoid-containing vaccine may be appropriate. For example, a child who has an uncertain immunization history or no immunization record should receive all indicated vaccines.

Administrative issues

In addition to implementation considerations, administrative matters such as record keeping and costs must be addressed.

Record keeping that is thorough and up to date is vital to ensure complete and timely immunization of a child. Incomplete or scattered records may contribute to reduced vaccination coverage, resulting in an increased risk of disease and difficulty determining individual immunization needs.19–21

When multiple injections are administered at a single visit, it may be time-consuming to keep complete and accurate vaccination records. Record keeping for combination vaccines may be less cumbersome. For example, after MMR vaccine was introduced, the use of an MMR box on the immunization record reduced the entries from three (measles, mumps, and rubella vaccines separately) to one. However, because vaccination records would be more confusing if there were an additional line for each licensed combination vaccine, providers may choose to continue to document vaccines using the current forms with separate lines for individual antigens (such as Hep B and Hib) and common combinations (for instance, DTaP and MMR).

In addition to recording the name of the vaccine and date of administration, health-care providers are federally mandated to record the vaccine manufacturer and lot number, the vaccinator's name, address, and title, and, for the Vaccine Information Statement (VIS), the date the VIS was given to the patient or parent and the version date printed on the back. Documenting the vaccine elements for a combination vaccine may be less time-consuming than for separate vaccines, but no change is anticipated in the recording of vaccinator or VIS information. Recording other elements that are useful but not federally required (such as vaccination route and site) could be facilitated by use of a combination vaccine.

Vaccine manufacturers are developing and using technologies to help record product-specific information in the patient's medical record, such as peel-off stickers on vaccine vials for use in medical charts, and bar codes on vaccine packaging for scanning into electronic medical records. These stickers and bar codes would contain the vaccine name, manufacturer, and lot number. National standardization of a uniform vaccination medical record form would be a step toward ensuring accurate vaccine identification.9

Statewide immunization registries are vaccination history databases intended to make it easy for vaccination providers to determine the immunization needs of their patients.19,22 Registries consolidate immunization records from multiple health-care providers, which is essential because nearly 25% of children under the age of 3 years receive vaccinations from more than one provider.21 Registry planners should develop mechanisms to accurately enter and retrieve combination vaccine data.

Costs and reimbursement. Because vaccines that protect against five or six diseases have not been available in the US until now, it has been impossible to compare their cost with the aggregate cost of individual vaccines. In the case of Pediarix, the per dose acquisition cost in the private sector is $82.54; the cost of giving DTaP, Hep B, and IPV individually is $78.18. Higher direct costs of combination vaccines might be offset to some extent by other factors.

Combination vaccines could reduce costs by reducing the number of syringes and needles needed, the inventory of separate vaccines, and required storage space. In offices that (despite recommendations to the contrary) sharply limit the number of injections given at a single visit, combination vaccines may reduce the number of extra health-care visits and the attendant costs. Personnel time may well be reduced for vaccine preparation. Two recent time-motion studies found that nurses spend, on average, between 1.6 and 2.4 minutes preparing and administering separate vaccine injections.23,24 In an economic study, it was estimated that direct medical costs for each injection are $5 in a large health maintenance organization (HMO), and the overall savings from eliminating excessive injections was almost $23.25 These data can be used to help determine the value of new combination vaccines and, ultimately, to make purchasing decisions based on direct and indirect costs.26

It is essential, however, that physicians be properly reimbursed by third-party payers for the costs incurred in providing vaccines. Because of a reduction in administration fees, it is possible that a provider could lose revenues by providing a combination vaccine in place of the current, standard vaccines. Many providers recognize the benefits of reduced injections, personnel time, and supplies and better immunization records, and will choose combination vaccines for use in their practices even if administration fees are reduced. Advocacy to prevent reduced administration fees could make the use of combination vaccines more widespread. As is being done on the issue of increased costs for safety needles necessary for Occupational Safety and Health Administration (OSHA) compliance,27 efforts can be made on three fronts:

  • Nationally, the AAP could lobby the insurance industry

  • State Immunization Advisory Councils could enact policies that mandate fair and adequate reimbursement

  • Local physicians who sit on HMO advisory boards could make very clear to the HMOs what costs are involved in these upgrades.

Health-care providers are also concerned that they may not be reimbursed if extra doses of an antigen are administered.28 The recommendation from ACIP is that, when justified, administering extra antigens "is acceptable practice and should be reimbursed on the patient's behalf by indemnity health insurance and managed-care systems."9 The federally funded Vaccines for Children (VFC) program does not penalize providers for use of combination vaccines that duplicate a completed series.

Educating parents

Parents want to limit the number of vaccine injections their infants receive at a single visit to minimize the pain and psychological trauma perceived to be associated with multiple injections.5–7 As noted, some parents question vaccine safety. The Institute of Medicine (IOM), at the request of the CDC and the National Institutes of Health (NIH), established an independent expert panel in 2000 to examine vaccine safety issues.29 In April 2001, the IOM Committee released its first report, which addressed MMR vaccine and autism. In February 2002, the IOM released a report that addressed multiple immunizations and immune dysfunction. The following information should help health-care providers become familiar with these issues so they can knowledgeably address parents' concerns.

Does MMR cause autism?

A subject of public debate during the past few years has been whether measles vaccine, administered as the combination vaccine MMR, causes autism. Intensive reviews of the MMR-autism hypothesis have been conducted independently by the AAP and the IOM. Both groups determined that available evidence does not support the hypothesis that MMR vaccine causes autism or related disorders.30,31 Accumulating epidemiologic evidence has failed to show a relationship between MMR vaccination and changes in apparent rates of autism.32,33 Moreover, the IOM Committee could find no biological mechanisms that would explain such a relationship.31

Do vaccines overwhelm the immune system?

A recent national survey found that 25% of parents expressed concern that vaccines might weaken the immune system.8 In contrast, scientists report that infants are capable of generating protective immune responses to multiple vaccines given simultaneously and have the capacity to respond to an extremely large number of antigens. Offit and colleagues conservatively estimate that, if 11 vaccines were given simultaneously to an infant, approximately 0.1% of the immune system capacity would be used.3 In addition, even though children receive more vaccines than in the past, they are exposed to fewer antigens. After reviewing clinical and epidemiologic data, the IOM reported that multiple immunizations do not increase the risk of developing type 1 diabetes or various infections (for example, ear infections, pneumonia, meningitis), but could not find conclusive evidence regarding asthma.34

Helping parents learn about the remarkable safety record of the vaccines in the recommended childhood immunization schedule, in the context of an increased number of vaccines and more protection than ever before, is an important part of the pediatric provider's educational responsibility.

A welcome development

New combination vaccines that provide protection against five or six diseases may be viewed as beneficial by parents and health-care providers alike. Use of combination vaccines decreases the number of injections required in the first two years of life and may aid in adherence to the recommended childhood immunization schedule. They may also reduce vaccination administration errors, because the person giving the vaccine has fewer syringes to prepare and inject. Further, fewer injections may result in fewer needlestick injuries, although the risk of such injuries is already very low in an office that is in compliance with OSHA standards.27

Incorporating combination vaccines into a practice will require adjustments to clinicians' immunization practices, but knowledgeable planning will ease the transition.


1. Centers for Disease Control and Prevention: Notice to readers: Recommended childhood immunization schedule–United States, 2002. MMWR Morb Mortal Wkly Rep 2002;51:31

2. American Academy of Pediatrics, Committee on Infectious Diseases: Recommended childhood immunization schedule—United States, 2002. Pediatrics 2002;109:162

3. Offit PA, Quarles J, Gerber MA, et al: Addressing parents' concerns: Do multiple vaccines overwhelm or weaken the infant's immune system? Pediatrics 2002;109:124

4. Atkinson W, Wolfe C: Epidemiology and Prevention of Vaccine-Preventable Diseases, ed 7. Atlanta, Ga., Centers for Disease Control and Prevention, US Department of Health and Human Services, 2002

5. Madlon-Kay DJ, Harper PG: Too many shots? Parent, nurse, and physician attitudes toward multiple simultaneous childhood vaccinations. Arch Fam Med 1994;3:610

6. Melman ST, Chawla T, Kaplan JM, et al: Multiple immunizations: Ouch! Arch Fam Med 1994;3:615

7. Woodin KA, Rodewald LE, Humiston SG, et al: Physician and parents opinions: Are children becoming pincushions from immunization? Arch Pediatr Adolesc Med 1995;149:845

8. Gellin BG, Maibach EW, Marcuse EK, for the National Network for Immunization Steering Committee: Do parents understand immunizations? A national telephone survey. Pediatrics 2000;106:1097

9. Centers for Disease Control and Prevention: Combination vaccines for childhood immunization. MMWR Morb Mortal Wkly Rep 1999;48(RR05):1

10. Decker MD, Edwards KM: Combination vaccines: Problems and promise. J Pediatr 2000;137:291

11. Bush LM, Moonsammy GI, Boscia JA: Evaluation of initiating a hepatitis B vaccination schedule with one vaccine and completing it with another. Vaccine 1991;9:807

12. Seto D, West DJ, Gilliam RR, et al: Antibody responses of healthy neonates to two mixed regimens of hepatitis B vaccine. Pediatr Infect Dis J 1999;18:840

13. Anderson EL, Decker MD, Englund JA, et al: Interchangeability of conjugated Haemophilus influenzae type b vaccines in infants. JAMA 1995;273:849

14. Bewley KM, Schwab JG, Ballanco GA, et al: Interchangeability of Haemophilus influenzae type b vaccines in the primary series: Evaluation of a two-dose mixed regimen. Pediatrics 1996;198:898

15. Goldblatt D, Fairley CK, Cartwright K, et al: Interchangeability of conjugated Haemophilus influenzae type b vaccines during primary immunization of infants. BMJ 1996;312:817

16. Greenberg DP, Lieberman JM, Marcy M, et al: Enhanced antibody response in infants given different sequences of heterogeneous Haemophilus influenzae type b conjugate vaccines. J Pediatr 1995;126:206

17. Yeh SH, Ward JI, Partridge S, et al: Safety and immunogenicity of a pentavalent diphtheria, tetanus, pertussis, hepatitis B and polio combination vaccine in infants. Pediatr Infect Dis J 2001;20:973

18. Greenberg DP, Pickering LK, Senders SD, et al: Interchangeability of 2 diphtheria-tetanus-acellular pertussis vaccines in infancy. Pediatrics 2002;109:666

19. Cordero JE, Orenstein WA: The future of immunization registries. Am J Prev Med 1997;13(suppl 2):122

20. Feikema SM, Klevens RM, Washington ML, et al: Extraimmunization among US children. JAMA 2000; 283:1311

21. Stokley S, Rodewald LE, Maes EF: The impact of record scattering on the measurement of immunization coverage. Pediatrics 2001;107:91

22. Centers for Disease Control and Prevention: Immunization registry use and progress–United States, 2001. MMWR Morb Mortal Wkly Rep 2002;51:53

23. LeBaron CW, Rodewald L, Humiston S: How much time is spent on well-child care and vaccinations? Arch Pediatr Adolesc Med 1999;153:1154

24. Pellissier JM, Coplan PM, Jackson LA, et al: The effect of additional shots on the vaccine administration process: Results of a time-motion study in 2 settings. Am J Managed Care 2000;6:1038

25. Lieu TA, Black SB, Ray GT, et al: The hidden costs of infant vaccination. Vaccine 2000;19:33

26. Sewell EC, Jacobson SH, Weniger BG: "Reverse engineering" a formulary selection algorithm to determine the economic value of pentavalent and hexavalent combination vaccines. Pediatr Infect Dis J 2001; 20(suppl):S45

27. Occupational Safety and Health Administration: Occupational exposure to bloodborne pathogens; needlestick and other sharps injuries; final rule [29 CFR Part 1910; Docket No. H370A]. Federal Register 2001; 66(12):5318

28. Glodé MP: Combination vaccines: Practical considerations for public health and private practice. Pediatr Infect Dis J 2001;20(suppl):S19

29. Centers for Disease Control and Prevention, 2002: Institute of Medicine (IOM Report). Immunization safety review: Multiple immunizations and immune dysfunction. Available at: http://www.cdc.gov/nip/vacsafe/concerns/gen/multiplevac_iom.htm . Accessed April 2, 2002

30. Halsey NA, Hyman SL, and the Conference Writing Panel: Measles-mumps-rubella vaccine and autistic spectrum disorder: Report from the New Challenges in Childhood Immunization Conference convened in Oak Brook, Illinois, June 12–13, 2000. Pediatrics 2001;107(5). Available at: http://www.pediatrics.org/cgi/content/full/107/5/e84

31. Institute of Medicine; Stratton KR, Gabel A, Shetty P, McCormack M (eds): Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism. Washington, D.C., National Academy Press, 2001

32. Taylor B, Miller E, Farrington CP, et al: Autism and measles, mumps, and rubella vaccine: No epidemiological evidence for a causal association. Lancet 1999; 352:2026

33. Dales L, Hammer SJ, Smith NJ: Time trends in autism and in MMR immunization coverage in California. JAMA 2001;285:1183

34. Institute of Medicine: Infant immunizations not shown to be harmful to children's immune system [press release]. The National Academies; February 20, 2002. Available at: http://www4.nationalacademies.org/newsnsf/isbn/0309083281?OpenDocument . Accessed April 4, 2002

DR. HUMISTON is assistant professor of emergency medicine and pediatrics, department of emergency medicine, University of Rochester School of Medicine and Dentistry, Rochester, N.Y. Dr. Humiston received payment from a medical publishing group working on behalf of GlaxoSmithKline for writing the manuscript of this article before its submission to Contemporary Pediatrics. She gives continuing medical education talks for Aventis Pasteur and GlaxoSmithKline.
DR. JUDELSOHN is medical director, Erie County Department of Health, and clinical associate professor, department of pediatrics, School of Medicine, State University of New York at Buffalo, N.Y. He is a member of the speakers' program with GlaxoSmithKline, Merck, Wyeth-Lederle, and Aventis Pasteur.


Sharon Humiston, Richard Judelsohn. A practical guide to using the new combination vaccines.

Contemporary Pediatrics


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