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PEDIATRICS Vol. 103 No. 5 May 1999, pp. 1064-1077
Neal A. Halsey, MD, Chairperson Jon S. Abramson, MD P. Joan Chesney, MD Margaret C. Fisher, MD Michael A. Gerber, MD S. Michael Marcy, MD Dennis L. Murray, MD Gary D. Overturf, MD Charles G. Prober, MD Thomas N. Saari, MD Leonard B. Weiner, MD Richard J. Whitley, MD Ex-Officio Georges Peter, MD Larry K. Pickering, MD Carol J. Baker, MD Liason Representatives Anthony Hirsch, MD AAP Council on Pediatric Practice Richard F. Jacobs, MD American Thoracic Society Noni E. MacDonald, MD Canadian Paediatric Society Ben Schwartz, MD Centers for Disease Control and Prevention Walter A. Orenstein, MD Centers for Disease Control and Prevention M. Carolyn Hardegree, MD Food and Drug Administration N. Regina Rabinovich, MD National Institutes of Health Robert F. Breiman, MD National Vaccine Program Office
SUMMARY. An increasing
number of new and improved vaccines to prevent childhood diseases are
being introduced. Combination vaccines represent one solution to the
problem of increased numbers of injections during single clinic visits.
This statement provides general guidance on the use of combination
vaccines and related issues and questions.
To minimize the number of injections children receive,
parenteral combination vaccines should be used, if licensed and
indicated for the patient's age, instead of their equivalent component
vaccines. Hepatitis A, hepatitis B, and Haemophilus
influenzae type b vaccines, in either monovalent or combination
formulations from the same or different manufacturers, are
interchangeable for sequential doses in the vaccination series.
However, using acellular pertussis vaccine product(s) from the same
manufacturer is preferable for at least the first three doses, until
studies demonstrate the interchangeability of these vaccines.
Immunization providers should stock sufficient types of combination and
monovalent vaccines needed to vaccinate children against all diseases
for which vaccines are recommended, but they need not stock all
available types or brand-name products. When patients have already
received the recommended vaccinations for some of the components in a
combination vaccine, administering the extra antigen(s) in the
combination is often permissible if doing so will reduce the number of
injections required.
To overcome recording errors and ambiguities in the names
of vaccine combinations, improved systems are needed to enhance the
convenience and accuracy of transferring vaccine-identifying information into medical records and immunization registries. Further
scientific and programmatic research is needed on specific questions
related to the use of combination vaccines. The introduction of vaccines for newly preventable diseases
poses a challenge for their incorporation into an already complex immunization schedule. To complete the 1999 Recommended Childhood Immunization Schedule in the United States,1,2 a minimum
of 13 separate injections are needed to immunize a child from birth to
age 6 years, using vaccines licensed in the United States as of April
10, 1999. During some office or clinic visits, the administration of
three or four separate injections can be indicated.
Combination vaccines merge into a single product antigens that
prevent different diseases or that protect against multiple strains of
infectious agents causing the same disease. Thus, they reduce the
number of injections required to prevent some diseases. Combination
vaccines available for many years include diphtheria and tetanus
toxoids and whole-cell pertussis vaccine (DTwP); measles-mumps-rubella vaccine (MMR); and trivalent inactivated polio vaccine (IPV). Combinations licensed in recent years in the United States include diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP),3-6 DTwP-Haemophilus influenzae type b
(Hib) vaccine (DTwP-Hib),7,8
DTaP-Hib Combination vaccines have some drawbacks. Chemical
incompatibility or immunologic interference when different antigens are combined into one vaccine could be difficult to
overcome.12-16 Vaccine combinations that require
different schedules might cause confusion and uncertainty when children
are treated by multiple vaccine providers who use different products.
The trend to develop combination products could encourage vaccine
companies to merge to acquire the needed intellectual
property.17 Competition and innovation might be reduced if
companies with only a few vaccine antigens are discouraged from
developing new products.
This report, published simultaneously by the Advisory Committee on
Immunization Practices (ACIP),18 the American Academy of
Pediatrics,19 and the American Academy of Family
Physicians,20 provides general recommendations for the
optimal use of existing and anticipated parenteral combination vaccines, along with relevant background, rationale, and discussion of
questions raised by the use of these products. Principal
recommendations are classified by the strength and quality of evidence
supporting them (Appendix B).21-24
The use of licensed combination vaccines is preferred over
separate injection of their equivalent component vaccines. Only combinations approved by the US Food and Drug Administration (FDA) should be used.
Rationale
The use of combination vaccines is a practical way to overcome the
constraints of multiple injections, especially for starting the
immunization series for children behind schedule. The use of
combination vaccines might improve timely vaccination coverage. Some
immunization providers and parents object to administering more than
two or three injectable vaccines during a single visit because of a
child's fear of needles and pain25-30 and because of
unsubstantiated concerns regarding safety.31,32
Other potential advantages of combination vaccines include a) reducing
the cost of stocking and administering separate vaccines, b) reducing
the cost for extra health-care visits, and c) facilitating the addition
of new vaccines into immunization programs. The price of a new
combination vaccine can sometimes exceed the total price of separate
vaccines for the same diseases. However, the combination vaccine might
represent a better economic value if one considers the direct and
indirect costs of extra injections, delayed or missed vaccinations, and
additional handling and storage.11
Combining Separate Vaccines Without FDA Approval
Immunization providers should not combine separate vaccines into
the same syringe to administer together unless such mixing is indicated
for the patient's age on the respective product label inserts approved
by the FDA. The safety, immunogenicity, and efficacy of such unlicensed
combinations are unknown.33
In general, vaccines from different manufacturers that protect
against the same disease may be administered interchangeably in
sequential doses in the immunization series for an individual patient
(eg, hepatitis A vaccine [HepA], HepB, and Hib). However, until data
supporting interchangeability of acellular pertussis vaccines (eg,
DTaP) are available, vaccines from the same manufacturer should be
used, whenever feasible, for at least the first three doses in the
pertussis series. Immunization providers who cannot determine which
DTaP vaccine was previously administered, or who do not have the same
vaccine, should use any of the licensed acellular pertussis products to
continue the immunization series.
Interchangeability of Formulations
The FDA generally licenses a combination vaccine based on studies
indicating that the product's immunogenicity (or efficacy) and safety
are comparable with or equivalent to monovalent or combination products
licensed previously.16,34 FDA approval also generally
indicates that a combination vaccine may be used interchangeably with
monovalent formulations and other combination products with similar
component antigens produced by the same manufacturer to continue the
vaccination series. For example, DTaP, DTaP-Hib, and future
DTaP-combination vaccines (Appendix A) that contain similar acellular
pertussis antigens from the same manufacturer may be used
interchangeably, if approved for the patient's age.
Interchangeability of Vaccines From Different Manufacturers
The licensure of a vaccine does not necessarily indicate that
interchangeability with products of other manufacturers has been
demonstrated. Such data are ascertained and interpreted more easily for
diseases with known correlates of protective immunity (eg, specific
antibodies). For diseases without such surrogate laboratory markers,
field efficacy (phase III) trials, or postlicensure surveillance
generally are required to determine protection.35,36
Diseases With Serologic Correlates of Immunity
Studies of serologic responses that have been correlated with
protection against specific diseases support the interchangeability of
vaccines from different manufacturers for HepA, HepB, and Hib.
1,9 and Hib-hepatitis B (HepB)
vaccine (Hib-Hep B).10 In the future, combination vaccines
might include increasing numbers of components in different arrays to
protect against these and other diseases, including hepatitis A,
Neisseria meningitidis, Streptococcus pneumoniae,
and varicella (Appendix A).11
PREFERENCE FOR COMBINATION VACCINES
INTERCHANGEABILITY OF VACCINE PRODUCTS
Diseases Without Serologic Correlates of Immunity Despite extensive research, no serologic correlates of immunity have been identified for pertussis. Limited data exist concerning the safety, immunogenicity, or efficacy of administering acellular 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 available regarding the interchangeability of acellular pertussis products from different manufacturers for the first three pertussis doses scheduled at ages 2, 4, and 6 months. Thus, use of the same manufacturer's acellular pertussis vaccine product(s) is preferred for at least the first three doses in the series.5,49
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VACCINE SUPPLY |
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Immunization clinics and providers should maintain a supply of vaccines that will protect children from all diseases specified in the current Recommended Childhood Immunization Schedule.1,2 This responsibility can be fulfilled by stocking several combination and monovalent vaccine products. However, not stocking all available combination and monovalent vaccines or multiple products of each is acceptable.
New and potential combination vaccines can contain different but overlapping groups of antigens (Appendix A). Thus, not all such vaccines would need to be available for the age-appropriate vaccination of children. Those responsible for childhood vaccination can stock several vaccine types and products, or they may continue to stock a limited number, as long as they prevent all diseases recommended in the immunization schedule.1,2 Potential advantages of stocking a limited number of vaccines include reducing a) confusion and potential errors when staff must handle redundant products and formulations, b) wastage when less commonly used products expire, c) cold storage capacity requirements, and d) administrative overhead in accounting, purchasing, and handling.
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EXTRA DOSES OF VACCINE ANTIGENS |
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Using combination vaccines containing some antigens not indicated at the time of administration to a patient might be justified when a) products that contain only the needed antigens are not readily available or would result in extra injections, and b) potential benefits to the child outweigh the risk of adverse events associated with the extra antigen(s). An extra dose of many live-virus vaccines and Hib or HepB vaccines has not been found to be harmful. However, the risk of adverse reactions might increase when extra doses are administered earlier than the recommended interval for certain vaccines (eg, tetanus toxoid vaccines and pneumococcal polysaccharide vaccine).22,50
General Immunization Practice
Patients commonly receive extra doses of vaccines or vaccine antigens for diseases to which they are immune. For example, some children receiving recommended second or third doses of many vaccines in the routine immunization series will already have immunologic protection from previous dose(s). Because serologic testing for markers of immunity is usually impractical and costly, multiple doses for all children are justified for both clinical and public health reasons to decrease the number of susceptible persons, which ensures high overall rates of protection in the population.
Extra vaccine doses also are sometimes administered when an immunization provider is unaware that the child is already up-to-date for some or all of the antigens in a vaccine (see Improving Immunization Records). During National Immunization Days and similar mass campaigns, millions of children in countries around the world are administered polio vaccine51,52 and/or measles vaccine,53,54 regardless of prior vaccination status.
Extra Doses of Combination Vaccine Antigens
ACIP, AAP, and AAFP recommend that combination vaccines may be used whenever any components of the combination are indicated and its other components are not contraindicated.1,2 An immunization provider might not have vaccines available that contain only those antigens indicated by a child's immunization history. Alternatively, the indicated vaccines might be available, but the provider nevertheless might prefer to use a combination vaccine to reduce the required number of injections. In such cases, the benefits and risks of administering the combination vaccine with an unneeded antigen should be compared.
Live-Virus Vaccines Administering an extra dose of live, attenuated virus vaccines to immunocompetent persons who already have vaccine-induced or natural immunity has not been demonstrated to increase the risk of adverse events. Examples of these include MMR, varicella, rotavirus, and oral polio vaccines.
Inactivated Vaccines When inactivated (killed) or subunit vaccines (which are often adsorbed to aluminum-salt adjuvants) are administered, the reactogenicity of the vaccine must be considered in balancing the benefits and risks of extra doses. Because clinical experience suggests low reactogenicity, an extra dose of Hib or HepB vaccine may be administered as part of a combination vaccine to complete a vaccination series for another component of the combination. Administration of extra doses of tetanus toxoid-containing vaccines earlier than the recommended intervals can increase the risk of hypersensitivity reactions.55-61 Examples of such vaccines include DTaP, DTaP-Hib, diphtheria and tetanus toxoids for children (DT), tetanus and diphtheria toxoids for adolescents and adults (Td), and tetanus toxoid. Extra doses of tetanus toxoid-containing vaccines might be appropriate in certain circumstances, including for children who received prior DT vaccine and need protection from pertussis (in DTaP) or for immigrants with uncertain immunization histories.
Impact of Reimbursement Policies
Administering extra antigens contained in a combination vaccine, when justified as previously described, is acceptable practice and should be reimbursed on the patient's behalf by indemnity health insurance and managed-care systems. Otherwise, high levels of timely vaccination coverage might be discouraged.
Conjugate Vaccine Carrier Proteins
Some carrier proteins in existing conjugated Hib vaccines62 also are used as conjugates in new vaccines in development (eg, for pneumococcal and meningococcal disease).63 Protein conjugates used in Hib conjugate vaccines include a mutant diphtheria toxin (in HbOC), an outer membrane protein from Neisseria meningitidis (in PRP-OMP), and tetanus and diphtheria toxoids (in PRP-T and PRP-D [polyribosylribitol phosphate polysaccharide conjugated to a diphtheria toxoid], respectively). Administering large amounts of tetanus toxoid carrier protein simultaneously with PRP-T conjugate vaccine has been associated with a reduction in the response to PRP64 (see Future Research and Priorities).
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IMPROVING IMMUNIZATION RECORDS |
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Improving the convenience and accuracy of transferring vaccine-identifying information into medical records and immunization registries should be a priority for immunization programs. Priority also should be given to ensuring that providers have timely access to the immunization histories of their patients.
As new combination vaccines with longer generic names and novel trade names are licensed (Appendix A), problems with accurate recordkeeping in medical charts and immunization registries will likely be exacerbated.
Monitoring Vaccine Safety, Coverage, and Efficacy
All health-care providers are mandated by law to document in
each patient's medical record the identity, manufacturer, date of
administration, and lot number of certain specified vaccines, including
most vaccines recommended for children.65,66 Although such
data are essential for surveillance and studies of vaccine safety,
efficacy, and coverage, these records are often incomplete and
inaccurate. Two major active67 and
passive68,69 surveillance systems monitoring vaccine
safety in the United States have detected substantial rates of missing
and erroneous data (
10%) in the recording of vaccine type, brand, or
lot number in the medical records of vaccine recipients (CDC,
unpublished data, 1997). Similar rates of incomplete and incorrect
vaccination medical records were encountered by the National
Immunization Survey and the National Health Interview Survey (CDC,
unpublished data, 1997).
Patient Migration Among Immunization Providers
Changing immunization providers during the course of a child's vaccination series is common in the United States. The 1994 National Health Interview Survey documented that approximately 25% of children were vaccinated by more than one provider during the first 2 years of life (CDC, unpublished data, 1997). Eligibility for Medicaid and resulting enrollment in Medicaid managed-care health plans tend to be sporadic, with an average duration of 9 months and a median of <12 months in 1993 (Health Care Financing Administration, unpublished data, 1998).
The vaccination records of children who have changed immunization providers are often unavailable and incomplete. Missing or inaccurate information regarding the vaccines received previously might preclude accurate determination of which vaccines are indicated at the time of a visit, resulting in the administration of extra doses.
Strategies for Accurate Vaccine Identification
Potential strategies to improve the accuracy and timely availability of vaccination information include the following:
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FUTURE RESEARCH AND PRIORITIES |
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Further efforts are needed to study and obtain more data on the following key subjects related to combination vaccines:
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FOOTNOTES |
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* The following CDC staff member prepared this report: Bruce G. Weniger, MD, MPH, Epidemiology and Surveillance Division, National Immunization Program.
As of April 10, 1999, DTaP-Hib vaccine was licensed only for
the fourth dose recommended at age 15-18 months in the vaccination series.
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ABBREVIATIONS |
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For a complete list of abbreviations, see page 1071.
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REFERENCES |
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