Combination Vaccine Use and Vaccination Quality in a Managed Care Population

Published Online: September 01, 2007
Laura E. Happe, PharmD, MPH; Orsolya E. Lunacsek, PhD; Gary S. Marshall, MD; Tamara Lewis, MD, MPA, MPH; and Shannon Spencer, RN

Objective: To evaluate the impact of a pentavalent combination vaccine on childhood immunization coverage rates and timeliness within a managed care organization.

Study Design: Retrospective matched-cohort analysis of encounter data from administrative claims and a state immunization registry.

Methods: Children were stratified into 2 demographically matched cohorts (combination and reference), based on receipt of the DTaP/HepB/IPV combination vaccine. Children were followed until 24 months of age, and coverage rates and on-time rates were assessed. Outcomes were measured for the HEDIS Combination 2 vaccine series (4 doses of diphtheria/tetanus/pertussis, 3 doses of polio, 1 dose of measles/mumps/ rubella, 3 doses of Haemophilus influenzae type b, 3 doses of hepatitis B, and 1 dose of varicella) and each vaccine series individually.

Results: Children in the combination cohort were significantly more likely to be fully vaccinated for the HEDIS Combination 2 series by 2 years of age and to be vaccinated within the recommended age ranges. In the combination cohort 86.9% (752/865) of patients were fully covered compared with only 74.1% (641/865) of the reference cohort (P <.001). In the combination cohort 45.2% (391/865) of patients received vaccinations on time versus 37.5% (324/865) of the reference cohort, P = .001.

Conclusions: Receipt of DTaP/HepB/IPV was associated with improved coverage and age-appropriate immunization in a managed care population.
(Am J Manag Care. 2007;13:506-512)

Childhood vaccines are among the top 10 public health advances of our time,1 resulting in the eradication of disease, decreases in mortality, and cost savings.2,3 The 2007 Harmonized Childhood and Adolescent Immunization Schedule recommended by the Advisory Committee on Immunization Practices (ACIP) provides a guide for vaccination against 14 diseases during the first 2 years of life.4 As many as 24 separate shots may be administered to a child by age 2, with many visits requiring multiple injections. This vaccination schedule presents a burden to patients and practitioners. The number of shots may be associated with discomfort for the parent and child, logistical challenges for the pediatrician and family practitioner, and ultimately deferral of recommended immunizations.5,6 Despite these challenges, immunization rates in the United States remained at or near all-time high levels in 2005.7 Coverage rates of 76%, however, leave a considerable percentage of children in the United States not receiving all of their recommended immunizations and, therefore, at risk for disease.7

More than 90% of America's managed care health plans report immunization coverage rates for their insured populations to the National Committee for Quality Assurance (NCQA). Based on the Health Plan Employer Data and Information Set (HEDIS) criteria, a set of standardized and objective measures developed by NCQA, plans report the percentage of children turning 2 years of age who have received the complete recommended immunization series according to administrative claims and chart review data (HEDIS childhood immunization measure). Among reporting commercial plans in 2005, the childhood immunization coverage rate was 77.7% for the HEDIS Combination 2 series (4 doses of diphtheria, tetanus, acellular pertussis vaccine [DTaP]; 3 doses of inactivated polio vaccine [IPV]; 1 dose of measles, mumps, and rubella vaccine [MMR]; 3 doses of Haemophilus influenzae type b conjugate vaccine [Hib]; 3 doses of hepatitis B vaccine [HepB]; and 1 dose of varicella vaccine),8 indicating suboptimal coverage for approximately one quarter of all children.

Coverage rates, however, are not the only measure of quality. Immunization timeliness, or age-appropriate immunization, is another important measure of immunization delivery. This concept refers to the administration of each specific vaccine dose within the age range specified by the harmonized schedule. Failure to receive immunizations within the recommended age ranges may make achieving optimal protection difficult, leaving children at risk for disease. Immunization timeliness is particularly important for vaccine-preventable diseases such as pertussis. Of 10 650 children with pertussis from 1990 to 1996, fewer than half were found to have received their DTaP immunizations on time.9 Recent data reveal a potential problem with immunization timeliness in the United States. One study using data from the National Immunization Survey (NIS) showed that only 26% of children received the recommended immunizations within the specified age ranges,10 uncovering a significant need for improving immunization timeliness. On-time immunizations have also been shown to positively predict the completion of the vaccine series,11 potentially leading to improved coverage rates.

A potential solution to the increasingly crowded immunization schedule and the challenges of vaccine delivery is the use of combination vaccines, products that deliver multiple antigens in single injections. Combination vaccines have the potential to minimize patient discomfort, decrease logistical challenges, reduce extra healthcare visits, and decrease costs. As far back as 1999, the ACIP expressed a preference for the use of combination vaccines as a way to overcome the challenges of multiple injections12; however, limited empirical data exist to quantify the effect of combination vaccines on immunization coverage rates and timeliness. The objective of this study was to evaluate the impact of a  pentavalent vaccine on childhood immunization coverage rates and timeliness in a managed care organization. SelectHealth is a subsidiary of Intermountain Healthcare, a not-for-profit integrated healthcare system in Utah. SelectHealth has more than 460 000 enrollees. Due to product availability and uptake of the combination product, SelectHealth members were an ideal population in which to study the effect of a combination vaccine on immunization quality.


Study Design and Data Source
A retrospective matched cohort study was conducted utilizing encounter data (administrative claims combined with immunization registry records) from SelectHealth. The study vaccine was a DTaP, HepB, and IPV combination (DTaP/ HepB/IPV [Pediarix, GlaxoSmithKline]) that entered the US market on January 1, 2003. The vaccine fits into the recommended schedule for administration at 2, 4, and 6 months of age for a potential decrease of up to 5 injections. Because practices and providers in the SelectHealth network had immediate access to and reimbursement for the product, uptake was rapid, with substantial utilization occurring as early as March 2003.

Administrative claims data were extracted from the billing records of SelectHealth. These data were then cross-referenced using a unique patient identification number assigned to each member by the Utah Statewide Immunization Information System, a voluntary statewide immunization registry. The resultant encounter data provided consolidated patient immunization histories across multiple providers and vaccine delivery sites, including the date of vaccine administration and corresponding Current Procedural Terminology (CPT) code indicating the product administered. These data were used to assess immunization coverage and timeliness, as described below. The study was conducted in compliance with the Health Insurance Portability and Accountability Act and the study was approved by the New England Institutional Review Board.

Patient Selection
Infants born between January 1, 2003 (date of study combination vaccine market entry) and October 1, 2003 (last date of data abstraction to provide 2 years of follow-up) with continuous enrollment in SelectHealth for 24 months were eligible for inclusion. Continuous enrollment in the health plan was required to increase the likelihood that all vaccines administered were captured in the encounter data. Gaps in enrollment of longer than 7 days were considered to be disruptions in continuous enrollment and rendered children ineligible for the study. In addition, to allow for an equal opportunity for immunization at baseline, a minimum of 4 immunization-related office visits were required for study inclusion.

Eligible children were stratified into 2 cohorts: the combination cohort and the reference cohort. The combination cohort consisted of children who received at least 1 dose of DTaP/HepB/IPV. Children who did not receive DTaP/HepB/ IPV were assigned to the reference cohort. Receipt of other combination vaccines (eg, Hib/HepB or DTaP/Hib) did not affect eligibility; these children were placed in the combination or reference cohort as determined by receipt of DTaP/HepB/IPV.

Demographic factors including maternal marital status, race, socioeconomic status, and infant's sex have been shown to influence coverage rates and timeliness and have been controlled for in previous analyses.10,13 Thus, children from the reference cohort were matched 1:1 with children from the combination cohort based on demographic characteristics. The matching criteria included sex, rural versus urban residency, date of birth within 30 days, and historical provider coverage within 5%. Historical provider coverage was defined as the coverage rate for the HEDIS Combination 2 series in 2001 for the provider of each child included in the study. This factor was included as a matching characteristic to minimize the effect of the provider's immunization practices on the outcome. Other demographic data such as race, maternal marital status, and socioeconomic status were not available.


Coverage Rates. Coverage rates were calculated as the proportion of children who received at least the required number of doses for each vaccine series by 24 months of age, as recommended by the 2003 harmonized schedule.14 The number of vaccine doses for a given vaccine series was obtained by taking a simple frequency count of the vaccine doses received for each child by 24 months of age. Coverage rates were determined for the HEDIS Combination 2 series as well as each individual vaccine series. The vaccine series assessed and number of vaccine doses required to be classified as covered are described in Table 1.

Timeliness. Timeliness was measured as the proportion of children who received all of the recommended vaccine doses within the age ranges specified by the 2003 harmonized schedule (Table 2).14 On-time rates were determined for the HEDIS Combination 2 series as well as each individual vaccine series according to a methodology previously described by Luman et al.10 For Hib, 2 possible schedules, 3-dose or 4-dose, were specified, based on Luman et al.10 Children who had 2 or fewer doses of Hib were considered to be on the 3-dose schedule, children who had 4 or more doses were considered to be on the 4-dose schedule, and children with 3 doses were classified as being on the 3-dose or 4-dose schedule depending on the product type of their third Hib dose. Children with PedvaxHIB [Haemophilus b Conjugate Vaccine (meningococcal protein conjugate)] (Merck)15 as their third Hib dose were considered to be on the 3-dose schedule, and children with ActHIB [Haemophilus b Conjugate Vaccine (tetanus toxoid conjugate)] (Sanofi Pasteur Inc.)16 as their third dose were considered to be on the 4-dose schedule.

With the exception of the Hib series variations as described above, the same immunization series were assessed in both the coverage and timeliness analyses. Records of 2 doses of the same vaccine administered within 14 days of each other were considered erroneous (ie, duplicate) records, and the later of the 2 records was excluded. Pneumococcal conjugate vaccine (PCV-7) was not studied because of supply disruptions during the time frame of the data collection.

Statistical Analyses
Coverage and on-time rates for the combination and reference cohorts were compared using 2-tailed Fisher's exact tests. Significance level (a) and power (ß) were set a priori to 0.05 and 0.80, respectively. SAS (SAS Institute, Cary, NC) version 9.1 was used to perform all statistical analyses.


Study Population
A total of 5362 infants were born in the SelectHealth population from January 1, 2003, to October 1, 2003. After applying exclusion criteria and the matching process, 1730 children formed the matched cohorts: 865 children in the combination cohort and 865 children in the reference cohort. Most birth dates occurred between April and September (79.9%), 52.4% of the cohorts were male, and samples were primarily urban (99.0%). The historical provider coverage rate for HEDIS Combination 2 from 2001 was 68.1%. Eighteen percent of the combination cohort received only 1 dose of DTaP/HepB/IPV, while 21% received 2 doses and 61% received 3 doses.

Coverage Rates
A total of 86.9% of children in the combination cohort were fully covered for all of the recommended immunizations (HEDIS Combination 2) compared with only 74.1% of children in the reference cohort (P <.001; Table 3). Higher coverage rates for each of the individual antigens contained in the combination product were also observed in the combination cohort compared with the reference cohort (DTaP, P = .002; IPV, P <.001; and HepB, P <.001). For the remaining immunization series studied (MMR, Hib, and varicella), differences between the combination and reference cohort coverage rates did not reach statistical significance.

A total of 45.2% of children in the combination cohort were on time for all of the recommended immunizations (HEDIS Combination 2) compared with only 37.5% of children in the reference cohort (P = .001; Table 3). Higher on-time rates also were observed for polio (P <.001), Hib (P <.001), and hepatitis B (P <.001) in the combination cohort. On-time rates did not differ significantly between the combination and reference cohorts for the DTaP series, MMR, and varicella.


The use of combination vaccines has been proposed to improve vaccination timeliness and coverage rates. In this study, improved coverage and timeliness were seen despite the fact that 39% of children in the combination cohort did not receive the combination product for each of the 3 opportunities in the schedule (2, 4, and 6 months). More complete exposure to the combination product might have resulted in more pronounced effects.

While coverage rates have been the historical standard to measure immunization quality, timeliness is increasingly being recognized as an important quality measure.10,17-20 Delays in vaccine administration may be a potential cause of the resurgence of certain vaccine-preventable diseases, such as pertussis. 21-23 In addition to placing children at risk of disease, delayed immunizations present logistical challenges for providers. Previous research has revealed that providers have difficulty assessing immunization status24 and determining the appropriate catch-up schedule for children who fall behind due to delayed immunizations.25 Finally, improving timeliness has the potential to improve coverage rates, since by definition children who are on time are also considered covered, and research has shown that children with delayed immunizations are less likely to be fully covered.11 Given these outcomes, systems to improve timeliness could be essential to improving the appropriate delivery of vaccines and increasing coverage rates.

Previous analyses have assessed timeliness and coverage rates in the general population in Utah.7,18 According to the NIS results from Utah, coverage for the HEDIS Combination 2 series was 68.1%,7 compared with 74.1% in this study's reference cohort and 86.9% in the combination cohort. Although the NIS does not stratify by products, coverage rates were generally higher in our study population, particularly in the combination cohort. This finding may be attributed to the fact that our study population was limited to children who had had at least 4 immunization-related visits.

Despite the ACIP preference statement for the use of combination vaccines, uptake of the DTaP/HepB/IPV combination product has not reached its optimal potential. Data are needed to understand and remove any barriers to increased use of combination products, particularly in light of these new findings.

An important strength of this study is the richness of the encounter data. The data used were extracted from the health plan's administrative claims and supplemented with state immunization registry data, minimizing the chance for an immunization encounter that was not captured. The possibility does exist, however, that a vaccine was given in a setting that was not reimbursed by the health plan or was not reported to the state immunization registry, which is a voluntary reporting system. This circumstance would potentially result in children who were fully immunized being misclassified as not covered or not on time. Because the DTaP/HepB/IPV combination vaccine is provided at no cost in Utah through the Vaccines for Children program, it is unlikely that this potential bias would differ between the study cohorts.

Certain limitations to the data warrant discussion. First, information on characteristics which have been shown to affect vaccine delivery, such as race, marital status, and socioeconomic status, were not available and thus these factors could not be controlled for in the analysis. It is also well accepted that vaccine delivery is related to factors such as health insurance coverage and geographic disparity. However, this analysis was conducted in a generally homogeneous population with health insurance coverage and limited geographic variability. These factors limit the ability to generalize from these results to the general population, particularly to the uninsured. In addition, the data do not provide reasons why a given vaccine may have been delayed or deferred at a particular time. The reasons may have included parental preference, contraindications, supply shortages, or other causes that are not attributable to the use of a combination vaccine. Further studies are needed to understand and quantify the reasons for deferral, particularly as they relate to combination and single-antigen vaccines. Lastly, it should be noted that because these data were collected retrospectively and extraneous factors may have affected the results, causality cannot be ascertained.

Two other "modern" combination vaccines were licensed and available for use in the United States at the time of the study, DTaP/Hib and HepB/Hib. Children receiving these other combination products were included in the analysis and placed in their respective cohorts depending on use of the DTaP/HepB/IPV product. Use of these other combination products may have had an impact on the results that were not controlled for in the analysis. However, it is expected that use of other modern combination vaccines was limited primarily to the designated reference cohort in this analysis. Thus, if their use did have a favorable impact on coverage and timeliness, the observed differences between the cohorts would have been reduced, minimizing the apparent impact of DTaP/HepB/IPV.

In summary, the timely and complete delivery of childhood vaccinations remains suboptimal. Combination vaccines deliver the same number of antigens in fewer injections, but limited empirical data have existed to support their impact on vaccine delivery. In this study, the use of a pentavalent DTaP/HepB/IPV combination vaccine was associated with improved coverage and age-appropriate immunization in a managed care population. Further research is necessary to determine the applicability of these findings to other populations with varied demographics. Barriers to the use of combination products should be assessed.

Take-Away Points

A potential solution to the increasingly crowded immunization schedule and the challenges of vaccine delivery is the use of combination vaccines

Receipt of the combined DTaP/HepB/IPV vaccine was associated with improved coverage and age-appropriate immunization

This study provides managed care decision-makers with real-world data to support relevant formulary and reimbursement decisions and improve healthcare quality among their members

Laura E. Happe, PharmD, MPH, Associate Director, Xcenda, 4114 Woodlands Pkwy, Ste 500, Palm Harbor, FL 34685. E-mail: lhappe@xcenda.com.

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Issue: September 2007
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