Impact of MMRV Combination Vaccine on Childhood Vaccination Compliance
December 17, 2012, 12:00:00 AM
Bradley K. Ackerson, MD; Lina S. Sy, MPH; Janis F. Yao, MS; Craig T. Cheetham, PharmD, MS; and Steven J. Jacobsen, MD, PhD
Childhood immunizations have markedly reduced an increasing number of vaccine-preventable diseases.1 However, vaccination rates among children remain less than optimal, with nearly 30% of children failing to receive all recommended vaccines by 2 years of age2 and as many as 90% of children failing to receive all recommended doses at age-appropriate intervals.3
In an attempt to improve childhood vaccination coverage rates, the standards for pediatric immunization practices direct providers to administer simultaneously all vaccines for which children are eligible at each visit.4 However, concerns of parents and providers about the pain and psychological trauma associated with the administration of multiple injections result in a reluctance to administer more than 2 to 3 injections simultaneously.5-7 This frequently results in vaccine deferral,8,9 which substantially reduces vaccine coverage rates.10-14 The importance of simultaneous administration of vaccines will grow as the number of vaccines included in the childhood vaccine schedule increases. Between 1991 and 2000, the number of injections necessary to provide all recommended vaccinations for children through age 23 months increased from 11 to 17, assuming the use of all combination vaccines then licensed in the United States.15,16 However, development of combination vaccines may decrease the number of injections required to provide the increasing number of recommended vaccines, potentially improving immunization rates.
ProQuad (MMRV; Merck and Co, Inc, Summit, New Jersey), a combination of measles, mumps, and rubella (MMR) and varicella vaccines, was developed primarily to increase varicella vaccine coverage in children. However, we hypothesized that decreasing the number of injections required for children at 12 to 15 months of age, when the recommended vaccination schedule is particularly injection dense,17 might increase the simultaneous uptake of other childhood vaccines recommended by the Advisory Committee for Immunization Practices (ACIP). The objective of this study was to assess the impact of combining the MMR and varicella vaccines on the uptake of other vaccines given at the same time as MMRV or the MMR vaccine and varicella vaccine separately (MMR+V) in children 12 to 15 months of age.
Subjects for this study had been included in a phase-IV post-licensure retrospective cohort study that was conducted by Kaiser Permanente Southern California (KPSC) to evaluate the safety of a combined MMRV vaccine licensed in the United States in 2005 as previously described.18 Briefly, children 12 to 60 months of age who received a first dose of MMRV between February 2006 and June 2007 or MMR+V between November 2003 and January 2006 in KPSC were included in the study. Subjects who received MMRV were optimally matched without replacement on age, sex, and month and day of vaccination to children who received MMR+V. Children were excluded if they had a history of measles, mumps, rubella, or varicella disease, or a history of vaccination for any of these diseases. To allow validation of these criteria, subjects were required to be continuously enrolled in the Kaiser Foundation Health Plan from age 6 months until 90 days following vaccination. We compared the proportions of children aged 12 to 15 months who received either MMRV or MMR+V and the vaccinations recommended in the routine childhood vaccination schedule19 either simultaneously (concomitantly) or during recommended age intervals (on time). Study subjects were members of KPSC, the largest managed care organization in Southern California, serving 3.4 million members who are broadly representative of the diverse racial, ethnic, and socioeconomic background of the source population in Southern California. Vaccinations may be administered to members without charge at any visit including no-cost nurse visits. Immunizations are tracked by KPSC through the Kaiser Immunization Tracking System, one of the largest immunization tracking systems in the United States.
Several changes in the schedule of recommended childhood vaccines occurred during the study that affected measurements of compliance with vaccination recommendations (Figure). Due to a nationwide shortage of pneumococcal conjugate vaccine (PCV7), the fourth and the third PCV7 doses were suspended for low-risk children in February 2004 and March 2004, respectively; as the shortage resolved, these doses were reinstituted in July 2004 and September 2004, respectively.20-23 Therefore, compliance with recommendations to administer PCV7 dose 4 in the MMR+V recipients was corrected by excluding children who received MMR+V between February 2004 and September 2004 when PCV7 dose 4 was suspended.20,23 The recommendation to administer hepatitis A vaccine (HAV) at 12 months of age was made in January 200624 just prior to introduction of MMRV at KPSC on February 1, 2006.
In order to estimate the impact of combining MMR and varicella vaccines on varicella vaccine uptake and to estimate the relative compliance of the source population for each cohort, we compared the uptake of MMRV with the uptake of MMR+V in 1-year samples of children drawn from the source population from which the cohorts were drawn for the phase-IV postlicensure study described previously.18 Vaccinated children were required to have had continuous membership from 6 months of age to the time of vaccination. The percentage of children born between March 1, 2005, and February 28, 2006, who received the first dose of MMRV at age 12 to 15 months was compared with the percentage of children born between March 1, 2003, and February 28, 2004, who received the first dose of MMR+V at age 12 to 15 months.
Race and ethnicity data were available from health plan files for 82% of members included in this study and were complete for 90% after surname analysis and geocoding imputation.25
Chi-square tests were used to compare the percentages. All tests were conducted using SAS software (SAS Enterprise Guide, version 4.1, SAS Institute Inc, Cary, North Carolina). This study was approved by the KPSC Institutional Review Board.
Of the 31,298 children each in the MMRV and MMR+V cohorts,18 29,711 and 29,716 were between 12 to 15 months of age, respectively. The demographics of the cohorts were similar (Table 1).
Compliance Among MMRV and MMR+V Recipients
The on-time and concomitant uptake of recommended childhood vaccines among children who received MMRV or MMR+V between 12 and 15 months of age is shown in Table 2. Concomitant administration of the booster doses of diphtheria, tetanus, and pertussis (DTaP), PCV7, and Haemophilus influenzae b (Hib) was greater with MMRV than with MMR+V (P <.001 to P <.04). However, most differences were small (0.7%-10.5%). Concomitant administration of inactivated polio vaccine (IPV) dose 3 was low for MMRV and MMR+V (1.83%-1.92%). Similarly, on-time administration of booster doses of PCV7 and Hib vaccines was greater with MMRV than with MMR+V, though the differences were small (0.7%-13.0%). On the other hand, on-time administration of DTaP booster and IPV dose 3 was greater with MMR+V than MMRV (P <.001), but the differences were small (0.8%- 1.3%). The hepatitis A vaccine was given more often both concomitantly and on-time with MMRV than with MMR+V (P <.001).
Combined on-time administration of all recommended vaccines (DTaP, PCV7, Hib, and IPV) was greater with use of MMRV than with MMR+V. This result held both with inclusion and exclusion of HAV from analysis (64.6% vs 18.5% and 74.1% vs 60.5%, respectively; both P <.001).
Uptake of MMRV vs MMR+V in Young Children
In 1-year samples of children from the cohort source populations, 81.4% of children who were born between March 1, 2005, and February 28, 2006, received MMRV at 12 to 15 months of age and 81.7% of children born between March 1, 2003, and February 28, 2004, received MMR+V at 12 to 15 months of age (P = .26) (Table 3).
The recommended vaccine schedule has become increasingly injection dense, particularly at the 1-year visit. Strategies to address this situation have included giving vaccines at other ages and developing combination vaccines. However, many vaccines cannot be given at less than 12 months of age due to diminished efficacy.26 In addition, deferring vaccination results in decreased uptake.10-14,27,28 Combination vaccines make it possible to administer vaccines on schedule while reducing the number of injections given to patients.18,29 In this study, we evaluated the potential effect of combining MMR and varicella vaccines on the uptake of other recommended vaccines in children 12 to 15 months of age. While an increase was seen in the combined uptake of vaccines given concomitantly as well as on time with MMRV compared with MMR+V, the statistically significant but small increase in uptake of individual vaccines noted in this study is likely of limited clinical significance.
There are several possible reasons why a greater increase in vaccines given with MMRV compared with MMR+V was not seen. First, the recommendation to give HAV at the 12-month visit was made nearly simultaneously with the use of MMRV instead of MMR+V. Therefore, the number of injections recommended at the 12- to 15-month visit for nearly the entire MMRV cohort was same as that recommended for the MMR+V cohort. This is likely why on-time uptake of all recommended vaccines, including HAV, when MMRV was used (64.6%) was similar to on-time uptake of all recommended vaccines, not including HAV, when MMR+V was used (60.5%). However, while the number of injections received by each cohort was the same (n = 6), MMRV recipients were protected against 1 additional illness.
In addition, we compared 2 populations that received MMR-containing vaccine, making them more likely to be compliant with receipt of other vaccines.30 A slight reduction in the number of injections administered to compliant cohorts may have had less impact than it would have had in populations more reluctant to accept vaccines. Furthermore, the high compliance seen in both cohorts in this managed care setting may have had a ceiling effect, limiting further achievable increases in compliance. Moreover, vaccines are provided within KPSC without copayment and at no-cost visits. Hence, the reduced cost to caregivers of 1 less injection resulting from the use of MMRV rather than MMR+V seen in some settings was not a factor in this study setting.31 For these reasons, the results of this study conducted in a single managed care organization may not be generalizable to other populations and more diverse settings.
Finally, school and day care vaccine requirements may have increased compliance in both cohorts, thereby blunting any increase in compliance due to a decreased number of doses of vaccines that might otherwise have been seen in the MMRV cohort.32-34
Combination vaccines have been found to increase compliance with vaccine administration recommendations.35 However, the minimal increase in uptake of individual vaccines and the continued suboptimal combined on-time uptake of all recommended vaccines seen following the introduction of MMRV in place of MMR+V suggest that other barriers to vaccination compliance need to be addressed. In addition, complications may arise as a result of combining vaccines. Shortly after completion of this study, ACIP withdrew its recommendation to administer MMRV preferentially as the first dose of MMR-containing vaccine in young children as a result of an increased incidence of febrile seizures following administration of MMRV compared with MMR+V.18,36
While the observed increase in compliance with vaccine administration recommendations among children 12 to 15 months of age following the use of MMRV in place of MMR+V was small, this increase was seen despite the addition of HAV to the recommended immunization schedule at 12 to 15 months of age shortly after the introduction of MMRV. Given that new vaccines likely will be added to the recommended immunization schedule, combination vaccines will likely continue to play an important role in improving the acceptance of additional vaccines by patients and caregivers. However, while additional combination vaccines may offset decreases in compliance that might otherwise be seen with the addition of vaccines to the recommended immunization schedule, the continued suboptimal uptake of all recommended vaccines seen in this study following the introduction of combination MMRV indicates that additional barriers to vaccination uptake will need to be identified and addressed to achieve further improvements in vaccine compliance.1. Centers for Disease Control and Prevention. Impact of vaccines universally recommended for children—United States, 1990-1998. MMWR Morb Mortal Wkly Rep. 1999;48(12):243-248.
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36. Klein NP, Fireman B, Yih WK, et al; Vaccine Safety Datalink. Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures. Pediatrics. 2010;126(1):e1-e8. Acknowledgments
The authors thank Laura Loftsgaarden for providing assistance with the preparation of this paper.
Author Affiliations: From Pediatrics and Pediatric Infectious Diseases (BKA), Southern California Permanente Medical Group, Harbor City, CA; Department of Research and Evaluation (LSS, JFY, CTC, SJJ), Kaiser Permanente Southern California, Pasadena, CA.
Funding Source: Kaiser Permanente Southern California received funding from Merck to conduct a phase IV postlicensure safety study (completed 2009).
Author Disclosures: The authors (BKA, LSS, JFY, CTC, SJJ) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information: Concept and design (BKA, LSS, CTC, SJJ); acquisition of data (JFY, SJJ); analysis and interpretation of data (BKA, LSS, JFY, CTC, SJJ); drafting of the manuscript (BKA, JFY); critical revision of the manuscript for important intellectual content (BKA, LSS, JFY, CTC, SJJ); statistical analysis (BKA, JFY); obtaining funding (LSS, JFY, CTC, SJJ); administrative, technical, or logistic support (LSS, SJJ); and supervision (BKA).
Address correspondence to: Bradley K. Ackerson, MD, Department of Research and Evaluation, Kaiser Permanente Southern California, 100 S Los Robles, 2nd Fl, Pasadena, CA 91101. E-mail: email@example.com.