Impact of MMRV Combination Vaccine on Childhood Vaccination Compliance

Objective:

To assess the impact of using the combined measles, mumps, rubella, and varicella vaccine (MMRV) instead of the measles, mumps, and rubella vaccine and the varicella vaccine separately (MMR+V) on uptake of vaccines recommended by the Advisory Committee for Immunization Practices (ACIP) in young children.

Study Design:

Retrospective cohort study.

Methods:

Electronic immunization records of children 12 to 15 months of age who received either MMR+V (n = 29,716) or MMRV (n = 29,711) between November 2003 and June 2007 while enrolled in Kaiser Permanente Southern California were evaluated. Proportions of children who received either MMRV or MMR+V and other ACIP-recommended vaccines either simultaneously or during recommended age intervals were compared.

Results:

Concomitant administration of DTaP (76.3 vs 75.6%), PCV7 (89.1 vs 78.6%), Hib (92.3 vs 91.3%), and hepatitis A vaccine (HAV) (44.2 vs 0.1%) and on-time administration of PCV7 (91.7 vs 78.7%), Hib (93.9 vs 93.2%), and HAV (86.8 vs 24.3%) were greater with MMRV than with MMR+V. On-time administration of DTaP (91.4 vs 90.5%) and IPV (91.3 vs 90.0%) was greater with MMR+V than with MMRV.

Conclusions:

Concomitant and on-time administration of most ACIP-recommended vaccines was greater with MMRV than with MMR+V despite the addition of HAV to the recommended schedule after introduction of MMRV. However, the modest compliance increases suggest that focusing on other barriers to compliance may be important to increasing adherence to future vaccination recommendations.

(Am J Manag Care. 2012;18(12):e440-e445)Vaccination compliance improved slightly following the introduction of MMRV combination vaccine in place of the MMR and varicella vaccines given separately.

• This increase was detected in spite of addition of another vaccine to the immunization schedule at the same time that MMRV was introduced.

• The increase in compliance was small, suggesting that other barriers to vaccination compliance may need to be addressed in order to optimize adherence to future vaccinationrecommendations.

• Combination vaccines will continue to be important to maintaining vaccine complianceas new vaccines are added to the recommended immunization schedule.

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.

METHODS

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.

Figure

Several changes in the schedule of recommended childhood vaccines occurred during the study that affected measurements of compliance with vaccination recommendations (). 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.

RESULTSCohort Characteristics

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

Table 2

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 . 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

Table 3

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) ().

DISCUSSION

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

CONCLUSIONS

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.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: bradley.k.ackerson@kp.org.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.

2. Centers for Disease Control and Prevention. Vaccination coverage in the U.S. http://www.cdc.gov/vaccines/stats-surv/imz-coverage.htm#nis. Last modified on September 6, 2012. Accessed January 11, 2010.

3. Luman ET, McCauley MM, Stokley S, Chu SY, Pickering LK. Timelines of childhood immunizations. Pediatrics. 2002;110(5):935-939.

4. Standards for pediatric immunization practices. Recommended by the National Vaccine Advisory Committee. MMWR Recomm Rep. 1993;42(RR-5):1-10.

5. Madlon-Kay D, Harper PG. Too many shots? parent, nurse and physician attitudes toward multiple simultaneous childhood vaccinations. Arch Fam Med. 1994;3(7):610-613.

6. Reis EC, Jacobson RM, Tarbell S, Weniger BG. Taking the sting out of shots: control of vaccination-associated pain and adverse reactions. Pediatr Ann. 1998;27(6):375-386.

7. Woodin KA, Rodewald LE, Humiston SG, Carges MS, Schaffer SJ, Szilagyi PG. Physician and parent opinions: are children becoming pincushions from immunizations? Arch Pediatr Adolesc Med. 1995;149(8):845-849.

8. Szilagyi PG, Rodewald LE, Humiston SG, et al. Immunization practices of pediatricians and family physicians in the United States. Pediatrics. 1994;94(4, pt 1):517-523.

9. Askew GL, Finelli L, Lutz J, DeGraaf J, Siegel B, Spitalny K. Beliefs and practices regarding childhood vaccination among urban pediatric providers in New Jersey. Pediatrics. 1995;96(5, pt 1):889-892.

10. Dietz VJ, Stevenson J, Zell ER, Cochi S, Hadler S, Eddins D. Potential impact on vaccination levels by administering vaccines simultaneously and reducing dropout rates. Arch Pediatr Adolesc Med. 1994;148(9):943-948.

11. Lieu TA, Black SB, Sorel ME, Ray P, Shinefield HR. Would better adherence to guidelines improve childhood immunization rates? Pediatrics. 1996;98(6, pt 1):1062-1068.

12. Hutchins SS, Escolan J, Markowitz LE, et al. Measles outbreak among unvaccinated preschool-aged children: opportunities missed by health care providers to administer measles vaccine. Pediatrics. 1989;83(3):369-374.

13. Jones JE, White KE, Campbell KL, et al. Simultaneous childhood vaccine administration: a strategy to improve primary vaccine series completion. In: Proceedings of the 22nd National Immunization Conference; San Antonio, TX; June 1988. Atlanta, GA: Centers for Disease Control and Prevention; 1988:145-148.

14. Standards for pediatric immunization practices. Ad Hoc Working Group for the Development of Standards for Pediatric Practices. JAMA. 1993;269(14):1817-1822.

15. American Academy of Pediatrics. Active and passive immunization. In: Peter G, ed. 1991 Red Book: Report of the Committee on Infectious Diseases. 22nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 1991:7-66.

16. Centers for Disease Control and Prevention (CDC). Recommended childhood immunization schedule: United States, 2000. MMWR Morb Mortal Wkly Rep. 2000;49(2):35-38, 47.

17. Centers for Disease Control and Prevention. Recommended immunization schedules for persons aged 0-18 years: United States, 2008. http://www.cdc.gov/mmwr/PDF/wk/mm5701-Immunization.pdf. MMWR. 2008;57(01):Q1-Q4.

18. Jacobsen S, Ackerson B, Sy L, et al. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting. Vaccine. 2009;27(34):4656-4661.

19. Centers for Disease Control and Prevention. 2010 child and adolescent immunization schedules for persons aged 0-6 years, 7-18 years and “catch-up schedules.” http://www.cdc.gov/vaccines/schedules/index.html. Last updated May 31, 2012. Accessed May 14, 2010.

20. Centers for Disease Control and Prevention. Limited supply of pneumococcal conjugate vaccine: suspension of recommendations for fourth dose [Notice to Readers]. http://www.cdc.gov/mmwr/PDF/wk/mm5305.pdf. MMWR Morb Mortal Wkly Rep. 2004;53:108-109.

21. Centers for Disease Control and Prevention (CDC). Updated recommendations on the use of pneumococcal conjugate vaccine: suspension of recommendations for third and fourth dose [Notice to Readers]. MMWR Morb Mortal Wkly Rep. 2004;53(8):177-178.

22. Centers for Disease Control and Prevention (CDC). Updated recommendations for use of pneumococcal vaccine: reinstatement of the third dose [Notice to Readers]. http://www.cdc.gov/mmwr/PDF/wk/mm5326.pdf. MMWR Morb Mortal Wkly Rep. 2004;53:589-590.

23. Centers for Disease Control and Prevention. Pneumococcal conjugate vaccine shortage resolved [Notice to Readers]. http://www.cdc.gov/mmwr/PDF/wk/mm5336.pdf. MMWR Morb Mortal Wkly Rep. 2004;53:851-852.

24. American Academy of Pediatrics Committee on Infectious Diseases. Recommended childhood and adolescent immunization schedule— United States, 2006. Pediatrics. 2006;117(1):239-240.

25. Derose S, Rutkowski MP, Levin NW, et al. Incidence of end-stage renal disease and death among insured African Americans with chronic kidney disease. Kidney Int. 2009;76(6):629-637.

26. Marks JS, Halpin TJ and Orenstein WA. Measles vaccine efficacy in children previously vaccinated at 12 months of age. Pediatrics. 1978;62(6):955-960.

27. Ball TM, Serwint JR. Missed opportunities for vaccination and the delivery of preventive care. Arch Pediatr Adolesc Med. 1996;150(8):858-861.

28. The measles epidemic: the problems, barriers, and recommendations: the National Vaccine Advisory Committee. JAMA. 1991;266(11):1547-1552

29. Halsey NA. Safety of combination vaccines: perception versus reality. Pediatr Infect Dis J. 2001;20(11)(suppl):S40-S44.

30. Brown KF, Kroll JS, Hudson, MJ, et al. Factors underlying parental decisions about combination childhood vaccinations including MMR: a systematic review. Vaccine. 2010;28(26):4235-4248.

31. Marcy SM. Pediatric combination vaccines: their impact on patients, providers, managed care organizations and manufacturers [Author Reply]. Am J Manag Care. 2003;9(8):526, 528.

32. Lopez AS, Kolassa MS, Seward JF. Status of school entry requirements for varicella vaccination and vaccination coverage 11 years after implementation of the varicella vaccination program. J Infect Dis. 2008;197(suppl 2):S76-S81.

33. Jacobs RJ, Meyerhoff AS. Effect of middle school entry requirements on hepatitis B vaccination coverage. J Adolesc Health. 2004;34(5):520-423.

34. Averhoff F, Linton L, Peddlecord KM, Edwards C, Wang W, Fishbein D. A middle school immunization law rapidly and substantially increases immunization coverage among adolescents. Am J Public Health. 2004;94(6):978-984.

35. Marshall GS, Happe LE, Lunacsek OE, et al. Use of combination vaccines is associated with improved coverage rates. Pediatr Infect Dis J. 2007;26(6):496-500.

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.

Download PDF: Impact of MMRV Combination Vaccine on Childhood Vaccination Compliance