Immunogenicity and safety of intramuscular versus subcutaneous administration of a combined measles, mumps, rubella, and varicella vaccine to children 12 to 18 months of age

Hervé Haas, Patrick Richard, Cécile Eymin, Anne Fiquet, Barbara Kuter, Benoit Soubeyrand, Hervé Haas, Patrick Richard, Cécile Eymin, Anne Fiquet, Barbara Kuter, Benoit Soubeyrand

Abstract

This randomized trial conducted in France compared intramuscular (IM) and subcutaneous (SC) administration of two doses of a measles, mumps, rubella, and varicella (MMRV) combination vaccine (ProQuad®) administered one month apart to 405 children 12-18 months of age (NCT00402831). The 2-dose regimen of MMRV administered IM was shown to be as immunogenic as the 2-dose regimen administered SC for all antigens 6 weeks post-vaccination for the subjects who were initially seronegative for measles, mumps, rubella, or varicella (lower bounds of the two-sided 95% CIs for the difference in response rates for all antigens greater than -10% [range -2.1 for varicella to -3.0 for mumps]). The antibody response rates for all vaccine antigens 6 weeks after the second dose of MMRV were > 99% in both the IM and SC groups. Fewer subjects in the IM group experienced injection-site AEs compared with the SC group (17.8% and 28.6% post-dose 1, and 20.4% and 29.5% post-dose 2, respectively). From Day 0 to Day 4 post-dose 2, fewer subjects reported erythema and swelling in the IM group than in the SC group (15.4% and 27.0%, and 6.0% and 12.5%, respectively). In both groups, most injection-site AEs started during the first four days after vaccination; their intensity was mainly mild or ≤2.5 cm. The rates of fever were comparable between the two groups after each dose of MMRV. In conclusion, two doses of the MMRV vaccine were highly immunogenic and well tolerated when administered either SC or IM. ClinicalTrials.gov Identifier: NCT00402831.

Keywords: IM; Measles; ProQuad; SC; mumps; route of administration; rubella; varicella vaccine.

Figures

Figure 1.
Figure 1.
Disposition of trial participants

References

    1. Andre FE, Booy R, Bock HL, Clemens J, Datta SK, John TJ, Lee BW, Lolekha S, Peltola H, Ruff TA, et al. Vaccination greatly reduces disease, disability, death and inequity worldwide. Bull World Health Organ. 86;2008:140–146.
    1. World Health Organisation Global measles and rubella strategic plan 2012 – 2020 2012. [accessed 2016 December 6]. .
    1. World Health Organisation Varicella and herpes zoster vaccines: WHO position paper, June 2014. Wkly Epidemiol Rec. 2014;89:265–287.
    1. Baxter R, Ray P, Tran TN, Black S, Shinefield HR, Coplan PM, Lewis E, Fireman B, Saddier P.. Long-term effectiveness of varicella vaccine: a 14-year, prospective cohort study. Pediatrics. 2013;131:e1389–96. doi:10.1542/peds.2012-3303.
    1. Baxter R, Tran TN, Ray P, Lewis E, Fireman B, Black S, Shinefield HR, Coplan PM, Saddier P. Impact of vaccination on the epidemiology of varicella: 1995-2009. Pediatrics. 2014;134:24–30. doi:10.1542/peds.2013-4251.
    1. Leung J, Harpaz R, Molinari NA, Jumaan A, Zhou F. Herpes zoster incidence among insured persons in the United States, 1993-2006: evaluation of impact of varicella vaccination. Clin Infect Dis. 2011;52:332–340. doi:10.1093/cid/ciq077.
    1. European Centre for Disease Prevention and Control Varicella vaccination in the European Union 2015. .
    1. Ackerson BK, Sy LS, Yao JF, Cheetham CT, Jacobsen SJ. Impact of MMRV combination vaccine on childhood vaccination compliance. Am J Manag Care. 18;2012:e440–5.
    1. Scott LJ. Measles-mumps-rubella-varicella combination vaccine (ProQuad): a guide to its use in children in the. E.U. Paediatric Drug. 2015;17:167–174. doi:10.1007/s40272-015-0123-7.
    1. Herzog C. Influence of parenteral administration routes and additional factors on vaccine safety and immunogenicity: a review of recent literature. Expert Rev Vaccines. 2014;13:399–415. doi:10.1586/14760584.2014.883285.
    1. Ajana F, Sana C, Caulin E. Are there differences in immunogenicity and safety of vaccines according to the injection method?. Med Mal Infect. 2008;38:648–657. doi:10.1016/j.medmal.2008.09.012.
    1. Cook IF. Evidence based route of administration of vaccines. Hum Vaccin. 4;2008:67–73.
    1. EMA ProQuad Summary of Product Characteristics (SmPC). 2014. [accessed 2014 December 5]..
    1. Klopfer SO, Stek JE, Petrecz M, Reisinger KS, Black SB, Goveia MG, Nicholson O, Gardner JL, Grosso AD, Brown ML, et al. Analysis of safety data in children after receiving two doses of ProQuad® (MMRV). Vaccine. 2014;32:7154–7160. doi:10.1016/j.vaccine.2014.08.067.
    1. Knuf M, Zepp F, Meyer CU, Habermehl P, Maurer L, Burow H-M, Behre U, Janssens M, Willems P, Bisanz H, et al. Safety, immunogenicity and immediate pain of intramuscular versus subcutaneous administration of a measles-mumps-rubella-varicella vaccine to children aged 11-21 months. Eur J Pediatr. 2010;169:925–933. doi:10.1007/s00431-010-1142-6.
    1. Silber JL, Chan IS, Wang WW, Matthews H, Kuter BJ. Immunogenicity of Oka/Merck varicella vaccine in children vaccinated at 12-14 months of age versus 15-23 months of age. Pediatr Infect Dis J. 2007;26:572–576. doi:10.1097/INF.0b013e318060d33d.
    1. Vesikari T, Becker T, Gajdos V, Fiquet A, Thomas S, Richard P, Baudin M. Immunogenicity and safety of a two-dose regimen of a combined measles, mumps, rubella and varicella live vaccine (ProQuad®) in infants from 9 months of age. Vaccine. 2012;30:3082–3089. doi:10.1016/j.vaccine.2012.02.062.
    1. Gillet Y, Habermehl P, Thomas S, Eymin C, Fiquet A. Immunogenicity and safety of concomitant administration of a measles, mumps and rubella vaccine (M-M-RVAX PRO) and a varicella vaccine (VARIVAX) by intramuscular or subcutaneous routes at separate injection sites: a randomised clinical trial. BMC Med. 2009;7:16. doi:10.1186/1741-7015-7-16.
    1. Bernstein HH, Eves K, Campbell K, Black SB, Twiggs JD, Reisinger KS, Conti RM, Flodmark C-E, Rombo L, Klopfer S, et al. Comparison of the safety and immunogenicity of a refrigerator-stable versus a frozen formulation of ProQuad (measles, mumps, rubella, and varicella virus vaccine live). Pediatrics. 2007;119:e1299–305. doi:10.1542/peds.2006-2283.
    1. Diez-Domingo J, Weinke T, de Lomas JG, Meyer CU, Bertrand I, Eymin C, Thomas S, Sadorge C. Comparison of intramuscular and subcutaneous administration of a herpes zoster live-attenuated vaccine in adults aged >/=50 years: A randomised non-inferiority clinical trial. Vaccine. 2015;33:789–795. doi:10.1016/j.vaccine.2014.12.024.
    1. Leung JH, Hirai HW, Tsoi KK. Immunogenicity and reactogenicity of tetravalent vaccine for measles, mumps, rubella and varicella (MMRV) in healthy children: a meta-analysis of randomized controlled trials. Expert Rev Vaccines. 2015;14:1149–1157. doi:10.1586/14760584.2015.1057572.
    1. Jacobsen SJ, Ackerson BK, Sy LS, Tran TN, Jones TL, Yao JF, Xie F, Cheetham TC, Saddier P. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting. Vaccine. 2009;27:4656–4661. doi:10.1016/j.vaccine.2009.05.056.
    1. World Health Organisation Global vaccine action plan 2011-2020. 2013. [accessed 2017 June 22]. .
    1. Hammond O, Wang Y, Green T, Antonello J, Kuhn R, Motley C, Stump P, Rich B, Chirmule N, Marchese RD. The optimization and validation of the glycoprotein ELISA assay for quantitative varicella-zoster virus (VZV) antibody detection. J Med Virol. 2006;78:1679–1687. doi:10.1002/jmv.20754.
    1. Shehab ZM, Brunell PA, Cobb E. Epidemiological standardization of a test for susceptibility to mumps. J Infect Dis. 149;1984:810–812.
    1. Johnson CD, Kumar ML, Whitwell JK, Staehle BO, Rome LP, Dinakar C, Hurni W, Nalin DR. Antibody persistence afer primary measles-mumps-rubella vaccine and response to a second dose given at four to six vs eleven to thirteen years. Pediatr Infect Dis J. 15;1996:687–692.
    1. Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med. 9;1990:1447–1454.
    1. Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 4;1985:213–226.

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