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ABSTRACT
Vaccination against measles, mumps, rubella, and varicella is recommended for all children in the US. Limitations manufacturing Oka/Merck strain varicella-zoster virus have hampered the availability of the combination vaccine (MMRV) against these 4 viruses, which drove the need to investigate an alternative manufacturing process. Healthy children 12-to-23 months of age at 71 US sites were randomized (1:1) to receive MMRV manufactured using an alternative process (MMRVAMP) or the currently licensed MMRV. Subjects received 2 0.5 mL doses 3 months apart. Sera were collected before and 6 weeks after Dose-1. Adverse experiences (AEs) were collected for 42 d after each dose and serious AEs and events of special interest for 180 d after Dose-2. Overall, 706 subjects were randomized to MMRVAMP and 706 to MMRV and 698 and 702 received at least 1 dose of study vaccine, respectively. The risk difference in response rates and geometric mean concentrations of antibody to measles, mumps, rubella, and varicella viruses 6 weeks after Dose-1 met non-inferiority criteria for MMRVAMP versus, MMRV. Response rates met acceptability criteria for each virus, and the seroconversion rate to varicella-zoster virus was 99.5% in both groups. Vaccine-related AEs were mostly mild-to-moderate in intensity and somewhat more common after MMRVAMP. Febrile seizures occurred at similar rates in both groups during the first 42 d after each vaccine dose. MMRVAMP is non-inferior to MMRV and represents an important advancement in maintaining an adequate supply of vaccines against these diseases.
Sponsor's role
This study was funded by Merck & Co., Inc. (sponsor). Although the sponsor formally reviewed a penultimate draft, the opinions expressed are those of the authorship and may not necessarily reflect those of the sponsor. All co-authors approved the final version of the manuscript.
Abbreviations
| AAP | = | American Academy of Pediatrics |
| ACIP | = | Advisory Committee on Immunization Practices |
| AE | = | Adverse experience |
| AMP | = | Alternative manufacturing process |
| CI | = | Confidence interval |
| ELISA | = | Enzyme-linked immunosorbant assay |
| GMC | = | Geometric mean concentration |
| gpELISA | = | Glycoprotein enzyme-linked immunosorbant assay |
| MMR | = | Measles: mumps: and rubella vaccine |
| MMRV | = | Measles: mumps: rubella: and varicella vaccine |
| Oka/Merck-VZV | = | Oka/Merck strain varicella-zoster virus |
| SAE | = | Serious adverse experience |
| US | = | United States |
| VAR | = | Varicella vaccine |
| VRC | = | Vaccination report card |
| VZV | = | Varicella-zoster virus |
Disclosure of potential conflicts of interest
Gary Marshall has been an investigator on clinical trials funded by Glaxo-SmithKline, Merck, Novartis, Pfizer, and Sanofi Pasteur. He also has received honoraria from these companies for service on advisory boards.
Gary Marshall, Shelly Senders, Julie Shepard, and Jerry Twiggs were investigators for the sponsor supported by research grants.
Julie Gardner, Darcy Hille, Jonathan Hartzel, Jon Stek, and Frans Helmond are employees of the sponsors and may hold stock and/or stock options from the sponsors.
Rowan Valenzuela is an employee of Covance which was contracted by the sponsor to conduct this study.
Acknowledgments
The authors would like to thank all the subjects who participated in this study and their parents or legal guardian; K. Beck (Merck & Co., Inc.) for her contributions to clinical trial operations; The Protocol 027 Study group: A. Acevedo, G. Adams, J. Alvey, W. Anderson, T. Benton, H. Bernstein, J. Calcagno, D. Cardona, K. Coverston, W. Daly, D. DeSantis, W. Douglas, R. Dracker, C. Duffy, M. Fernando, N. Forbush, E.R. Franklin, D. Freeman, A. Gabrielsen, A.G. Garscadden, U. Goswami, M.W. Halenkamp, B. Harvey, J. Hedrick, W. Hitchcock, J. Hoekstra, M. Husseman, A.J. Infante, A. Ituriaga, C. Jordan, R. Khaira, S. Khamis, R. Kratz, B. Lantry, T. Latiolas, M. Leonardi, M. Levinson, W. Lorentz, M.F. Drusano, E. Malacaman, S.R. Manson, C. Marchant, T.A. J. McAreavey, McKnight, K. McLelland, D. Mitchell, R. Mussleman, C.G. Nassim, B.W. Nauert, A. Naz, S. Owens, W. Parker, A. Pruitt, M.M. Rey, K. Rouse, R. Rupp, V. Sanchez-Bal, Z.G. Sanders, M. Schane, G. Schlichter, S. Shapiro, R. Sheikh, L.C. Sigg, P. Silas, C.K. Stratford, R. Strzinek, T. Sullivan, M. Tipton, M. Varman, L. Weiner, J. White, R. Yogev, M. Yudovich, A.M. Zomcik.
Funding
Funding for this research was provided by Merck & Co., Inc.
Author contributions
Gary Marshall, Shirley Senders, Julie Shepard, and Jerry Twiggs: enrollment of subjects and/or data collection, analysis and interpretation of data, and preparation of manuscript.
Darcy Hille, Rowan Valenzuela, Jon Stek, and Frans Helmond: analysis and interpretation of data, and preparation of manuscript.
Julie Gardner and Jonathan Hartzel: study concept and design, analysis and interpretation of data, and preparation of manuscript.