Protection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine versus one dose of monovalent varicella vaccine: a multicentre, observer-blind, randomised, controlled trial.
BACKGROUND
Rates of varicella have decreased substantially in countries implementing routine varicella vaccination. Immunisation is possible with monovalent varicella vaccine or a combined measles-mumps-rubella-varicella vaccine (MMRV). We assessed protection against varicella in naive children administered one dose of varicella vaccine or two doses of MMRV.


METHODS
This study was done in ten European countries with endemic varicella. Healthy children aged 12-22 months were randomised (3:3:1 ratio, by computer-generated randomisation list, with block size seven) to receive 42 days apart (1) two doses of MMRV (MMRV group), or (2) MMR at dose one and monovalent varicella vaccine at dose two (MMR+V group), or (3) two doses of MMR (MMR group; control). Participants and their parents or guardians, individuals involved in assessment of any outcome, and sponsor staff involved in review or analysis of data were masked to treatment assignment. The primary efficacy endpoint was occurrence of confirmed varicella (by detection of varicella zoster virus DNA or epidemiological link) from 42 days after the second vaccine dose to the end of the first phase of the trial. Cases were graded for severity. Efficacy analyses were per protocol. Safety analyses included all participants who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, number NCT00226499.


RESULTS
Between Sept 1, 2005, and May 10, 2006, 5803 children (mean age 14·2 months, SD 2·5) were vaccinated. In the efficacy cohort of 5285 children, the mean duration of follow-up in the MMRV group was 36 months (SD 8·8), in the MMR+V group was 36 months (8·5) and in the MMR group was 35 months (8·9). Varicella cases were confirmed for 37 participants in the MMRV group (two moderate to severe), 243 in the MMR+V group, and 201 in the MMR group. Second cases occurred for three participants (all in the MMR+V group). Varicella cases were moderate to severe for two participants in the MMRV group, 37 in the MMR+V group (one being a second case that followed a mild first case); and 117 in the MMR group. Efficacy of two-dose MMRV against all varicella was 94·9% (97·5% CI 92·4-96·6), and against moderate to severe varicella was 99·5% (97·5-99·9). Efficacy of one-dose varicella vaccine against all varicella was 65·4% (57·2-72·1), and against moderate to severe varicella (post hoc) was 90·7% (85·9-93·9). The most common adverse event in all groups was injection-site redness (up to 25% of participants). Within 15 days after dose one, 57·4% (95% CI 53·9-60·9) of participants in the MMRV group reported fever of 38°C or more, by contrast with 44·5% (41·0-48·1) with MMR+V, and 39·8% (33·8-46·1) with MMR. Eight serious adverse events were deemed related to vaccination (three MMRV, four MMR+V, one MMR). All resolved within the study period.


CONCLUSIONS
These results support the implementation of two-dose varicella vaccination on a short course, to ensure optimum protection from all forms of varicella disease.


BACKGROUND
GlaxoSmithKline Vaccines.
University Hospital, Hradec Kralove, Czech Republic.
Roman
R
Prymula
Department of Vaccines, Norwegian Institute of Public Health, Oslo, Norway.
Marianne Riise
MR
Bergsaker
Pediatric Highly Intensive Care Unit, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Susanna
S
Esposito
Swedish Institute for Communicable Disease Control, Stockholm, Sweden; Department of Clinical Sciences Pediatrics, Umeå University, Umeå, Sweden.
Leif
L
Gothefors
University of Medicine and Pharmacy Iuliu Haţieganu, Cluj-Napoca, Romania.
Sorin
S
Man
Institute of Immunology, Moscow, Russia.
Nadezhda
N
Snegova
Department of Epidemiology, Regional Office of Public Health, Trencín, Slovak Republic.
Mária
M
Štefkovičova
Vilnius University, Clinic of Paediatrics, Vilnius, Lithuania.
Vytautas
V
Usonis
University School of Medical Sciences, Poznan, Poland; Regional Medical Center for Mother and Child, Poznan, Poland.
Jacek
J
Wysocki
GlaxoSmithKline Vaccines, Wavre, Belgium.
Martine
M
Douha
GlaxoSmithKline Vaccines, Wavre, Belgium.
Ventzislav
V
Vassilev
GlaxoSmithKline Vaccines, King of Prussia, PA, USA. Electronic address: ouzama.n.henry@gsk.com.
Ouzama
O
Nicholson
GlaxoSmithKline Vaccines, King of Prussia, PA, USA.
Bruce L
BL
Innis
GlaxoSmithKline Vaccines, Wavre, Belgium.
Paul
P
Willems
D000293:Adolescent; D002644:Chickenpox / Q000276:immunology* / Q000517:prevention & control*; D019433:Chickenpox Vaccine / Q000008:administration & dosage*; D002648:Child; D005060:Europe; D005260:Female; D019983:Guideline Adherence; D006801:Humans; D008297:Male; D022542:Measles-Mumps-Rubella Vaccine / Q000008:administration & dosage*; D016896:Treatment Outcome; D017778:Vaccines, Combined / Q000008:administration & dosage; D055815:Young Adult
D019433:Chickenpox Vaccine; D022542:Measles-Mumps-Rubella Vaccine; D017778:Vaccines, Combined; C050102:measles, mumps, rubella, varicella vaccine