VACCINE REPORTS
The Pediatric Infectious Disease Journal • Volume31,Number5,May2012 www.pidj.com | 487
Safety, Reactogenicity and Immunogenicity of the Human
Rotavirus Vaccine in Preterm European Infants:
A Randomized Phase IIIb Study
Felix Omenaca, MD, PhD,* Jean Sarlangue, MD, MSc,† Leszek Szenborn, MD,‡ Marta Nogueira, MD,§
Pemmaraju V. Suryakiran, MSc,¶ Igor V. Smolenov, MD, PhD,¶ Htay H. Han, MB BS,¶ and ROTA-054 Study Group
Background: Rotavirus disease is more severe in preterm infants than in
full-term infants. This study assessed the safety, reactogenicity and immu-
nogenicity of a human rotavirus vaccine, RIX4414, in European preterm
infants.
Methods: A total of 1009 preterm infants were randomized (2:1,
vaccine:placebo) and stratified into 2 groups: 20% of early (27–30 weeks,
group 1) and 80% of late (31–36 weeks, group 2) gestational age preterm
infants in each group. Two doses of RIX4414/placebo were administered
to these preterm infants according to the recommended chronologic age
for full-term infants with an interval of 30–83 days between doses. Seri-
ous adverse events were recorded throughout the study period. Solicited
and unsolicited adverse events were recorded for 15 and 31 days post-each
dose. Antirotavirus IgA concentrations (enzyme-linked immunosorbent
assay cutoff 20 U/mL) and geometric mean concentration were deter-
mined pre-dose 1 and 30–83 days post-dose 2 in a subset of 300 infants.
This study is registered with ClinicalTrials.gov, number NCT00420745
(eTrack106481).
Results: Serious adverse events were reported at a similar frequency in
both groups (P 0.266). Fifty-seven infants reported at least 1 serious
adverse event (5.1% [3.5–7.0] in the RIX4414 group and 6.8% [4.3–10.0]
in the placebo group). During the 15-day postvaccination follow-up period,
diarrhea, vomiting and fever occurred at a similar frequency in both
groups; fever could have been due to concomitant vaccines. Five cases
(RIX4414 3, Placebo 2) of rotavirus gastroenteritis were reported.
The onset of rotavirus gastroenteritis in the RIX4414 group was 1–5 days
after vaccination (vaccine strain identified in all cases) and in the placebo
group it was 3–4 days after receiving placebo (wild-type rotavirus identi-
fied from both cases). Antirotavirus IgA seroconversion rates at 30–83
days post-dose 2 were 85.7% (79.0–90.9) in the RIX4414 group and
16.0% (8.8–25.9) in the placebo group. Geometric mean concentrations
were 202.2 U/mL (153.1–267.1) in the RIX4414 group and 20 U/mL
in the placebo group. Seroconversion rate in groups 1 and 2 in RIX4414
recipients were 75.9% (95% confidence interval [CI]: 56.5–89.7%) and
Accepted for publication December 30, 2011.
From the *La Paz Hospital, Madrid, Spain; †Hôpital des Enfants, CHU Bor-
deaux, France; ‡Department of Pediatric Infectious Diseases, Medical Uni-
versity, Wroclaw, Poland; §Maternidade Alfredo da Costa, Lisbon, Portugal;
and ¶GlaxoSmithKline Biologicals, Rixensart, Belgium.
This study was sponsored and funded by GlaxoSmithKline Biologicals, Rix-
ensart, Belgium. The sponsor was involved in all stages of the study, that
is, from study design to data analysis and writing of the report, and also
performed rotavirus enzyme-linked immunosorbent assay testing. The cor-
responding author had full access to all the data in the study and had final
responsibility for the decision to submit for publication.
P.V.S., H.H.H. and I.V.S. are employed by the GlaxoSmithKline Group of Com-
panies. H.H.H. and I.V.S. have stock ownership. J.W., H.C., F.O., X.C.,
J.R-C., E.R., J.D-D., D.M-P., J.M.M., F.C., J.C., J.A., J.C.T., J.S. and L.S.
received honoraria/paid expert testimony/travel grants from GlaxoSmithK-
line Biologicals. E.R. and J.A. received consulting fees. The authors have no
other funding or conflicts of interest to disclose.
Address for correspondence: Felix Omenaca, MD, PhD, Paseo de la Castellana
261, 28046 Madrid, Spain. E-mail: fomenaca.hulp@salud.madrid.org.
Copyright © 2012 by Lippincott Williams & Wilkins
ISSN: 0891-3668/12/3105-0487
DOI: 10.1097/INF.0b013e3182490a2c
88.1% (95% CI: 80.9–93.4%), respectively; the geometric mean concen-
trations in the respective groups were 110.2 U/mL (95% CI: 56.1–216.5)
and 234.8 U/mL (95% CI: 173.4–318.0; exploratory analysis).
Conclusions: Two doses of RIX4414 were immunogenic and well-tolerated
in European preterm infants.
Key Words: gastroenteritis, gestational age, transplacental antibody
transfer
(Pediatr Infect Dis J 2012;31: 487–493)
R
otavirus disease continues to claim the lives of thousands of
children 5 years of age, with the rate of hospital admission
being highest in the 12- to 18-month age group (42.5 admissions
per 10,000 children).
1
Worldwide, rotavirus accounts for 25 million
clinic visits, 2 million hospitalizations and 527,000 deaths each
year.
2,3
A live-attenuated, oral human rotavirus vaccine RIX4414,
developed from the parent G1P[8] 89-12 vaccine strain for the
immunization of infants
4
has been found to be highly efficacious in
2 doses in various phase III studies conducted on full-term infants
across Europe, Latin America and Asia in preventing severe rotavi-
rus gastroenteritis.
5–7
Effectiveness of RIX4414 against G2P[4] has
been demonstrated in a Latin American study.
8
Earlier studies have shown that preterm infants are at an
increased risk of hospitalization due to gastroenteritis
9
but are less
likely to receive vaccination in a timely manner due to complica-
tions related to preterm births.
10,11
Currently, the American Acad-
emy of Pediatrics and the Advisory Committee on Immunization
Practices recommend that all preterm infants regardless of their
gestational age receive rotavirus vaccination along with all other
childhood vaccines at the same chronologic age as the full-term
infants.
12,13
The present study assessed the safety, reactogenicity
and immunogenicity of the 2 oral doses of RIX4414 vaccine as
compared with placebo in preterm infants across 4 European
countries.
MATERIALS AND METHODS
Subjects and Study Design
This phase IIIb, randomized (2:1, vaccine:placebo), double-
blind placebo-controlled trial was conducted in 4 European coun-
tries—France, Portugal, Poland and Spain between January 2007
and March 2008. Vaccine doses were supplied by GlaxoSmithKline
Biologicals (Rixensart, Belgium) based on a computer-generated
randomization list. A block randomization system in the ratio of
2:1 (vaccine:placebo) was used to ensure balance between the
treatment arms; vaccine doses were supplied to each participating
country with respect to the randomization block size. The infants
were also stratified based on their gestational age (20% of preterm